Jasmohan S. Bajaj

The AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This guideline has been approved by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver and represents the position of both associations. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD/EASL Practice Guidelines Subcommittee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup, with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong (1) or weak (2). The literature databases and search strategies are outlined below. The resulting literature database was available to all members of the writing group (i.e., the authors). They selected references within their field of expertise and experience and graded the references according to the GRADE system.1 The selection of references for the guideline was based on a validation of the appropriateness of the study design for the stated purpose, a relevant number of patients under study, and confidence in the participating centers and authors. References on original data were preferred and those that were found unsatisfactory in any of these respects were excluded from further evaluation. There may be limitations in this approach when recommendations are needed on rare problems or problems on which scant original data are available. In such cases, it may be necessary to rely on less-qualified references with a low grading. As a result of the important changes in the treatment of complications of cirrhosis (renal failure, infections, and variceal bleeding [VB]), studies performed more than 30 years ago have generally not been considered for these guidelines. Hepatic encephalopathy (HE) is a frequent complication and one of the most debilitating manifestations of liver disease, severely affecting the lives of patients and their caregivers. Furthermore, cognitive impairment associated with cirrhosis results in utilization of more health care resources in adults than other manifestations of liver disease.2 Progress in the area has been hindered by the complex pathogenesis that is not yet fully elucidated. Apart from such biological factors, there remains the larger obstacle that there are no universally accepted standards for the definition, diagnosis, classification, or treatment of HE, mostly as a result of insufficient clinical studies and standardized definitions. Clinical management tends to be dependent on local standards and personal views. This is an unfavorable situation for patients and contrasts with the severity of the condition and the high level of standardization in other complications of cirrhosis. The lack of consistency in the nomenclature and general standards renders comparisons among studies and patient populations difficult, introduces bias, and hinders progress in clinical research for HE. The latest attempts to standardize the nomenclature were published in 2002 and suggestions for the design of HE trials in 2011. Because there is an unmet need for recommendations on the clinical management of HE, the EASL and the AASLD jointly agreed to create these practice guidelines. It is beyond the scope of these guidelines to elaborate on the theories of pathogenesis of HE, as well as the management of encephalopathy resulting from acute liver failure (ALF), which has been published as guidelines recently. Rather, its aim is to present standardized terminology and recommendations to all health care workers who have patients with HE, regardless of their medical discipline, and focus on adult patients with chronic liver disease (CLD), which is, by far, the most frequent scenario. As these guidelines on HE were created, the authors found a limited amount of high-quality evidence to extract from the existing literature. There are many reasons for this; the elusive character of HE is among them, as well as the lack of generally accepted and utilized terms for description and categorization of HE. This makes a practice guideline all the more necessary for future improvement of clinical studies and, subsequently, the quality of management of patients with HE. With the existing body of evidence, these guidelines encompass the authors' best, carefully considered opinions. Although not all readers may necessarily agree with all aspects of the guidelines, their creation and adherence to them is the best way forward, with future adjustments when there is emergence of new evidence. Advanced liver disease and portosystemic shunting (PSS), far from being an isolated disorder of the liver, have well-known consequences on the body and, notably, on brain functioning. The alterations of brain functioning, which can produce behavioral, cognitive, and motor effects, were termed portosystemic encephalopathy (PSE)3 and later included in the term HE.4 Unless the underlying liver disease is successfully treated, HE is associated with poor survival and a high risk of recurrence.5, 6 Even in its mildest form, HE reduces health-related quality of life and is a risk factor for bouts of severe HE.7-9 Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or PSS; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. This definition, in line with previous versions,10, 11 is based on the concept that encephalopathies are “diffuse disturbances of brain function”5 and that the adjective “hepatic” implies a causal connection to liver insufficiency and/or perihepatic vascular shunting.6 The incidence and prevalence of HE are related to the severity of the underlying liver insufficiency and PSS.12-15 In patients with cirrhosis, fully symptomatic overt HE (OHE) is an event that defines the decompensated phase of the disease, such as VB or ascites.7 Overt hepatic encephalopathy is also reported in subjects without cirrhosis with extensive PSS.8, 9 The manifestation of HE may not be an obvious clinical finding and there are multiple tools used for its detection, which influences the variation in the reported incidence and prevalence rates. The prevalence of OHE at the time of diagnosis of cirrhosis is 10%-14% in general,16-18 16%-21% in those with decompensated cirrhosis,7, 19 and 10%-50% in patients with transjugular intrahepatic portosystemic shunt (TIPS).20, 21 The cumulated numbers indicate that OHE will occur in 30%-40% of those with cirrhosis at some time during their clinical course and in the survivors in most cases repeatedly.22 Minimal HE (MHE) or covert HE (CHE) occurs in 20%-80% of patients with cirrhosis.23-27, 81 The prevalence of HE in prehepatic noncirrhotic portal hypertension (PH) is not well defined. The risk for the first bout of OHE is 5%-25% within 5 years after cirrhosis diagnosis, depending on the presence of risk factors, such as other complications to cirrhosis (MHE or CHE, infections, VB, or ascites) and probably diabetes and hepatitis C.28-32 Subjects with a previous bout of OHE were found to have a 40% cumulative risk of recurring OHE at 1 year,33 and subjects with recurrent OHE have a 40% cumulative risk of another recurrence within 6 months, despite lactulose treatment. Even individuals with cirrhosis and only mild cognitive dysfunction or mild electroencephalography (EEG) slowing develop approximately one bout of OHE per 3 years of survival.34, 35 After TIPS, the median cumulative 1-year incidence of OHE is 10%-50%36, 37 and is greatly influenced by the patient selection criteria adopted.38 Comparable data were obtained by PSS surgery.39 It gives an idea of the frequent confrontation of the health care system by patients with HE that they accounted for approximately 110,000 hospitalizations yearly (2005-2009)40 in the United States. Though numbers in the European Union (EU) are not readily available, these predictions are expected to be similar. Furthermore, the burden of CLD and cirrhosis is rapidly increasing,41, 42 and more cases will likely be encountered to further define the epidemiology of HE. Hepatic encephalopathy produces a wide spectrum of nonspecific neurological and psychiatric manifestations.10 In its lowest expression,43, 44 HE alters only psychometric tests oriented toward attention, working memory (WM), psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures.45, 46 As HE progresses, personality changes, such as apathy, irritability, and disinhibition, may be reported by the patient's relatives,47 and obvious alterations in consciousness and motor function occur. Disturbances of the sleep-wake cycle with excessive daytime sleepiness are frequent,48 whereas complete reversal of the sleep-wake cycle is less consistently observed.49, 50 Patients may develop progressive disorientation to time and space, inappropriate behavior, and acute confusional state with agitation or somnolence, stupor, and, finally, coma.51 The recent ISHEN (International Society for Hepatic Encephalopathy and Nitrogen Metabolism) consensus uses the onset of disorientation or asterixis as the onset of OHE.65 In noncomatose patients with HE, motor system abnormalities, such as hypertonia, hyper-reflexia, and a positive Babinski sign, can be observed. In contrast, deep tendon reflexes may diminish and even disappear in coma,52 although pyramidal signs can still be observed. Rarely, transient focal neurological deficits can occur.53 Seizures are very rarely reported in HE.54-56 Extrapyramidal dysfunction, such as hypomimia, muscular rigidity, bradykinesia, hypokinesia, monotony and slowness of speech, parkinsonian-like tremor, and dyskinesia with diminished voluntary movements, are common findings; in contrast, the presence of involuntary movements similar to tics or chorea occur rarely.52, 57 Asterixis or “flapping tremor” is often present in the early to middle stages of HE that precede stupor or coma and is, in actuality, not a tremor, but a negative myoclonus consisting of loss of postural tone. It is easily elicited by actions that require postural tone, such as hyperextension of the wrists with separated fingers or the rhythmic squeezing of the examiner's fingers. However, asterixis can be observed in other areas, such as the feet, legs, arms, tongue, and eyelids. Asterixis is not pathognomonic of HE because it can be observed in other diseases57 (e.g., uremia). Notably, the mental (either cognitive or behavioral) and motor signs of HE may not be expressed, or do not progress in parallel, in each individual, therefore producing difficulties in staging the severity of HE. Hepatic myelopathy (HM)58 is a particular pattern of HE possibly related to marked, long-standing portocaval shunting, characterized by severe motor abnormalities exceeding the mental dysfunction. Cases of paraplegia with progressive spasticity and weakness of lower limbs with hyper-reflexia and relatively mild persistent or recurrent mental alterations have been reported and do not respond to standard therapy, including ammonia lowering, but may reverse with liver transplantation (LT).59 Persistent HE may present with prominent extrapyramidal and/or pyramidal signs, partially overlapping with HM, in which postmortem brain examination reveals brain atrophy.60 This condition was previously called acquired hepatolenticular degeneration, a term currently considered obsolete. However, this cirrhosis-associated parkinsonism is unresponsive to ammonia-lowering therapy and may be more common than originally thought in patients with advanced liver disease, presenting in approximately 4% of cases.61 Apart from these less-usual manifestations of HE, it is widely accepted in clinical practice that all forms of HE and their manifestations are completely reversible, and this assumption still is a well-founded operational basis for treatment strategies. However, research on liver-transplanted HE patients and on patients after resolution of repeated bouts of OHE casts doubt on the full reversibility. Some mental deficits, apart from those ascribable to other transplantation-related causes, may persist and are mentioned later under transplantation.135 Likewise, episodes of OHE may be associated with persistent cumulative deficits in WM and learning.14 Hepatic encephalopathy should be classified according to all of the following four factors.10 According to the underlying disease, HE is subdivided into According to the severity of manifestations. The continuum that is HE has been arbitrarily subdivided. For clinical and research purposes, a scheme of such grading is provided (Table 2). Operative classifications that refer to defined functional impairments aim at increasing intra- and inter-rater reliability and should be used whenever possible. According to its time course, HE is subdivided into According to the existence of precipitating factors, HE is subdivided into No universal criteria for diagnosis Local standards and expertise required • Trivial lack of awareness • Euphoria or anxiety • Shortened attention span • Impairment of addition or subtraction • Altered sleep rhythm • Lethargy or apathy • Disorientation for time • Obvious personality change • Inappropriate behavior • Dyspraxia • Asterixis • Somnolence to semistupor • Responsive to stimuli • Confused • Gross disorientation • Bizarre behavior A fifth classification, according to whether or not the patient has acute-on-chronic liver failure (ACLF), has recently been suggested.64 Although the management, mechanism, and prognostic impact differ, this classification is still a research area. The diagnosis requires the detection of signs suggestive of HE in a patient with severe liver insufficiency and/or PSS who does not have obvious alternative causes of brain dysfunction. The recognition of precipitating factors for HE (e.g., infection, bleeding, and constipation) supports the diagnosis of HE. The differential diagnosis should consider common disorders altering the level of consciousness (Table 4). 1. Hepatic encephalopathy should be classified according to the type of underlying disease, severity of manifestations, time course, and precipitating factors (GRADE III, A, 1). 2. A diagnostic workup is required, considering other disorders that can alter brain function and mimic HE (GRADE II-2, A, 1). Every case and bout of HE should be described and classified according to all four factors, and this should be repeated at relevant intervals according to the clinical situation. The recommendations are summarized in Table 5. Judging and measuring the severity of HE is approached as a continuum.65 The testing strategies in place range from simple clinical scales to sophisticated psychometric and neurophysiological tools; however, none of the current tests are valid for the entire spectrum.11, 66 The appropriate testing and diagnostic options differ according to the acuity of the presentation and the degree of impairment.67 The diagnosis of OHE is based on a clinical examination and a clinical decision. Clinical scales are used to analyze its severity. Specific quantitative tests are only needed in study settings. The gold standard is the West Haven criteria (WHC; Table 2, including clinical description). However, they are subjective tools with limited interobserver reliability, especially for grade I HE, because slight hypokinesia, psychomotor slowing, and a lack of attention can easily be overlooked in clinical examination. In contrast, the detection of disorientation and asterixis has good inter-rater reliability and thus are chosen as marker symptoms of OHE.67 Orientation or mixed scales have been used to distinguish the severity of HE.68, 69 In patients with significantly altered consciousness, the Glasgow Coma Scale (GCS; Table 6) is widely employed and supplies an operative, robust description. Diagnosing cognitive dysfunction is not difficult. It can be established from clinical observation as well as neuropsychological or neurophysiological tests. The difficulty is to assign them to HE. For this reason, OHE still remains a diagnosis of exclusion in this patient population that is often susceptible to mental status abnormalities resulting from medications, alcohol abuse, drug use, effects of hyponatremia, and psychiatric disease (Table 4). Therefore, as clinically indicated, exclusion of other etiologies by laboratory and radiological assessment for a patient with altered mental status in HE is warranted. Minimal hepatic encephalopathy and CHE is defined as the presence of test-dependent or clinical signs of brain dysfunction in patients with CLD who are not disoriented or display asterixis. The term “minimal” conveys that there is no clinical sign, cognitive or other, of HE. The term “covert” includes minimal and grade 1 HE. Testing strategies can be divided into two major types: psychometric and neurophysiological.70, 71 Because the condition affects several components of cognitive functioning, which may not be impaired to the same degree, the ISHEN suggests the use of at least two tests, depending on the local population norms and availability, and preferably with one of the tests being more widely accepted so as to serve as a comparator. Testing for MHE and CHE is important because it can prognosticate OHE development, indicate poor quality of life and reduced socioeconomic potential, and help counsel patients and caregivers about the disease. The occurrence of MHE and CHE in patients with CLD seems to be as high as 50%,72 so, ideally, every patient at risk should be tested. However, this strategy may be costly,73 and the consequences of the screening procedure are not always clear and treatment is not always recommended. An operational approach may be to test patients who have problems with their quality of life or in whom there are complaints from the patients and their relatives.74 Tests positive for MHE or CHE before stopping HE drug therapy will identify patients at risk for recurrent HE.33, 75 Furthermore, none of the available tests are specific for the condition,76 and it is important to test only patients who do not have confounding factors, such as neuropsychiatric disorders, psychoactive medication, or current alcohol use. Testing should be done by a trained examiner adhering to scripts that accompany the testing tools. If the test result is normal (i.e., negative for MHE or CHE), repeat testing in 6 months has been recommended.77 A diagnosis of MHE or CHE does not automatically mean that the affected subject is a dangerous driver.78 Medical providers are not trained to formally evaluate fitness to drive and are also not legal representatives. Therefore, providers should act in the best interests of both the patient and society while following the applicable local laws.78 However, doctors cannot evade the responsibility of counseling patients with diagnosed HE on the possible dangerous consequences of their driving, and, often, the safest advice is to stop driving until the responsible driving authorities have formally cleared the patient for safe driving. In difficult cases, the doctor should consult with the authorities that have the expertise to test driving ability and the authority to revoke the license. Although the above-described tests have been used to test for MHE and CHE, there is, most often, a poor correlation between them because HE is a multidimensional dysfunction.86 Learning effect is often observed with psychometric tests and it is unclear whether current HE therapy plays a role in the test performance. Therefore, interpretation of these tests and consideration of the results for further management need an understanding of the patient's history, current therapy, and effect on the patient's daily activities, if signs of HE are found. For multicenter studies, the diagnosis of MHE or CHE by consensus should utilize at least two of the current validated testing strategies: paper-pencil (PHES) and one of the following: computerized (CRT, ICT, SCAN, or Stroop) or neurophysiological (CFF or EEG).66 In the clinical routine or single-center studies, investigators may use tests for assessing the severity of HE with which they are familiar, provided that normative reference data are available and the tests have been validated for use in this patient population.66 High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients with CLD.87 However, in case an ammonia level is checked in a patient with OHE and it is normal, the diagnosis of HE is in question. For ammonia-lowering drugs, repeated measurements of ammonia may be helpful to test the efficacy. There may be logistic challenges to accurately measure blood ammonia, which should be taken into consideration. Ammonia is reported either in venous, arterial blood, or plasma ammonia, so the relevant normal should be used. Multiple methods are available, but measurements should only be employed when laboratory standards allow for reliable analyses. Computed tomography (CT) or magnetic resonance (MR) or other image modality scans do not contribute diagnostic or grading information. However, the risk of intracerebral hemorrhage is at least 5-fold increased in this patient group,88 and the symptoms may be indistinguishable, so a brain scan is usually part of the diagnostic workup of first-time HE and on clinical suspicion of other pathology. 3. Hepatic encephalopathy should be treated as a continuum ranging from unimpaired cognitive function with intact consciousness through coma (GRADE III, A, 1). 4. The diagnosis of HE is through exclusion of other causes of brain dysfunction (GRADE II-2, A, 1). 5. Hepatic encephalopathy should be divided into various stages of severity, reflecting the degree of self-sufficiency and the need for care (GRADE III, B, 1). 6. Overt hepatic encephalopathy is diagnosed by clinical criteria and can be graded according the WHC and the GCS (GRADE II-2, B, 1). 7. The diagnosis and grading of MHE and CHE can be made using several neurophysiological and psychometric tests that should be performed by experienced examiners (GRADE II-2, B, 1). 8. Testing for MHE and CHE could be used in patients who would most benefit from testing, such as those with impaired quality of life or implication on employment or public safety (GRADE III, B, 2). 9. Increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with CLD. A normal value calls for diagnostic reevaluation (GRADE II-3, A, 1). At this time, only OHE is routinely treated.10 Minimal hepatic encephalopathy and CHE, as its title implies, is not obvious on routine clinical examination and is predominantly diagnosed by techniques outlined in the previous section. Despite its subtle nature, MHE and CHE can have a significant effect on a patient's daily living. Special circumstances can prevail where there may be an indication to treat such a patient (e.g., impairment in driving skills, work performance, quality of life, or cognitive complaints). Liver transplantation is mentioned under the treatment recommendations. General recommendations for treatment of episodic OHE type C include the following: 10. An episode of OHE (whether spontaneous or precipitated) should be actively treated (GRADE II-2, A, 1). 11. Secondary prophylaxis after an episode for overt HE is recommended (GRADE I, A, 1). 12. Primary prophylaxis for prevention of episodes of OHE is not required, except in patients with cirrhosis with a known high risk to develop HE (GRADE II-3, C, 2). 13. Recurrent intractable OHE, together with liver failure, is an indication for LT (GRADE I). A four-pronged approach to management of HE is recommended (GRADE II-2, A, 1): 14. Initiation of care for patients with altered consciousness 15. Alternative causes of altered mental status should be sought and treated. 16. Identification of precipitating factors and their correction 17. Commencement of empirical HE treatment Patients with higher grades of HE who are at risk or unable to protect their airway need more intensive monitoring and are ideally managed in an intensive care setting. Alternative causes of encephalopathy are not infrequent in patients with advanced cirrhosis. Technically, if other causes of encephalopathy are present, then the episode of encephalopathy may not be termed HE. In the clinical setting, what transpires is treatment of both HE and non-HE. Controlling precipitating factors in the management of OHE is of paramount importance, because nearly 90% of patients can be treated with just correction of the precipitating factor.89 Careful attention to this issue is still the cornerstone of HE management. In addition to the other elements of the four-pronged approach to treatment of HE, specific drug treatment is part of the management. Most drugs have not been tested by rigorous randomized, controlled studies and are utilized based on circumstantial observations. These agents include nonabsorbable disaccharides, such as lactulose, and antibiotics, such as rifaximin. Other therapies, such as oral branched-chain amino acids (BCAAs), intravenous (IV) L-ornithine L-aspartate (LOLA), probiotics, and other antibiotics, have also been used. In the hospital, a nasogastric tube can be used to administer oral therapies in patients who are unable to swallow or have an aspiration risk. Lactulose is generally used as initial treatment for OHE. A large meta-analysis of trial data did not completely support lactulose as a therapeutic agent for treatment of OHE, but for technical reasons, it did not include the largest trials, and these agents continue to be used widely.90 Lack of effect of lactulose should prompt a clinical search for unrecognized precipitating factors and competing causes for the brain impairment. Though it is assumed that the prebiotic effects (the drug being a nondigestible substance that promotes the growth of beneficial microorganisms in the intestines) and acidifying nature of lactulose have an additional benefit beyond the laxative effect, culture-independent studies have not borne those out.75, 91 In addition, most recent trials on lactulose have been open label in nature. Cost considerations alone add to the argument in support of lactulose.92 In some centers, lactitol is preferred to lactulose, based on small meta-analyses of even smaller trials.93, 94 In populations with a high prevalence of lactose intolerance, the use of lactose has been suggested.95 However, the only trial to show that stool-acidifying enemas (lactose and lactulose) were superior to tap-water enemas was underpowered.96 The use of polyethylene glycol preparation97 needs further validation. The dosing of lactulose should be initiated98 when the three first elements of the four-pronged approach are completed, with 25 mL of lactulose syrup every 1-2 hours until at least two soft or loose bowel movements per day are produced. Subsequently, the dosing is titrated to maintain two to three bowel movements per day. This dose reduction should be implemented. It is a misconception that lack of effect of smaller amounts of lactulose is remedied by much larger doses. There is a danger for overuse of lactulose leading to complications, such as aspiration, dehydration, hypernatremia, and severe perianal skin irritation, and overuse can even precipitate HE.99 Rifaximin has been used for the therapy of HE in a number of trials100 comparing it with placebo, other antibiotics, nonabsorbable disaccharides, and in dose-ranging studies. These trials showed effect of rifaximin that was equivalent or superior to the compared agents with good tolerability. Long-term cyclical therapy over 3-6 months with rifaximin for patients with OHE has also been studied in three trials (two compared to nonabsorbable disaccharides and one against neomycin) showing equivalence in cognitive improvement and ammonia lowering. A multinational study101 with patients having two earlier OHE bouts to maintain remission showed the superiority of rifaximin versus placebo (in the background of 91% lactulose use). No solid data support the use of rifaximin alone. Many drugs have been used for treatment of HE, but data to support their use are limited, preliminary, or lacking. However, most of these drugs can safely be used despite their limited proven efficacy. An updated meta-analysis of eight randomized, controlled trials (RCTs) indicated that oral BCAA-enriched formulations improve the manifestations of episodic HE whether OHE or MHE.102, 130 There is no effect of IV BCAA on the episodic bout of HE.127 These agents, through their metabolism, a

To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD - defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled "Personalized Care for Portal Hypertension". The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of cACLD and CSPH, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. A summary of the most important conclusions/recommendations derived from the workshop is reported here. The statements are classified as unchanged, changed, and new in relation to Baveno VI.

We examine the latest research on the emerging bile acid-gut microbiome axis and its role in health and disease. Our focus revolves around two key microbial pathways for degrading bile salts, and the impact of bile acid composition in the gut on the gut microbiome and host physiology.Bile acid pool size has recently been shown to be a function of microbial metabolism of bile acids in the intestines. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. Bile acids are emerging as regulators of the gut microbiome at the highest taxonomic levels. The role of bile acids as hormones and potentiators of liver cancer is also emerging.The host and microbiome appear to regulate bile acid pool size. The host produces a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in intestine and liver. Members of the microbiome utilize bile acids and their conjugates resulting in agonism of FXR in intestine and liver resulting in a smaller, unconjugated hydrophobic bile acid pool. Hydrophilicity of the bile acid pool is associated with disease states. Reduced bile acid levels in the gut are associated with bacterial overgrowth and inflammation. Diet, antibiotic therapy, and disease states affect the balance of the microbiome-bile acid pool.

The gut microbiome is altered in cirrhosis; however its evolution with disease progression is only partly understood. We aimed to study changes in the microbiome over cirrhosis severity, its stability over time and its longitudinal alterations with decompensation.Controls and age-matched cirrhotics (compensated/decompensated/hospitalized) were included. Their stool microbiota was quantified using multi-tagged pyrosequencing. The ratio of autochthonous to non-autochthonous taxa was calculated as the cirrhosis dysbiosis ratio (CDR); a low number indicating dysbiosis. Firstly, the microbiome was compared between controls and cirrhotic sub-groups. Secondly, for stability assessment, stool collected twice within 6months in compensated outpatients was analyzed. Thirdly, changes after decompensation were assessed using (a) longitudinal comparison in patients before/after hepatic encephalopathy development (HE), (b) longitudinal cohort of hospitalized infected cirrhotics MELD-matched to uninfected cirrhotics followed for 30days.244 subjects [219 cirrhotics (121 compensated outpatients, 54 decompensated outpatients, 44 inpatients) and 25 age-matched controls] were included. CDR was highest in controls (2.05) followed by compensated (0.89), decompensated (0.66), and inpatients (0.32, p<0.0001) and negatively correlated with endotoxin. Microbiota and CDR remained unchanged in stable outpatient cirrhotics (0.91 vs. 0.86, p=0.45). In patients studied before/after HE development, dysbiosis occurred post-HE (CDR: 1.2 to 0.42, p=0.03). In the longitudinal matched-cohort, microbiota were significantly different between infected/uninfected cirrhotics at baseline and a low CDR was associated with death and organ failures within 30days.Progressive changes in the gut microbiome accompany cirrhosis and become more severe in the setting of decompensation. The cirrhosis dysbiosis ratio may be a useful quantitative index to describe microbiome alterations accompanying cirrhosis progression.

The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression.Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC-MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin.Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p<0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r=0.57, p<0.008) while Ruminococcaceae were positively correlated with DCA (r=0.4, p<0.05). A positive correlation between Ruminococcaceae and DCA/CA (r=0.82, p<0.012) and Blautia with LCA/CDCA (r=0.61, p<0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios.Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa.

Background & Aims:Clostridium difficile–associated disease has increased significantly in North American medical centers. The impact of C difficile on patients with IBD (Crohn’s disease, ulcerative colitis) at the present time is unknown. Methods: A retrospective, observational study evaluating IBD patients followed in a referral center to evaluate the impact of C difficile was performed. Diagnosis was confirmed with stool toxin analysis. Demographic information, diagnosis, anatomic location, IBD therapy, antibiotic exposure, hospitalizations, and surgeries were recorded. Available endoscopic and histologic data were evaluated. Results: Rate of C difficile infection increased from 1.8% of IBD patients in 2004 to 4.6% in 2005 (P < .01). Proportion of IBD patients within the total number of C difficile infections at our institution increased from 7% in 2004 to 16% in 2005 (P < .01). IBD colonic involvement was found in the majority of C difficile–infected patients in 2005 (91%), and the majority contracted infection as an outpatient (76%). Antibiotic exposure was identified in 61% of IBD patients with C difficile infection in 2005. Pseudomembranes and fibrinopurulent eruptions were not seen endoscopically or histologically. During 2004–2005 more than half of the infected IBD patients required hospitalization, and 20% required colectomy. Univariate and multivariate analysis identified maintenance immunomodulator use and colonic involvement as independent risk factors for C difficile infection in IBD. Conclusions:C difficile infection has increased significantly in IBD patients and negatively impacts clinical outcome. Increased vigilance regarding this infection in IBD patients with colitis activity is warranted. Background & Aims:Clostridium difficile–associated disease has increased significantly in North American medical centers. The impact of C difficile on patients with IBD (Crohn’s disease, ulcerative colitis) at the present time is unknown. Methods: A retrospective, observational study evaluating IBD patients followed in a referral center to evaluate the impact of C difficile was performed. Diagnosis was confirmed with stool toxin analysis. Demographic information, diagnosis, anatomic location, IBD therapy, antibiotic exposure, hospitalizations, and surgeries were recorded. Available endoscopic and histologic data were evaluated. Results: Rate of C difficile infection increased from 1.8% of IBD patients in 2004 to 4.6% in 2005 (P < .01). Proportion of IBD patients within the total number of C difficile infections at our institution increased from 7% in 2004 to 16% in 2005 (P < .01). IBD colonic involvement was found in the majority of C difficile–infected patients in 2005 (91%), and the majority contracted infection as an outpatient (76%). Antibiotic exposure was identified in 61% of IBD patients with C difficile infection in 2005. Pseudomembranes and fibrinopurulent eruptions were not seen endoscopically or histologically. During 2004–2005 more than half of the infected IBD patients required hospitalization, and 20% required colectomy. Univariate and multivariate analysis identified maintenance immunomodulator use and colonic involvement as independent risk factors for C difficile infection in IBD. Conclusions:C difficile infection has increased significantly in IBD patients and negatively impacts clinical outcome. Increased vigilance regarding this infection in IBD patients with colitis activity is warranted. See CME exam on page 266. An increased incidence and virulence of Clostridium difficile, the anaerobic spore-forming bacillus associated with diarrheal illness and pseudomembranous colitis, has recently been identified in multiple North American medical centers.1Bartlett J.G. Perl T.M. The new Clostridium difficile: what does it mean?.N Engl J Med. 2005; 353: 2503-2505Crossref PubMed Scopus (144) Google Scholar, 2McDonald L.C. Killgore G.E. Thompson A. et al.An epidemic, toxin gene-variant strain of Clostridium difficile.N Engl J Med. 2005; 353: 2433-2441Crossref PubMed Scopus (1741) Google Scholar, 3Loo V.G. Poirier L. Miller M.A. et al.A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.N Engl J Med. 2005; 353: 2442-2449Crossref PubMed Scopus (1675) Google Scholar, 4Dial S. Delaney J.A. Barkun A.N. et al.Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease.JAMA. 2005; 294: 2989-2995Crossref PubMed Scopus (813) Google Scholar U.S. hospital discharges have documented a doubling of C difficile–associated disease between 1996–2003.5McDonald L.C. Owings M. Jernigan D.B. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003.Emerg Infect Dis. 2006; 12: 409-415Crossref PubMed Google ScholarC difficile produces several exotoxins, including toxin A and toxin B, which lead to a clinical syndrome manifesting as diarrhea, pseudomembranous colitis, and in its most severe forms toxic megacolon, sepsis, perforation, and death. In addition to the serious morbidity and mortality, C difficile–associated disease significantly increases the costs of care among patients who contract this infection. Historically, subgroups of patients are known to be at increased risk for the acquisition of C difficile–associated disease.6Bignardi G.E. Risk factors for Clostridium difficile infection.J Hosp Infect. 1998; 40: 1-15Abstract Full Text PDF PubMed Scopus (526) Google Scholar Patients recently treated with broad-spectrum antibiotics,7Wistrom J. Norrby S.R. Myhre E.B. et al.Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study.J Antimicrob Chemother. 2001; 47: 43-50Crossref PubMed Scopus (327) Google Scholar hospitalized patients,8McFarland L.V. Mulligan M.E. Kwok R.Y. et al.Nosocomial acquisition of Clostridium difficile infection.N Engl J Med. 1989; 320: 204-210Crossref PubMed Scopus (1145) Google Scholar, 9Johnson S. Clabots C.R. Linn F.V. et al.Nosocomial Clostridium difficile colonisation and disease.Lancet. 1990; 336: 97-100Abstract PubMed Scopus (287) Google Scholar oncology patients, and immunocompromised individuals as well as the elderly are believed to be at increased risk for C difficile–associated disease. Patients with the 2 major forms of IBD, Crohn’s disease and ulcerative colitis, share many of these same clinical risk factors for the development of C difficile–associated disease. Many IBD patients are maintained on long-term immunosuppression, frequently require antibiotic use for their treatment, and are often hospitalized. Past reports published during the 1980s from both the U.S. and Europe did not demonstrate an increased association of C difficile infection in IBD patients who were experiencing disease flare. More recent reports have suggested that up to 20% of IBD flare was associated with a positive stool analysis for C difficile.10Meyer A.M. Ramzan N.N. Loftus Jr, E.V. et al.The diagnostic yield of stool pathogen studies during relapses of inflammatory bowel disease.J Clin Gastroenterol. 2004; 38: 772-775Crossref PubMed Scopus (104) Google Scholar Given that the ability to clear infection is dependent on the generation of an immune response against C difficile toxin A,11Kyne L. Warny M. Qamar A. et al.Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.Lancet. 2001; 357: 189-193Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar IBD patients are a particularly high-risk subgroup. Because IBD exacerbation is routinely treated with high-dose corticosteroids, the ability to mount an effective antibody response against C difficile might be compromised, further worsening this infectious complication. The impact of C difficile on IBD patients in the present age of increased infection rates and more severe disease is not defined. We examined the impact of C difficile on a tertiary referral population of IBD patients during the past 5 years (2000–2005). We report the following findings: (1) a significant increase in the number and rate of IBD patients who contracted C difficile–associated disease; (2) a significant association between IBD diagnosis and contraction of C difficile infection compared with the general hospital and clinic population; (3) a significant association of IBD colitis and maintenance immunomodulator use in patients who contracted C difficile infection; (4) a majority of IBD patients acquired C difficile as outpatients; and (5) the severe deleterious effect of C difficile on the clinical course of IBD, which frequently leads to hospitalization and colectomy. This was a retrospective, observational study evaluating all patients who were followed in the Medical College of Wisconsin’s Inflammatory Bowel Disease Center between the years 2000–2005. Patients who tested positive for the C difficile toxin A and/or toxin B stool enzyme-linked immunosorbent assay (ELISA) were considered infected if they presented with concomitant symptoms of colitis (ie, diarrhea, increased stool frequency, rectal bleeding, cramping, and/or tenesmus). No patients with presumptive C difficile infection in the absence of a positive toxin assay were included in this analysis. The total number of IBD patients followed during the calendar years 2004 and 2005 were recorded and used to determine rates of C difficile infection. The total number of C difficile–infected patients who were followed at Froedtert Hospital, the Medical College of Wisconsin’s major adult teaching hospital, in Milwaukee, WI were recorded annually. Finally, the total number of outpatient visits and inpatient admissions for all of Froedtert Hospital and its associated clinics as well as the total number of IBD Center patient encounters (admissions and outpatient visits) were tabulated and used to compare overall rates of C difficile infection during 2004 and 2005. IBD patient demographics, including age, gender, type of IBD (ie, Crohn’s disease, ulcerative colitis), anatomic distribution of disease (isolated small bowel vs any colonic involvement), type of therapy (mesalamine, immunomodulators [azathioprine, 6-mercaptopurine, methotrexate]), anti–tumor necrosis factor–α therapy (ie, infliximab [Remicade; Centocor, Horsham, PA]), adalimumab (Humira; Abbott Laboratories, Abbott Park, IL), antibiotics, corticosteroids (systemic [ie, prednisone] vs topical [ie, budesonide]), and smoking history were recorded. Among the IBD patients who tested positive, known risk factors for the diagnosis of C difficile were recorded. This included recent hospitalization within 2 months of the time of C difficile detection and use of antibiotics within 2 months of the time of infection. Statistical analysis was performed with χ2 analysis, as well as univariate and multivariate logistic regression analysis, by using MINITAB (Minitab Inc, State College, PA). This study was approved by the Medical College of Wisconsin’s human research review committee. Demographic and disease characteristics for IBD patients from the year 2005 with and without C difficile are displayed in Table 1. Patients who were positive for C difficile in 2005 were statistically more likely to have colonic involvement, more likely to be on immunomodulator therapy, and had significantly shorter disease duration than those without C difficile (Table 1). Seven C difficile–infected patients presented at the time of IBD diagnosis.Table 1IBD Patient Demographic and Disease Characteristics in 2005C difficile positive (n = 46)C difficile negative (n = 953)P valueAge (y)38.8 ± 14.643.2 ± 14.6NSFemale25535NSMale21418Crohn’s disease30 (65%)707 (74%)NSUlcerative colitis16 (35%)246 (26%)Duration of IBD (mean ± standard deviation, y)7.5 ± 8.013.9 ± 11.8.004Colonic IBD involvement42 (91%)675 (71%).002Immunomodulator maintenance34 (74%)535 (56%).02Biologic therapy13 (28%)208 (22%)NSCurrent tobacco use10 (27%)153 (16%)NSNOTE. Immunomodulator maintenance included azathioprine, 6-mercaptopurine, and methotrexate. Biologic therapy included infliximab and adalimumab. Open table in a new tab NOTE. Immunomodulator maintenance included azathioprine, 6-mercaptopurine, and methotrexate. Biologic therapy included infliximab and adalimumab. C difficile was rarely detected in IBD patients before 2003 and increased to 14 cases in 2004 and 46 cases in 2005 (Figure 1). This corresponded to a significant increase in the rate of C difficile infection from 1.8% in 2004 to 4.6% of the IBD Center patient population in 2005 (P < .01, χ2 analysis). The total number of C difficile–infected patients followed in our hospital system increased between the years 2000–2005, with 207 cases in 2004 and 287 detected in 2005 (Figure 2). IBD patients accounted for 4% of the total C difficile–infected patient cohort in 2003, which increased to 7% in 2004 and 16% in 2005. The percentage of C difficile–infected patients who had concomitant IBD increased significantly between 2004–2005 (P < .01, χ2 analysis). We next compared the rates of C difficile infection between the total cohort of patients who were followed in our hospital system and the IBD patients followed in our center. Rates of C difficile infection in non-IBD patients were higher in 2005 compared with 2004 (Table 2), and patients with IBD were at increased risk of developing C difficile infection compared with non-IBD patients in 2004 and 2005 (Table 2).Table 2Rate of C difficile Infections in 2004 and 200520042005Total non-IBD patient encounters (admissions and outpatient visits)455,682475,715Non-IBD cases with C difficile193241aSignificantly higher proportion of IBD patients with C difficile compared with non-IBD patients in 2005, compared with 2004 (P = .002).Total IBD patient encounters (admissions and outpatient visits)2,5472,349IBD cases with C difficile1446bSignificantly higher proportion of IBD patients with C difficile in 2005 compared with 2004 (P = .0001).NOTE. Odds ratio for developing C difficile in IBD patients compared with non-IBD patients: 13.0 (95% confidence interval, 7.5–22.4) in 2004 and 38.6 (95% confidence interval, 28.1–53.1) in 2005. Non-IBD patient encounters include both hospital admissions to Froedtert Hospital and visits to its affiliated outpatient clinics during 2004 and 2005. IBD patient encounters include inpatient admissions to Froedtert Hospital as well as outpatient clinic visits to the IBD Center during both 2004 and 2005.a Significantly higher proportion of IBD patients with C difficile compared with non-IBD patients in 2005, compared with 2004 (P = .002).b Significantly higher proportion of IBD patients with C difficile in 2005 compared with 2004 (P = .0001). Open table in a new tab NOTE. Odds ratio for developing C difficile in IBD patients compared with non-IBD patients: 13.0 (95% confidence interval, 7.5–22.4) in 2004 and 38.6 (95% confidence interval, 28.1–53.1) in 2005. Non-IBD patient encounters include both hospital admissions to Froedtert Hospital and visits to its affiliated outpatient clinics during 2004 and 2005. IBD patient encounters include inpatient admissions to Froedtert Hospital as well as outpatient clinic visits to the IBD Center during both 2004 and 2005. In 2004 Crohn’s disease accounted for 64% of the IBD patients who contracted C difficile and 65% of the diagnoses in 2005, with the remaining patients having UC. This preponderance of patients with Crohn’s disease was reflective of our IBD Center patient population, in which approximately 74% of the patients carried a diagnosis of Crohn’s disease in 2005. We then evaluated anatomic involvement in IBD patients who contracted C difficile infection. Colonic involvement was found in 93% of the 2004 patients and was present in 91% of the 2005 patients. Isolated small bowel Crohn’s disease was found in the remaining C difficile–infected IBD patients. The C difficile–infected IBD patients required 11 hospitalizations in 2004, which increased to 27 in 2005 (Figure 3). These admissions corresponded with 5 colectomies in 2004 and 7 colectomies in 2005. The rate of colectomy in hospitalized patients with IBD colitis with C difficile infection decreased from 45% in 2004 to 25% in 2005. During this time period colectomies for C difficile infection in non-IBD patients were performed in 3 patients during 2004 and 2 patients in 2005 at our institution. This implied that the majority of C difficile–associated colectomies occurred in IBD patients. The mean number of hospital days required for the care of IBD patients admitted with C difficile infection was 13.5 ± 8.8 days (mean ± standard deviation). During 2005, there were 12 hospitalizations for ulcerative colitis patients who were not C difficile–infected, and their mean length of stay was 6.0 ± 4.0 days (mean ± standard deviation). All IBD patients who tested positive for C difficile in the setting of colitis symptoms were treated with antibiotic therapy directed at the infection. This included the oral antibiotics vancomycin (oral or enema administration) or rifaximin (oral) and metronidazole (oral or intravenous). Hospitalized patients who were unable to tolerate oral medication were treated with intravenous metronidazole. Because of the high colectomy rate associated with C difficile during 2004, the antibiotic approach at our institution shifted from using metronidazole to vancomycin as the primary antibiotic. In addition, hospitalized patients with C difficile infection during 2005 had their treatment regimen for IBD adjusted, with a rapid decrease in steroid dosing emphasized after detection of the infection. This alteration in the treatment regimen correlated with a lower rate of surgery compared with the 2004 experience in our IBD cohort. The diagnosis of C difficile is most commonly based on the detection of exotoxin A and B in stool samples by ELISA. We retrospectively reviewed the pattern of stool ELISA analysis in the IBD patients diagnosed with C difficile in 2005. Fifty-four percent of the infected IBD patients were diagnosed with the first stool sample, 75% were diagnosed by the second stool sample, 78% were diagnosed by the third stool sample, and 92% were diagnosed by the fourth stool analysis. One hospitalized IBD colitis patient was diagnosed with C difficile infection on the 8th stool sample after a prolonged hospitalization. Next we analyzed whether the IBD patients contracted C difficile as a result of hospitalization (nosocomial infection) versus community-acquired infection. Patients who tested positive within 48 hours of hospital admission were labeled community-acquired for this analysis. Community-acquired C difficile was detected in 79% of cases in 2004 and in 76% of cases in 2005. Immunosuppression is a known risk factor for the development of C difficile–associated disease.11Kyne L. Warny M. Qamar A. et al.Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.Lancet. 2001; 357: 189-193Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 12Dallal R.M. Harbrecht B.G. Boujoukas A.J. et al.Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.Ann Surg. 2002; 235: 363-372Crossref PubMed Scopus (517) Google Scholar, 13Johnson S. Gerding D.N. Clostridium difficile-associated diarrhea.Clin Infect Dis. 1998; 26: 1027-1036Crossref PubMed Scopus (343) Google Scholar We analyzed the overall use of immunosuppressive medications in IBD patients with C difficile infection. In 2004, 64% of the IBD patients were receiving immunosuppressive medications (ie, azathioprine, 6-mercaptopurine, methotrexate, infliximab, and/or adalimumab) at the time that they contracted C difficile. In 2005, the rate of immunosuppression among IBD patients who contracted C difficile was 78%. Infliximab use among the IBD patients who contracted C difficile was identified in 14% in 2004 and in 28% of patients in 2005. Among the IBD patients who contracted C difficile in 2005, 46% were receiving a purine analog (ie, azathioprine or 6-mercaptopurine) for maintenance therapy alone or in combination with infliximab, whereas 13% were on methotrexate maintenance alone or in combination with infliximab. Dosages of the immunomodulators were individualized on the basis of routine clinical practice, while taking into account patient ability to tolerate the drug and adverse reactions. The classic endoscopic finding in C difficile–associated disease is the presence of pseudomembranes on the colonic mucosal surfaces, which have been estimated to occur in approximately 50% of infected patients.14Kelly C.P. LaMont J.T. Clostridium difficile infection.Annu Rev Med. 1998; 49: 375-390Crossref PubMed Scopus (368) Google Scholar, 15Fekety R. Shah A.B. Diagnosis and treatment of Clostridium difficile colitis.JAMA. 1993; 269: 71-75Crossref PubMed Scopus (318) Google Scholar In the 60 IBD patients who exhibited C difficile infection during the years 2004–2005, there were 16 who underwent endoscopic assessment. No IBD patient with C difficile infection who underwent endoscopy exhibited the presence of discrete pseudomembranes. In contrast, the presence of a nonspecific mucopus was the most commonly encountered endoscopic finding (Figure 4). The classic histologic finding in C difficile–associated colitis is a volcanic eruption of pseudomembranes from the mucosa, composed of polymorphonuclear leukocytes, fibrin, chronic inflammatory cells, and epithelial debris. When colonic endoscopic pinch biopsies (n = 12 patient biopsy samples from a total of 16 endoscopies) and colectomy specimens (n = 12 specimens) from C difficile–infected IBD patients were evaluated histologically between 2004–2005, no classic fibrin eruptions or pseudomembranes were detected (Figure 5). We analyzed established risk factors for the acquisition of C difficile infection in the IBD patients who acquired disease in 2005. Sixty-one percent of the patients had a history of antibiotic use within 2 months of the detection of C difficile infection. The most commonly used antibiotic was the oral fluoroquinolone, ciprofloxacin. Thirty-nine percent of the patients did not have antibiotic exposure during the 2-month time period immediately before C difficile detection. An additional potential risk factor for the acquisition of C difficile infection in the IBD patients who tested positive included a healthcare occupation with patient contact in an institutional setting (7%). To determine associations between IBD clinical parameters and emergence of C difficile infection, univariate and multivariate logistic regression analysis was performed. Patients with C difficile infection during 2005 (n = 46) were analyzed compared with the entire cohort of IBD patients followed at the Medical College of Wisconsin’s IBD Center during 2005 (n = 999). Data on the following clinical parameters from 2005 were analyzed: Crohn’s disease versus ulcerative colitis; anatomic involvement (isolated small intestine vs any colonic involvement); tobacco history (any history of smoking); gender; hospitalization; surgery; use of isolated mesalamine treatment; use of immunomodulator maintenance therapy (azathioprine, 6-mercaptopurine, methotrexate); and use of biologic therapy (infliximab, adalimumab). Univariate analysis demonstrated that presence of IBD colonic involvement (P = .03; 95% confidence interval, 1.10–7.22; odds ratio, 2.82) and use of immunomodulators (P = .011; 95% confidence interval, 1.23–4.86; odds ratio, 2.44) were significantly associated with the development of C difficile infection. None of the other parameters tested, including use of biologic treatment, were significantly associated with C difficile infection in patients with IBD. Multivariate logistic regression analysis confirmed that both colonic involvement (P = .018; odds ratio, 3.12; 95% confidence interval, 1.22–8.02) and maintenance immunosuppression (P = .008; odds ratio, 2.56; 95% confidence interval, 1.28–5.12) were independently associated with the emergence of C difficile infection in patients with IBD. We report that C difficile–associated disease has significantly increased among patients with IBD who were followed in a tertiary referral setting during the past several years. IBD patients with colonic involvement exhibited a significant association with development of C difficile infection, with both Crohn’s colitis and ulcerative colitis patients comprising the majority of those infected. Immunosuppression was used in the majority of IBD patients who contracted C difficile infection and was significantly associated with the emergence of this infection by using univariate and multivariate regression analysis. The majority of IBD patients contracted C difficile infection as outpatients and did not manifest classic endoscopic or histologic features including pseudomembranes and fibrinous exudate. More than half of the C difficile–infected IBD patients required hospitalization, and the colectomy rate in this cohort during a 2-year period was 20%. Perhaps most important, IBD patients comprised a disproportionate percentage of all the patients who contracted C difficile infection in our institution during the past 2 years, which suggests that IBD colitis is an important and previously unrecognized risk factor for the development of this infection. C difficile is a gram-positive, spore-forming anaerobic bacteria that can colonize the large intestine, producing a range of clinical activity from asymptomatic carriage to severe fulminant colitis in humans.14Kelly C.P. LaMont J.T. Clostridium difficile infection.Annu Rev Med. 1998; 49: 375-390Crossref PubMed Scopus (368) Google Scholar, 16Hurley B.W. Nguyen C.C. The spectrum of pseudomembranous enterocolitis and antibiotic-associated diarrhea.Arch Intern Med. 2002; 162: 2177-2184Crossref PubMed Scopus (193) Google Scholar There are 2 prerequisites for developing C difficile–associated diarrhea: disruption of the normal gastrointestinal flora causing diminished colonization resistance favoring C difficile and acquisition of the organism from an exogenous source.13Johnson S. Gerding D.N. Clostridium difficile-associated diarrhea.Clin Infect Dis. 1998; 26: 1027-1036Crossref PubMed Scopus (343) Google ScholarC difficile–associated disease is frequently but not always an iatrogenic complication of broad-spectrum antibiotics and often complicates the clinical course of hospitalized patients. Other important clinical factors include host susceptibility, virulence of the C difficile strain concerned, and the nature and extent of antimicrobial exposure.17McFarland L.V. Alternative treatments for Clostridium difficile disease: what really works?.J Med Microbiol. 2005; 54: 101-111Crossref PubMed Scopus (155) Google Scholar We found that recent use of antibiotics, specifically oral fluoroquinolones, occurred in the majority of IBD patients who contracted C difficile. Indeed, many of the patients, particularly those with Crohn’s disease colitis, had received ciprofloxacin in an attempt to provide treatment for IBD flare. Our data suggest that the empiric use of broad-spectrum antibiotics, which are associated with the development of C difficile, as a routine treatment of IBD flare should be considered cautiously. Recent reports have described a significant increase in the incidence of C difficile–associated disease throughout North America. The National Nosocomial Infection Surveillance system has reported a significant increase in the C difficile rates between 1987–2001.5McDonald L.C. Owings M. Jernigan D.B. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003.Emerg Infect Dis. 2006; 12: 409-415Crossref PubMed Google Scholar, 18National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003.Am J Infect Control. 2003; 31: 481-498Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar Individual medical centers, including the University of Pittsburgh, described a doubling in the incidence rate of C difficile–associated disease in 2000–2001 compared with 1990–1999.12Dallal R.M. Harbrecht B.G. Boujoukas A.J. et al.Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.Ann Surg. 2002; 235: 363-372Crossref PubMed Scopus (517) Google Scholar Case series from a Canadian hospital in Sherbrooke, Quebec, have described a 10-fold increase in C difficile incidence.19Pepin J. Valiquette L. Alary M.E. et al.Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity.CMAJ. 2004; 171: 466-472Crossref PubMed Scopus (949) Google Scholar Our data suggest that this increased detection of C difficile in hospitalized patients has been paralleled by increased infection in patients with IBD. C difficile–associated disease accounts for considerable increases in the length of hospital stay and more than $1.1 billion in healthcare costs each year in the United States.20Kyne L. Hamel M.B. Polavaram R. et al.Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile.Clin Infect Dis. 2002; 34: 346-353Crossref PubMed Scopus (613) Google Scholar Each case of C difficile–associated disease has been estimated to result in more than $3600 in excess healthcare costs per patient at the present time. Our experience with C difficile infection in IBD was similar, with hospitalization and surgery emerging as frequent complications in patients who contracted this illness, in which the mean duration of admission was close to 2 weeks. The severity of illness and resultant economic burden from C difficile might be linked to increased virulence of isolates identified at the present time.2McDonald L.C. Killgore G.E. Thompson A. et al.An epidemic, toxin gene-variant strain of Clostridium difficile.N Engl J Med. 2005; 353: 2433-2441Crossref PubMed Scopus (1741) Google Scholar In a recent report, 50% of C difficile isolates from 8 healthcare facilities in 6 states belonged to BI/NAP1 that were positive for the binary toxin CDT. This C difficile isotype carries a higher rate of resistance to gatifloxacin and moxifloxacin and has been blamed for epidemics both inside and outside the U.S. Increased virulence of C difficile has also translated into an increased case-fatality rate. Published data from Quebec, Canada suggest that the proportion of cases that were complicated increased from 7.1% (12/169) in 1991–1992 to 18.2% (71/390) in 2003 (P < .001), and the proportion of patients who died within 30 days after diagnosis increased from 4.7% (8/169) in 1991–1992 to 13.8% (54/390) in 2003 (P < .001). Fortunately, no deaths were seen in the IBD patients during the time of C difficile infection at our center. None of our C difficile–infected IBD patients underwent specific microbiologic isolate identification. The epidemiology of C difficile–associated disease has changed during the past decade. Traditional risk factors, including advanced age (ie, age older than 65 years) and use of broad-spectrum antibiotics, must now include use of fluoroquinolone as a major risk factor.21Pepin J. Saheb N. Coulombe M.A. et al.Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec.Clin Infect Dis. 2005; 41: 1254-1260Crossref PubMed Scopus (820) Google Scholar Our multivariate analysis demonstrated that immunomodulator use and presence of IBD colitis (either ulcerative colitis or Crohn’s colitis) are also significant risk factors for the development of C difficile infection. The larger question of why C difficile–associated disease has increased over recent years remains unanswered. This question is highlighted by the fact that 39% of the IBD patients in our cohort who contracted C difficile in 2005 did not have identifiable antibiotic exposure during the recent time period before manifesting infection, suggesting that other mechanisms for the acquisition of the pathogen might be involved. C difficile infection in IBD patients followed in our referral cohort had significant clinical ramifications and posed additional challenges in management. A majority of the C difficile–infected patients required hospitalization during the 2004–2005 time period. Detection of C difficile was often difficult, because classic endoscopic and histologic features were not readily identified in our IBD patients. Stool ELISA analysis for the presence of toxin A and B also demonstrated low sensitivity, mandating that multiple samples be routinely processed to accurately diagnose patients. Therefore, heightened vigilance regarding C difficile infection in IBD patients experiencing disease flare is warranted, because it occurs more commonly, fails to demonstrate classic morphologic features, and will frequently require multiple stool assays to detect. Patients with immunosuppression from chemotherapy or as a desired therapeutic goal in the setting of organ transplantation are known to be at increased risk for C difficile–associated disease. Our multivariate analysis confirmed that the use of maintenance immunomodulator therapy in IBD patients was significantly associated with C difficile infection. Interestingly, use of anti–tumor necrosis factor–α antibody therapy did not correlate with increased risk for acquisition of C difficile–associated disease in patients with IBD. These findings suggest that specific regimens of immunosuppression might carry differential risk for the acquisition of C difficile infection and associated disease. Colonic involvement with IBD was also significantly associated with C difficile infection, and isolated small bowel Crohn’s disease was found in a disproportionately lower number of patients. The reason for IBD colitis predisposing to C difficile infection is not clear. We hypothesize that the previously damaged and chronically inflamed colonic mucosa that was subject to chronic inflammation becomes more susceptible to infection with C difficile. We also suspect that the lack of pseudomembranes and fibrinous exudate encountered during endoscopic and histologic evaluation in IBD patients was related to preexisting mucosal changes associated with chronic inflammation as well. Although our article did not evaluate specific treatment regimens, 3 different antibiotics were used against C difficile among the 46 IBD patients who tested positive during 2005. Antibiotics included metronidazole, oral vancomycin, and rifaximin.22Mignini F. Falcioni E. Prenna M. et al.Antibacterial activity of rifaximin against Clostridium difficile, Campylobacter jejunii and Yersinia spp.J Chemother. 1989; 1: 220-222PubMed Google Scholar Initial courses of antibiotic were unsuccessful in 58% of the patients (27/46), who required additional courses of treatment for recurrent C difficile infection. A diminished therapeutic response to metronidazole was reported by Musher et al23Musher D.M. Aslam S. Logan N. et al.Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole.Clin Infect Dis. 2005; 40: 1586-1590Crossref PubMed Scopus (427) Google Scholar in 2005, who described a failure rate of 50% in C difficile–infected patients, which is in contrast to response rates of 90% described a decade prior. We found similar problems with metronidazole in our cohort of IBD patients infected with C difficile, and we changed our practice pattern in 2005 to use oral vancomycin as the primary antibiotic against this infection. Use of oral vancomycin in C difficile–infected IBD patients in 2005 corresponded with a diminished colectomy rate compared with our experience in 2004. However, vancomycin treatment of C difficile is also challenged by high rates of recurrence, and precise algorithms for treatment, including optimal dosages, combinations of agents, durations of therapy, and use of antibiotic tapering regimens, have yet to be defined. The reasons underlying the loss of response to metronidazole in C difficile infections at the present time have not been defined. Past published information regarding C difficile infection in IBD patients from 2 decades ago suggested that this was a minor clinical issue.24Rolny P. Jarnerot G. Mollby R. et al.Occurrence of Clostridium difficile toxin in inflammatory bowel disease.Scand J Gastroenterol. 1983; 18: 61-64Crossref PubMed Scopus (58) Google Scholar A Scandinavian study from 1983 stated “In our region there is no need for routine screening for this in symptomatic patients with IBD.” A U.S. study from pediatric patients in 1985 concurred,25Hyams J.S. McLaughlin J.C. Lack of relationship between Clostridium difficile toxin and inflammatory bowel disease in children.J Clin Gastroenterol. 1985; 7: 387-390Crossref PubMed Scopus (17) Google Scholar stating “Routine screening for C difficile toxin in children with inflammatory bowel disease appears unwarranted.” Our findings from the present age directly challenge these conclusions. C difficile has significantly increased during the past several years, and this trend is especially evident in patients with IBD, who appear to be at marked risk of infection. Our findings suggest that IBD patients with colonic involvement and those using maintenance immunomodulator therapy appear to be at highest risk for contracting C difficile. Detection of this infection in IBD patients is challenging, because classic pseudomembranes are not commonly encountered, and multiple stool samples are necessary to detect C difficile toxin in half of patients. Clinically, C difficile negatively impacts IBD patients, and a majority require hospitalization for management. In summary, clinicians must be vigilant regarding the potential for C difficile to contribute to colitis flare to rapidly identify and optimally treat IBD patients. We would like to thank H. Brandenburg for expert assistance with preparation of the manuscript. Exams 1 and 2Clinical Gastroenterology and HepatologyVol. 5Issue 3Preview Full-Text PDF

Infections worsen survival in cirrhosis; however, simple predictors of survival in infection-related acute-on-chronic liver failure (I-ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End-stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥ 7) and 30-day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30-day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I-ACLF was defined as ≥ 2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non-SBP infections. Independent predictors of poor 30-day survival were I-ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin.Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I-ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival.

Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We aimed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach. Multitag pyrosequencing (MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. Patients with HE were compared with those without HE using a correlation-network analysis. A select group of patients with HE (n = 7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days. Twenty-five patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 without HE, age 56 ± 6 yr, model for end-stage liver disease score 16 ± 6] and ten controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae) compared with controls. We found altered flora (higher Veillonellaceae), poor cognition, endotoxemia, and inflammation (IL-6, TNF-α, IL-2, and IL-13) in HE compared with cirrhotics without HE. In the cirrhosis group, Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment. Fusobacteriaceae, Veillonellaceae, and Enterobacteriaceae were positively and Ruminococcaceae negatively related to inflammation. Network-analysis comparison showed robust correlations (all P < 1E-5) only in the HE group between the microbiome, cognition, and IL-23, IL-2, and IL-13. Lactulose withdrawal did not change the microbiome significantly beyond Fecalibacterium reduction. We concluded that cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared with healthy individuals. Specific bacterial families (Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in HE.

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout.FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727-1738).

Although hepatic encephalopathy (HE) is linked to the gut microbiota, stool microbiome analysis has not found differences between HE and no-HE patients. This study aimed to compare sigmoid mucosal microbiome of cirrhotic patients to controls, between HE vs. no-HE patients, and to study their linkage with cognition and inflammation. Sixty cirrhotic patients (36 HE and 24 no-HE) underwent cognitive testing, stool collection, cytokine (Th1, Th2, Th17, and innate immunity), and endotoxin analysis. Thirty-six patients (19 HE and 17 no-HE) and 17 age-matched controls underwent sigmoid biopsies. Multitag pyrosequencing (including autochthonous genera, i.e., Blautia, Roseburia, Fecalibacterium, Dorea) was performed on stool and mucosa. Stool and mucosal microbiome differences within/between groups and correlation network analyses were performed. Controls had significantly higher autochthonous and lower pathogenic genera compared with cirrhotic patients, especially HE patients. HE patients had worse MELD (model for end-stage liver disease) score and cognition and higher IL-6 and endotoxin than no-HE. Mucosal microbiota was different from stool within both HE/no-HE groups. Between HE/no-HE patients, there was no difference in stool microbiota but mucosal microbiome was different with lower Roseburia and higher Enterococcus, Veillonella, Megasphaera, and Burkholderia abundance in HE. On network analysis, autochthonous genera (Blautia, Fecalibacterium, Roseburia, and Dorea) were associated with good cognition and decreased inflammation in both HE/no-HE, whereas genera overrepresented in HE (Enterococcus, Megasphaera, and Burkholderia) were linked to poor cognition and inflammation. Sigmoid mucosal microbiome differs significantly from stool microbiome in cirrhosis. Cirrhotic, especially HE, patients' mucosal microbiota is significantly different from controls with a lack of potentially beneficial autochthonous and overgrowth of potentially pathogenic genera, which are associated with poor cognition and inflammation.

Corrigendum to “Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases” [J Hepatol 2014;61:642–659]Journal of HepatologyVol. 63Issue 4PreviewA type error regrettably occurred in the dosage of lactulose in the following paragraph and the authors owe thanks to an observant Gloucestershire reader for noting it. The type error does not occur in the Hepatology version of the guideline. The Editorial office apologise for any inconvenience caused. Full-Text PDF Interaction between infection and hepatic encephalopathyJournal of HepatologyVol. 62Issue 3PreviewWe read with interest “The Hepatic Encephalopathy Practice Guidelines” published in the September issue of the Journal of Hepatology [1]. Full-Text PDF Open Access These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD/EASL Practice Guidelines Subcommittee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup, with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong (1) or weak (2).Table 1GRADE system for evidence. Open table in a new tab The literature databases and search strategies are outlined below. The resulting literature database was available to all members of the writing group (i.e., the authors). They selected references within their field of expertise and experience and graded the references according to the GRADE system [[1]Guyatt G.H. Oxman A.D. Vist G.E. Kunz R. Falck-Ytter Y. Alono-Coello P. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar]. The selection of references for the guideline was based on a validation of the appropriateness of the study design for the stated purpose, a relevant number of patients under study, and confidence in the participating centers and authors. References on original data were preferred and those that were found unsatisfactory in any of these respects were excluded from further evaluation. There may be limitations in this approach when recommendations are needed on rare problems or problems on which scant original data are available. In such cases, it may be necessary to rely on less-qualified references with a low grading. As a result of the important changes in the treatment of complications of cirrhosis (renal failure, infections, and variceal bleeding [VB]), studies performed more than 30 years ago have generally not been considered for these guidelines.

Bacterial infections are an important cause of mortality in cirrhosis, but there is a paucity of multicenter studies. The aim was to define factors predisposing to infection-related mortality in hospitalized patients with cirrhosis. A prospective, cohort study of patients with cirrhosis with infections was performed at eight North American tertiary-care hepatology centers. Data were collected on admission vitals, disease severity (model for endstage liver disease [MELD] and sequential organ failure [SOFA] scores), first infection site, type (community-acquired, healthcare-associated [HCA] or nosocomial), and second infection occurrence during hospitalization. The outcome was mortality within 30 days. A multivariate logistic regression model predicting mortality was created. 207 patients (55 years, 60% men, MELD 20) were included. Most first infections were HCA (71%), then nosocomial (15%) and community-acquired (14%). Urinary tract infections (52%), spontaneous bacterial peritonitis (SBP, 23%) and spontaneous bacteremia (21%) formed the majority of the first infections. Second infections were seen in 50 (24%) patients and were largely preventable: respiratory, including aspiration (28%), urinary, including catheter-related (26%), fungal (14%), and Clostridium difficile (12%) infections. Forty-nine patients (23.6%) who died within 30 days had higher admission MELD (25 versus 18, P < 0.0001), lower serum albumin (2.4 g/dL versus 2.8 g/dL, P = 0.002), and second infections (49% versus 16%, P < 0.0001) but equivalent SOFA scores (9.2 versus 9.9, P = 0.86). The case fatality rate was highest for C. difficile (40%), respiratory (37.5%), and spontaneous bacteremia (37%), and lowest for SBP (17%) and urinary infections (15%). The model for mortality included admission MELD (odds ratio [OR]: 1.12), heart rate (OR: 1.03) albumin (OR: 0.5), and second infection (OR: 4.42) as significant variables. Conclusion: Potentially preventable second infections are predictors of mortality independent of liver disease severity in this multicenter cirrhosis cohort. (HEPATOLOGY 2012;56:2328–2335)

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. Methods Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. Results There was a significant improvement in cognition(six of seven tests improved,p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. Conclusions Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. Trial Registration ClinicalTrials.gov NCT01069133

Cirrhosis and chronic liver disease adversely affect neurocognitive functioning.1 These deficits range from neurological complications such as hepatic myelopathy to cognitive and mental status changes such as hepatic encephalopathy (HE).2 These neurocognitive difficulties can also severely restrict the patient's functioning and result in morbidity and mortality.3-6 The most prominent neurocognitive complication of cirrhosis is HE, which reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease.7 The current system for studying HE is based on a subjective clinical classification largely based on mental status changes, the West Haven scale.2, 7-9 In addition to the mental status changes detected by clinical scales such as the West Haven scale, there are significant neurocognitive disturbances in those with normal mental status, which is characterized by impaired neuropsychological and perceptual motor dysfunction.10 The current system of HE classification does not take into account the continuum of this neurocognitive dysfunction in HE, which forms a spectrum of neurocognitive impairment in cirrhosis (SONIC).7, 11, 12 This spectrum spans a patient's performance from normal to overt HE to coma. The continuous nature of these impairments is supported by the presence of psychometric and neurophysiological impairments in patients even before they reach overt HE,13 poorer performance on tests in patients with treated overt HE than those without overt HE,1, 14 and persistence of psychometric deficits even after adequate resolution of an episode of overt HE.15 In addition, the worse clinical outcomes in patients with poor psychometric performance as a continuous measure have also been described.16 This review focuses on the available techniques and systems for characterizing HE and discusses the need for an approach for gauging severity of early HE as a continuum based on relevant clinical outcomes. The overall neurological complications of cirrhosis can be HE-related or independent of HE, and it is important to review these separately. Patients with cirrhosis can benefit from a detailed neurological examination; traditional teaching is that patients with difficulties in consciousness who also exhibit focal neurological deficits do not have HE. However, there is a high prevalence of focal deficits in patients with cirrhosis that is unrelated to HE, which may be due to (1) prior alcohol use resulting in cirrhosis and focal deficits, such as neuropathy and cerebellar signs17; (2) direct effects of cirrhosis on the nervous system, such as hepatic myelopathy and extra-pyramidal signs18, 19; (3) deficits unrelated to liver disease, such as residual deficits of prior strokes; and (4) diseases that affect the brain and liver concurrently, such as Wilson's disease.20 Therefore, the mere presence of focal deficits does not specifically exclude HE. Existing focal neurological deficits are also dependent on the depth of examination. A study by Krieger et al.21 revealed that 50% of patients with HE had “focal neurological signs”; these signs were mostly observed in those with a history of prior overt HE. However, most patients that have been included in recent studies do not have any specific focal neurological signs. Hepatic myelopathy is diagnosed as a spastic paraparesis and hyperreflexia without sensory loss; it does not improve with HE therapies but can reverse after liver transplantation.22, 23 Less than 1% of cirrhotic patients also present with acquired hepatolenticular degeneration with extrapyramidal and cerebellar symptoms. Unlike hepatic myelopathy, this responds to HE therapy.18 Although the above syndromes are important in our overall understanding of the neurological complications of cirrhosis, HE remains the most prevalent of these complications. BDT, Block Design test; CFF, critical flicker frequency; DST, digit symbol test; EEG, electroencephalogram; HE, hepatic encephalopathy; HESA, hepatic encephalopathy scoring algorithm; ICT, inhibitory control test; MHE, minimal hepatic encephalopathy; NCT-A/B, number connection tests A/B; PHES, Psychometric Hepatic Encephalopathy Score; RBANS, repeatable battery for assessment of neuropsychological status. HE is clinically divided into normal or overt HE. However when psychometric or neurophysiological tests are also used, it can be divided into normal, minimal HE (MHE), and overt HE.7, 24 This is because minimal HE cannot be diagnosed using just the clinical examination without these specialized tests. The well-known West Haven criteria have been used in several studies, but these criteria suffer from a lack of consistency in their application (Table 1).9, 24 There is a lack of reproducibility apart from the extremes of consciousness.24 Recent studies have shown that there is good agreement among observers in grading patients who are in a coma and those who are completely alert.7, 25 The Glasgow Coma Scale is used to further classify patients with HE who are in a coma.24, 26 The clinical hepatic encephalopathy staging scale (CHESS) is promising for mental status assessment but is currently undergoing validation trials.27 Although the clinical scales are easy to apply, there remains a large gray zone in the quantification of changes between the two extremes of normal and coma (Fig. 1).8, 25 Agreement of clinical scales in HE. There is insufficient agreement between observers in the clinical scales of HE except in the extremes. The large population of HE that exists between coma and appearing clinically normal is prone to misclassification using pure clinical scales, which leads to subjectivity. Stage 0 encompasses patients with normal cognitive function and minimal HE, the only definition being that patients have no current clinical signs and symptoms of overt HE.24 This differentiation between stage 0 and stage 1 of the West Haven criteria, which is critical for inclusion or exclusion into research trials or therapy, is clouded in uncertainty due to the nonspecificity of signs and symptoms of stage 1 HE (Fig. 2).9 The problem is this: What profile constitutes symptoms of HE in patients who are otherwise ambulatory? This is a difficult question when using pure clinical scales, as evidenced anecdotally by clinicians and through systematic studies. Characterization of HE stages using clinical and psychometric/neurophysiological tests. Using clinical and specialized testing, patients evaluated for HE are classified as normal, minimal HE, or overt HE. Depending on the specialized tests used and the availability of population norms, the diagnosis of MHE versus normal can vary between populations. In addition, the important distinction between stage I overt HE using West Haven criteria and minimal HE is often blurred due to the inability of the clinical scales to accurately define this stage. This furthers the subjectivity of this categorical approach in the initial stages of HE. The assessment of stage II, when patients begin to exhibit disorientation, is fairly reliable between raters. In addition to the difficulties faced in dividing patients into normal (stage 0) and stage 1, there is even more controversy surrounding the division of stage 0 into normal and MHE. MHE is defined as cognitive dysfunction without clinical signs of overt HE.13, 28 The diagnosis of MHE is only possible through specialized psychometric and neurophysiological measures.29 These methods are sensitive and reproducible to a large extent, but the applications across several populations are limited because of lack of norms and lack of appropriate language forms.29 Cognitive dysfunction in patients with MHE is characterized by attention deficit, working memory problems, and defects in executive functions such as response inhibition.1, 30 There is no evidence of long-term memory or language function decline in patients with MHE. Therefore, testing strategies for MHE are traditionally focused on these neurocognitive domains. Details of individual psychometric and neurophysiological tests are listed in Table 2, and the specific domains are shown in Fig. 3. Although these tests are sensitive, their specificity is in question, because patients with other metabolic and traumatic insults to the brain can have similar deficits. Therefore, the test performances have to be interpreted in the context of the patient's overall medical history, examination findings, and socio-economic status. Psychometric testing in order of complexity and functions tested. From the bottom up, there is an increasing complexity of functions tested by the various methods. Clinical scales primarily establish orientation, whereas psychometric tests start from the basic reaction times and proceed to complex executive functions. The tests must be used judiciously given the background of the particular patient and domains that need to be tested. The tests also may worsen in the reverse order with worsening HE. The traditional batteries used are paper-pencil batteries, which have the benefit of being portable, easily translatable, and with alternate forms to prevent learning effects. The recommended battery is the portosystemic encephalopathy syndrome test or Psychometric Hepatic Encephalopathy Score (PHES).1, 7, 10, 30 This battery consists of five tests: the number connection tests A and B (NCT-A/B), digit symbol test (DST), serial dotting test, and line tracing test. The NCT-A (or trails test A) tests for psychomotor function, whereas the NCT-B analyzes divided attention and executive function. The DST is a test of attention and processing speed. Serial dotting and line tracing are also tests of processing speed. All these tests are compared against age- and education-matched controls, and from these five tests, six scores are generated (the line tracing test has a score for time and errors), which are added to give a composite. The total score is a summation of the number of standard deviations (>−1 to <−3) from the age-corrected mean values. Scores between −5 to −18 are considered abnormal. This battery has been validated in Europe, but does not have norms for the United States.31 The working group on HE recommendeds that the PHES—or, in its absence, any two of the following four tests: NCT-A, NCT-B, DST, or Block Design test (BDT)—must be abnormal to be called MHE.7 The BDT tests for constructional praxis and visuo-motor processing. Currently, the BDT and DST are available as components of the Wechsler's Adult Intelligence Scale.32 The International Society for Hepatic Encephalopathy and Nitrogen Metabolism recommended the use of PHES or Repeatable Battery for Assessment of NeuroPsychological Status (RBANS).33 The RBANS consists of five domains: immediate memory, delayed memory, language, attention, and visuo-spatial skills.34, 35 Composite and individual cognitive domain scores are generated at the end of the test. The RBANS has been used for evaluating dementia and in unselected cirrhotic patients, but a systematic experience with RBANS in HE is currently lacking.35, 36 Psychometric tests administered with a computer have the advantage of being automated; however, a familiarity with computers is often needed in some tests. Three testing systems—the inhibitory control test, the drug research test, and the Sternberg paradigm—have been used recently to diagnose cognitive dysfunction in cirrhosis. With over 50 parallel forms of each task, the cognitive drug research system (Cognitive Drug Research Ltd, Goring-on-Thames, United Kingdom) is widely used for the assessment of cognitive function in clinical trials in the United Kingdom.37 It has five domains: power of attention, continuity of attention, speed of memory, quality of working memory, and quality of episodic memory. This system was validated in outpatients with cirrhosis; performance on key domains worsened after transvenous intrahepatic portosystemic shunt placement and improved after liver transplantation.37 The inhibitory control test (ICT) is a modification of the continuous performance test in which patients are instructed to respond to alternating presentations of X and Y (called targets) and to avoid responding to nonalternating presentations called lures that are interspersed within the test.38 The ICT assesses vigilance, sustained attention, response inhibition, and working memory.39, 40 ICT lures can differentiate between cirrhotic patients with and without cognitive dysfunction. ICT performance also predicts the development of overt HE, worsens after transvenous intrahepatic portosystemic shunt placement, and improves after therapy.39, 40 A recent study revealed that the ICT was associated with motor vehicle crashes.16 The ICT is available for free download at www.hecme.tv. The scan test is a computerized digit-recognizing task based on the Sternberg paradigm that measures the mean reaction times and the percentage of errors in recognition of patterns of digits.41, 42 The scan test is influenced by visual stimulus encoding, altered memory scanning, sustained attention, and psychomotor processing defects.42 Performance on this test was associated with survival; however, it was not shown to be influenced by the glutamine challenge, and therefore the test needs further validation.41, 43 A compendium of neurophysiological tests has been used to characterize cognitive dysfunction in cirrhosis ranging from simple electroencephalogram (EEG) to complex oddball paradigms for evoked potentials and the critical flicker frequency. The advantages of neurophysiological testing are the absence of learning effects and the relative specificity of the response.7 The need for expensive equipment, low sensitivity, and the lack of accompanying behavioral information are drawbacks of these methods. The simple EEG has some value in determining the advanced stages of HE with the characteristic “triphasic waves.”44 In the earlier stages of HE, the mean dominant frequency of the EEG and spectral EEG analysis are useful and can predict the development of overt HE and liver-related death, at least in patients with advanced liver disease.11 A recent study reaffirmed the use of bispectral index of the EEG in advanced overt HE. However, the EEG has low concordance with PHES, in part due to its restriction to studying cortical activity.31 The latency between application of a stimulus and the brain's ability to sense it can be measured as evoked potentials. Some evoked potential components can even be useful in a deep coma when the EEG is suppressed.45 The specific evoked potentials tested are visual, somatosensory, and auditory. Visual evoked potentials, which can be flash, pattern-reversed, or motion-elicited, have been examined in HE. Pattern visual evoked potentials are insensitive to change in HE and require active patient cooperation, making them only useful for early stages of HE.45 Somato-sensory evoked potential abnormalities were seen in 48% with abnormal inter-peak latencies N20-N65, but there was no correlation with psychometric tests in later studies.46 Brain electrical responses can be measured in response to stimuli that are administered visually or through auditory means. An auditory P300 is when a patient receives an infrequent stimulus embedded in a series of otherwise irrelevant frequent stimuli (oddball paradigm); the subject is asked to identify the rare stimuli (oddballs) by pressing a button or to keep a mental count of their occurrence. The brain shows a response typically 300 milliseconds after the oddball stimulus; delay in brain response (i.e., after a 300-millisecond gap) indicates dysfunction. Most studies of this technique have included stage 1 HE patients along with MHE patients, and most of the changes were observed in alcoholics.47, 48 Visual P300 responses were found to be abnormal in 78% compared with psychometric abnormalities in only 41% of patients but were related to a decline in hepatic metabolic capacity; these are not recommended due to their inconsistent results.11, 49 Auditory P300 does have good diagnostic potential and can be used when available for evaluation of neurophysiological function in cirrhosis.11, 47, 48, 50 Critical flicker frequency (CFF) evaluates the maximum frequency at which a flickering light source can still be perceived to flicker and measures a threshold for the fusion of these lights.14 The threshold is achieved by increasing and decreasing frequency over several trials. The CFF score has been used as a continuous variable in several studies, which have shown good sensitivity in the diagnosis of overt and MHE.14, 51 It has been validated for use in Europe and India. A CFF of 39 Hz showed a 100% separation between overt HE versus controls/nonovert HE.14 Separation between MHE versus no MHE was lower, with a sensitivity of 55% and specificity of 100% in the earlier studies.14 More recent studies have shown increased sensitivity of the CFF in MHE.52, 53 The CFF, however, does require patient cooperation and binocular vision. Because the West Haven criteria (Table 1) are of limited sensitivity in evaluating HE, scales that blend psychometric/neurophysiological measures with clinical measures have been developed.9 The portosystemic encephalopathy index developed by Conn et al.9 includes the clinical assessment of mental state, the trail-making test score, EEG, asterixis, and arterial ammonia. However, this index has been criticized because the number connection tests were not controlled for age and education, and some criteria were inter-dependent.7 The hepatic encephalopathy scoring algorithm (HESA) is a blended scale consisting of clinical and neuropsychological measures.25, 54 The HESA divides patients with HE into four grades and is a modification of the West Haven criteria. This scale provides an assessment of mental status and neuropsychological state from early overt HE to coma. Experience with HESA in a multicenter trial of hepatic replacement therapy demonstrated its applicability and the need for better criteria than the existing West Haven criteria. Agreements on the HESA were highest in both extremes, but there remained a significant difference in assessments between sites in the interim. In addition, HESA alone has not been proven to be sensitive for the diagnosis of minimal HE, because the cognitive tests used are relatively simple.54, 55 A simple division of HE into low-grade or high-grade HE has been proposed by Haussinger and colleagues.56 Although such a method is easy and practical, it has not been adopted widely, because it may be an oversimplification of a multifaceted problem. A continuous rather than categorical approach to gauge the neurocognitive impairment in HE is required due to (1) an inherent subjectivity of the clinical assessments in the earlier and middle stages of the disease; (2) no consensus regarding the multiplicity of tools to diagnose cognitive dysfunction; (3) a lack of population norms for most tools in the United States, which invalidates data interpretation; and (4) imperfect prediction of important clinical and psycho-social outcomes based on the test performances. The continuous nature of this neurocognitive impairment is missed by the current system of arbitrary cutoffs, most often >2 standard deviations impaired beyond comparable controls.7 In therapeutic HE trials, the decision for HE reversal versus persistence can therefore often boil down to a few seconds or limited change in raw scores on the individual tests, which can result in important changes in patient classification. The current system could also be improved by focusing on hard outcomes such as development of overt HE and traffic accidents. Prior studies have shown that MHE patients are more likely to develop overt HE and be involved in traffic accidents; however, this is by no means a foolproof prediction, because the majority of MHE patients do not develop overt HE and are not involved in traffic accidents.6, 16, 57 A better method would be to first focus on the outcomes and then determine which criteria predicted those outcomes with accuracy. It is also likely that the considerable uncertainty between the various methods to divide patients into normal, minimal HE, and overt HE would be overcome by approaching neurocognitive performance in cirrhosis as a whole as this continuum. The proposed spectrum of neurocognitive impairment in cirrhosis (SONIC) requires validation in a large, prospective study. This study would involve administration of several measures assessing psychometric and neurophysiological domains (because none of the available tests is capable as a stand-alone tool) while permitting the development of clinically relevant outcomes. In conclusion, there are several tests and grading methods for HE. The current system of grading patients into separate categories of normal, minimal HE, and overt HE methods can increase subjectivity. Treating this neurocognitive dysfunction as a continuum (i.e., the spectrum of neurocognitive impairment in cirrhosis) with patient-specific outcomes could improve the understanding of this disease and its application in patients' daily lives.

The gut-liver axis is widely implicated in the pathogenesis of liver diseases, where it is increasingly the focus of clinical research. Recent studies trialling an array of therapeutic and preventative strategies have yielded promising results. Considering these strategies, the armamentarium for targeting the gut-liver axis will continue to expand. Further clinical trials, translated from our current knowledge of the gut-liver axis, promise an exciting future in liver treatment.

Aliment Pharmacol Ther 2011; 33: 739–747 Summary Background The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field. Aims To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials. Methods A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy. Results It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers. Conclusions The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed.

OBJECTIVES: Cirrhosis and hepatic encephalopathy (HE) can adversely affect survival, but their effect on socioeconomic and emotional burden on the family is not clear. The aim was to study the emotional and socioeconomic burden of cirrhosis and HE on patients and informal caregivers. METHODS: A cross-sectional study in two transplant centers (Veterans and University) of cirrhotic patients and their informal caregivers was performed. Demographics for patient/caregivers, model-for-end-stage liver disease (MELD) score, and cirrhosis complications were recorded. Patients underwent a cognitive battery, sociodemographic, and financial questionnaires. Caregivers were given the perceived caregiver burden (PCB; maximum=155) and Zarit Burden Interview (ZBI)-Short Form (maximum=48) and questionnaires for depression, anxiety, and social support. RESULTS: A total of 104 cirrhotics (70% men, 44% previous HE, median MELD 12, 49% veterans) and their caregivers (66% women, 77% married, relationship duration 32±14 years) were included. Cirrhosis severely impacted the family unit with respect to work (only 56% employed), finances, and adherence. Those with previous HE had worse unemployment (87.5 vs. 19%,P=0.0001) and financial status (85 vs. 61%,P=0.019) and posed a higher caregiver burden; PCB (75 vs. 65,P=0.019) and ZBI (16 vs. 11,P=0.015) compared with others. Cognitive performance and MELD score were significantly correlated with employment and caregiver burden. Veterans and non-veterans were equally affected. On regression, depression score, MELD, and cognitive tests predicted both PCB and ZBI score. CONCLUSIONS: Previous HE and cognitive dysfunction are associated with worse employment, financial status, and caregiver burden. Cirrhosis-related expenses impact the family unit's daily functioning and medical adherence. A multidisciplinary approach to address this burden is required.

Patients with minimal hepatic encephalopathy (MHE) have impaired driving skills, but association of MHE with motor vehicle crashes is unclear. Standard psychometric tests (SPT) or inhibitory control test (ICT) can be used to diagnose MHE. The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1-year follow-up. Patients with cirrhosis were diagnosed with MHE by ICT (MHEICT) and SPT (MHESPT). Self and department-of-transportation (DOT)-reports were used to determine crashes and violations over the preceding year. Agreement between self and DOT-reports was analyzed. Patients then underwent 1-year follow-up for crash/violation occurrence. Crashes in those with/without MHEICT and MHESPT were compared. 167 patients with cirrhosis had DOT-reports, of which 120 also had self-reports. A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self-report (17% vs 0.0%, P = 0.0004) and DOT-reports (17% vs 3%, P = 0.004, relative risk: 5.77). SPT did not differentiate between those with/without crashes. A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT, both self-reported (100% vs 50%, P = 0.03) and DOT-reported (89% vs 44%, P = 0.01). There was excellent agreement between self and DOT-reports for crashes and violations (Kappa 0.90 and 0.80). 109 patients were followed prospectively. MHEICT patients had a significantly higher future crashes/violations compared to those without (22% vs 7%, P = 0.03) but MHESPT did not. MHEICT (Odds ratio: 4.51) and prior year crash/violation (Odds ratio: 2.96) were significantly associated with future crash/violation occurrence.Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospective follow-up compared to patients without MHE. ICT, but not SPT performance is significantly associated with prior and future crashes and violations. There was an excellent agreement between self- and DOT-reports.

A picture is now starting to emerge regarding the liver-bile acid-microbiome axis. Increasing levels of the primary bile acid cholic acid (CA) causes a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa and increasing production of the harmful secondary bile acid deoxycholic acid (DCA). During progression of cirrhosis, the microbiome, both through their metabolism, cell wall components (LPS) and translocation lead to inflammation. Inflammation suppresses synthesis of bile acids in the liver leading to a positive-feedback mechanism. Decrease in bile acids entering the intestines appears to favor overgrowth of pathogenic and pro-inflammatory members of the microbiome including Porphyromonadaceae and Enterobacteriaceae. Decreasing bile acid concentration in the colon in cirrhosis is also associated with decreases in Clostridium cluster XIVa, which includes bile acid 7α-dehydroxylating bacteria which produce DCA. Rifaximin treatment appears to act by suppressing DCA production, reducing endotoxemia and harmful metabolites without significantly altering microbiome structure. Taken together, the bile acid pool size and composition appear to be a major regulator of microbiome structure, which in turn appears to be an important regulator of bile acid pool size and composition. The balance between this equilibrium is critical for human health and disease.

Background & AimsIn patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE).MethodsCognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (ΔL1–2) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE.ResultsIn study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (ΔL1–2 ≥1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed ≥1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = −0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing.ConclusionsIn cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning. In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE). Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (ΔL1–2) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE. In study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (ΔL1–2 ≥1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed ≥1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = −0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing. In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning.

Background & AimsAlcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease.MethodsWe used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse.ResultsAnalyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls.ConclusionsIn humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease. Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.

Altered gut microbiome is associated with systemic inflammation and cirrhosis decompensation. However, the correlation of the oral microbiome with inflammation in cirrhosis is unclear. Our aim was to evaluate the oral microbiome in cirrhosis and compare with stool microbiome. Outpatients with cirrhosis (with/without hepatic encephalopathy [HE]) and controls underwent stool/saliva microbiome analysis (for composition and function) and also systemic inflammatory evaluation. Ninety‐day liver‐related hospitalizations were recorded. Salivary inflammation was studied using T helper 1 cytokines/secretory immunoglobulin A (IgA), histatins and lysozyme in a subsequent group. A total of 102 patients with cirrhosis (43 previous HE) and 32 age‐matched controls were included. On principal component analysis (PCA), stool and saliva microbiome clustered far apart, showing differences between sites as a whole. In salivary microbiome, with previous HE, relative abundance of autochthonous families decreased whereas potentially pathogenic ones ( Enterobacteriaceae , Enterococcaceae ) increased in saliva. Endotoxin‐related predicted functions were significantly higher in cirrhotic saliva. In stool microbiome, relative autochthonous taxa abundance reduced in previous HE, along with increased Enterobacteriaceae and Enterococcaceae . Cirrhotic stool microbiota demonstrated a significantly higher correlation with systemic inflammation, compared to saliva microbiota, on correlation networks. Thirty‐eight patients were hospitalized within 90 days. Their salivary dysbiosis was significantly worse and predicted this outcome independent of cirrhosis severity. Salivary inflammation was studied in an additional 86 age‐matched subjects (43 controls/43 patients with cirrhosis); significantly higher interleukin (IL)−6/IL‐1β, secretory IgA, and lower lysozyme, and histatins 1 and 5 were found in patients with cirrhosis, compared to controls. Conclusions: Dysbiosis, represented by reduction in autochthonous bacteria, is present in both saliva and stool in patients with cirrhosis, compared to controls. Patients with cirrhosis have impaired salivary defenses and worse inflammation. Salivary dysbiosis was greater in patients with cirrhosis who developed 90‐day hospitalizations. These findings could represent a global mucosal‐immune interface change in cirrhosis. (H epatology 2015;62:1260‐1271)

Acute clinical deterioration in patients with chronic liver disease may result in multisystem organ failure and is associated with significant morbidity and mortality, with per-patient costs associated with intensive care ranging between $116,000 and $180,000 in the United States.1Olson J. Wendon J. Kramer D. et al.Intensive care of the patient with cirrhosis.Hepatology. 2011; 54: 1864-1872Crossref PubMed Scopus (193) Google Scholar Mortality in these patients, however, has remained unchanged over the past 20 years at >50%. As a means of identifying patients with cirrhosis at high risk for acute deterioration, both the Asia-Pacific Association for the Study of the Liver (APASL) and a joint conference of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) proposed definitions of this condition termed acute-on-chronic liver failure (ACLF).2Jalan R. Gines P. Olson J. et al.Acute on chronic liver failure.J Hepatol. 2012; 57: 1336-1348Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 3Sarin S. Kumar A. Almeida J. et al.Acute on chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2009; 3: 269-282Crossref PubMed Scopus (639) Google Scholar The differences between the 2 definitions have resulted in confusion rather than clarification of the problem. For example, APASL includes noncirrhotic chronic liver disease but not decompensated cirrhosis as representing “chronic,” whereas EASL-AASLD include only cirrhosis, either compensated or decompensated to define chronic liver disease. This perspective serves to resolve some of these issues and outline an approach to better define ACLF.Definition of ACLFIn the simplest terms, ACLF is abrupt hepatic decompensation in patients with chronic liver disease. Therefore, any definition of ACLF has to encompass the duration over which the deterioration occurs (to define “acute”), characterize “chronic,” and identify the degree of hepatic dysfunction to define “failure.”2Jalan R. Gines P. Olson J. et al.Acute on chronic liver failure.J Hepatol. 2012; 57: 1336-1348Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar The APASL definition of ACLF is “acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease.”3Sarin S. Kumar A. Almeida J. et al.Acute on chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2009; 3: 269-282Crossref PubMed Scopus (639) Google Scholar EASL/AASLD describes ACLF as “an acute deterioration of pre-existing chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multisystem organ failure.”2Jalan R. Gines P. Olson J. et al.Acute on chronic liver failure.J Hepatol. 2012; 57: 1336-1348Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar Differences between the APASL and AASLD/EASL definitions relate to duration of illness, what qualifies as “chronic,” and the type of precipitating events.4Bajaj J. Defining acute-on-chronic liver failure: will East and West ever meet?.Gastroenterology. 2013; 144: 1337-1339Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar The precipitating events in the APASL statement are primarily hepatic in origin, whereas the EASL-AASLD definition includes sepsis. Further hampering the proposal for a standard definition is the variability in observer experience and the lack of standard management for these patients.To appropriately define ACLF as a separate entity, the following requirements should be met: (1) The condition should be distinct from acute liver failure (ALF) and (2) distinguishable from “decompensated cirrhosis”; (3) pathophysiology should be defined; (4) specific clinical signs and laboratory or other tests that confirm the diagnosis and exclude other diseases should be stated; and (5) a validated clinical scoring system to assess severity of ACLF should be available. Therefore, the proposed definition of ACLF should characterize the condition as being distinct from ALF or decompensated cirrhosis without extrahepatic organ failure using clinical, biochemical, radiologic, and/or histologic criteria. Such a definition would be possible only with extensive, prospectively collected and validated data and should be applicable in all parts of the world. As an initial step, patients with all chronic liver disease (with or without cirrhosis) should be included for data collection to ultimately arrive at a definition of ACLF. There are limited prospectively collected data from the East on acute deterioration of chronic liver disease related to hepatitis B virus and hepatitis E virus infections. Recently, 2 prospective studies using large cohorts of patients in Europe (CANONIC study)5Moreau R. Jalan R. Gines P. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1685) Google Scholar and in North America (NACSELD study)6Bajaj J. O'Leary J. Reddy K. et al.Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American Consortium for the Study of End-Stage Liver Disease (NACSELD).Hepatology. 2012; 56: 2328-2835Crossref PubMed Scopus (285) Google Scholar attempted to define a group of patients with cirrhosis at risk for multiple organ failure. Both the CANONIC and NACSELD studies included only patients with cirrhosis. In the CANONIC study, hospitalized patients with acute decompensation defined by the “acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of these” were included. ACLF was then diagnosed based on predefined criteria for organ failure and a 28-day mortality rate of 15%. Renal failure as defined was associated with a greater risk of mortality than other organ failures. The importance of extrahepatic organ failure was highlighted by the fact that even among patients with elevated serum bilirubin levels, the mortality was only 4% if they did not have extrahepatic organ failure. The NACSELD study demonstrated that the presence of ≥2 extrahepatic organ failures was associated with increased mortality in infected cirrhotic patients; the increase in mortality with only a single organ failure was low, but this study included only patients with bacterial infections and not all cirrhotic patients requiring hospital admission.7Bajaj J. O'Leary J. Reddy K. et al.on behalf of NACSELDSurvival in sepsis-related acute-on-chronic liver failure is defined by extrahepatic organ failures.Hepatology. 2014 Feb 20; (Epub ahead of print)PubMed Google Scholar If ACLF is to be defined as a condition wherein patients are at significantly increased risk for mortality, the definition of ACLF should include extrahepatic organ failure. It may seem counterintuitive to define “liver failure” by “extrahepatic organ failure”; nonetheless, the precedence already exists of ALF being defined by the presence of encephalopathy occurring within a period of 1–8 weeks after the onset of jaundice in patients without preexisting liver disease.8Trey C. Davidson C. The management of fulminant hepatic failure.Prog Liver Dis. 1970; 3: 282-298PubMed Google Scholar Similarly, subfulminant hepatic failure, subacute hepatic failure, or late-onset hepatic failure have been defined by different authors as the onset of hepatic encephalopathy within a period ranging between 2–24 weeks after the onset of jaundice.9Bernau J. Rueff B. Benhamou J. Fulminant and subfulminant liver failure: definitions and causes.Semin Liver Dis. 1986; 6: 97-106Crossref PubMed Scopus (529) Google Scholar, 10O'Grady J. Schalm S. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 373Abstract Scopus (39) Google Scholar It should be recognized in all patients with liver disease that multiple organ failure may not be a consequence of liver failure alone, but may be a result of sepsis. Because of limited, well-designed studies in the field, any definition of ACLF proposed can only be an interim one and requires validation in geographically diverse populations, both in the East as well as in the West. Chronic liver diseases included may be cirrhotic or noncirrhotic. Because there is “acute deterioration,” the duration between the precipitating event and onset of organ failure defining ACLF cannot be >6 months, the currently accepted interval of time to define “chronic.” The interval to define “acute” is probably weeks between the insult and extrahepatic organ failure, but needs to be defined. The duration of increased mortality risk in the CANONIC study was very evident at 28 days and 3 months after enrollment. The AASLD/EASL consensus proposed a period of increased mortality risk of 3 months based on data on ACLF that develops in patients with compensated cirrhosis undergoing major surgery.11Teh S. Nagorney D. Stevens S. et al.Risk factors for mortality after surgery in patients with cirrhosis.Gastroenterology. 2007; 132: 1261-1269Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar Cirrhotic patients may develop rapid hepatic decompensation and then multiple organ failure after surgery; most patients develop infections before death. Postoperative mortality is increased for ≤3 months compared with controls with cirrhosis not undergoing surgery. In these patients, multiple organ failure as reflected by an American Society for Anesthesia score of V was the only variable associated with 7 day postoperative mortality.11Teh S. Nagorney D. Stevens S. et al.Risk factors for mortality after surgery in patients with cirrhosis.Gastroenterology. 2007; 132: 1261-1269Abstract Full Text Full Text PDF PubMed Scopus (388) Google ScholarBecause of limited prospective data from the East, a consensus working definition of “ACLF” that serves at this time only to identify patients from whom data are to be collected to ultimately arrive at a validated definition is as follows: “ACLF is a syndrome in patients with chronic liver disease with or without previously diagnosed cirrhosis which is characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the INR [International Normalized Ratio]) and one or more extrahepatic organ failures that is associated with increased mortality within a period of 28 days and up to 3 months from onset.” Such a definition identifies patients with well-compensated or decompensated cirrhosis or underlying undiagnosed chronic hepatitis with reactivation of hepatitis B; superimposed alcoholic, viral, or drug-induced liver injury; or major surgery. Figure 1 summarizes the current understanding of the pathogenesis of ACLF.Prognostic Features and Clinical Scoring System for ACLFThus far, generic scoring systems have been used for determining prognosis in what is thought to be ACLF. There are liver specific scoring systems such as the Child-Turcotte-Pugh score12Pugh R. Murray-Lyon I. Dawson J. et al.Transection of the oesophagus for bleeding oesophageal varices.Br J Surg. 1973; 60: 646-649Crossref PubMed Scopus (6665) Google Scholar and the Model for End-stage Liver Disease score.13Kamath P. Wiesner R. Malinchoc M. et al.A model to predict survival in patients with end-stage liver disease.Hepatology. 2001; 33: 464-470Crossref PubMed Scopus (3667) Google Scholar Generic organ failure scores such as the Sequential Organ Failure Assessment score (SOFA)14Vincent J. Moreno R. Takala J. et al.The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (6932) Google Scholar are also used. At this time, there are no scores specific for ACLF, but the proposed CLIF-SOFA score5Moreau R. Jalan R. Gines P. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1685) Google Scholar is an important step in this direction. Similarly, data from NACSELD also suggest that extrahepatic organ failure assessment has important prognostic value.7Bajaj J. O'Leary J. Reddy K. et al.on behalf of NACSELDSurvival in sepsis-related acute-on-chronic liver failure is defined by extrahepatic organ failures.Hepatology. 2014 Feb 20; (Epub ahead of print)PubMed Google Scholar Whether scores developed thus far are “prognostic” and not reflective of the dying process will need to be validated. Scores that can be updated regularly may be particularly useful in determining when treatments such as intensive care alone, artificial liver support, or liver transplantation are most appropriate.A Multimodal Classification That May Identify Clinical, Prognostic, and Pathophysiologic SubtypesIt is very likely that ACLF is not 1 disease, but rather a syndrome. The defining point of this condition is multisystem organ failure, which can occur irrespective of the inciting event or underlying etiology of chronic liver disease. The initial clinical presentations may be variable and the prognosis may differ depending on the specific precipitating factor. The CANONIC study does provide the basis for differentiation of ACLF from decompensated cirrhosis.5Moreau R. Jalan R. Gines P. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1685) Google Scholar In that prospective study of hospitalized cirrhotics, 303 patients had ACLF as per the predetermined criteria at admission, and 112 developed ACLF within 28 days with, a mortality rate of 34% at 28 days and 51% at 90 days. Mortality among those who did not develop ACLF was only 1.9% at 28 days and 9.7% at 90 days. The presence of extrahepatic organ failure in differentiating ACLF from decompensated cirrhosis was critical because presenting symptoms alone were not different between patients with ACLF and decompensated cirrhosis. Patients with ACLF were younger, more frequently alcoholic and infected, and with higher white blood cell counts and plasma C-reactive protein than patients with decompensated cirrhosis. An intriguing and important finding was that patients without prior hepatic decompensation had higher short-term mortality than patients with prior hepatic decompensation that supports the position that ACLF can be distinguished from decompensated cirrhosis.ACLF may be divided into 3 categories depending on whether or not there is underlying cirrhosis, and in patients with cirrhosis, whether or not there is a history of previous hepatic decompensation. Extrahepatic organ failure is common to all types of ACLF. Decompensated cirrhosis without extrahepatic organ failure does not fit into this spectrum and such patients should not be included among the ACLF group. When patients with decompensated cirrhosis do develop multiple organ failure, often as a terminal event, such patients would be deemed to have ACLF.Type A ACLFNoncirrhotic ACLF is a type of liver failure that may be seen in patients with noncirrhotic chronic liver disease with an acute flare resulting in liver failure, including hepatic encephalopathy, and is often indistinguishable on clinical presentation from acute or subacute liver failure. Such patients include: Reactivation of hepatitis B, hepatitis A or hepatitis E infection superimposed upon chronic hepatitis B,15Zhang W. Ke W. Xie J. et al.Comparison of effects of hepatitis E or A viral superinfection in patients with chronic hepatitis B.Hepatol Int. 2010; 4: 615-620Crossref PubMed Scopus (41) Google Scholar autoimmune hepatitis, hepatitis E virus infection in patients at risk for nonalcoholic steatohepatitis,16Kumar A. Sarasat V. Hepatitis E and acute-on-chronic liver failure.J Clin Exp Hep. 2013; 3: 225-230Abstract Full Text Full Text PDF Scopus (50) Google Scholar, 17Singh K. Panda S. Shalimar et al.Patients with diabetes mellitus are prone to develop severe hepatitis and liver failure due to hepatitis virus infections.J Clin Exp Hep. 2013; 3: 275-280Abstract Full Text Full Text PDF Scopus (21) Google Scholar and those with or at risk for chronic liver disease such as fatty liver with superimposed drug-induced liver injury.18Graham D. Drinkard C. Shatin D. Incidence of idiopathic acute liver failure and hospitalized liver injury in patients treated with troglitazone.Am J Gastro. 2003; 98: 175-179Crossref PubMed Scopus (81) Google Scholar, 19Chalasani N. Fontana R. Bonkovsky H. et al.Drug-induced liver injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar, 20Fromenty B. Drug-induced liver injury in obesity.J Hepatol. 2013; 58: 824-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google ScholarAnalysis of the database from the Department of Veterans Affairs in the United States also confirms that patients with either underlying chronic liver disease or with diabetes are at higher risk for liver failure with superimposed viral hepatitis.21El-Serag H. Everhart J. Diabetes increases the risk of acute hepatic failure.Gastroenterology. 2002; 122: 1822-1828Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Current data suggest that type A ACLF may occur more commonly in the East (hepatitis B virus and hepatitis E virus infection) and may be distinguishable from ALF only by the presence of significant hepatic fibrosis (chronicity) on liver biopsy (Table 1).Table 1Spectrum of Liver FailureVariableAccepted types of liver failureProposed types of ACLFAcute liver failureSubacute liver failureType A: noncirrhotic ACLFType B: cirrhotic ACLFType C: cirrhotic ACLF with previous hepatic decompensationInterval between symptoms (jaundice) and organ failure<8 weeks8Trey C. Davidson C. The management of fulminant hepatic failure.Prog Liver Dis. 1970; 3: 282-298PubMed Google Scholar; <2 weeks9Bernau J. Rueff B. Benhamou J. Fulminant and subfulminant liver failure: definitions and causes.Semin Liver Dis. 1986; 6: 97-106Crossref PubMed Scopus (529) Google Scholar; <4 weeks10O'Grady J. Schalm S. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 373Abstract Scopus (39) Google Scholar2–12 weeks9Bernau J. Rueff B. Benhamou J. Fulminant and subfulminant liver failure: definitions and causes.Semin Liver Dis. 1986; 6: 97-106Crossref PubMed Scopus (529) Google Scholar; 5–12 weeks10O'Grady J. Schalm S. Williams R. Acute liver failure: redefining the syndromes.Lancet. 1993; 342: 373Abstract Scopus (39) Google Scholar; 8–24 weeks21El-Serag H. Everhart J. Diabetes increases the risk of acute hepatic failure.Gastroenterology. 2002; 122: 1822-1828Abstract Full Text Full Text PDF PubMed Scopus (133) Google ScholarVariable (wks) and to be defined by dataVariable (wks) and to be defined by dataVariable (mo) interval between hepatic decompensation and organ failureEtiologySeveral, including viral and drugSeveral, including viral and drugFlare of hepatitis B; HEV or HAV infections superimposed on HBV or NASH; autoimmune hepatitisAny etiology for cirrhosisAny etiology of cirrhosisPrecipitating eventUnknownUnknownSpontaneous or discontinuation of therapy in HBV, viral infection such as HEV or HAVViral, drug, surgery, alcoholic hepatitis, and infection in patients with cirrhosis; Wilson diseaseVariable, including all events listed under type BCerebral edemaPresentUncommonMay be presentUncommon22Jalan R. Sen S. Cheshire L. et al.Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study.Crit Care. 2012; 16: R227Crossref PubMed Scopus (87) Google ScholarUncommon22Jalan R. Sen S. Cheshire L. et al.Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study.Crit Care. 2012; 16: R227Crossref PubMed Scopus (87) Google ScholarMultisystem organ failureEarlyLateEarlyEarly and required for diagnosisRequired for diagnosisLiver histologyMassive necrosis; no chronicitySubmassive necrosis; evidence of early fibrosisSubmassive necrosis and fibrosis; no cirrhosisCirrhosis: Specific histology awaits further studies, but cholestasis often present on the background of alcoholic etiologyCirrhosis: Specific histology awaits further studies, but cholestasis often present on the background of alcoholic etiologyPrognosisSpontaneous recovery possible depending on etiology, but liver transplant often required; mortality 45%–90% without liver transplant depending on etiologySpontaneous recovery unusual; mortality almost invariable in absence of liver transplantVariable and to be studied; treatment of underlying condition such as HBV may result in recovery to baselineVariable and to be studied. CLIF-C score to be validated; recovery to baseline might be possible with intensive care; artificial liver support remains unprovenPrognosis correlates with MELD and CLIF-C score; lower 28-day mortality than patients without previous hepatic decompensationImprovement in survival with liver transplantationYesYesYesYesYesACLF, acute-on-chronic liver failure; CLIF-C, CLIF consortium; HAV, hepatitis A virus; HBV, hepatitis B virus; HEV, hepatitis E virus; MELD, Model for End-stage Liver Disease; NASH, nonalcoholic steatohepatitis. Open table in a new tab Type B ACLFType B ACLF or cirrhotic ACLF is seen in patients with well-compensated cirrhosis who rapidly deteriorate after a major hepatic insult such as acute viral, drug, or alcoholic hepatitis, infection, or surgery; however, a precipitating event may not always be identified. Clinical features of cirrhosis may be more obvious in such patients. Extrahepatic organ failure develops usually within 4 weeks of the precipitating event. Alcoholic hepatitis superimposed on cirrhosis may be the most common cause of ACLF in some areas of the world.Type C ACLFCirrhotic ACLF with previous hepatic decompensation (type C ACLF) occurs in patients with a previous history of jaundice and/or complications of portal hypertension such as variceal bleeding, ascites, or hepatic encephalopathy and possible hospitalization. Short-term mortality in the CANONIC study in patients with previous decompensation (type C ACLF) was significantly lower than in patients without previous hepatic decompensation (type B ACLF).Definition of Principles of Management Including Role of Liver Support DevicesManagementThe “PIRO” concept (predisposition, insult, response, organ failure)22Jalan R. Sen S. Cheshire L. et al.Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study.Crit Care. 2012; 16: R227Crossref PubMed Scopus (87) Google Scholar can be considered a useful framework to determine optimal management (Table 2); a detailed discussion of individual interventions is beyond the scope of this perspective.Table 2The Predisposition, Insult, Response, Organ Failure (PIRO) Concept Principles of Management of Acute-on-Chronic Liver FailureAssessmentInterventionPredisposition Severity of cirrhosisEtiology,Early identification,CTP score,Risk stratification,MELD scorePreventative strategiesInjury Precipitating eventHepatic: virus, drugs, alcohol, etcRapid intervention example: tenofovir for hepatitis BExtrahepatic: infectionRapid treatment of infectionAlbumin for SBPVariceal bleedingEarly TIPS for high-risk patientsResponse InflammationInflammationGoal-directed approachesImmune failure[Novel interventions such as caspase inhibition, GCSF]? PlasmapheresisOrgan Organ failureScores such as SOFA, APACHE, CLIF-C scoreIntensive care, organ support, artificial/bioartificial liver support systems, liver transplantationACLF, acute-on-chronic liver failure; APACHE, Acute Physiology And Chronic Health Evaluation; CLIF-C, CLIF consortium; CTP, Child-Turcotte-Pugh; GCSF, granulocyte colony-stimulating factor; HAV, hepatitis A virus; HBV, hepatitis B virus; HEV, hepatitis E virus; MELD, Model for End-stage Liver Disease; NASH, nonalcoholic steatohepatitis; SBP, spontaneous bacterial peritonitis; SOFA, Sequential Organ Failure Assessment score; TIPS, transjugular intrahepatic portosystemic shunt. Open table in a new tab Role of Liver TransplantationLiver transplantation has been undertaken in carefully selected patients with alcoholic hepatitis with excellent results.23Mathurin P. Moreno C. Samuel D. et al.Liver transplantation has been carried out in select patients with alcoholic hepatitis with excellent results (Early liver transplantation for severe alcoholic hepatitis).N Engl J Med. 2011; 365: 1790-1800Crossref PubMed Scopus (595) Google Scholar, 24Singal A. Bashar H. Anand B. et al.Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database.Hepatology. 2012; 55: 1398-1405Crossref PubMed Scopus (132) Google Scholar Patients with ACLF unrelated to alcoholic hepatitis from the CANONIC study in the United States and the East have also been demonstrated to benefit from liver transplantation. The US data suggest that Model for End-stage Liver Disease score is the appropriate scoring system to prioritize organ allocation for transplantation in these patients.25Bahirwani R. Shaked O. Bewtra M. et al.Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes.Transplantation. 2011; 92: 952-957Crossref PubMed Scopus (62) Google Scholar Further studies, however, are needed to determine optimal selection of patients and timing of liver transplantation and whether ACLF patients should be prioritized on par with patients with ALF.Clarification of Important Research QuestionsAlthough the definition of ACLF at this time is only a proposal, it is clear that the syndrome is distinct from decompensated cirrhosis without extrahepatic organ failure. Future endeavors should be targeted at prospective collection of data for further refinement of the existing proposals (Table 3). Specifically, data from Asia on patients with reactivation of hepatitis B and hepatitis E superimposed on chronic liver disease are necessary to clearly define the natural history and prognosis of type A ACLF. Biobanks and sample collections are required to outline the pathophysiology of the disease for the specific subtypes of ACLF. Survival data are required to develop scoring systems to determine which patient would benefit from intensive care, which patients would resolve with treatment directed at the specific insult (eg, hepatitis B26Garg H. Sarin S. Kumar M. et al.Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure.Hepatology. 2011; 53: L774-L780Crossref PubMed Scopus (198) Google Scholar), which patients would benefit from novel therapies such as granulocyte colony-stimulating factor,27Garg V. Garg H. Khan A. et al.Granulocyte-colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure.Gastroenterology. 2012; 142: 505-512Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar or artificial liver support, which patients require early liver transplantation, and in whom treatment would be futile. Determining prognosis is possible only if there is a uniform management strategy in all patients studied, including standardization of intensive care.1Olson J. Wendon J. Kramer D. et al.Intensive care of the patient with cirrhosis.Hepatology. 2011; 54: 1864-1872Crossref PubMed Scopus (193) Google Scholar The role of noninvasive markers of hepatic fibrosis in detecting “chronic liver disease” at the time of diagnosis of ACLF needs to be evaluated in this population. Biomarkers are needed to optimize diagnosis and understand the pathophysiology of complications,28Bajaj J. Heuman D. Hylemon P. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar especially for patients who have no apparent precipitating factors for ACLF development, and for prognostication. The role of extracorporeal liver support systems, stimulation of hepatic regeneration, and drugs that inhibit apoptosis and systemic inflammation need to be explored further. The time frame to reach a validated definition of ACLF, develop prognostic scores, and reach a better understanding of the pathogenesis of multiple organ failure in this situation is likely to be 3–5 years.Table 3Acute-on-Chronic Liver Failure: Research NeedsImmediate priorities Pool prospective data from the East and West to allow definition of ACLF and characterize clinical course Standardize management protocols for treatment of precipitating events and organ failure Develop and characterize animal models of ACLF to help define pathophysiology and allow development of novel therapiesIntermediate and long-term priorities To understand ACLF betterClinical- and biomarkers to understand pathophysiology and outline subtypes of ACLFNoninvasi

Minimal hepatic encephalopathy (MHE), the preclinical stage of overt hepatic encephalopathy (OHE), is a significant condition affecting up to 60% of cirrhotics. All MHE therapies modify gut microflora, but consensus regarding MHE treatment and long-term adherence studies is lacking. The aim was to determine the effect of probiotic supplementation in the form of a food item, probiotic yogurt, on MHE reversal and adherence.Nonalcoholic MHE cirrhotics (defined by a standard psychometric battery) were randomized with unblinded allocation to receive probiotic yogurt (with proven culture stability) or no treatment (no Rx) for 60 days in a 2:1 ratio. Quality of life (short form [SF]-36), adherence, venous ammonia, model of end-stage liver disease (MELD) scores, and inflammatory markers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6) were also measured. Outcomes were MHE reversal using blinded scoring, OHE development, and adherence.Twenty-five patients (17 yogurt, 8 no Rx; 84% Child class A) were enrolled. A significantly higher percentage of yogurt patients reversed MHE compared to no Rx patients (71%vs 0%, P= 0.003, intention-to-treat). Yogurt patients demonstrated a significant improvement in number connection test-A (NCT-A), block design test (BDT), and digit symbol test (DST) compared to baseline/no Rx group. Twenty-five percent of no Rx versus 0% of yogurt patients developed OHE during the trial. Eighty-eight percent of yogurt patients were adherent. No adverse effects or change in covariates were observed. All patients who completed the yogurt arm were agreeable to continue yogurt for 6 months if needed.This trial demonstrated a significant rate of MHE reversal and excellent adherence in cirrhotics after probiotic yogurt supplementation with potential for long-term adherence.

Corrigendum to “Management of the critically ill patients with cirrhosis: A multidisciplinary perspective”Journal of HepatologyVol. 65Issue 2PreviewAn error was introduced in the ‘Clinical and laboratory tests to assess the risk of bleeding and thrombosis – Recommendations’ section of this article. Full-Text PDF Use of antifungals in critically ill cirrhotic patients with spontaneous peritonitisJournal of HepatologyVol. 64Issue 4PreviewWe read with great interest the paper entitled “Management of the critically ill patients with cirrhosis: A multidisciplinary perspective” recently published in Journal of Hepatology. The authors assert that antifungal prophylaxis may be used in intensive care unit (ICU) patients without clinical improvement in high prevalence areas or in those with multiple risk factors for infection (corticosteroid use, prolonged microbial use, central venous catheter, total parenteral nutrition, high APACHE score, renal replacement therapy, or malnutrition) [1]. Full-Text PDF

Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear.The primary aim of this phase I study was to evaluate the safety, tolerability of probiotic Lactobacillus GG (LGG) compared to placebo, while secondary ones were to explore its mechanism of action using cognitive, microbiome, metabolome and endotoxin analysis in MHE patients.Cirrhotic patients with MHE patients were randomised 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed up for 8 weeks. Serum, urine and stool samples were collected at baseline and study end. Safety was assessed at Weeks 4 and 8. Endotoxin and systemic inflammation, microbiome using multi-tagged pyrosequencing, serum/urine metabolome were analysed between groups using correlation networks.Thirty MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhoea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomised group, endotoxemia and TNF-α decreased, microbiome changed (reduced Enterobacteriaceae and increased Clostridiales Incertae Sedis XIV and Lachnospiraceae relative abundance) with changes in metabolite/microbiome correlations pertaining to amino acid, vitamin and secondary BA metabolism. No change in cognition was found.In this phase I study, Lactobacillus GG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis.

<h3>Background & Aims</h3> Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1. <h3>Methods</h3> Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013. <h3>Results</h3> Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (<i>P</i> = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (<i>P</i> = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (<i>P</i> < .001). Decreases in SCr and survival were correlated (<i>r</i>² = .882; <i>P</i> < .001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (<i>P</i> < .001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (<i>P</i> = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events. <h3>Conclusions</h3> Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.

Background & AimsParticipants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection.MethodsWe followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI.ResultsIn total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child–Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001).ConclusionsAmong patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure. Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child–Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

Patients with cirrhosis and minimal hepatic encephalopathy (MHE) have driving difficulties but the effects of therapy on driving performance is unclear. We evaluated whether performance on a driving simulator improves in patients with MHE after treatment with rifaximin.Patients with MHE who were current drivers were randomly assigned to placebo or rifaximin groups and followed up for 8 weeks (n = 42). Patients underwent driving simulation (driving and navigation tasks) at the start (baseline) and end of the study. We evaluated patients' cognitive abilities, quality of life (using the Sickness Impact Profile), serum levels of ammonia, levels of inflammatory cytokines, and model for end-stage-liver disease scores. The primary outcome was the percentage of patients who improved in driving performance, calculated as follows: total driving errors = speeding + illegal turns + collisions.Over the 8-week study period, patients given rifaximin made significantly greater improvements than those given placebo in avoiding total driving errors (76% vs 31%; P = .013), speeding (81% vs 33%; P = .005), and illegal turns (62% vs 19%; P = .01). Of patients given rifaximin, 91% improved their cognitive performance, compared with 61% of patients given placebo (P = .01); they also made improvements in the psychosocial dimension of the Sickness Impact Profile compared with the placebo group (P = .04). Adherence to the assigned drug averaged 92%. Neither group had changes in ammonia levels or model for end-stage-liver disease scores, but patients in the rifaximin group had increased levels of the anti-inflammatory cytokine interleukin-10.Patients with MHE significantly improve driving simulator performance after treatment with rifaximin, compared with placebo.

Abstract Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians with biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort is used for external validation. Subjects are classified into three subgroups according to histological spectra of NAFLD or fibrosis severity. Significant alterations in microbiome diversity are observed according to fibrosis severity in non-obese, but not obese, subjects. Ruminococcaceae and Veillonellaceae are the main microbiota associated with fibrosis severity in non-obese subjects. Furthermore, stool bile acids and propionate are elevated, especially in non-obese subjects with significant fibrosis. Fibrosis-related Ruminococcaceae and Veillonellaceae species undergo metagenome sequencing, and four representative species are administered in three mouse NAFLD models to evaluate their effects on liver damage. This study provides the evidence for the role of the microbiome in the liver fibrosis pathogenesis, especially in non-obese subjects.

Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single‐blind, placebo‐controlled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End‐Stage Liver Disease) &lt;17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide‐binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow‐up with SOC maintenance was performed until 5 months. FMT‐assigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post‐FMT, duodenal mucosal diversity ( P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post‐FMT in sigmoid ( P = 0.04) and stool ( P = 0.05). Duodenal E‐cadherin ( P = 0.03) and defensin alpha 5 ( P = 0.03) increased whereas interleukin‐6 ( P = 0.02) and serum LBP ( P = 0.009) reduced post‐FMT. EncephalApp performance improved post‐FMT only ( P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.

In smaller single‐center studies, patients with cirrhosis are at a high readmission risk, but a multicenter perspective study is lacking. We evaluated the determinants of 3‐month readmissions among inpatients with cirrhosis using the prospective 14‐center North American Consortium for the Study of End‐Stage Liver Disease cohort. Patients with cirrhosis hospitalized for nonelective indications provided consent and were followed for 3 months postdischarge. The number of 3‐month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions and for hepatic encephalopathy (HE), renal/metabolic, and infection‐related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. Of the 1353 patients enrolled, 1177 were eligible on discharge and 1013 had 3‐month outcomes. Readmissions occurred in 53% (n = 535; 316 with one, 219 with two or more), with consistent rates across sites. The leading causes were liver‐related (n = 333; HE, renal/metabolic, and infections). Patients with cirrhosis and with worse Model for End‐Stage Liver Disease score or diabetes, those taking prophylactic antibiotics, and those with prior HE were more likely to be readmitted. The admission model included Model for End‐Stage Liver Disease and diabetes (c‐statistic = 0.64, after split‐validation 0.65). The discharge model included Model for End‐Stage Liver Disease, proton pump inhibitor use, and lower length of stay (c‐statistic = 0.65, after split‐validation 0.70). Thirty percent of readmissions could not be predicted. Patients with liver‐related readmissions consistently had index‐stay nosocomial infections as a predictor for HE, renal/metabolic, and infection‐associated readmissions (odds ratio = 1.9‐3.0). Conclusions: Three‐month readmissions occurred in about half of discharged patients with cirrhosis, which were associated with cirrhosis severity, diabetes, and nosocomial infections; close monitoring of patients with advanced cirrhosis and prevention of nosocomial infections could reduce this burden. (H epatology 2016;64:200–208)

The North American Consortium for the Study of End‐Stage Liver Disease's definition of acute‐on‐chronic liver failure (NACSELD‐ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD‐ACLF's ability to predict 30‐day survival (defined as in‐hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol‐induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End‐Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD‐ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End‐Stage Liver Disease score, and presence of infection. The c‐statistics were 0.8073 for the training set and 0.8532 for the validation set. Conclusion: Although infection status remains an important predictor of death, NACSELD‐ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30‐day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (H epatology 2018;67:2367‐2374).

Minimal hepatic encephalopathy (MHE) detection is difficult because of the unavailability of short screening tools. Therefore, MHE patients can remain undiagnosed and untreated. The aim of this study was to use a Stroop smartphone application (app) (EncephalApp_Stroop) to screen for MHE. The app and standard psychometric tests (SPTs; 2 of 4 abnormal is MHE, gold standard), psychometric hepatic encephalopathy score (PHES), and inhibitory control tests (ICTs) were administered to patients with cirrhosis (with or without previous overt hepatic encephalopathy; OHE) and age-matched controls from two centers; a subset underwent retesting. A separate validation cohort was also recruited. Stroop has an “off” state with neutral stimuli and an “on” state with incongruent stimuli. Outcomes included time to complete five correct runs as well as number of trials needed in on (Ontime) and off (Offtime) states. Stroop results were compared between controls and patients with cirrhosis with or without OHE and those with or without MHE (using SPTs, ICTs, and PHES). Receiver operating characteristic analysis was performed to diagnose MHE in patients with cirrhosis with or without previous OHE. One hundred and twenty-five patients with cirrhosis (43 previous OHE) and 134 controls were included in the original cohort. App times were correlated with Model for End-Stage Liver Disease (Offtime: r = 0.57; Ontime: r = 0.61; P < 0.0001) and were worst in previous OHE patients, compared to the rest and controls. Stroop performance was also significantly impaired in those with MHE, compared to those without MHE, according to SPTs, ICTs, and PHES (all P < 0.0001). A cutoff of >274.9 seconds (Ontime plus Offtime) had an area under the curve of 0.89 in all patients and 0.84 in patients without previous OHE for MHE diagnosis using SPT as the gold standard. The validation cohort showed 78% sensitivity and 90% specificity with the >274.9-seconds Ontime plus Offtime cutoff. App result patterns were similar between the centers. Test-retest reliability in controls and those without previous OHE was good; a learning effect on Ontime in patients with cirrhosis without previous OHE was noted. Conclusion: The Stroop smartphone app is a short, valid, and reliable tool for screening of MHE. (Hepatology 2013;58:1122-1132)

Comorbid conditions are associated with poor prognosis in COVID-19. Registry data show that patients with cirrhosis may be at high risk. However, outcome comparisons among patients with cirrhosis+COVID-19 versus patients with COVID-19 alone and cirrhosis alone are lacking. The aim of this study was to perform these comparisons.A multicentre study of inpatients with cirrhosis+COVID-19 compared with age/gender-matched patients with COVID-19 alone and cirrhosis alone was performed. COVID-19 and cirrhosis characteristics, development of organ failures and acute-on-chronic liver failure (ACLF) and mortality (inpatient death+hospice) were compared.37 patients with cirrhosis+COVID-19 were matched with 108 patients with COVID-19 and 127 patients with cirrhosis from seven sites. Race/ethnicity were similar. Patients with cirrhosis+COVID-19 had higher mortality compared with patients with COVID-19 (30% vs 13%, p=0.03) but not between patients with cirrhosis+COVID-19 and patients with cirrhosis (30% vs 20%, p=0.16). Patients with cirrhosis+COVID-19 versus patients with COVID-19 alone had equivalent respiratory symptoms, chest findings and rates of intensive care unit transfer and ventilation. However, patients with cirrhosis+COVID-19 had worse Charlson Comorbidity Index (CCI 6.5±3.1 vs 3.3±2.5, p<0.001), lower presenting GI symptoms and higher lactate. Patients with cirrhosis alone had higher cirrhosis-related complications, maximum model for end-stage liver disease (MELD) score and lower BiPAP/ventilation requirement compared with patients with cirrhosis+COVID-19, but CCI and ACLF rates were similar. In the entire group, CCI (OR 1.23, 95% CI 1.11 to 1.37, p<0.0001) was the only variable predictive of mortality on multivariable regression.In this multicentre North American contemporaneously enrolled study, age/gender-matched patients with cirrhosis+COVID-19 had similar mortality compared with patients with cirrhosis alone but higher than patients with COVID-19 alone. CCI was the only independent mortality predictor in the entire matched cohort.

Chronic liver disease is rising in western countries and liver cirrhosis is the 12th leading cause of death worldwide. Simultaneously, use of gastric acid suppressive medications is increasing. Here, we show that proton pump inhibitors promote progression of alcoholic liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis in mice by increasing numbers of intestinal Enterococcus spp. Translocating enterococci lead to hepatic inflammation and hepatocyte death. Expansion of intestinal Enterococcus faecalis is sufficient to exacerbate ethanol-induced liver disease in mice. Proton pump inhibitor use increases the risk of developing alcoholic liver disease among alcohol-dependent patients. Reduction of gastric acid secretion therefore appears to promote overgrowth of intestinal Enterococcus, which promotes liver disease, based on data from mouse models and humans. Recent increases in the use of gastric acid-suppressive medications might contribute to the increasing incidence of chronic liver disease.Proton pump inhibitors (PPIs) reduce gastric acid secretion and modulate gut microbiota composition. Here Llorente et al. show that PPIs induce bacterial overgrowth of enterococci, which, in turn, exacerbate ethanol-induced liver disease both in mice and humans.

Cirrhosis is a prevalent cause of morbidity and mortality, especially for those at an advanced decompensated stage. Cirrhosis development and progression involves several important interorgan communications, and recently, the gut microbiome has been implicated in pathophysiology of the disease. Dysbiosis, defined as a pathological change in the microbiome, has a variable effect on the compensated versus decompensated stage of cirrhosis. Adverse microbial changes, both in composition and function, can act at several levels within the gut (stool and mucosal) and have also been described in the blood and oral cavity. While dysbiosis in the oral cavity could be a source of systemic inflammation, current cirrhosis treatment modalities are targeted toward the gut-liver axis and do not address the oral microbiome. As interventions designed to modulate oral dysbiosis may delay progression of cirrhosis, a better understanding of this process is of the utmost importance. The concept of oral microbiota dysbiosis in cirrhosis is relatively new; therefore, this review will highlight the emerging role of the oral-gut-liver axis and introduce perspectives for future research.

Cirrhosis is associated with brain dysfunction known as hepatic encephalopathy (HE). The mechanisms behind HE are unclear although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. We aimed to define the individual contribution of specific gut bacterial taxa towards astrocytic and neuronal changes in brain function using multi-modal MRI in patients with cirrhosis. 187 subjects (40 controls, 147 cirrhotic; 87 with HE) underwent systemic inflammatory assessment, cognitive testing, stool microbiota analysis and brain MRI analysis. MR spectroscopy (MRS) changes of increased Glutamate/glutamine, reduced myo-inositol and choline are hyperammonemia-associated astrocytic changes, while diffusion tensor imaging (DTI) demonstrates changes in neuronal integrity and edema. Linkages between cognition, MRI parameters and gut microbiota were compared between groups. We found that HE patients had a significantly worse cognitive performance, systemic inflammation, dysbiosis and hyperammonemia compared to controls and cirrhotics without HE. Specific microbial families (autochthonous taxa negatively and Enterobacteriaceae positively) correlated with MR spectroscopy and hyperammonemia-associated astrocytic changes. On the other hand Porphyromonadaceae, were only correlated with neuronal changes on DTI without linkages with ammonia. We conclude that specific gut microbial taxa are related to neuronal and astrocytic consequences of cirrhosis-associated brain dysfunction.

Hepatic encephalopathy (HE) is part of a spectrum of neurocognitive changes in cirrhosis. HE is divided into 2 broad categories based on severity: covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). CHE has a significant impact on a patient's quality of life, driving performance, and recently has been associated with increased hospitalizations and death. Likewise, OHE is associated with increased rates of hospitalizations and mortality, and poor quality of life. Given its significant burden on patients, care takers, and the health care system, early diagnosis and management are imperative. In addition, focus also should be directed on patient and family member education on the disease progression and adherence to medications. Treatment strategies include the use of nonabsorbable disaccharides, antibiotics (ie, rifaximin), and, potentially, probiotics. Other therapies currently under further investigation include L-ornithine-L-aspartate, ornithine phenylacetate, glycerol phenylbutyrate, molecular adsorbent recirculating system, and albumin infusion.

Activation of hepatic stellate cells (HSCs) represents the primary driving force to promote the progression of chronic cholestatic liver diseases. We previously reported that cholangiocyte-derived exosomal long noncoding RNA-H19 (lncRNA-H19) plays a critical role in promoting cholestatic liver injury. However, it remains unclear whether cholangiocyte-derived lncRNA-H19 regulates HSC activation, which is the major focus of this study. Both bile duct ligation (BDL) and Mdr2 knockout (Mdr2-/- ) mouse models were used. Wild-type and H19maternalΔExon1/+ (H19KO) mice were subjected to BDL. Mdr2-/- H19maternalΔExon1/+ (DKO) mice were generated. Exosomes isolated from cultured mouse and human cholangiocytes or mouse serum were used for in vivo transplantation and in vitro studies. Fluorescence-labeled exosomes and flow cytometry were used to monitor exosome uptake by hepatic cells. Collagen gel contraction and bromodeoxyuridine assays were used to determine the effect of exosomal-H19 on HSC activation and proliferation. Mouse and human primary sclerosing cholangitis (PSC)/primary biliary cholangitis (PBC) liver samples were analyzed by real-time PCR, western blot analysis, histology, and immunohistochemistry. The results demonstrated that hepatic H19 level was closely correlated with the severity of liver fibrosis in both mouse models and human patients with PSC and PBC. H19 deficiency significantly protected mice from liver fibrosis in BDL and Mdr2-/- mice. Transplanted cholangiocyte-derived H19-enriched exosomes were rapidly and preferentially taken up by HSCs and HSC-derived fibroblasts, and promoted liver fibrosis in BDL-H19KO mice and DKO mice. H19-enriched exosomes enhanced transdifferentiation of cultured mouse primary HSCs and promoted proliferation and matrix formation in HSC-derived fibroblasts. Conclusion: Cholangiocyte-derived exosomal H19 plays a critical role in the progression of cholestatic liver fibrosis by promoting HSC differentiation and activation and represents a potential diagnostic biomarker and therapeutic target for cholangiopathies.

The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans, accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an “endocrine organ” with potential to alter host physiology, perhaps to their own favor. We propose the term “sterolbiome” to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed.

Clostridium scindens biotransforms primary bile acids into secondary bile acids, and is correlated with inhibition of Clostridium difficile growth in vivo. The aim of the current study was to determine how C. scindens regulates C. difficile growth in vitro and if these interactions might relate to the regulation of gut microbiome structure in vivo. The bile acid 7α-dehydroxylating gut bacteria, C. scindens and C. sordellii, were found to secrete the tryptophan-derived antibiotics, 1-acetyl-β-carboline and turbomycin A, respectively. Both antibiotics inhibited growth of C. difficile and other gut bacteria. The secondary bile acids, deoxycholic acid and lithocholic acid, but not cholic acid, enhanced the inhibitory activity of these antibiotics. These antibiotics appear to inhibit cell division of C. difficile. The results help explain how endogenously synthesized antibiotics and secondary bile acids may regulate C. difficile growth and the structure of the gut microbiome in health and disease.

Alcohol use disorder (AUD) is associated with microbial alterations that worsen with cirrhosis. Fecal microbiota transplant (FMT) could be a promising approach.In this phase 1, double-blind, randomized clinical trial, patients with AUD-related cirrhosis with problem drinking (AUDIT-10 > 8) were randomized 1:1 into receiving one placebo or FMT enema from a donor enriched in Lachnospiraceae and Ruminococcaceae. Six-month safety was the primary outcome. Alcohol craving questionnaire, alcohol consumption (urinary ethylglucuronide/creatinine), quality of life, cognition, serum IL-6 and lipopolysaccharide-binding protein, plasma/stool short-chain fatty acids (SCFAs), and stool microbiota were tested at baseline and day 15. A 6-month follow-up with serious adverse event (SAE) analysis was performed. Twenty patients with AUD-related cirrhosis (65 ± 6.4 years, all men, Model for End-Stage Liver Disease 8.9 ± 2.7) with similar demographics, cirrhosis, and AUD severity were included. Craving reduced significantly in 90% of FMT versus 30% in placebo at day 15 (P = 0.02) with lower urinary ethylglucuronide/creatinine (P = 0.03) and improved cognition and psychosocial quality of life. There was reduction in serum IL-6 and lipopolysaccharide-binding protein and increased butyrate/isobutyrate compared with baseline in FMT but not placebo. Microbial diversity increased with higher Ruminococcaceae and other SCFAs, producing taxa following FMT but not placebo, which were linked with SCFA levels. At 6 months, patients with any SAEs (8 vs. 2, P = 0.02), AUD-related SAEs (7 vs. 1, P = 0.02), and SAEs/patient (median [interquartile range], 1.5 [1.25] vs. 0 [0.25] in FMT, P = 0.02) were higher in placebo versus FMT.This phase 1 trial shows that FMT is safe and associated with short-term reduction in alcohol craving and consumption with favorable microbial changes versus placebo in patients with alcohol-associated cirrhosis with alcohol misuse. There was also a reduction in AUD-related events over 6 months in patients assigned to FMT.

Recurrent hepatic encephalopathy (HE) leads to significant disability and mortality despite standard of care (SOC), that is, lactulose and add-on rifaximin.1Vilstrup H. et al.Hepatology. 2014; 60: 715-735Crossref PubMed Scopus (1107) Google Scholar It is associated with impairment of the gut–liver–brain axis, and fecal microbiota transplantation (FMT) may be useful. In recurrent Clostridium difficile, a single FMT has sustained cure rates of greater than 80% with a tolerable long-term safety profile.2Kelly C.R. et al.Gastroenterology. 2015; 149: 223-237Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar In a published safety trial, 10 recurrent HE participants each were randomly assigned to receive pretreatment antibiotics and FMT or to receive SOC, which was safe. As a secondary outcome, there was an improvement in short-term cognitive function and hospitalizations.3Bajaj J.S. et al.Hepatology. 2017; Google Scholar However, the long-term impact of FMT is unclear. Our aim was to determine the long-term impact of FMT on cognition, hospitalizations, and HE by extending the results of this trial.3Bajaj J.S. et al.Hepatology. 2017; Google Scholar For rational donor selection, the microbiome profiles of HE patients and healthy control individuals were assessed. HE patients showed a relative reduction of Lachnospiraceae and Ruminococcaceae species compared with control individuals. Leveraging the cross-sectional microbiome data, a donor was selected from the donor database by using random forest analysis, to complement the relative deficiencies of the patient microbiota.3Bajaj J.S. et al.Hepatology. 2017; Google Scholar The same donor was used for all FMT-assigned participants. These participants underwent 5 days of pre-FMT antibiotics, after which 90 mL (27 g of stool) of the donor material containing approximately 2.7 × 1012 colony-forming units was administered via enema. SOC participants did not undergo any interventions or antibiotic therapy. All participants were followed up in keeping with the visits reported in Figure 1A. There were no FMT-related serious adverse events in the 5 months after the study, as judged by the data safety monitoring board. For the long-term study, all participants were followed up prospectively at least every 2 months through chart review, phone calls, or in-person interview with specific focus on hospitalizations and HE episodes. Eligibility (Supplementary Table 1), cognitive testing, further donor selection and methods are in the Supplementary Methods section. At the long-term visit, we readministered cognitive tests (Psychometric Hepatic Encephalopathy Score [PHES] and EncephalApp Stroop) and obtained stool (Figure 1A).3Bajaj J.S. et al.Hepatology. 2017; Google Scholar Data were compared with pre-FMT, postantibiotics, and early post-FMT values. Microbial composition was studied by using 16S ribosomal RNA sequencing. Principal component and linear discriminant analysis effect size (LEFSe) analyses were performed. All participants were receiving lactulose, rifaximin, and proton pump inhibitors (PPIs) at trial initiation and continued taking these throughout. All participants were followed up for >12 months and up to 15 months (mean ± standard deviation [SD], 12.9 ± 2.9 months for FMT and 12.8 ± 3.7 months for SOC), but 3 were excluded: 2 from the SOC group (1 died, 1 liver transplant) and 1 from the FMT group who died (P = 1.0 between groups), with these events occurring a mean ± SD of 11.3 ± 2.9 months after randomization. Overall, in those assigned to FMT, the intervention was well tolerated and had a nonconcerning long-term safety profile, without infections or the need for new antibiotic initiation. There were significantly more hospitalizations and HE episodes in the SOC arm compared with the FMT arm during the long-term follow-up (Figure 1B and C). In the SOC arm, there were 10 hospitalizations (2 participants had 2 events each, and 6 participants had 1 event each) compared with 1 in the FMT arm (P = 0.05). The majority of the hospitalizations were liver related (SOC group: HE, n = 4, infection, n = 2, ascites, n = 2 vs FMT group: ascites = 1). The 2 SOC participants with infections (1 C. difficile and 1 pneumonia) required short courses of broad-spectrum antibiotics. In the SOC arm, there were 8 HE events (2 participants had 2 events each, and 4 participants had 1 event each) compared with 0 in the FMT arm (P = 0.03). In both arms, the Model for End-Stage Liver Disease (ie, MELD) score changes between preintervention and long-term postintervention for the surviving patients were similar (mean ± SD: SOC, 2.78 ± 4.7 vs FMT, 2.8 ± 4.5; P = 0.9). Cognitive function, which had improved in the FMT arm at day 20 after FMT, remained significantly better in the FMT arm compared with the SOC arm on both tests on long-term testing (Figure 1D and E). Stool samples were obtained from 7 in the FMT arm and 6 in the SOC arm at the long-term visit at the same time as cognitive testing. The remainder of patients had died (n = 2), had received a transplant (n = 1), or refused to provide samples (n = 4). There was an increase in the relative abundance of Burkholderiaceae species and decreased Acidaminococcaceae in the FMT arm long term (Figure 1F) on LEFSe. Lachnospiraceae and Ruminococcaceae species relative abundance remained similar between groups. On principal component analysis, there was a clustering of the long-term microbiota, with microbiota obtained at days 7 and 15 after FMT compared with pre-FMT microbiota (Figure 1G), indicating that the microbiota were similar after FMT regardless of short- or long-term follow-up, compared with pre-FMT microbial composition. The current study extends the experience of the first randomized clinical trial of FMT after antibiotics in cirrhosis and recurrent HE over more than 12 months. The results suggest long-term safety and sustained improvement in clinical and cognitive function parameters among patients who received FMT with pretreatment antibiotics.4Ji S.K. et al.Front Microbiol. 2017; 8: 1208Crossref PubMed Scopus (52) Google Scholar The most striking improvement was in the prevention of HE recurrence and liver-related hospitalizations in this recalcitrant population, which was associated with improved cognition compared with those receiving SOC. This occurred despite the continuation of lactulose, rifaximin, and PPIs across groups. Prior studies have shown cognitive impairment as a predictor for future HE episodes, and the alteration of the gut–liver–brain axis with this intervention could interrupt this cycle of readmissions.5Patidar K.R. et al.Am J Gastroenterol. 2014; 109: 1757-1763Crossref PubMed Scopus (127) Google Scholar The improvement in all-cause hospitalizations reflects prior data in C. difficile and alcoholic hepatitis.2Kelly C.R. et al.Gastroenterology. 2015; 149: 223-237Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, 6Philips C.A. et al.Clin Gastroenterol Hepatol. 2017; 15: 600-602Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar From a microbiome perspective, there were differences in profiles between the SOC and FMT arms at long-term analysis but not in Lachnospiraceae and Ruminococcaceae species relative abundance. These results are unlikely due to mitigation of the PPI microbiome effect, and they extend prior FMT studies showing that the ultimate microbial profile does not need to precisely reflect the donor to result in benefit.7Khanna S. et al.Microbiome. 2017; 5: 55Crossref PubMed Google Scholar, 8Kao D. et al.Hepatology. 2016; 63: 339-340Crossref PubMed Scopus (95) Google Scholar Functional evaluation is therefore needed to understand the potential mechanisms of action of microbiome therapeutics. Our study is limited by a small sample size and the use of pretreatment antibiotics without an FMT-alone arm; however, data suggest that antibiotics promote FMT engraftment.4Ji S.K. et al.Front Microbiol. 2017; 8: 1208Crossref PubMed Scopus (52) Google Scholar Overall, this preliminary experience shows that FMT after antibiotics may be safe and potentially effective in preventing long-term recurrence of HE. However, larger controlled trials with HE as the primary outcome are needed. Author contributions: Jasmohan Singh Bajaj conceptualized the study and was involved in all stages. Andrew Fagan and Edith A. Gavis were involved in research coordination and study conduct. Zain Kasam was involved in provision of donor material and study design. Masoumeh Sikaroodi and Patrick M. Gillevet were involved in microbiota analysis and bioinformatics. All authors contributed to the drafting of the manuscript. To select a donor, data from 174 16s rRNA sequences generated from samples collected in prior studies from the study centers were analyzed. These sequencing data were from HE patients and healthy control individuals. These data were used to train a random forest classifier, a machine learning classification technique used to distinguish HE patients from healthy individuals among the OpenBiome donors. The resulting classifier had an area under the curve of 0.94, which then gave each donor a classification score (formally, the percentage of trees in the random forest classifier that classify the sample as healthy). To corroborate these, the relative abundances of Lachnospiraceae and Ruminococcaceae bacterial families in each donor (taxa found to be depleted in HE patients) were calculated. All of these data were combined to rank the 28 stool donors in OpenBiome. Ultimately, the donor with the highest aggregate ranking was selected as the FMT donor for patients randomly assigned to FMT. This donor was a healthy 37-year-old man whose material had been used for at least 280 patients for the treatment of recurrent C. difficile without serious adverse events. This donor also had the highest relative abundances of Lachnospiraceae and Ruminococcaceae species among the potential donors. The same stool sample from this donor was used for each of the aliquots for the FMT-assigned groups. The PHES score is used to evaluate psychomotor speed, reaction time, and visuomotor coordination. It consists of 5 tests: number connection test A, number connection test B, digit symbol test, serial dotting test, and line tracing test (which has 2 components: time and errors). Population control norms are available for this battery, and the added score of each standard deviation beyond norms is the total PHES score. A low total score indicates poor cognitive performance. The EncephalApp Stroop uses a validated smartphone app version of the Stroop test that has On and Off stages. The Off stage tests psychomotor speed and accuracy, and the On stage also tests for cognitive flexibility. The easier Off stage requires participants to correctly identify the color of the pound signs presented, and the more difficult On stage requires them to correctly identify the color of a discordant word presented. The App has 2 practice runs and requires 5 correct runs in the Off and On stages. The total time required for 5 correct On and 5 correct Off stage runs is the “OffTime + OnTime,” which is of relevance in HE, and is recorded. A higher time required to complete the number of runs required indicates worse performance. The study was a randomized, open-label, phase 1 study with exploratory endpoints and pathophysiological evaluation of the FMT. Two groups of outpatients with cirrhosis (Supplementary Table 1) were randomly assigned with a random sequence generator into SOC and FMT groups. The FMT group received zFMP-30 × 3 at the same time (27 g of stool). The intervention was delivered by enema. Once patients were randomly assigned 1:1 into group 1 (FMT) and group 2 (SOC), both were followed over 35 days, and a 5 month follow-up phone call was included to assess serious adverse events. An optional long-term extension was performed as well for at least 12 months after FMT administration. We obtained written informed consent. After the patients consented and were found to be eligible, we performed a detailed medical history and physical examination at day 0. We then collected blood, urine, and stool for baseline testing, including for C. difficile, at day 0 using quantitative polymerase chain reaction. We excluded patients for whom the C. difficile test result was positive. We performed urine pregnancy tests in women of childbearing age, they were allowed to proceed only if the test result was negative and they agree to use effective contraception for the duration of the study and for 10 days before and 30 days after the study. We also performed cognitive testing. We prescribed an antibiotic regimen for patients (ciprofloxacin, 500 mg orally 2 times per day, amoxicillin 500 mg orally 3 times per day, and metronidazole 500 mg orally 3 times per day) for 5 days to set up a clear baseline. The doses were adjusted for end-stage liver disease (for metronidazole) and for creatinine clearance (for all 3 drugs). Drawing from ecological principles of microbial niche environments and data from recurrent C. difficile, pretreatment antibiotics are likely to increase the probability of disrupting the host’s intrinsic microbiota and creating an opportunity for a “healthy” microbiota from the FMT to engraft. At day 5, we reevaluated patients with a directed interval history and focused physical examination as needed. After ensuring that they were still candidates according to the inclusion/exclusion criteria, we again collected stool, urine and blood for pre-FMT evaluation and urine for pregnancy tests from eligible women. Cognitive testing was performed again. As per OpenBiome guidelines:1.Frozen material was thawed for 4 hours at room temperature. After thawing, material could remain at room temperature for up to 4 hours or be kept refrigerated/on ice for up to 8 hours.2.The standard protocol for handling biohazardous material was be used to avoid contamination and risk to health care handlers. At that point, we will delivered 90 mL of the fecal material, using universal precautions. The procedure was completed by trained study personnel. We ensured that patients were able to hold the enema for at least 30 minutes by positioning patients in the left lateral decubitus position. We was each patient in the clinic the day after FMT (day 6, or FMT + 1), day 12 (FMT + 7), day 20 (FMT + 15), and day 35 (FMT + 30), at which point we took a detailed history regarding abdominal symptoms, evaluation of infectious complications, hospitalizations, or complications of cirrhosis. Visits on days 6, 12, and 35 were purely safety associated, and on the day 20 visit, we repeated the pathophysiological studies. To ensure that we had enough samples in case patients were not able to return on day 20, we also collected all samples at day 12, but we analyzed them only in case the day 20 visit did not occur. These visits, apart from the visit after FMT, were ±2 days for patient convenience. At 5 months after FMT, participants were be followed up with a phone call to evaluate potential serious adverse events, new onset of transmitted infections, new onset or significant worsening of chronic medical conditions, or suspected unexpected serious adverse reactions that occurred between 35 days and 5 months, for reporting purposes. The SOC group had the same sample collections, follow-up, and cognitive testing as the FMT group, but without the 5-day antibiotic therapy or the FMT. In addition, we also did not perform the sample collection that was done after 5 days of antibiotics in this group because no reasonable change in microbiota were expected over 5 days without antibiotics. The follow-up of this group was same as that of the FMT group. The primary endpoints were safety and tolerability, defined by the rate of development of FMT-related serious adverse events and withdrawal from the study in the FMT vs SOC groups. The secondary endpoints were 1) microbiota composition and functional change and 2) cognitive function changes. Specific issues to be captured were as follows:1.Antibiotic-related adverse events/serious adverse events2.FMT procedure-related adverse events3.FMT material–related adverse events (eg, transmissible infection, allergic reaction)4.Short-term safety: Both solicited and unsolicited adverse events were recorded by clinical assessment at FMT, (day 6 or FMT + 1), day 12 (FMT + 7), day 20 (FMT + 15), and day 35 (FMT + 30). Participants had the ability to telephone the study team at any point during the study.5.Long-term safety: phone call at 5 months to evaluate for serious adverse events6.Long-term extension (see next section) We aimed to follow all participants for at least 12 months after enrollment in both groups after their initial study follow-up was completed. During this period, patients were called or seen in person at least every 2 months, their clinical course was monitored through active chart review, and after at least 12 months, they had stool collection, cognitive testing with PHES and EncephalApp, and an in-person evaluation for adverse events and serious adverse events as defined in the original protocol. Each intervening hospitalization was evaluated and recorded for causes, changes in medications, and outcomes. Specifically, infections were also recorded. Development of HE, defined as grade 2 or higher of West–Haven criteria that required admission, emergency department visits, or changes to therapy, were also recorded in detail. Patients had the option to agree to this, to participate in the follow-up via other protocols or ongoing studies, or not to participate at all. They also had the option to provide stool samples or not as they chose. We stopped follow-up after death or liver transplantation or after at least 12 months, based on the availability of the patient. Supplementary Table 1Detailed Eligibility CriteriaInclusion criteria:1.Cirrhosis diagnosed by any 1 of the following in a patient with chronic liver disease:a.Liver biopsyb.Radiologic evidence of varices, cirrhosis, or portal hypertensionc.Laboratory evidence of platelet count <100,000 or AST/ALT ratio > 1d.Endoscopic evidence of varices or portal gastropathy2.At least 2 episodes of HE, 1 within the last year but not within the last month (patient can be taking lactulose and rifaximin)3.Age between 21 and 75 years4.Able to give written informed consent (demonstrated by Mini-Mental Status Examination score > 25 at the time of consent)Exclusion criteria:1.MELD score > 172.White blood cell count < 1000 cells/mm33.Platelet count < 50,000/mm34.TIPS in place for < 1 month5.No HE episode within a month before the study6.Allergic to ciprofloxacin, penicillins, or metronidazole7.Currently taking absorbable antibiotics8.Infection at the time of the FMT (diagnosed by positive blood culture result, urinalysis, and paracentesis as needed)9.Hospitalization for any nonelective cause within the last 1 month10.Patients who are >75 years old11.Patients who are pregnant or nursing (will be checked with a urine pregnancy test)12.Patients who are incarcerated13.Patients who are incapable of giving their own informed consent14.Patients who are immunocompromised because of the following reasons:a.Human immunodeficiency virus infection (any CD4 count)b.Inherited/primary immune disordersc.Current or recent (<3 mo) treatment with antineoplastic agentd.Current or recent (<3 mo) treatment with any immunosuppressant medications (including but not limited to monoclonal antibodies to B and T cells, anti-TNF agents, glucocorticoids, antimetabolites [azathioprine, 6-mercaptopurine], calcineurin inhibitors [tacrolimus, cyclosporine], and mycophenolate mofetil). Patients who are otherwise immunocompetent and have discontinued any immunosuppressant medications 3 or more months before enrollment may be eligible to enroll.15.Patients with a history of severe (anaphylactic) food allergy16.Patients who have previously had FMT17.Patients receiving renal replacement therapy18.Patients who are unwilling or unable to hold the enemas19.Patients with untreated in situ colorectal cancer20.Patients with a history of chronic intrinsic gastrointestinal diseases such as inflammatory bowel disease (ulcerative colitis, Crohn’s disease, or microscopic colitis), eosinophilic gastroenteritis, celiac disease, or irritable bowel syndrome21.Major gastrointestinal or intra-abdominal surgery in the last 3 months22.Unable to comply with protocol requirements23.Patients with American Society of Anesthesiologists physical status classifications IV and V24.Patients with acute illness or fever on the day of planned FMT will be excluded, with the option of inclusion at a future date25.Any conditions for which, in opinion of the physician, the treatment may pose a health risk26.C. difficile in the stool at baseline (qPCR)27.Grade 2–4 or complicated hemorrhoidsALT, alanine aminotransferase; AST, aspartate aminotransferase; FMT, fecal microbial transplant; MELD, model for end-stage liver disease; qPCR, quantitative polymerase chain reaction; TIPS, transjugular intra-hepatic portosytemic shunt; TNF, tumor necrosis factor. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; FMT, fecal microbial transplant; MELD, model for end-stage liver disease; qPCR, quantitative polymerase chain reaction; TIPS, transjugular intra-hepatic portosytemic shunt; TNF, tumor necrosis factor. The Transplantation of Fecal Microbiota for Cirrhotic PatientsGastroenterologyVol. 157Issue 3PreviewI read with interest regarding the transplantation of fecal microbiota for cirrhotic patients to prevent recurrence of hepatic encephalopathy (HE).1 Although innovative and inspiring, several points warrant further clarification. Full-Text PDF

Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.

<h2>Summary</h2> Patients with chronic liver disease and cirrhosis demonstrate a global mucosal immune impairment, which is associated with altered gut microbiota composition and functionality. These changes progress along with the advancing degree of cirrhosis and can be linked with hepatic encephalopathy, infections and even prognostication independent of clinical biomarkers. Along with compositional changes, functional alterations to the microbiota, related to short-chain fatty acids, bioenergetics and bile acid metabolism, are also associated with cirrhosis progression and outcomes. Altering the functional and structural profile of the microbiota is partly achieved by medications used in patients with cirrhosis such as rifaximin, lactulose, proton pump inhibitors and other antibiotics. However, the role of faecal or intestinal microbiota transplantation is increasingly being recognised. Herein, we review the challenges, opportunities and road ahead for the appropriate and safe use of intestinal microbiota transplantation in liver disease.

Complications of portal hypertension, including ascites, gastrointestinal bleeding, hepatic hydrothorax, and hepatic encephalopathy, are associated with significant morbidity and mortality. Despite few high-quality randomized controlled trials to guide therapeutic decisions, transjugular intrahepatic portosystemic shunt (TIPS) creation has emerged as a crucial therapeutic option to treat complications of portal hypertension. In North America, the decision to perform TIPS involves gastroenterologists, hepatologists, and interventional radiologists, but TIPS creation is performed by interventional radiologists. This is in contrast to other parts of the world where TIPS creation is performed primarily by hepatologists. Thus, the successful use of TIPS in North America is dependent on a multidisciplinary approach and technical expertise, so as to optimize outcomes. Recently, new procedural techniques, TIPS stent technology, and indications for TIPS have emerged. As a result, practices and outcomes vary greatly across institutions and significant knowledge gaps exist. In this consensus statement, the Advancing Liver Therapeutic Approaches group critically reviews the application of TIPS in the management of portal hypertension. Advancing Liver Therapeutic Approaches convened a multidisciplinary group of North American experts from hepatology, interventional radiology, transplant surgery, nephrology, cardiology, pulmonology, and hematology to critically review existing literature and develop practice-based recommendations for the use of TIPS in patients with any cause of portal hypertension in terms of candidate selection, procedural best practices and, post-TIPS management; and to develop areas of consensus for TIPS indications and the prevention of complications. Finally, future research directions are identified related to TIPS for the management of portal hypertension.

In patients with cirrhosis and chronic liver disease, acute-on-chronic liver failure is emerging as a major cause of mortality. These guidelines indicate the preferred approach to the management of patients with acute-on-chronic liver failure and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.

Patients with cirrhosis are at increased risk for serious infections, including spontaneous bacterial peritonitis, multidrug-resistant infection, and infection with gut microorganisms. In-hospital mortality exceeds 50%. Empirical antibiotic coverage is used until a precise diagnosis can be made.

Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care.Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]).Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1β and endothelial dysfunction markers was also observed in the albumin group.In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction.www.gov NCT03585257.Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Aliment Pharmacol Ther 31, 537–547 Summary Background Hepatic encephalopathy, both overt and minimal, forms a continuum of cognitive change in cirrhosis. Strategies to diagnose and treat hepatic encephalopathy have evolved considerably. Aim To examine the updated diagnostic and treatment strategies for hepatic encephalopathy. Methods Techniques for the clinical, psychometric and neurophysiological evaluation of hepatic encephalopathy are reviewed. The methods reviewed include pure clinical scales (West-Haven), psychometric tests (PSE-syndrome test), neurophysiological tests (EEG, Critical flicker frequency, CFF) and computerized tests (Inhibitory control test, ICT). Results Clinical scales are limited, whereas psychometric tests (specifically PSE-syndrome test), CFF and ICT can be used to diagnose minimal hepatic encephalopathy. However, there is no single test that can capture the entire spectrum of cognitive impairment. Treatment options and goals depend on the acuity of hepatic encephalopathy. In-patient management should concentrate on supportive care, precipitating factor reversal and lactulose and/or rifaximin therapy. Out-patient therapy should aim to prevent recurrences, and both lactulose and rifaximin have evidence to support their use. Conclusions Diagnostic techniques for hepatic encephalopathy range from simple scales to sophisticated tools. Treatment options depend on the stage of hepatic encephalopathy. The future challenge is to evaluate cognitive function as a continuum with clinically relevant outcomes and to develop well-tolerated and inexpensive treatments for hepatic encephalopathy.

Background & AimsMinimal hepatic encephalopathy (MHE) is difficult to diagnose. The Inhibitory Control Test (ICT) measures response inhibition and has diagnosed MHE with 90% sensitivity and specificity in a selected population; high lure and low target rates indicated poor ICT performance. We studied the reliability and validity of ICT for MHE diagnosis.MethodsICT was compared with a psychometric battery (standard psychometric tests [SPT]) for MHE diagnosis and overt hepatic encephalopathy (OHE) prediction. ICT was administered twice for test-retest reliability, before/after transvenous intrahepatic portosystemic shunting (TIPS), and before/after yogurt treatment. The time taken by 2 medical assistants (MA) to administer ICT was recorded and compared with that of a psychologist for cost analysis.ResultsOne hundred thirty-six cirrhotic patients and 116 age/education-matched controls were studied. ICT (>5 lures) had 88% sensitivity for MHE diagnosis with 0.902 area under the curve for receiver operating characteristic. MHE-positive patients had significantly higher ICT lures (11 vs 4, respectively, P = .0001) and lower targets (92% vs 97%, respectively, P = .0001) compared with MHE-negative patients. The test/retest reliability for ICT lures (n = 50, r = 0.90, P = .0001) was high. ICT and SPT were equivalent in predicting OHE (21%). ICT lures significantly worsened after TIPS (n = 10; 5 vs 9, respectively; P = .02) and improved after yogurt supplementation (n = 18, 10 vs 5, respectively; P = .002). The MAs were successfully trained to administer ICT; the time required for test administration and the associated costs were smaller for ICT than for SPT.ConclusionsICT is a sensitive, reliable, and valid test for MHE diagnosis that can be administered inexpensively by MAs. Minimal hepatic encephalopathy (MHE) is difficult to diagnose. The Inhibitory Control Test (ICT) measures response inhibition and has diagnosed MHE with 90% sensitivity and specificity in a selected population; high lure and low target rates indicated poor ICT performance. We studied the reliability and validity of ICT for MHE diagnosis. ICT was compared with a psychometric battery (standard psychometric tests [SPT]) for MHE diagnosis and overt hepatic encephalopathy (OHE) prediction. ICT was administered twice for test-retest reliability, before/after transvenous intrahepatic portosystemic shunting (TIPS), and before/after yogurt treatment. The time taken by 2 medical assistants (MA) to administer ICT was recorded and compared with that of a psychologist for cost analysis. One hundred thirty-six cirrhotic patients and 116 age/education-matched controls were studied. ICT (>5 lures) had 88% sensitivity for MHE diagnosis with 0.902 area under the curve for receiver operating characteristic. MHE-positive patients had significantly higher ICT lures (11 vs 4, respectively, P = .0001) and lower targets (92% vs 97%, respectively, P = .0001) compared with MHE-negative patients. The test/retest reliability for ICT lures (n = 50, r = 0.90, P = .0001) was high. ICT and SPT were equivalent in predicting OHE (21%). ICT lures significantly worsened after TIPS (n = 10; 5 vs 9, respectively; P = .02) and improved after yogurt supplementation (n = 18, 10 vs 5, respectively; P = .002). The MAs were successfully trained to administer ICT; the time required for test administration and the associated costs were smaller for ICT than for SPT. ICT is a sensitive, reliable, and valid test for MHE diagnosis that can be administered inexpensively by MAs.

OBJECTIVES: Spontaneous bacterial peritonitis (SBP) is a frequent complication of cirrhosis. Bacterial contamination of ascites fluid leading to SBP is caused by bacterial translocation with subsequent bacteremia. Proton pump inhibitors (PPIs) suppress gastric acid secretion, allowing bacterial colonization of the upper gastrointestinal tract, and may predispose to bacterial overgrowth and translocation. The aim of this study was to determine whether PPI use in cirrhotics with ascites is associated with SBP. METHODS: A retrospective case-control study was performed. Seventy cirrhotics admitted with paracentesis-proven SBP between 2002 and 2007 were matched 1:1 (for age and Child's class) with comparable cirrhotics with ascites who were admitted for conditions other than SBP. We excluded patients on chronic antibiotic prophylaxis or with antecedent gastrointestinal bleeding. Outpatient PPI use at the time of admission was compared between groups, and the effect of covariates was analyzed. RESULTS: Patients with SBP had a significantly higher rate of prehospital PPI use (69%) compared with ascitic cirrhotics hospitalized without SBP (31%,P= 0.0001). There was no significant difference in demographics, diabetes, etiology, or survival between groups. On multivariate analysis, PPI use was independently associated with SBP (odds ratio (OR) 4.31, confidence interval (CI) 1.34-11.7), and ascitic fluid protein was protective (OR 0.1, CI 0.03-0.25). In total, 47% of cirrhotic patients receiving PPI in this study had no documented indication for PPI treatment. CONCLUSIONS: PPI therapy is associated with SBP in patients with advanced cirrhosis. Prospective studies are needed to determine whether PPI avoidance can reduce the incidence of SBP and improve outcomes.

OBJECTIVES MHE patients have impairment on driving tests. However, it is unclear whether this impairment is restricted to the testing environment or is associated with increased traffic violations and/or motor vehicle accidents. METHODS An anonymous driving history and driving behavior questionnaire (DBQ: self-scored, best score 104), coded according to MHE status, was sent to 200 cirrhotics without overt hepatic encephalopathy and 100 age/education-matched controls. The questionnaire inquired about demographics, alcohol/illegal drug use, and violations/accidents within 1 and 5 yr. The cirrhotics had been divided into those with MHE (MHE+), without MHE (MHE−), and those not tested for MHE because of psychoactive drug use, on a previous study. RESULTS Cirrhotics versus controls had similar driving duration, alcohol/illegal drug use but significantly higher percentage with violations within both 1 and 5 yr (25% vs 4% [5 yr]), 13% vs 2% [(1 yr]), accidents (17% vs 4% [5 yr]), 9% vs 1% [1 yr]), and both (34% vs 7% [5 yr], 18% vs 3% [1 yr]). MHE+ cirrhotics had significantly higher percentage with violations (36% [5 yr], 21% [1 yr]), accidents (33% [5 yr]), 17% [1 yr]), and both (53% [5 yr], 33% [1 yr]) versus other cirrhotics. DBQ score was significantly lower in cirrhotics than controls (92 vs 99). Within cirrhotics, DBQ score was highest in MHE– versus other groups. MHE+ status was the only risk factor (odds ratios: 4.2–7.6) for violations and for accidents on multivariate logistic regression. CONCLUSIONS Cirrhotics have a higher self-reported occurrence of violations and accidents compared to controls. MHE+ a is strong predictor for violations and accidents. Prospective studies investigating the effect of MHE treatment on violations and accidents are warranted.

We read with interest the recent article by Kale et al. describing the MR imaging of patients with cirrhosis with minimal hepatic encephalopathy (MHE) who were diagnosed using a battery of neuro-psychometric tests.1 MHE is a neurocognitive complication of cirrhosis which is associated with poor quality of life, increased rate of progression to overt hepatic encephalopathy (OHE) and driving skill impairment.2-6 MHE detection is not possible by clinical examination but can only be performed using neuropsychometric/neurophysiological techniques, as in the paper by Kale et al.1, 7-9 We set out to determine the diagnostic approaches of U.S.-based members of AASLD toward MHE systematically to identify potential barriers to routine testing. An anonymous questionnaire querying the practice profile, personal opinions regarding MHE diagnostic strategies, frequency of diagnosis, reasons for testing/not testing for MHE, measures that would increase their testing for MHE and treatment for MHE, was e-mailed to 246 AASLD members. One hundred thirty-seven replies were received, of which 98 (72%) were in academic programs, 33 (24%) in private practice, and 6 (4%) were trainees. The majority of respondents believed that MHE was a problem and agreed that it should be tested for. However, only a minority was able to test for it >50% of the time and 52 (38%) respondents never tested for it (Table 1). The reasons for testing or not testing for MHE are displayed in the table. The majority who tested for MHE tested all cirrhotics (56%), the rest restricted testing to those driving (18%), operating machinery (15%), working full-time (9%), and not actively drinking (8%). Of the respondents, 85% believed that simple and rapid tests for MHE diagnosis which can be administered by clinic personnel would increase the likelihood of testing for MHE; other factors that would increase their likelihood for MHE testing are displayed in the table. In addition, 85% believed that MHE, once diagnosed, should be treated. Lactulose was the preferred agent for 78%, rifaximin 18%, zinc 8%, and the rest believed other treatments would be effective. In conclusion, although the majority of AASLD respondents believe that MHE is a significant problem which should be tested for, only a minority are able to test for it routinely. Barriers to routine MHE testing include added time, resource and personnel requirements and lack of standardized tests in the United States population. Simple and rapid tests for diagnosis of MHE would likely increase the probability of testing for MHE in the future. Jasmohan Singh Bajaj*, Ashkan Etemadian*, Muhammad Hafeezullah*, Kia Saeian*, * Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI.

OBJECTIVES: Clostridium difficile–associated disease (CDAD) is associated with antibiotic use, acid suppression, and hospitalization, all of which occur frequently in cirrhosis. The aim was to define the effect of CDAD on outcomes and identify risk factors for its development in cirrhosis. METHODS: Case–control studies using the de-identified national (Nationwide Inpatient Sample, NIS) and an identified liver transplant center database of hospitalized cirrhotics with and without CDAD were performed. The NIS 2005 was queried for mortality, charges, and length of stay (LOS) in cirrhotics with/without CDAD. Outcomes of cirrhosis and infections were also analyzed. In the transplant center database, risk factors for CDAD were defined in hospitalized cirrhotics with/without CDAD who were age matched in a 1:2 ratio. RESULTS: The NIS 2005 included 1,165 cirrhotics with and 82,065 without CDAD. Cirrhotics with CDAD had a significantly higher mortality (13.8% vs. 8.2%,P<0.001), LOS (14.4 days vs. 6.7 days,P<0.001), and charges ($79,351 vs. $35,686,P<0.001) compared with those without CDAD. On multivariate analysis, CDAD was associated with higher mortality (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.29–1.85), charges, and LOS despite controlling for cirrhosis complications and infections. In the transplant center database, 54 cirrhotics with and 108 cirrhotics without CDAD were included. Outpatient spontaneous bacterial peritonitis prophylaxis (35% vs. 13%,P=0.01), inpatient antibiotic (63% vs. 35%,P=0.0001), and proton pump inhibitor (PPI) use (74% vs. 31%,P=0.0001) were significantly higher in those with CDAD. CONCLUSIONS: Cirrhotics with CDAD have a higher mortality, LOS, and charges on the NIS 2005 compared with those without CDAD. Antibiotic and PPI use are risk factors for CDAD development in hospitalized cirrhotics.

OBJECTIVES: Despite the high prevalence of covert hepatic encephalopathy (CHE) in cirrhotics without previous overt HE (OHE), its independent impact on predicting clinically relevant outcomes is unclear. The aim of this study was to define the impact of CHE on time to OHE, hospitalization, and death/transplant in prospectively followed up patients without previous OHE. METHODS: Outpatient cirrhotics without OHE were enrolled and were administered a standard paper–pencil cognitive battery for CHE diagnosis. They were systematically followed up and time to first OHE development, hospitalization (liver-related/unrelated), and transplant/death were compared between CHE and no-CHE patients at baseline using Cox regression. RESULTS: A total of 170 cirrhotic patients (55 years, 58% men, 14 years of education, Model for End-Stage Liver Disease (MELD 9), 53% hepatitis C virus (HCV), 20% nonalcoholic etiology) were included, of whom 56% had CHE. The entire population was followed up for 13.0±14.6 months, during which time 30% developed their first OHE episode, 42% were hospitalized, and 19% had a composite death/transplant outcome. Age, gender, etiology, the MELD score, and CHE status were included in Cox regression models for time to first OHE episode, hospitalization, death, and composite death/transplant outcomes. On Cox regression, despite controlling for MELD, those with CHE had a higher risk of developing OHE (hazard ratio: 2.1, 95% confidence interval 1.01–4.5), hospitalization (hazard ratio: 2.5, 95% confidence interval 1.4–4.5), and death/transplant (hazard ratio: 3.4, 95% confidence interval 1.2–9.7) in the follow-up period. CONCLUSIONS: Covert HE is associated with worsened survival and increased risk of hospitalization and OHE development, despite controlling for the MELD score. Strategies to detect and treat CHE may improve these risks.

Alcohol abuse with/without cirrhosis is associated with an impaired gut barrier and inflammation. Gut microbiota can transform primary bile acids (BA) to secondary BAs, which can adversely impact the gut barrier. The purpose of this study was to define the effect of active alcohol intake on fecal BA levels and ileal and colonic inflammation in cirrhosis. Five age-matched groups {two noncirrhotic (control and drinkers) and three cirrhotic [nondrinkers/nonalcoholics (NAlc), abstinent alcoholic for &gt;3 mo (AbsAlc), currently drinking (CurrAlc)]} were included. Fecal and serum BA analysis, serum endotoxin, and stool microbiota using pyrosequencing were performed. A subgroup of controls, NAlc, and CurrAlc underwent ileal and sigmoid colonic biopsies on which mRNA expression of TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (Cox-2) were performed. One hundred three patients (19 healthy, 6 noncirrhotic drinkers, 10 CurrAlc, 38 AbsAlc, and 30 NAlc, age 56 yr, median MELD: 10.5) were included. Five each of healthy, CurrAlc, and NAlc underwent ileal/colonic biopsies. Endotoxin, serum-conjugated DCA and stool total BAs, and secondary-to-primary BA ratios were highest in current drinkers. On biopsies, a significantly higher mRNA expression of TNF-α, IL-1β, IL-6, and Cox-2 in colon but not ileum was seen in CurrAlc compared with NAlc and controls. Active alcohol use in cirrhosis is associated with a significant increase in the secondary BA formation compared with abstinent alcoholic cirrhotics and nonalcoholic cirrhotics. This increase in secondary BAs is associated with a significant increase in expression of inflammatory cytokines in colonic mucosa but not ileal mucosa, which may contribute to alcohol-induced gut barrier injury.

Patients with minimal hepatic encephalopathy (MHE) have attention, response inhibition, and working memory difficulties that are associated with driving impairment and high motor vehicle accident risk. Navigation is a complex system needed for safe driving that requires functioning working memory and other domains adversely affected by MHE. The aim of this study was to determine the effect of MHE on navigation skills and correlate them with psychometric impairment. Forty-nine nonalcoholic patients with cirrhosis (34 MHE+, 15 MHE-; divided on the basis of a battery of block design, digit symbol, and number connection test A) and 48 age/education-matched controls were included. All patients underwent the psychometric battery and inhibitory control test (ICT) (a test of response inhibition) and driving simulation. Driving simulation consisted of 4 parts: (1) training; (2) driving (outcome being accidents); (3) divided attention (outcome being missed tasks); and (4) navigation, driving along a marked path on a map in a "virtual city" (outcome being illegal turns). Illegal turns were significantly higher in MHE+ (median 1; P = 0.007) compared with MHE-/controls (median 0). Patients who were MHE+ missed more divided attention tasks compared with others (median MHE+ 1, MHE-/controls 0; P = 0.001). Similarly, accidents were higher in patients who were MHE+ (median 2.5; P = 0.004) compared with MHE- (median 1) or controls (median 2). Accidents and illegal turns were significantly correlated (P = 0.001, r = 0.51). ICT impairment was the test most correlated with illegal turns (r = 0.6) and accidents (r = 0.44), although impairment on the other tests were also correlated with illegal turns.Patients positive for MHE have impaired navigation skills on a driving simulator, which is correlated with impairment in response inhibition (ICT) and attention. This navigation difficulty may pose additional driving problems, compounding the pre-existing deleterious effect of attention deficits.

Minimal hepatic encephalopathy is a neuro-cognitive dysfunction which occurs in an epidemic proportion of cirrhotic patients, estimated as high as 80% of the population tested. It is characterized by a specific, complex cognitive dysfunction which is independent of sleep dysfunction or problems with overall intelligence. Although named "minimal", minimal hepatic encephalopathy (MHE) can have a far-reaching impact on quality of life, ability to function in daily life and progression to overt hepatic encephalopathy. Importantly, MHE has a profound negative impact on the ability to drive a car and may be a significant factor behind motor vehicle accidents. A crucial aspect of the clinical care of MHE patients is their driving history, which is often ignored in routine care and can add a vital dimension to the overall disease assessment. Driving history should be an integral part of care in patients with MHE. The lack of specific signs and symptoms, the preserved communication skills and lack of insight make MHE a difficult condition to diagnose. Diagnostic strategies for MHE abound, but are usually limited by financial, normative or time constraints. Recent studies into the inhibitory control and critical flicker frequency tests are encouraging since these tests can increase the rates of MHE diagnosis without requiring a psychologist. Although testing for MHE and subsequent therapy is not standard of care at this time, it is important to consider this in cirrhotics in order to improve their ability to live their life to the fullest.

To compare inhibitory control test (ICT), a simple/rapid test of attention, to a standard psychometric battery (SPT) to diagnose minimal hepatic encephalopathy (MHE) and predict development of overt hepatic encephalopathy (OHE) in cirrhotic patients.Fifty nonalcoholic cirrhotics and 50 age/educational-status-matched controls were given ICT and SPT in the same sitting. Performance impaired beyond two standard deviations of controls was considered MHE in cirrhotics. ICT results (lure/target response and lures/person) were compared between controls and cirrhotics and within cirrhotics with/without MHE. Receiver-operating characteristic analysis was used to study ICT for MHE diagnosis. Twenty subjects were administered SPT and ICT twice to assess test-retest reliability. All cirrhotics were followed routinely for the development of OHE.Cirrhotics performed worse than controls on SPT and ICT. Using SPT, 39 cirrhotics had MHE. ICT was administered faster than SPT (15 vs 37 min). Cirrhotics with MHE had significantly higher lure (28%vs 3%) and lower target response (91%vs 96%) compared with those without MHE. Lure/person >5 had 90% sensitivity/specificity for MHE diagnosis. AUC for receiver-operating characteristic for lures alone was 95.8%. Lure and target responses were highly correlated (r= 0.9) between sessions showing high test-retest reliability. Five (10%) patients developed OHE on f/u of 26 +/- 10 months; all five had been diagnosed with MHE using ICT and SPT. None of the five patients with discordant results on SPT and ICT developed OHE.ICT has good sensitivity/specificity for MHE diagnosis, is reliable and is equivalent to SPT for predicting OHE development.

Diagnosing minimal hepatic encephalopathy (MHE) is challenging, and point-of-care tests are needed. Stroop EncephalApp has been validated for MHE diagnosis in single-center studies. The objective of the study was to validate EncephalApp for MHE diagnosis in a multicenter study.Outpatient cirrhotics (with/without prior overt hepatic encephalopathy (OHE)) and controls from three sites (Virginia (VA), Ohio (OH), and Arkansas (AR)) underwent EncephalApp and two gold standards, psychometric hepatic encephalopathy score (PHES) and inhibitory control test (ICT). Age-/gender-/education-adjusted values for EncephalApp based on direct norms, and based on ICT and PHES, were defined. Patients were followed, and EncephalApp cutoff points were used to determine OHE prediction. These cutoff points were then used in a separate VA-based validation cohort.A total of 437 cirrhotics (230 VA, 107 OH, 100 AR, 36% OHE, model for end-stage liver disease (MELD) score 11) and 308 controls (103 VA, 100 OH, 105 AR) were included. Using adjusted variables, MHE was present using EncephalApp based on norms in 51%, EncephalApp based on PHES in 37% (sensitivity 80%), and EncephalApp based on ICT in 54% of patients (sensitivity 70%). There was modest/good agreement between sites on EncephalApp MHE diagnosis using the three methods. OHE developed in 13% of patients, which was predicted by EncephalApp independent of the MELD score. In the validation cohort of 121 VA cirrhotics, EncephalApp directly and based on gold standards remained consistent for MHE diagnosis with >70% sensitivity.In this multicenter study, EncephalApp, using adjusted population norms or in the context of existing gold standard tests, had good sensitivity for MHE diagnosis and predictive capability for OHE development.

Opioid use is epidemic in cirrhosis, which could precipitate hepatic encephalopathy (HE) potentially through gut dysbiosis and inflammation.To define the effect of opioids on readmissions and on gut microbiota composition and functionality.Cohort 1 had 200 cirrhotic in-patients (with/without opioid use) followed prospectively through the index hospitalisation and 6 months post discharge. Readmissions (HE-related/unrelated) were compared between patients discharged on opioids compared to the rest, including using a multi-variable analysis. Cohort 2 consisted of 72 cirrhotics on chronic opioids who were age/model for end-stage liver disease (MELD) and prior HE-balanced with 72 cirrhotics not on opioids. Stool microbiota composition (multi-tagged sequencing), predicted functionality (PiCRUST), endotoxemia and systemic inflammation (IL-6, IL-17) were compared.Cohort 1: Chronic opioid use was statistically similar between those admitted with/without HE, and was judged to be an HE precipitant in <5% of cases during the index hospitalisation. Of the 144 patients alive at 6 months, 82 were readmitted. The opioid users had a significantly higher all cause (69% vs. 48%, P = 0.008), but not HE-related readmissions (30% vs. 41%, P = 0.30). On regression, opioid therapy and female gender were predictive of readmission independent of MELD score and previous HE. Cohort 2: Significant dysbiosis was noted in the opioid cohort, especially in HE+opioid patients with lower autochthonous taxa and Bacteroidaceae relative abundance. PiCRUST showed highest aromatic amino acid and endotoxin production in opioid users. Opioid users also had higher endotoxemia and IL-6 but not IL-17.Chronic opioid use in cirrhosis is associated with increased endotoxemia, dysbiosis and all-cause readmissions.

Hepatic encephalopathy (HE), which consists of minimal (MHE) and overt (OHE) stages, is a model for impaired gut-liver-brain axis in cirrhosis. Microbiota changes in both stages have been associated with impaired cognition, endotoxemia, and inflammation. There is dysbiosis (reduced autochthonous taxa [Lachnospiraceae, Ruminococcaceae, and Clostridiales XIV] and increased Enterobacteriaceae and Streptococcaceae) with disease progression. In MHE, there is an increased abundance of Streptococcus salivarius linked to cognition and ammonia. In OHE, stool Alcaligenaceae and Porphyromonadaceae are associated with poor cognition. Colonic mucosal microbiome in cirrhosis is significantly different compared with stool and independently related to cognition. HE treatment can affect microbial composition and function; cognitive improvement in MHE after rifaximin, a non-absorbable antibiotic, occurred without significant stool microbiota composition change but improved metabolic linkages. Similarly, there are only modest lactulose and rifaximin-associated changes on microbiota composition in OHE. HE represents an important model to study microbiome-brain interactions.

Proton pump inhibitors (PPI) have been associated with infectious complications in cirrhosis, but their impact on distal gut microbiota composition and function is unclear. We aimed to evaluate changes in stool microbiota composition and function in patients with cirrhosis and healthy controls after omeprazole therapy. Both 15 compensated cirrhotic patients and 15 age-matched controls underwent serum gastrin measurement, stool microbiota profiling with multitagged pyrosequencing, and urinary metabolic profiling with NMR spectroscopy to assess microbial cometabolites before/after a 14-day course of 40 mg/day omeprazole under constant diet conditions. Results before (pre) and after PPI were compared in both groups, compared with baseline by systems biology techniques. Adherence was >95% without changes in diet or MELD (model for end-stage liver disease) score during the study. Serum gastrin concentrations significantly increased after PPI in cirrhosis (pre 38.3 ± 35.8 vs. 115.6 ± 79.3 pg/ml P < 0.0001) and controls (pre 29.9 ± 14.5 vs. 116.0 ± 74.0 pg/ml, P = 0.001). A significant microbiota change was seen in both controls and cirrhosis after omeprazole (QIIME P < 0.0001). Relative Streptococcaceae abundance, normally abundant in saliva, significantly increased postomeprazole in controls (1 vs. 5%) and cirrhosis (0 vs. 9%) and was correlated with serum gastrin levels (r = 0.4, P = 0.005). We found significantly reduced hippurate in cirrhosis vs. controls both pre- and postomeprazole and increased lactate in both groups post vs. preomeprazole, whereas dimethylamine (DMA) decreased in cirrhosis only. On correlation network analysis, significant changes in linkages of bacteria with metabolites (hippurate/DMA/lactate) were found postomeprazole, compared with pre-PPI in cirrhosis patients. In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth.

Background & AimsDetection of covert hepatic encephalopathy (CHE) is difficult, but point-of-care testing could increase rates of diagnosis. We aimed to validate the ability of the smartphone app EncephalApp, a streamlined version of Stroop App, to detect CHE. We evaluated face validity, test-retest reliability, and external validity.MethodsPatients with cirrhosis (n = 167; 38% with overt HE [OHE]; mean age, 55 years; mean Model for End-Stage Liver Disease score, 12) and controls (n = 114) were each given a paper and pencil cognitive battery (standard) along with EncephalApp. EncephalApp has Off and On states; results measured were OffTime, OnTime, OffTime+OnTime, and number of runs required to complete 5 off and on runs. Thirty-six patients with cirrhosis underwent driving simulation tests, and EncephalApp results were correlated with results. Test-retest reliability was analyzed in a subgroup of patients. The test was performed before and after transjugular intrahepatic portosystemic shunt placement, and before and after correction for hyponatremia, to determine external validity.ResultsAll patients with cirrhosis performed worse on paper and pencil and EncephalApp tests than controls. Patients with cirrhosis and OHE performed worse than those without OHE. Age-dependent EncephalApp cutoffs (younger or older than 45 years) were set. An OffTime+OnTime value of >190 seconds identified all patients with CHE with an area under the receiver operator characteristic value of 0.91; the area under the receiver operator characteristic value was 0.88 for diagnosis of CHE in those without OHE. EncephalApp times correlated with crashes and illegal turns in driving simulation tests. Test-retest reliability was high (intraclass coefficient, 0.83) among 30 patients retested 1–3 months apart. OffTime+OnTime increased significantly (206 vs 255 seconds, P = .007) among 10 patients retested 33 ± 7 days after transjugular intrahepatic portosystemic shunt placement. OffTime+OnTime decreased significantly (242 vs 225 seconds, P = .03) in 7 patients tested before and after correction for hyponatremia (126 ± 3 to 132 ± 4 meq/L, P = .01) 10 ± 5 days apart.ConclusionsA smartphone app called EncephalApp has good face validity, test-retest reliability, and external validity for the diagnosis of CHE. Detection of covert hepatic encephalopathy (CHE) is difficult, but point-of-care testing could increase rates of diagnosis. We aimed to validate the ability of the smartphone app EncephalApp, a streamlined version of Stroop App, to detect CHE. We evaluated face validity, test-retest reliability, and external validity. Patients with cirrhosis (n = 167; 38% with overt HE [OHE]; mean age, 55 years; mean Model for End-Stage Liver Disease score, 12) and controls (n = 114) were each given a paper and pencil cognitive battery (standard) along with EncephalApp. EncephalApp has Off and On states; results measured were OffTime, OnTime, OffTime+OnTime, and number of runs required to complete 5 off and on runs. Thirty-six patients with cirrhosis underwent driving simulation tests, and EncephalApp results were correlated with results. Test-retest reliability was analyzed in a subgroup of patients. The test was performed before and after transjugular intrahepatic portosystemic shunt placement, and before and after correction for hyponatremia, to determine external validity. All patients with cirrhosis performed worse on paper and pencil and EncephalApp tests than controls. Patients with cirrhosis and OHE performed worse than those without OHE. Age-dependent EncephalApp cutoffs (younger or older than 45 years) were set. An OffTime+OnTime value of >190 seconds identified all patients with CHE with an area under the receiver operator characteristic value of 0.91; the area under the receiver operator characteristic value was 0.88 for diagnosis of CHE in those without OHE. EncephalApp times correlated with crashes and illegal turns in driving simulation tests. Test-retest reliability was high (intraclass coefficient, 0.83) among 30 patients retested 1–3 months apart. OffTime+OnTime increased significantly (206 vs 255 seconds, P = .007) among 10 patients retested 33 ± 7 days after transjugular intrahepatic portosystemic shunt placement. OffTime+OnTime decreased significantly (242 vs 225 seconds, P = .03) in 7 patients tested before and after correction for hyponatremia (126 ± 3 to 132 ± 4 meq/L, P = .01) 10 ± 5 days apart. A smartphone app called EncephalApp has good face validity, test-retest reliability, and external validity for the diagnosis of CHE.

Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells, including cholangiocytes. Exosome‐mediated cell‐cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long noncoding RNA (lncRNA), H19, is mainly expressed in cholangiocytes, and its aberrant expression is associated with significant down‐regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2 −/− ) mice. However, how cholangiocyte‐derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte‐derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. Hepatic H19 level is correlated with severity of cholestatic injury in both fibrotic mouse models, including Mdr2 −/− mice, a well‐characterized model of primary sclerosing cholangitis (PSC), or CCl 4 ‐induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal‐H19 level is gradually up‐regulated during disease progression in Mdr2 −/− mice and patients with cirrhosis. H19‐carrying exosomes from the primary cholangiocytes of wild‐type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19 −/− mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and posttranscriptional levels. Importantly, transplant of H19‐carrying serum exosomes of old fibrotic Mdr2 −/− mice significantly promoted liver fibrosis (LF) in young Mdr2 −/− mice. Conclusion: Cholangiocyte‐derived exosomal‐H19 plays a critical role in cholestatic liver injury. Serum exosomal H19 represents a noninvasive biomarker and potential therapeutic target for cholestatic diseases. (H epatology 2018).

Minimal hepatic encephalopathy (MHE) in cirrhosis is associated with impaired driving skills and increased risk of motor vehicle accidents (MVAs). Detection and treatment of MHE has the potential to reduce costs and morbidity associated with MVAs. We conducted a cost-effectiveness analysis to assess the benefits of different strategies of MHE diagnosis and treatment for reducing MVA-related societal costs. The analyses compared five MHE management strategies: (1) presumptive treatment of all cirrhosis patients; (2) diagnosis by neuropsychological exam (NPE) with treatment; (3) diagnosis by standard psychometric tests (SPTs) with treatment; (4) diagnosis by rapid screening using inhibitory control test (ICT) with treatment; and (5) no MHE diagnosis or treatment (status quo). Treatments considered were lactulose or rifaximin, which were assumed to reduce the MVA rate to the level of similarly aged noncirrhosis patients with benefit adjusted for treatment compliance. A Markov model followed a simulated cohort of 1,000 cirrhosis patients without overt hepatic encephalopathy (OHE), from entry into treatment, through MHE development, and later OHE, when they exited the modeled cohort. Follow-up was for 5 years and included biannual MHE testing. The societal cost of a single MVA was estimated at $42,100. All four strategies with lactulose were cost-saving compared with the status quo. Diagnosis with ICT and lactulose was the most cost-effective approach (cost/MVA prevented: $24,454 ICT; $25,470 SPT; $30,469 presumptive treatment and $33,742 NPE). Net program savings over 5 years ranged from $1.7 to 3.6 million depending on the strategy. Rifaximin therapy was not cost-saving at current prices but would become so at a monthly cost of <$353. Conclusion: Detection of MHE, especially using the ICT, and subsequent treatment with lactulose could substantially reduce societal costs by preventing MVAs. (HEPATOLOGY 2012)

Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the 'leaky' gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

Objective Cirrhotics have a high rate of infections, which are increasingly fungal or culture-negative in nature. While infected cirrhotics have bacterial dysbiosis, the role of fungi is unclear. We aimed to evaluate gut bacterial and fungal dysbiosis in cross-sectional and longitudinal analyses of outpatient and inpatient cirrhotics and prediction of hospitalisations. Methods Cross-sectional: Age-matched controls, outpatients (with/without antibiotics) and hospitalised uninfected, culture-negative and culture-positive cirrhotics were included and followed for 90 days. Longitudinal: Three studies were conducted: (1) cirrhotics followed over 6 months, (2) outpatient cirrhotics administered antibiotics per standard of care for 5 days and (3) cirrhotics and controls administered omeprazole over 14 days. In all studies, stool bacterial/fungal profiles were analysed. Results Cross-sectional: In 143 cirrhotics and 26 controls, bacterial and fungal diversities were significantly linked. Outpatients on antibiotics and patients with culture-positive infections had the lowest diversities. Bacterial and fungal correlations were complex in uninfected, outpatient and control groups but were markedly skewed in infected patients. 21% were admitted on 90-day follow-up. A lower Bacteroidetes/Ascomycota ratio was associated with lower hospitalisations. Longitudinal: Fungal and bacterial profiles were stable on follow-up (5 days and 6 months). After antibiotics, a significantly reduced bacterial and fungal diversity, higher Candida and lower autochthonous bacterial relative abundance were seen. After omeprazole, changes in bacterial diversity and composition were seen but fungal metrics remained stable. Conclusion There is a significant fungal dysbiosis in cirrhosis, which changes differentially with antibiotics and proton pump inhibitor use, but is otherwise stable over time. A combined bacterial–fungal dysbiosis metric, Bacteroidetes/Ascomycota ratio, can independently predict 90-day hospitalisations in patients with cirrhosis. Clinical trial number NCT01458990.

We have developed a simple and accurate HPLC method for measurement of fecal bile acids using phenacyl derivatives of unconjugated bile acids, and applied it to the measurement of fecal bile acids in cirrhotic patients. The HPLC method has the following steps: <i>1</i>) lyophilization of the stool sample; <i>2</i>) reconstitution in buffer and enzymatic deconjugation using cholylglycine hydrolase/sulfatase; <i>3</i>) incubation with 0.1 N NaOH in 50% isopropanol at 60°C to hydrolyze esterified bile acids; <i>4</i>) extraction of bile acids from particulate material using 0.1 N NaOH; <i>5</i>) isolation of deconjugated bile acids by solid phase extraction; <i>6</i>) formation of phenacyl esters by derivatization using phenacyl bromide; and <i>7</i>) HPLC separation measuring eluted peaks at 254 nm. The method was validated by showing that results obtained by HPLC agreed with those obtained by LC-MS/MS and GC-MS. We then applied the method to measuring total fecal bile acid (concentration) and bile acid profile in samples from 38 patients with cirrhosis (17 early, 21 advanced) and 10 healthy subjects. Bile acid concentrations were significantly lower in patients with advanced cirrhosis, suggesting impaired bile acid synthesis.

Although survival times have increased for patients with cirrhosis, hepatic encephalopathy (HE) remains a major complication and its relative contribution toward mortality in North America is unclear. We investigated whether HE is associated with mortality independent of extrahepatic organ failures (EHOFs).We collected data from the North American Consortium for Study of End-stage Liver Disease database of hospitalized patients with cirrhosis at tertiary-care centers. EHOFs were defined as need for ventilation (respiratory failure), dialysis (renal failure), or shock (circulatory failure). We analyzed in-hospital and 30-day mortality for patients with varying HE grades and EHOF using adjusted models.We analyzed data from 1560 patients, 516 with HE (371 grade 1-2 and 145 grade 3-4). Patients with maximum HE grade 3-4 HE during hospitalization had a higher median model for end-stage liver disease (MELD) score (22) than patients with HE grade 1-2 (MELD score, 19) or no HE (MELD score, 18) (P < .0001). Thirty-day mortality for patients with HE grade 3-4 was significantly higher (38%) than for patients with HE grade 1-2 (8%) or no HE (7%). A total of 107 patients had 2 or more EHOFs, with or without HE; 151 had 1 EHOF and 1302 had no organ failure. Unadjusted mortality was highest for patients with HE of grade 3-4 with 2 EHOFs (n = 44). On regression analysis, HE severity was significantly associated with in-hospital and 30-day mortality, independent of any EHOF, white blood cell count, systemic inflammatory response syndrome, or MELD score (odds ratio, 3.3; P < .0001).In an analysis of more than 1500 patients hospitalized for cirrhosis, HE of grade 3 or 4 was associated with higher in-hospital and 30-day mortality, independently of failure of other organs.

Bacterial infections, particularly repeated infections, are significant causes of morbidity and mortality among patients with cirrhosis. We investigated and characterized risk factors for repeat infections in these patients.In a prospective study, we collected data from 188 patients hospitalized with cirrhosis and infections and enrolled in the North American Consortium for the Study of End-Stage Liver Disease (12 centers). Patients were followed up for 6 months after hospital discharge and data were analyzed on type of infections and factors associated with subsequent infections.Six months after hospital discharge, 14% of subjects had received liver transplants, 27% died, and 59% were alive without liver transplantation. After discharge, 45% had subsequent infections, but only 26% of the subsequent infections occurred at the same site. Compared with patients not re-infected, patients with repeat infections were older and a higher proportion used proton pump inhibitors (PPIs) (P = .006), rifaximin (P < .001), or prophylactic therapy for spontaneous bacterial peritonitis (SBP) (P < .001). Logistic regression showed that SBP prophylaxis (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.56-7.63), PPI use (OR, 2.94; 95% CI, 1.39-6.20), SBP at hospital admission (OR, 0.37; 95% CI, 0.15-0.91), and age (OR, 1.06; 95% CI, 1.02-1.11) were independent predictors of subsequent infections.Patients hospitalized with cirrhosis and infections are at high risk for subsequent infections, mostly at different sites, within 6 months of index infection resolution. Those at highest risk include previously infected older patients receiving PPIs and/or SBP prophylaxis, although these associations do not prove that these factors cause the infections. New strategies are needed to prevent infections in patients with cirrhosis.

In patients with cirrhosis, the gut microbiome are affected by multiple gut and systemic alterations. These changes lead to dysbiosis in the microbiota of different parts of the body, resulting in inflammation. The constant immune stimulation resulting in part from dysbiosis is associated with morbidity in patients with cirrhosis. Dysbiosis as a dynamic event worsens with decompensation such as with hepatic encephalopathy, infections or acute-on-chronic liver failure (ACLF). These microbial patterns could be applied as diagnostic and prognostic measures in cirrhosis in the outpatient and inpatient setting. Current therapies for cirrhosis have differing impacts on gut microbial composition and functionality. Dietary modifications and the oral cavity have emerged as newer targetable factors to modulate the microbiome, which could affect inflammation and, potentially improve outcomes. Additionally, fecal microbial transplant is being increasingly studied to provide compositional and functional modulation of the microbiome. Ultimately, a combination of targeted therapies may be needed to provide an optimal gut milieu to improve outcomes in cirrhosis.

Patients with cirrhosis are often exposed to antibiotics that can lead to resistance and fungal overgrowth. The role of fecal microbial transplant (FMT) in restoring gut microbial function is unclear in cirrhosis. In a Food and Drug Administration-monitored phase 1 clinical safety trial, patients with decompensated cirrhosis on standard therapies (lactulose and rifaximin) were randomized to standard-of-care (SOC, no antibiotics/FMT) or 5 days of broad-spectrum antibiotics followed by FMT from a donor enriched in Lachnospiraceae and Ruminococcaceae. Microbial composition (diversity, family-level relative abundances), function (fecal bile acid [BA] deconjugation, 7α-dehydroxylation, short-chain fatty acids [SCFAs]), and correlations between Lachnospiraceae, Ruminococcaceae, and clinical variables were analyzed at baseline, postantibiotics, and 15 days post-FMT. FMT was well tolerated. Postantibiotics, there was a reduced microbial diversity and autochthonous taxa relative abundance. This was associated with an altered fecal SCFA and BA profile. Correlation linkage changes from beneficial at baseline to negative after antibiotics. All of these parameters became statistically similar post-FMT to baseline levels. No changes were seen in the SOC group.In patients with advanced cirrhosis on lactulose and rifaximin, FMT restored antibiotic-associated disruption in microbial diversity and function. (Hepatology 2018; 00:000-000).

The prevalence of fatty liver diseases is increasing rapidly worldwide; after treatment of hepatitis C virus infection becomes more widespread, fatty liver diseases are likely to become the most prevalent liver disorders. Although fatty liver diseases are associated with alcohol, obesity, and the metabolic syndrome, their mechanisms of pathogenesis are not clear. The development and progression of fatty liver, alcoholic, and nonalcoholic liver disease (NAFLD) all appear to be influenced by the composition of the microbiota. The intestinal microbiota have been shown to affect precirrhotic and cirrhotic stages of liver diseases, which could lead to new strategies for their diagnosis, treatment, and study. We review differences and similarities in the cirrhotic and precirrhotic stages of NAFLD and alcoholic liver disease. Differences have been observed in these stages of alcohol-associated disease in patients who continue to drink compared with those who stop, with respect to the composition and function of the intestinal microbiota and intestinal integrity. NAFLD and the intestinal microbiota also differ between patients with and without diabetes. We also discuss the potential of microbial therapy for patients with NAFLD and ALD. The prevalence of fatty liver diseases is increasing rapidly worldwide; after treatment of hepatitis C virus infection becomes more widespread, fatty liver diseases are likely to become the most prevalent liver disorders. Although fatty liver diseases are associated with alcohol, obesity, and the metabolic syndrome, their mechanisms of pathogenesis are not clear. The development and progression of fatty liver, alcoholic, and nonalcoholic liver disease (NAFLD) all appear to be influenced by the composition of the microbiota. The intestinal microbiota have been shown to affect precirrhotic and cirrhotic stages of liver diseases, which could lead to new strategies for their diagnosis, treatment, and study. We review differences and similarities in the cirrhotic and precirrhotic stages of NAFLD and alcoholic liver disease. Differences have been observed in these stages of alcohol-associated disease in patients who continue to drink compared with those who stop, with respect to the composition and function of the intestinal microbiota and intestinal integrity. NAFLD and the intestinal microbiota also differ between patients with and without diabetes. We also discuss the potential of microbial therapy for patients with NAFLD and ALD. Patrick M. GillevetView Large Image Figure ViewerDownload Hi-res image Download (PPT)Jasmohan S. BajajView Large Image Figure ViewerDownload Hi-res image Download (PPT) The microbiota maintains a symbiotic relationship within the intestine and contributes to various functions such as digestion, vitamin synthesis, and resistance to colonization of the intestine by pathogens.1Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar The microbiota is hugely diverse. An estimated 10–100 trillion microorganisms are present in each gram of stool, with approximately 500–1000 highly prevalent species2Turnbaugh P.J. Gordon J.I. The core gut microbiome, energy balance and obesity.J. Physiol. 2009; 587: 4153-4158Crossref PubMed Scopus (713) Google Scholar; these strongly are linked to an individual’s gut metabolome. The microbiota provide its host with an extensive set of otherwise inaccessible metabolic capabilities and approximately 150-fold more genes than human cells.3Qin J. Yang F. Li A. et al.A human gut microbial gene catalogue established by metagenomic sequencing.Nature. 2010; 464: 59-65Crossref PubMed Scopus (7336) Google Scholar There are several methods to define and interpret the composition of the gut microbiota (Table 1). Ultimately, bacteria are presented as phylum, order, family, genus, or species, in relative abundance values. Before comparing different studies, the uniformity of the depth of coverage of each subject in the study (ie, number of reads per sample) should be taken into consideration.Table 1Strategies for Analyzing the MicrobiotaNameInputOutputPrimary FeaturesAnalysisQuantitative Insights into Microbial Ecology80Caporaso J.G. et al.QIIME allows analysis of high-throughput community sequencing data.Nat Methods. 2010; 7: 335-336Crossref PubMed Scopus (24708) Google Scholar16S RNA raw sequence data (FASTA sequences)i)Clustered OTU fileii)Taxonomy fileiii)BIOM fileiv)Newick formatted tree fileTool for performing microbial community analysisSequence alignments, clustering, α diversity analysis, network analysis, β diversity analysis, PCO, UNIFRAC, heat mapMothur81Schloss P.D. et al.Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities.Appl Environ Microbiol. 2009; 75: 7537-7541Crossref PubMed Scopus (14566) Google Scholar16S RNA raw sequence data (FASTA)i)Clustered OTU fileii)Taxonomy fileiii)BIOM fileiv)Newick formatted tree fileTool for performing microbial community analysisSequence alignments, clustering, α diversity analysis, network analysis, β diversity analysis, PCO, UNIFRAC, heat mapMetastats82White J.R. Nagarajan N. Pop M. Statistical methods for detecting differentially abundant features in clinical metagenomic samples.PLoS Comput Biol. 2009; 5: e1000352Crossref PubMed Scopus (1138) Google ScholarFeature abundance matrix (tabular format)P value, Q value, and varianceDetection of differentially abundant features (taxa, pathways, subsystems, and so forth) between clinical metagenomic data setsNonparametric t test with false-discovery ratesRibosomal Database Project83Cole J.R. et al.Ribosomal Database Project: data and tools for high throughput rRNA analysis.Nucleic Acids Res. 2014; 42: D633-D642Crossref PubMed Scopus (2676) Google Scholar16S RNA raw sequence data (FASTA)Abundance table, Bayesian probabilities (taxa information, probabilities)Assignment of relative abundance to sequencesBayesian probability of genera abundanceLEfSE 84Segata N. et al.Metagenomic biomarker discovery and explanation.Genome Biol. 2011; 12: R60Crossref PubMed Scopus (7654) Google ScholarFeature abundance matrix (tabular format)Linear discriminant scores, histogram, cladogramsDetection of differential featuresKruskal–Wallis testWilcoxon testLinear discriminant analysisCorrelation analysis85Available: https://mbac.gmu.edu/galaxy. Accessed December 1, 2015.Google ScholarFeature abundance matrix (tabular format)Correlation network (matrix format)Spearman correlationPICRUSt86Langille M.G.I. et al.Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences.Nat Biotechnol. 2013; 31: 814-821Crossref PubMed Scopus (5793) Google Scholar16S RNA raw sequence data (FASTA)KEGG pathway scores, COG scoresPrediction of KEGG pathwaysGene content predictionHUMAnN87Abubucker S. et al.Metabolic reconstruction for metagenomic data and its application to the human microbiome.PLoS Comput Biol. 2012; 8: e1002358Crossref PubMed Scopus (706) Google ScholarRaw sequence data (FASTA)KEGG pathway scoresPrediction of KEGG pathwaysGene content predictionMetaPhlAn88Segata N. et al.Metagenomic microbial community profiling using unique clade-specific marker genes.Nat Methods. 2012; 9: 811-814Crossref PubMed Scopus (1106) Google ScholarRaw sequence data (FASTA), CDC calls (the list of gene or hypothetical gene start and end nucleotide positions), taxonomic classification of the genomesProfiling microbial communitiesEstimation of the relative abundance of microbial cells, identify microbes populating a microbial communityMetAMOS89Treangen T.J. et al.MetAMOS: a metagenomic assembly and analysis pipeline for AMOS.Genome Biol. 2011; 12: 1-25Crossref Google ScholarRaw sequence datai)FASTA sequence of the contigs, scaffolds, or variant motifs belonging to specified taxonomic levelsii)Collection of all unclassified or potentially novel contigs contained in the assemblyiii)HTML report with detailed assembly statistics and summary chartsMetagenomic de novo assemblyClassification methods, de novo assemblyBIOM, biological observation matrix; CDC, Centers for Disease Control; COG, Clusters of Orthologs Groups; OTU, operational taxonomy units; PCO, principal component analysis; UNIFRAC, unique fraction metric. Open table in a new tab BIOM, biological observation matrix; CDC, Centers for Disease Control; COG, Clusters of Orthologs Groups; OTU, operational taxonomy units; PCO, principal component analysis; UNIFRAC, unique fraction metric. The gut microbiota elicits innate and adaptive immune mechanisms that cooperate to protect the host and maintain intestinal homeostasis. Activation of innate host defense depends on specific pattern-recognition receptors, including the family of Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein-like receptors. Of the 11 TLRs that have been identified in human beings, TLRs 2, 4, and 9 are involved in interactions between the gut microbiota host immune response, recognizing and becoming activated by gram-positive and gram-negative bacteria.4Neish A.S. Microbes in gastrointestinal health and disease.Gastroenterology. 2009; 136: 65-80Abstract Full Text Full Text PDF PubMed Scopus (970) Google Scholar The liver regulates systemic metabolism and the distribution of substances through the human gut, and also regulates numerous hormone and immune responses.5Henao-Mejia J. Elinav E. Thaiss C.A. et al.The intestinal microbiota in chronic liver disease.Adv Immunol. 2013; 117: 73-97Crossref PubMed Scopus (53) Google Scholar Communication between the liver and the intestine is facilitated by bile acids, which mediate absorption of dietary fats and vitamins and act as ligands for receptors that include nuclear-receptor farnesoid X receptor (FXR) and G-protein–coupled bile acid receptor 1 (or TGR5), which regulate the enterohepatic circulation.1Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar A decrease in total fecal bile acids directly affects overgrowth of intestinal bacteria. FXR-deficient mice are protected from genetic- and diet-induced obesity but not hepatic steatosis.6Prawitt J. et al.Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity.Diabetes. 2011; 60: 1861-1871Crossref PubMed Scopus (233) Google Scholar The intestinal microbiota therefore might contribute to liver disease by modifying intestinal bile acids and regulating FXR signaling. Studies of expression patterns of bacterial genes and profiles of bile acids might help to determine how modulation of FXR could contribute to liver disease. Human beings do not have enzymes that digest cellulose, xylans, resistant starch, or inulin. Intestinal microbes ferment these carbohydrates to produce short-chain fatty acids.7Salyers A.A. Gherardini F. O’Brien M. Utilization of xylan by two species of human colonic Bacteroides.Appl Environ Microbiol. 1981; 41: 1065-1068PubMed Google Scholar Cholic acid and chenodeoxycholic acid are the primary bile acids synthesized from cholesterol in the human liver. However, these primary acids can be converted into secondary bile acids by the intestinal microbiota.8Prabha V. Ohri M. Review: bacterial transformations of bile acids.World J Microbiol Biotechnol. 2005; 22: 191-196Crossref Scopus (21) Google Scholar Intestinal microorganisms therefore have an important role in metabolizing bile acid. For example, Clostridium species help catalyze the breakdown of the most abundant bile acid, cholic acid, to deoxycholic acid, via a 7α-dehydroxylation reaction.9Yadav H. Lee J.-H. Lloyd J. et al.Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion.J Biol Chem. 2013; 288: 25088-25097Crossref PubMed Scopus (443) Google Scholar Bile acids suppress overgrowth of bacteria in the gut and have a strong antimicrobial role in maintaining a healthy gut.10Kurdi P. Kawanishi K. Mizutani K. et al.Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria.J Bacteriol. 2006; 188: 1979-1986Crossref PubMed Scopus (230) Google Scholar Bile acids have been proposed to be enteroprotective, probably via their detergent properties and a sophisticated mechanism of activation of FXR, which protects the distal small intestine from bacterial proliferation and its detrimental effects. This mechanism involves activation of genes regulated by FXR in the ileum, including angiopoietin 1, nitric oxide synthase 2, and interleukin-18 (IL18).11Inagaki T. et al.Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.Proc Natl Acad Sci U S A. 2006; 103: 3920-3925Crossref PubMed Scopus (819) Google Scholar In 8- to 10-month-old mice with bile duct ligation, as well as FXR-knockout mice, expression levels of angiopoietin 1, Fgf15, Shp, Car12, and Ibabp correlated with FXR-mediated enteroprotection, indicating that the protective effects of FXR involve expression of these genes.11Inagaki T. et al.Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.Proc Natl Acad Sci U S A. 2006; 103: 3920-3925Crossref PubMed Scopus (819) Google Scholar These pathways are part of inflammatory signaling pathways that are activated in mice with bile duct ligation, showing that FXR is important for protecting the distal small intestine against bacterial overgrowth and the resulting disruption of the epithelial barrier. Microbes that can tolerate physiologic concentrations of bile acids survive in the gut; feeding cholic acid to rats significantly increased the ratio of Firmicutes to Bacteriodetes.12Islam K.B. Fukiya S. Hagio M. et al.Bile acid is a host factor that regulates the composition of the cecal microbiota in rats.Gastroenterology. 2011; 141: 1773-1781Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar Therefore, the deconjugation and 7α-dehydroxylation of bile acids in stool are important markers of gut health. Gut hormones promote intestinal epithelial proliferation and reduce gut permeability. Glucagon-like peptide-1 (GLP1) is an incretin secreted by intestinal L cells that maintains glucose-dependent insulin secretion and augmentation of β-cell mass; GLP1 inhibits glucagon release, gastric emptying, and food intake.13Lim G.E. Brubaker P.L. Glucagon-like peptide 1 secretion by the L-cell the view from within.Diabetes. 2006; 55: S70-S77Crossref PubMed Scopus (156) Google Scholar A healthy gut microbiota produces short-chain fatty acids that activate the G-protein–coupled receptors GPR41 and GPR43, promoting secretion of GLP1.9Yadav H. Lee J.-H. Lloyd J. et al.Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion.J Biol Chem. 2013; 288: 25088-25097Crossref PubMed Scopus (443) Google Scholar GLP2 is secreted along with GLP1 and helps maintain the gut barrier integrity, slows gastric emptying, improves nutrient absorption, and increases immune function.14Dubé P.E. Brubaker P.L. Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators.Am J Physiol Endocrinol Metab. 2007; 293: E460-E465Crossref PubMed Scopus (124) Google Scholar, 15Shi X. et al.Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons.Cell Metab. 2013; 18: 86-98Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Microbial dysbiosis is associated with type 2 diabetes as well as obesity.16Ley R.E. et al.Obesity alters gut microbial ecology.Proc Natl Acad Sci U S A. 2005; 102: 11070-11075Crossref PubMed Scopus (4363) Google Scholar, 17Ley R.E. Turnbaugh P.J. Klein S. Gordon J.I. Microbial ecology: human gut microbes associated with obesity.Nature. 2006; 444: 1022-1023Crossref PubMed Scopus (6188) Google Scholar Studies also have shown an increase in the relative abundance of Bacteriodetes and Betaproteobacteria and reductions in Firmicutes and Clostridia. These findings associate obesity and diabetes with reductions in butyrate-producing bacteria and increases in pathogens.18Zhang X. et al.Human gut microbiota changes reveal the progression of glucose intolerance.PLoS One. 2013; 8: e71108Crossref PubMed Scopus (539) Google Scholar, 19Qin J. et al.A metagenome-wide association study of gut microbiota in type 2 diabetes.Nature. 2012; 490: 55-60Crossref PubMed Scopus (4019) Google Scholar, 20Karlsson F.H. et al.Gut metagenome in European women with normal, impaired and diabetic glucose control.Nature. 2013; 498: 99-103Crossref PubMed Scopus (1861) Google Scholar The gut microbiota is partly responsible for body fat deposition in mice—colonized animals have a higher fat content than germ-free animals. Inoculation of germ-free mice with microbiota from colonized adult mice resulted in a 57% increase in total body fat.21Flint H.J. Obesity and the gut microbiota.J Clin Gastroenterol. 2011; 45: S128-S132Crossref PubMed Scopus (108) Google Scholar, 22Finelli C. Tarantino G. Is there any consensus as to what diet or lifestyle approach is the right one for NAFLD patients?.J Gastrointest Liver Dis. 2012; 21: 293-302PubMed Google Scholar, 23Wolf G. Gut microbiota: a factor in energy regulation.Nutr Rev. 2006; 64: 47-50Crossref PubMed Google Scholar The proportions of Firmicutes and Bacteriodetes vary between obese and lean mice—obese mice have a higher ratio of Firmicutes to Bacteriodetes, which also has been observed in human beings.24DiBaise J.K. et al.Gut microbiota and its possible relationship with obesity.Mayo Clin Proc. 2008; 83: 460-469Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 25Kallus S.J. Brandt L.J. The intestinal microbiota and obesity.J Clin Gastroenterol. 2012; 46: 16-24Crossref PubMed Scopus (158) Google Scholar A different balance of Bifidobacterium species and Staphylococcus aureus has been observed in children of normal weight compared with those who become overweight or obese, indicating that the microbiome might be used to predict obesity.26Kalliomäki M. Collado M.C. Salminen S. et al.Early differences in fecal microbiota composition in children may predict overweight.Am J Clin Nutr. 2008; 87: 534-538Crossref PubMed Scopus (794) Google Scholar A high-fat diet can cause reduce the proportions of Eubacterium rectale, Clostridium coccoides, and Bifidobacterium species.27Cani P.D. Delzenne N.M. The role of the gut microbiota in energy metabolism and metabolic disease.Curr Pharm Des. 2009; 15: 1546-1558Crossref PubMed Scopus (707) Google Scholar Ultimately, studies of changes in the gut microbiota must be performed in the context of their function and composition, as well as their effect on the host. An overview of human and animal studies in microbiota of ALD and NAFLD are shown in Table 2, Table 3, respectively. Nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver diseases, is characterized by fat accumulation, mainly as triglycerides, in the hepatocytes. The disease is associated with factors such as obesity, metabolic syndrome, insulin resistance, and dyslipidemia.28Vanni E. et al.From the metabolic syndrome to NAFLD or vice versa?.Dig Liver Dis. 2010; 42: 320-330Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 29Bellentani S. Scaglioni F. Marino M. et al.Epidemiology of non-alcoholic fatty liver disease.Dig Dis. 2010; 28: 155-161Crossref PubMed Scopus (699) Google Scholar An energy-rich diet of fat and carbohydrates leads to dysregulation of adipocytes to adapt in terms of proliferation and differentiation.30Gregor M.F. Hotamisligil G.S. Thematic review series: adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease.J Lipid Res. 2007; 48: 1905-1914Crossref PubMed Scopus (458) Google Scholar NAFLD encompasses a spectrum of hepatic pathologies, and can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.Table 2Clinical Studies of ALD and NASHStudyComparisonSequencing technique, sample sourcePhylumClassOrderFamilyGenusHealthy (n = 26)NAFLD (n = 13)Healthy children vs NAFLD90Michail S. et al.Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease.FEMS Microbiol Ecol. 2015; 91: 1-9Crossref PubMed Scopus (15) Google ScholarIon One Touch System (Life Technologies Corporation, Carlsbad, CA)stool samplesActinobacteriaBacteroidetesFirmicutesFusobacteriaLentisphaeraeProteobacteriaVerrucomicrobiaActinobacteridae ↓Coriobacteridae ↓Bacteroidia ↓Bacilli ↓, Clostridia ↑, Erysipelotrichi ↑Fusobacteria ↓LentisphaeriaNAAlphaproteobacteria ↑, Betaproteobacteria ↑,Deltaproteobacteria↑, Epsilonproteobacteria↓,Gammaproteobacteria↓,Verrucomicrobiae↑Prevotella ↓Healthy (n = 30)NAFLD (n = 30)Healthy vs NAFLD91Raman M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11 (e1–3): 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar16s rRNA gene pyrosequencingStool sampleFirmicutesBacilliClostridiaClostridiaLactobacillalesClostridialesClostridialesLactobacillaceae ↓Lachnospiraceae↓Ruminococaceae ↑,OscillospiraceaeLactobacillus↓,Robinsoniella↓,Roseburia↓, Dorea↓Oscillibacter↑No NASH (n = 22)NASH (n = 35)No NASH vs NASH78Boursier J. et al.The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.Hepatology. 2016; 63: 764-765Crossref PubMed Scopus (740) Google Scholar16s rRNA gene MiSeqstool samplesActinobacteria ↑Bacteriodetes ↑Firmicutes ↓Proteobacteria ↑Bifidobacteriaceae ↓Bacteroidaceae ↓Porphyromonadaceae ↑Prevotellaceae ↑Rikenellaceae ↑Paraprevotellaceae ↓Clostridiales ↑Lachnospiraceae ↓,Ruminococcaceae ↑, Veillonellaceae ↓, Erysipelotrichaceae ↓Alcaligenaceae ↑, Enterobacteriaceae ↑Bifidobacterium ↓Bacteriodetes ↓Parabacteriodes ↑, Prevotella ↑Blautia ↓Ruminococcus ↓MegasphaeraNASutterella ↑Healthy (n = 25)Cirrhotic patients (alcoholic = 43, not alcoholic = 170)Control patients vs alcoholic cirrhotic patients 58Bajaj J.S. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar16s rRNA gene pyrosequencingStool samplesFirmicutesProteobacteriaClostridiaGammabacteriaClostridialesEnterobacterialesOceanospirillalesFamily XIV Incertae sedis ↑,Lachnospiraceae ↑,Ruminococcaceae ↑Enterobacteriaceae ↓,Holomonadaceae ↓Healthy (n = 18)alcoholics without cirrhosis (n = 29)Alcoholics with cirrhosis (n = 19)Healthy vs alcoholic cirrhotic patients48Mutlu E.A. et al.Colonic microbiome is altered in alcoholism.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G966-G978Crossref PubMed Scopus (511) Google Scholar16s rRNA gene pyrosequencingSigmoid, mucosal biopsyBacteriodetesBacteroidiaBacteroidalesBaceteroidaceae ↑Nonalcoholic patients (n = 5)Alcoholic patients with cirrhosis, patients with active alcohol abuse (n = 5)Nonalcoholic cirrhotic patients vs alcoholic cirrhotic patients55Kakiyama G. et al.Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-G937Crossref PubMed Scopus (128) Google Scholar16s rRNA gene pyrosequencingstool samplesBacteroidetesFirmicutesBacteroidiaNegativicutesBacteroidalesSelenomonadalesBacteroidaceae ↑Veilonellaceae ↓NOTE. Comparison of condition A vs condition B. ↑ Indicates higher in condition A relative to condition B, ↓ indicates decrease in condition A relative to condition B.FGF, fibroblast growth factor; IBABP, intestinal bile acid-binding protein; NA, no significant difference; rRNA, ribosomal RNA; SHP, small heterodimer partner. Open table in a new tab Table 3Studies of the Microbiota in Animal Models of NASH and ALDStudyComparisonSequencing technology, sample sourcePhylumClassOrderFamilyGenusMaintenance food–fed mice,high-calorie diet-fed miceHealthy vs high-fat diet92Matsushita N. et al.Effect of lipopolysaccharide on the progression of non-alcoholic fatty liver disease in high caloric diet-fed mice.Scand J Immunol. 2016; 83: 109-118Crossref PubMed Scopus (23) Google Scholar16s rRNA gene pyrosequencingStool samplesBacteroidaceae ↓, Peptostreptococcaceae ↓, Erysipelotrichaceae ↓, Lachnospiraceae ↑Healthy mice, carbon tetrachloride-induced liver injury miceHealthy vs liver injury mice93Fouts D.E. Torralba M. Nelson K.E. et al.Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease.J Hepatol. 2012; 56: 1283-1292Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar16s rRNA gene pyrosequencingcecal contents, mucosaFirmicutes ↓Actinobacteria ↓Lactobacillus ↓, Dorea ↓, Lachnospiraceae Incertae Sedis↓Coriobacteriaceae ↓Mice fed choline-deficent or methionine-choline–deficient diets (n = 12)Normal choline diet mice vs methionine-choline–deficient mice, induced NASH94Okubo H. et al.Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model.Am J Physiol Gastrointest Liver Physiol. 2015; 308: G151-G158Crossref PubMed Scopus (19) Google ScholarQuantitative reverse-transcription polymerase chain reactionStool samplesClostridium coccoides ↑, C leptum subgroup ↓, Bacteroides fragilies ↓, Bifidobacterium ↑, Prevotella ↑, L gasseri subgroup ↑, L reuteri subgroup ↑, L ruminis subgroup ↑, Enterobacteriaceae ↓, Enterococcus ↓Healthy mice (n = 8),mice fed alcohol (n = 8)Healthy vs alcohol53Bull-Otterson L. et al.Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment.PLoS One. 2013; 8: e53028Crossref PubMed Scopus (360) Google Scholar16s rRNA gene454 FLX-titaniumstool samplesBacteriodetesFirmicutesActinobacteriaProteobacteriaBacteroides↑, Parabacteroides↑, Tannerella↑, Hallella↑Lachnospiraceae other↑, Ruminococcaceae Incertae sedis↑, Ruminococcaceae other↑, Aerococcus ↓, Listeria ↓, Clostridiales other ↓, Allobaculum ↓, Lactobacillus ↓Corynebacterium↓Alcaligenes ↓Healthy mice (n = 3), mice fed alcohol (n = 3)Healthy vs alcohol51Yan A.W. et al.Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology. 2011; 53: 96-105Crossref PubMed Scopus (538) Google Scholar16s rRNA gene pyrosequencing, cecum samplesBacteroidetes ↓Firmicutes ↑VerrucomicrobiotaBacteroidia ↓BacilliErysipelotrichiaVerrucomicrobiaeBacteroidalesLactobacillales ↑ErysipelotrichalesVerrucomicrobialesBacteroidaceaeEnterococcaceaeLactobacillaceae ↑LeuconostocaceaeStreptococcaceaeErysipelotrichaceae ↓VerrucomicrobiaceaeBacteroides species ↓Enterococcus species ↓Lactobacillus species ↑Pediococcus species ↑Leuconostoc species ↑Lactococcus species ↑Akkesrmansia muciniphila ↓Healthy mice, mice fed alcohol (n = 2–7)Healthy vs alcohol95Chen P. Stärkel P. Turner J.R. et al.Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice.Hepatology. 2015; 61: 883-894Crossref PubMed Scopus (199) Google Scholar16s rRNA gene pyrosequencing, cecum samplesBacteroidetes ↓Firmicutes ↑BacilliLactobacillaLactobacillaceaeL rhamnosus ↑Lactobacillus species ↑NASH, mice fed a high-fat dietHealthy vs NASH36Henao-Mejia J. et al.Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature. 2012; 482: 179-185Crossref PubMed Scopus (1697) Google Scholar16s rRNA pyrosequencingPorphyromonadaceae ↓NOTE. Comparison of condition A vs condition B. ↑ Indicates higher in condition A relative to condition B, ↓ indicates decrease in condition A relative to condition B.NA, no significant; rRNA, ribosomal RNA. Open table in a new tab NOTE. Comparison of condition A vs condition B. ↑ Indicates higher in condition A relative to condition B, ↓ indicates decrease in condition A relative to condition B. FGF, fibroblast growth factor; IBABP, intestinal bile acid-binding protein; NA, no significant difference; rRNA, ribosomal RNA; SHP, small heterodimer partner. NOTE. Comparison of condition A vs condition B. ↑ Indicates higher in condition A relative to condition B, ↓ indicates decrease in condition A relative to condition B. NA, no significant; rRNA, ribosomal RNA. Patients with NAFLD have lower proportions of Bacteroidetes and higher proportions of Prevotella and Porphyromonas species compared with healthy controls.31Zhu L. et al.Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH.Hepatology. 2013; 57: 601-609Crossref PubMed Scopus (1023) Google Scholar Predisposition to NAFLD is associated with increased expression of TLR4, TLR9, or the tumor necrosis factor (TNF) receptor. The gut microbiota might control the severity of NAFLD by increasing production of ethanol, activating TLR signaling and TNF production in the liver, or altering the bile acid profile. In a study of C129S6 mice, a high-fat diet shifted the metabolome of the intestinal microbiota toward a choline-degradation profile, resulting in low circulation levels of plasma phosphatidylcholine and high urinary excretion of methylamines.

Cirrhosis is associated with gut microbial dysbiosis, high readmissions and proton pump inhibitor (PPI) overuse, which could be inter-linked. Our aim was to determine the effect of PPI use, initiation and withdrawl on gut microbiota and readmissions in cirrhosis.Four cohorts were enrolled. Readmissions study: Cirrhotic inpatients were followed throughout the hospitalization and 30/90-days post-discharge. PPI initiation, withdrawal/continuation patterns were analyzed between those with/without readmissions. Cross-sectional microbiota study: Cirrhotic outpatients and controls underwent stool microbiota analysis. Beneficial autochthonous and oral-origin taxa analysis vis-à-vis PPI use was performed. Longitudinal studies: Two cohorts of decompensated cirrhotic outpatients were enrolled. Patients on chronic unindicated PPI use were withdrawn for 14 days. Patients not on PPI were started on omeprazole for 14 days. Microbial analysis for oral-origin taxa was performed pre/post-intervention.Readmissions study: 343 inpatients (151 on admission PPI) were enrolled. 21 were withdrawn and 45 were initiated on PPI resulting in a PPI use increase of 21%. PPIs were associated with higher 30 (p = 0.002) and 90-day readmissions (p = 0.008) independent of comorbidities, medications, MELD and age. Cross-sectional microbiota: 137 cirrhotics (59 on PPI) and 45 controls (17 on PPI) were included. PPI users regardless of cirrhosis had higher oral-origin microbiota while cirrhotics on PPI had lower autochthonous taxa compared to the rest. Longitudinal studies: Fifteen decompensated cirrhotics tolerated omeprazole initiation with an increase in oral-origin microbial taxa compared to baseline. PPIs were withdrawn from an additional 15 outpatients, which resulted in a significant reduction of oral-origin taxa compared to baseline.PPIs modulate readmission risk and microbiota composition in cirrhosis, which responds to withdrawal. The systematic withdrawal and judicious use of PPIs is needed from a clinical and microbiological perspective in decompensated cirrhosis.

Summary Background There is increasing evidence that proton pump inhibitors ( PPI s) increase the rate of infections in patients with decompensated cirrhosis. Aims To estimate the extent to which proton pump inhibitors ( PPI s) increase the rate of infections among patients with decompensated cirrhosis. Methods We conducted a retrospective propensity‐matched new user design using US Veterans Health Administration data. Only decompensated cirrhotic patients from 2001 to 2009 were included. New PPI users after decompensation ( n = 1268) were 1:1 matched to those who did not initiate gastric acid suppression. Serious infections, defined as infections associated with a hospitalisation, were the outcomes. These were separated into acid suppression‐related ( SBP , bacteremia, C lostridium difficile and pneumonia) and non‐acid suppression‐related. Time‐varying Cox models were used to estimate adjusted hazard ratios ( HR ) and 95% CI s of serious infections. Parallel analyses were conducted with H2 receptor antagonists ( H 2 RA ). Results More than half of persons with decompensated cirrhosis were new users of gastric acid suppressants, with most using PPI s (45.6%) compared with H 2 RA s (5.9%). In the PPI propensity‐matched analysis, 25.3% developed serious infections and 25.9% developed serious infections in the H 2 RA analysis. PPI users developed serious infections faster than nongastric acid suppression users (adjusted HR : 1.66; 95% CI : 1.31–2.12). For acid suppression‐related serious infections, PPI users developed the outcome at a rate 1.75 times faster than non‐users (95% CI : 1.32–2.34). The H 2 RA findings were not statistically significant ( HR serious infections: 1.59; 95% CI : 0.80–3.18; HR acid suppression‐related infections: 0.92; 95% CI : 0.31–2.73). Conclusion Among patients with decompensated cirrhosis, proton pump inhibitors but not H2 receptor antagonists increase the rate of serious infections.

The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.

OBJECTIVES: Bacterial infections are associated with negative outcomes in cirrhosis but fungal infections are being increasingly recognized. The objective of this study is to define risk factors for fungal infection development and impact on 30-day survival. METHODS: In a large, multi-center cirrhotic inpatient cohort, demographics, cirrhosis details, intensive care unit (ICU), organ failures/acute-on-chronic liver failure (ACLF), and 30-day survival were compared between patients without infections and with bacterial infections alone, with those with fungal infections. Variables associated with fungal infection development were determined using multi-variable regression. Ordinal variables (0=no infection, 1=community-acquired bacterial infection, 2=nosocomial bacterial, and 3=fungal infection) were input into a 30-day survival model. RESULTS: A total of 2,743 patients (1,691 no infection, 918 bacterial, and 134 fungal infections) were included. Patients with fungal infection, all of which were nosocomial, were more likely to be admitted with bacterial infections, on spontaneous bacterial peritonitis prophylaxis, and have diabetes and advanced cirrhosis. Bacterial infection types did not predict risk for fungal infections. Multi-variable analysis showed male gender to be protective, whereas diabetes, longer stay, ICU admission, acute kidney injury (AKI), and admission bacterial infection were associated with fungal infection development (area under the curve (AUC)=0.82). Fungal infections were associated with significantly higher ACLF, inpatient stay, ICU admission, and worse 30-day survival. The case fatality rate was 30% with most fungal infections but >50% for fungemia and fungal peritonitis. On a multi-variable analysis, age, AKI, model for end-stage liver disease, ICU admission, and ordinal infection variables impaired survival (P<0.0001, AUC=0.83). CONCLUSIONS: Fungal infections are associated with a poor 30-day survival in hospitalized cirrhotic patients compared with uninfected patients, and those with bacterial infections. Patients with diabetes, AKI, and those with an admission bacterial infection form a high-risk subgroup.

The diagnosis of cirrhosis, especially in the advanced/decompensated stages, is made using simple and inexpensive clinico-radiologic-pathological techniques1. Qin et al.2, whose paper has replicated prior studies3–5, reported a relatively novel profile to diagnose cirrhosis using complex stool metagenomics despite having a majority (65% discovery and 76% validation cohorts) decompensated cirrhotic population. We have found that the decompensated cirrhosis cohort, which does not require these complicated diagnostic strategies, was responsible for a significant proportion of these microbiota changes on further analysis of their metagenomics data and using a new cohort of 360 subjects. Therefore, given several confounders and the ease of decompensated cirrhosis diagnosis using current techniques, a careful re-interpretation of newer microbiota-based diagnostic strategies that do not a priori differentiate between early (compensated) and decompensated cirrhosis and treat all people with cirrhosis as one uniform population should be performed. There is a Reply to this Brief Communication Arising by Qin, N. et al. Nature 5xx, http://dx.doi.org/10.1038/nature14852 (2015). A major confounder in people with cirrhosis are standard of care therapies such as lactulose, rifaximin, antibiotics and acid-suppressants that can affect the gut milieu1,6. These alone could explain a large portion of the metagenomics changes and have not been accounted for5,7–9. These medications, especially proton pump inhibitors, could also be a major reason why oral origin bacteria are found in the intestine, as has been shown in prospective cirrhotic and non-cirrhotic studies10,11. We hypothesized that there was a significant difference in compensated versus decompensated cirrhotic microbiota in Qin et al.2, which needs to be accounted for in the interpretation. Using 66 enriched/depleted metagenomic sequences (MGS) provided by S. D. Ehrlich, we performed linear discriminant analysis (LDA) effect size (LEfSe)12 after classifying them into healthy, compensated and decompensated subjects. LEFSe uses a factorial Kruskal–Wallis and LDA test to detect features with significant differential abundance. We found that even in the selected data set the authors provided, 17 of 66 MGS were different between compensated and decompensated groups (10 MGS overexpressed and 7 MGS underexpressed, Fig. 1a). These included several oral origin species (Streptococcus oralis and several Veillonella spp.), which were the primary study results. We then enrolled 360 age-matched subjects (45 healthy individuals (age 54 ± 3 years, no chronic diseases), 171 compensated (age 54 ± 4 years, median Child–Pugh score 6) and 141 decompensated cirrhotic patients (age 55 ± 2 years, median Child–Pugh score 9)) for stool multi-tagged pyrosequencing (MTPS)13. Using Kruskal–Wallis analysis of relative microbial family abundance >1%, we found that compensated and decompensated patients were significantly different (Fig. 1b). Proteobacteria levels, specifically Enterobacteriaceae, were significantly higher in decompensated cirrhotic patients. This pattern is also seen in other recent MTPS studies4,14. Although MGS and MTPS are not completely comparable, it is interesting that both resulted in similar conclusions. Therefore, there are significant microbiota differences between compensated and decompensated patients that need to be separated in cirrhosis microbial studies. Figure 1 Microbiota distribution between compensated and decompensated cirrhotic subjects In addition, in Qin et al.2 the calculation of the model for end-stage liver disease (MELD) score in Supplementary Table 1 is inaccurate, casting doubt on figure 2. The authors compared diabetes patients with cirrhotic patients to inform their cirrhosis-associated profile. However, diabetes is prevalent and is associated with a poor prognosis in cirrhosis15. Therefore these results are not generalizable to patients with cirrhosis and diabetes. The present need is not for complicated profiles that are unlikely to supplant currently available simple diagnostic strategies, but rather for improving prognostication. This is because gut microbiota are associated with several cirrhosis-related pre-terminal events such as hepatic encephalopathy and infections1. A prior study has shown that altered stool microbiota can predict poor outcomes, but further work is required8. Therefore, the careful separation of the two groups within cirrhosis, which have different diagnostic criteria and prognoses, and the control of confounders owing to drugs mentioned above are important for the correct interpretation of these results and to avoid epiphenomena.

Inpatients with cirrhosis are prone to develop acute-on-chronic liver failure (ACLF). ACLF is associated with dysbiosis of the intestinal microbiota, which might serve as a prognostic factor. We investigated whether features of the intestinal microbiota associate organ failure, transfer to intensive care, and mortality within 30 days in patients admitted to the hospital with cirrhosis.Stool samples were collected from 181 patients with cirrhosis (age 56 years; mean model for end-stage liver disease score, 21; 43% with infections) at time of admission, from multiple hospitals in North America. Patients were followed for 30 days for development of ACLF, extra-hepatic organ failures, and death or hospice care. Microbiota were analyzed by 16s rRNA sequencing for alpha diversity (within groups), beta diversity (between groups), cirrhosis dysbiosis ratio (CDR), and taxa that differed between groups with vs without negative outcomes (individual organ failures, transfer to intensive care, ACLF, death, or hospice). Regression analyses were performed using microbial and clinical variables for each outcome.ACLF developed in 8% of study subjects; 16% were transferred to intensive care and 21% died. Beta diversity of the intestinal microbiome was significantly different, whereas alpha diversity was similar, between subjects with vs without outcomes. The CDR was lower in subjects who developed ACLF, especially among those with renal failure. Taxa belonging to phylum Proteobacteria (Enterobacteriaceae, Campylobacteriaceae, and Pasteurellaceae) and Firmicutes (Enterococcaceae and Streptococcaceae) were associated with development of negative outcomes, whereas other Firmicutes members (Lachnospiraceae and Clostridiales) reduced risk of negative outcomes. Changes in the microbiota associated with extra-hepatic organ failure, transfer to intensive care, ACLF, and death, independently on logistic regression analyses.In hospitalized patients with cirrhosis, dysbiosis of the intestinal microbiota on admission (particularly changes in Protebacteria constituents) associates with increased risk of extra-hepatic organ failure, ACLF, and death, independent of clinical factors. Strategies to reduce gut dysbiosis might improve outcomes of patients with cirrhosis.

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

The mechanisms behind the development of hepatic encephalopathy (HE) are unclear, although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. The aim of this work was to define the individual contribution of hyperammonemia and systemic inflammation on neuroinflammation in cirrhosis using germ‐free (GF) and conventional mice. GF and conventional C57BL/6 mice were made cirrhotic using CCl 4 gavage. These were compared to their noncirrhotic counterparts. Intestinal microbiota, systemic and neuroinflammation (including microglial and glial activation), serum ammonia, intestinal glutaminase activity, and cecal glutamine content were compared between groups. GF cirrhotic mice developed similar cirrhotic changes to conventional mice after 4 extra weeks (16 vs. 12 weeks) of CCl 4 gavage. GF cirrhotic mice exhibited higher ammonia, compared to GF controls, but this was not associated with systemic or neuroinflammation. Ammonia was generated through increased small intestinal glutaminase activity with concomitantly reduced intestinal glutamine levels. However, conventional cirrhotic mice had intestinal dysbiosis as well as systemic inflammation, associated with increased serum ammonia, compared to conventional controls. This was associated with neuroinflammation and glial/microglial activation. Correlation network analysis in conventional mice showed significant linkages between systemic/neuroinflammation, intestinal microbiota, and ammonia. Specifically beneficial, autochthonous taxa were negatively linked with brain and systemic inflammation, ammonia, and with Staphylococcaceae, Lactobacillaceae , and Streptococcaceae. Enterobacteriaceae were positively linked with serum inflammatory cytokines. Conclusion : Gut microbiota changes drive development of neuroinflammatory and systemic inflammatory responses in cirrhotic animals. (H epatology 2016;64:1232‐1248)

Background Cirrhosis and alcohol can independently affect the gut–liver axis with systemic inflammation. However, their concurrent impact in humans is unclear. Methods Our aim was to determine the effect of continued alcohol misuse on the gut‐liver axis in cirrhotic patients. Age‐ and MELD ‐balanced cirrhotic patients who were currently drinking (Alc) or abstinent ( NA lc) and healthy controls underwent serum and stool collection. A subset underwent upper endoscopy and colonoscopy for biopsies and duodenal fluid collection. The groups were compared regarding (i) inflammation/intestinal barrier : systemic tumor necrosis factor levels, intestinal inflammatory cytokine (duodenum, ileum, sigmoid), and ileal antimicrobial peptide expression; (ii) microbiota composition : 16Sr RNA sequencing of duodenal, ileal, and colonic mucosal and fecal microbiota; and (iii) microbial functionality : duodenal fluid and fecal bile acid ( BA ) profile (conjugation and dehydroxylation status), intestinal BA transporter ( ASBT , FXR , FGF ‐19, SHP ) expression, and stool metabolomics using gas chromatography/mass spectrometry. Results Alc patients demonstrated a significant duodenal, ileal, and colonic mucosal and fecal dysbiosis, compared to NA lc and controls with lower autochthonous bacterial taxa. BA profile skewed toward a potentially toxic profile (higher secondary and glycine‐conjugated BA s) in duodenal fluid and stool in Alc patients. Duodenal fluid demonstrated conjugated secondary BA s only in the Alc group. There was a greater expression of all ileal BA transporters in Alc patients. This group also showed higher endotoxemia, systemic and ileal inflammatory expression, and lower amino acid and bioenergetic‐associated metabolites, without change in antimicrobial peptide expression. Conclusions Despite cirrhosis, continued alcohol misuse predisposes patients to widespread dysbiosis with alterations in microbial functionality such as a toxic BA profile, which can lead to intestinal and systemic inflammation.

The relative ranking of cirrhosis-related deaths differs between high-/middle-income countries. Gut microbiome is affected in cirrhosis and is related to diet. Our aim was to determine the effect of differing dietary habits on gut microbiota and clinical outcomes. Outpatient compensated/decompensated patients with cirrhosis and controls from Turkey and the United States underwent dietary and stool microbiota analysis. Patients with cirrhosis were followed till 90-day hospitalizations. Shannon diversity and multivariable determinants (Cox and binary logistic) of microbial diversity and hospitalizations were studied within/between groups. Two hundred ninety-six subjects (157 U.S.: 48 controls, 59 compensated, 50 decompensated; 139 Turkey: 46 controls, 50 compensated, 43 decompensated) were included. Patients with cirrhosis between cohorts had similar Model for End-Stage Liver Disease (MELD) scores. American patients with cirrhosis had more men, greater rifaximin/lactulose use, and higher hepatitis C/alcohol etiologies. Coffee intake was higher in Americans whereas tea, fermented milk, and chocolate intake were higher in Turkey. The entire Turkish cohort had a significantly higher microbial diversity than Americans, which did not change between their controls and patients with cirrhosis. In contrast, microbial diversity changed in the U.S.-based cohort and was the lowest in decompensated patients. Coffee, tea, vegetable, chocolate, and fermented milk intake predicted a higher diversity whereas MELD score, lactulose use, and carbonated beverage use predicted a lower microbial diversity. The Turkish cohort had a lower risk of 90-day hospitalizations. On Cox and binary logistic regression, microbial diversity was protective against 90-day hospitalizations, along with coffee/tea, vegetable, and cereal intake.In this study of patients with cirrhosis and healthy controls from the United States and Turkey, a diet rich in fermented milk, vegetables, cereals, coffee, and tea is associated with a higher microbial diversity. Microbial diversity was associated with an independently lower risk of 90-day hospitalizations. (Hepatology 2018;68:234-247).

Acute on chronic liver failure (ACLF) is the culmination of chronic liver disease and extrahepatic organ failures, which is associated with a high short‐term mortality and immense health care expenditure. There are varying definitions for organ failures and ACLF in Europe, North America, and Asia. These differing definitions need to be reconciled to enhance progress in the field. The pathogenesis of ACLF is multifactorial and related to interactions between the immunoinflammatory system, microbiota, and the various precipitating factors. Individual organ failures related to the kidney, brain, lungs, and circulation have cumulative adverse effects on mortality and are often complicated or precipitated by infections. Strategies to prevent and rapidly treat these organ failures are paramount in improving survival. With the aging population and paucity of organs for liver transplant, the prognosis of ACLF patients is poor, highlighting the need for novel therapeutic strategies. The role of liver transplant in ACLF is evolving and needs further investigation across large consortia. A role for early palliative care and management of frailty as approaches to alleviate disease burden and improve patient‐reported outcomes is being increasingly recognized. Conclusion : ACLF is a clinically relevant syndrome that is epidemic worldwide and requires a dedicated multinational approach focused on prognostication and management; investigations are underway worldwide to prepare ACLF for prime time. (H epatology 2018; 00:000‐000)

The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid, and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in the intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic, and disease progression in cirrhosis, metabolic syndrome, and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal, and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly &lt;i&gt;Clostridium&lt;/i&gt; cluster XIVa, and increasing production of deoxycholic acid. Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis, and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide insight into the pathogenesis of inflammation in humans.

Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients with cirrhosis, but the effect of LT on microbial composition, especially with poor post-LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score [PHES]), health-related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre-/post-LT data were compared with age-matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End-Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre-LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907-914 2017 AASLD.

The gut microbiome is the natural intestinal inhabitant that has been recognized recently as a major player in the maintenance of human health and the pathophysiology of many diseases. Those commensals produce metabolites that have various effects on host biological functions. Therefore, alterations in the normal composition or diversity of microbiome have been implicated in various diseases, including liver cirrhosis and nonalcoholic fatty liver disease. Moreover, accumulating evidence suggests that progression of dysbiosis can be associated with worsening of liver disease. Here, we review the possible roles for gut microbiota in the development, progression, and complication of liver disease.

Gut microbiota changes are important in determining the occurrence and progression of chronic liver disease related to alcohol, nonalcoholic fatty liver disease, and cirrhosis. Specifically, the systemic inflammation, endotoxemia, and the vasodilation that leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy could be related to the gut milieu. Given the poor prognosis of these events, their prevention and early management are essential. Microbiota may be an essential component of the gut milieu that can impact these clinical events, and the study of their composition and function in a culture-independent manner could help understand the prognosis. Recent human and animal studies have shown that the relative abundance and the functional changes of microbiota in the stool, colonic mucosa, and saliva have varying consequences on the presence and prognosis of chronic liver disease and cirrhosis. The impact of therapies on the microbiota is slowly being understood and will likely lead to a more targeted approach to gut microbiota modification in chronic liver disease and cirrhosis. Gut microbiota changes are important in determining the occurrence and progression of chronic liver disease related to alcohol, nonalcoholic fatty liver disease, and cirrhosis. Specifically, the systemic inflammation, endotoxemia, and the vasodilation that leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy could be related to the gut milieu. Given the poor prognosis of these events, their prevention and early management are essential. Microbiota may be an essential component of the gut milieu that can impact these clinical events, and the study of their composition and function in a culture-independent manner could help understand the prognosis. Recent human and animal studies have shown that the relative abundance and the functional changes of microbiota in the stool, colonic mucosa, and saliva have varying consequences on the presence and prognosis of chronic liver disease and cirrhosis. The impact of therapies on the microbiota is slowly being understood and will likely lead to a more targeted approach to gut microbiota modification in chronic liver disease and cirrhosis.

OBJECTIVES: Rifaximin has clinical benefits in minimal hepatic encephalopathy (MHE) but the mechanism of action is unclear. The antibiotic-dependent and -independent effects of rifaximin need to be elucidated in the setting of MHE-associated microbiota. To assess the action of rifaximin on intestinal barrier, inflammatory milieu and ammonia generation independent of microbiota using rifaximin. METHODS: Four germ-free (GF) mice groups were used (1) GF, (2) GF+rifaximin, (3) Humanized with stools from an MHE patient, and (4) Humanized+rifaximin. Mice were followed for 30 days while rifaximin was administered in chow at 100 mg/kg from days 16–30. We tested for ammonia generation (small-intestinal glutaminase, serum ammonia, and cecal glutamine/amino-acid moieties), systemic inflammation (serum IL-1β, IL-6), intestinal barrier (FITC-dextran, large-/small-intestinal expression of IL-1β, IL-6, MCP-1, e-cadherin and zonulin) along with microbiota composition (colonic and fecal multi-tagged sequencing) and function (endotoxemia, fecal bile acid deconjugation and de-hydroxylation). RESULTS: All mice survived until day 30. In the GF setting, rifaximin decreased intestinal ammonia generation (lower serum ammonia, increased small-intestinal glutaminase, and cecal glutamine content) without changing inflammation or intestinal barrier function. Humanized microbiota increased systemic/intestinal inflammation and endotoxemia without hyperammonemia. Rifaximin therapy significantly ameliorated these inflammatory cytokines. Rifaximin also favorably impacted microbiota function (reduced endotoxin and decreased deconjugation and formation of potentially toxic secondary bile acids), but not microbial composition in humanized mice. CONCLUSIONS: Rifaximin beneficially alters intestinal ammonia generation by regulating intestinal glutaminase expression independent of gut microbiota. MHE-associated fecal colonization results in intestinal and systemic inflammation in GF mice, which is also ameliorated with rifaximin.

Cirrhosis and hepatic encephalopathy (HE) is associated with an altered gut-liver-brain axis. Fecal microbial transplant (FMT) after antibiotics improves outcomes in HE, but the impact on brain function is unclear. The aim of this study is to determine the effect of colonization using human donors in germ-free (GF) mice on the gut-liver-brain axis. GF and conventional mice were made cirrhotic using carbon tetrachloride and compared with controls in GF and conventional state. Additional GF mice were colonized with stool from controls (Ctrl-Hum) and patients with cirrhosis (Cirr-Hum). Stools from patients with HE cirrhosis after antibiotics were pooled (pre-FMT). Stools from the same patients 15 days after FMT from a healthy donor were also pooled (post-FMT). Sterile supernatants were created from pre-FMT and post-FMT samples. GF mice were colonized using stools/sterile supernatants. For all mice, frontal cortex, liver, and small/large intestines were collected. Cortical inflammation, synaptic plasticity and gamma-aminobutyric acid (GABA) signaling, and liver inflammation and intestinal 16s ribosomal RNA microbiota sequencing were performed. Conventional cirrhotic mice had higher degrees of neuroinflammation, microglial/glial activation, GABA signaling, and intestinal dysbiosis compared with other groups. Cirr-Hum mice had greater neuroinflammation, microglial/glial activation, and GABA signaling and lower synaptic plasticity compared with Ctrl-Hum mice. This was associated with greater dysbiosis but no change in liver histology. Pre-FMT material colonization was associated with neuroinflammation and microglial activation and dysbiosis, which was reduced significantly with post-FMT samples. Sterile pre-FMT and post-FMT supernatants did not affect brain parameters. Liver inflammation was unaffected. Conclusion: Fecal microbial colonization from patients with cirrhosis results in higher degrees of neuroinflammation and activation of GABAergic and neuronal activation in mice regardless of cirrhosis compared with those from healthy humans. Reduction in neuroinflammation by using samples from post-FMT patients to colonize GF mice shows a direct effect of fecal microbiota independent of active liver inflammation or injury.

Chronic liver disease, cirrhosis, and its complications are epidemic worldwide. Most complications are mediated through a dysfunctional gut-liver axis. New techniques have made culture-independent analysis of the gut microbiome widespread. With insight into an unfavorable microbiome (dysbiosis) and how it affects liver disease, investigators have discovered new targets to potentially improve outcomes. Dysbiosis is associated with endotoxemia and propagates liver injury due to nonalcoholic steatohepatitis and alcohol. The composition and functionality of the microbiome changes with the development of cirrhosis, decompensation, and with treatments for these conditions. Gut microbiota can be used to predict clinically relevant outcomes in cirrhosis.

Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.

Inpatients with cirrhosis have high rates of acute-on-chronic failure (ACLF) development and high mortality within 30 days of admission to the hospital. Better biomarkers are needed to predict these outcomes. We performed metabolomic analyses of serum samples from patients with cirrhosis at multiple centers to determine whether metabolite profiles might identify patients at high risk for ACLF and death.We performed metabolomic analyses, using liquid chromatography, of serum samples collected at time of admission to 12 North American tertiary hepatology centers from 602 patients in the North American Consortium for the Study of End-Stage Liver Disease sites from 2015 through 2017 (mean age, 56 years; 61% men; mean model for end-stage liver disease score, 19.5). We performed analysis of covariance, adjusted for model for end-stage liver disease at time of hospital admission, serum levels of albumin and sodium, and white blood cell count, to identify metabolites that differed between patients who did vs did not develop ACLF and patients who did vs did not die during hospitalization and within 30 days. We performed random forest analysis to identify specific metabolite(s) that were associated with outcomes and area under the curve (AUC) analyses to analyze them in context of clinical parameters. We analyzed microbiomes of stool samples collected from 133 patients collected at the same time and examined associations with serum metabolites.Of the 602 patients analyzed, 88 developed ACLF (15%), 43 died in the hospital (7%), and 72 died within 30 days (12%). Increased levels of compounds of microbial origin (aromatic compounds, secondary or sulfated bile acids, and benzoate) and estrogen metabolites, as well as decreased levels of phospholipids, were associated with development of ACLF, inpatient, and 30-day mortality and were also associated with fecal microbiomes. Random forest analysis and logistic regression showed that levels of specific microbially produced metabolites identified patients who developed ACLF with an AUC of 0.84 (95% confidence interval [CI] 0.78-0.88; P = .001), patients who died while in the hospital with an AUC of 0.81 (95% CI 0.74-0.85; P = .002), and patients who died within 30 days with an AUC of 0.77 (95% CI 0.73-0.81; P = .02). The metabolites were significantly additive to clinical parameters for predicting these outcomes. Metabolites associated with outcomes were also correlated with microbiomes of stool samples.In an analysis of serum metabolites and fecal microbiomes of patients hospitalized with cirrhosis at multiple centers, we associated metabolites of microbial origin and lipid moieties with development of ACLF and death as an inpatient or within 30 days, after controlling for clinical features.

Background & AimsLiver transplantation is the only treatment that increases survival times of patients with decompensated cirrhosis. Patients who live farther away from a transplant center are disadvantaged. Health care delivery via telehealth is an effective way to manage patients with decompensated cirrhosis remotely. We investigated the effects of telehealth on the liver transplant evaluation process.MethodsWe performed a retrospective study of 465 patients who underwent evaluation for liver transplantation at the Richmond Veterans Affairs Medical Center from 2005 through 2017. Of these, 232 patients were evaluated via telehealth, and 233 via in-person evaluation. Using regression models, we evaluated the differential effects of telehealth vs usual care on placement on the liver transplant waitlist. We also investigated the effects of telehealth on time from referral to initial evaluation by a transplant hepatologist, liver transplantation, and mortality.ResultsPatients in the telehealth group were evaluated significantly faster than patients evaluated in person, without or with adjustment for potential confounders (21.7 vs 79.5 d; P < .01). Telehealth also was associated with a significantly shorter time on the liver transplant waitlist (138.8 vs 249 d; P < .01). After propensity-matched analysis, telehealth was associated with a reduction in the time from referral to evaluation (hazard ratio, 0.15; 95% CI, 0.09–0.21; P < .01) and listing (hazard ratio, 0.26; 95% CI, 0.12–0.40; P < .01), but not to transplantation. In the intent-to-treat analysis of all referred patients, we found no significant difference in pretransplant mortality between patients evaluated via telehealth vs in-person. There was statistically significant interaction between model for end-stage liver disease (MELD)-Na scores and time to evaluation (P = .009) and placement on the transplant waitlist (P = .002), with telehealth offering greater benefits to patients with low MELD-Na scores.ConclusionsUse of telehealth is associated with a substantial reduction in time from referral to initial evaluation by a hepatologist and placement on the liver transplant waitlist, especially for patients with low MELD scores, with no changes in time to transplantation or pretransplant mortality. More studies are needed, particularly outside of the Veterans Administration Health System, to confirm that telehealth is a safe and effective way to expand access for patients undergoing evaluation for liver transplantation. Liver transplantation is the only treatment that increases survival times of patients with decompensated cirrhosis. Patients who live farther away from a transplant center are disadvantaged. Health care delivery via telehealth is an effective way to manage patients with decompensated cirrhosis remotely. We investigated the effects of telehealth on the liver transplant evaluation process. We performed a retrospective study of 465 patients who underwent evaluation for liver transplantation at the Richmond Veterans Affairs Medical Center from 2005 through 2017. Of these, 232 patients were evaluated via telehealth, and 233 via in-person evaluation. Using regression models, we evaluated the differential effects of telehealth vs usual care on placement on the liver transplant waitlist. We also investigated the effects of telehealth on time from referral to initial evaluation by a transplant hepatologist, liver transplantation, and mortality. Patients in the telehealth group were evaluated significantly faster than patients evaluated in person, without or with adjustment for potential confounders (21.7 vs 79.5 d; P < .01). Telehealth also was associated with a significantly shorter time on the liver transplant waitlist (138.8 vs 249 d; P < .01). After propensity-matched analysis, telehealth was associated with a reduction in the time from referral to evaluation (hazard ratio, 0.15; 95% CI, 0.09–0.21; P < .01) and listing (hazard ratio, 0.26; 95% CI, 0.12–0.40; P < .01), but not to transplantation. In the intent-to-treat analysis of all referred patients, we found no significant difference in pretransplant mortality between patients evaluated via telehealth vs in-person. There was statistically significant interaction between model for end-stage liver disease (MELD)-Na scores and time to evaluation (P = .009) and placement on the transplant waitlist (P = .002), with telehealth offering greater benefits to patients with low MELD-Na scores. Use of telehealth is associated with a substantial reduction in time from referral to initial evaluation by a hepatologist and placement on the liver transplant waitlist, especially for patients with low MELD scores, with no changes in time to transplantation or pretransplant mortality. More studies are needed, particularly outside of the Veterans Administration Health System, to confirm that telehealth is a safe and effective way to expand access for patients undergoing evaluation for liver transplantation.

Chronic liver disease is reaching epidemic proportions with the increasing prevalence of obesity, nonalcoholic liver disease, and alcohol overuse worldwide. Most patients are not candidates for liver transplantation even if they have end-stage liver disease. There is growing evidence of a gut microbial basis for many liver diseases, therefore, better diagnostic, prognostic, and therapeutic approaches based on knowledge of gut microbiota are needed. We review the questions that need to be answered to successfully translate our knowledge of the intestinal microbiome and the changes associated with liver disease into practice.