Paolo Angeli

Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD.We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%).Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD.We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.

EASL Clinical Practice Guidelines for the management of

Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients.Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use.The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis.The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients.

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries.The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections.The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

Acute-on-chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short-term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD.These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249-1264).

Acute renal failure (ARF) is a common complication in patients with decompensated cirrhosis. The traditional diagnostic criteria of renal failure in these patients were proposed in 19961 and have been refined in subsequent years.2 According to these criteria, ARF is defined as an increase in serum creatinine (sCr) of ≥50% from baseline to a final value >1.5 mg/dL (133 µmol/L). However, the threshold value of 1.5 mg/dL (133 µmol/L) sCr to define renal failure in patients with decompensated cirrhosis has been challenged.3 ,4 In addition, the timeframe to distinguish acute from chronic renal failure has not been clearly identified, the only exception being type 1 hepatorenal syndrome (HRS). Meanwhile, new definitions for ARF, now termed acute kidney injury (AKI), have been proposed and validated in patients without cirrhosis.5–7 Recently these new criteria were also proposed and applied in the diagnosis of AKI in patients with cirrhosis.3 ,8–15 Thus, in December 2012, the International Club of Ascites (ICA) organised a consensus development meeting in Venice, Italy, in order to reach a new definition of AKI in patients with cirrhosis. The discussion among the experts continued thereafter for 2 years, both online and through several meetings, between those experts who had different positions on crucial points on the subject. This paper reports the scientific evidence supporting the final proposal of a new approach to the diagnosis and treatment of this condition, on which the experts agreed. AKI is defined as an acute significant reduction in the glomerular filtration rate (GFR). sCr remains the most practical biomarker of renal function in patients with ARF (with or without cirrhosis). However, sCr as a biomarker of renal function has many limitations in clinical practice since it is influenced by bodyweight, race, age, and gender. The use of sCr in patients with cirrhosis is …

Background & Aims: Paracentesis associated with P plasma expanders is widely used for the treatment of aracentesis associated with plasma volume expansion is an effective and safe therapy of tense ascites in ascites in cirrhosis.This study investigated the clinicirrhosis.[3][4] cation.Methods: A total of 289 cirrhotic patients with Other investigations have subsequently confirmed these ascites were randomized to treatment by total paradata. [5][7][8][9] centesis plus intravenous albumin (97 patients), dex-When paracentesis is performed without plasma voltran 70 (93 patients), or polygeline (99 patients). ume expansion, a circulatory dysfunction that leads to aPostparacentesis circulatory dysfunction was defined marked activation of the renin-angiotensin-aldosterone as an increase in plasma renin activity on the sixth system and may be associated with an impairment in day after paracentesis of more than 50% of the pretreatment value to a level ú4 ngrmL 01 rh 01 .Results:renal function frequently develops. [10][1][12][13][14] Because thesePostparacentesis circulatory dysfunction occurred changes are prevented by intravenous infusion of albumore frequently in patients treated with dextran 70 min, 10,11,15 paracentesis is generally performed in associa-(34.4%;P Å 0.018) or polygeline (37.8%;P Å 0.004)tion with the administration of this plasma expander.than in those receiving albumin (18.5%).The plasma However, the clinical relevance of postparacentesis circuexpander used and the volume of ascites removed latory dysfunction is not known. 16,17 The use of syntheticwere independent predictors of this complication.plasma expanders, such as dextran 70, dextran 40, orPostparacentesis circulatory dysfunction persisted polygeline, after therapeutic paracentesis is another asduring follow-up and was associated with a shorter pect that remains controversial.Some investigations sugtime to first readmission (1.3 { 0.5 vs. 3.5 { 0.8 gest that albumin is more effective than the synthetic months, median { SEM; P Å 0.03) and shorter plasma expanders in preventing postparacentesis circulasurvival (9.3 { 4.2 vs. 16.9 { 4.3 months; P Å 0.01).tory dysfunction, but a similar efficacy has been observedCreatinine and sodium levels in serum, and Child -Pugh score at inclusion, and postparacentesis circuin other studies. 4,16,18,19 latory dysfunction were independent predictors of In this article, we report the results of a multicenter survival.Conclusions: Postparacentesis circulatory trial of cirrhotic patients with tense ascites who were dysfunction is not spontaneously reversible and is associated with a shorter time to first readmission and Abbreviation used in this paper: PRA, plasma renin activity.shorter survival.Albumin is the best plasma expander

The aim of the study was to verify the effects of the administration of an inhibitor of the release of endogenous vasodilators together with a vasoconstrictor agent in patients with hepatorenal syndrome (HRS). This new medical perspective was compared with a traditional medical approach for HRS, such as the infusion of nonpressor doses of dopamine to produce renal vasodilation. Thirteen patients with type 1 HRS were enrolled in the study. Five of them were treated with the oral administration of midodrine and the parenteral administration of octreotide. In addition, the patients received 50 to 100 mL of 20% human albumin solution daily for 20 days. Midodrine and octreotide were dosed to obtain a stable increase of at least 15 mm Hg of mean arterial pressure. Eight patients were treated with the intravenous administration of nonpressor doses of dopamine (2-4 μg/kg/min) and the same daily amount of albumin. After 20 days of treatment with midodrine and octreotide, an impressive improvement in renal plasma flow (RPF), glomerular filtration rate, and urinary sodium excretion was observed in patients. This was accompanied by a significant reduction in plasma renin activity, plasma vasopressin, and plasma glucagon. No side effects were observed. Three patients were discharged from the hospital. One of them successfully underwent liver transplantation. One of the two remaining patients is still alive after 472 days with a preserved renal function, and the other died from terminal liver failure after 76 days. One of the two patients who were not discharged from the hospital successfully underwent liver transplantation, and the other died from pneumonia after 29 days. Seven out of eight patients who were treated with dopamine experienced a progressive deterioration in renal function and died during the first 12 days. Only one patient recovered renal function and underwent liver transplantation. In conclusion, the long-term administration of midodrine and octreotide seems to be an effective and safe treatment of type 1 HRS in patients with cirrhosis

Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days.Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.

The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.

Acute renal failure (ARF) is a common complication in patients with decompensated cirrhosis. The traditional diagnostic criteria of renal failure in these patients were proposed in 19961 and have been refined in subsequent years.2 According to these criteria, ARF is defined as an increase in serum creatinine (sCr) of ≥50% from baseline to a final value >1.5 mg/dL (133 µmol/L). However, the threshold value of 1.5 mg/dL (133 µmol/L) sCr to define renal failure in patients with decompensated cirrhosis has been challenged.3 ,4 In addition, the timeframe to distinguish acute from chronic renal failure has not been clearly identified, the only exception being type 1 hepatorenal syndrome (HRS). Meanwhile, new definitions for ARF, now termed acute kidney injury (AKI), have been proposed and validated in patients without cirrhosis.5–7 Recently these new criteria were also proposed and applied in the diagnosis of AKI in patients with cirrhosis.3 ,8–15 Thus, in December 2012, the International Club of Ascites (ICA) organised a consensus development meeting in Venice, Italy, in order to reach a new definition of AKI in patients with cirrhosis. The discussion among the experts continued thereafter for 2 years, both online and through several meetings, between those experts who had different positions on crucial points on the subject. This paper reports the scientific evidence supporting the final proposal of a new approach to the diagnosis and treatment of this condition, on which the experts agreed. AKI is defined as an acute significant reduction in the glomerular filtration rate (GFR). sCr remains the most practical biomarker of renal function in patients with ARF (with or without cirrhosis). However, sCr as a biomarker of renal function has many limitations in clinical practice since it is influenced by bodyweight, race, age, and gender. The use of sCr in patients with cirrhosis is …

To evaluate the prevalence, incidence and clinical relevance of bacterial infection in predominantly non-alcoholic cirrhotic patients hospitalised for decompensation.A total of 405 consecutive admissions in 361 patients (249 males and 112 females; 66 Child-Pugh class B and 295 class C) were analysed. Blood, urine, ascitic and pleural fluid cultures were performed within the first 24 hours, during hospitalisation whenever infection was suspected, and again before discharge.Over a one year period, 150 (34%) bacterial infections (89 community- and 61 hospital-acquired) involving urinary tract (41%), ascites (23%), blood (21%) and respiratory tract (17%) were diagnosed. The prevalence of bacterial peritonitis was 12%. Infections were asymptomatic in 69 cases (46%) and 130 (87%) involved a single site. Enteric flora accounted for 62% of infections, Escherichia Coli being the most frequent pathogen (25%). Community-acquired infections were associated with more advanced liver disease (Child-Pugh mean score 10.2+/-2.1 versus 9.5+/-1.9, p<0.05), renal failure (p<0.05), and high white blood cell count (p<0.01). Hospital-acquired infections occurred more frequently in patients admitted for gastrointestinal bleeding (p<0.05). The in-hospital mortality was significantly higher in infected than in non-infected patients (15% versus 7%, p<0.05), and infection emerged as an independent variable affecting survival. Moreover bacterial infection accounted for a significantly prolonged hospital stay.Bacterial infection, regardless of the aetiology, is a severe complication of decompensated cirrhosis, and, although frequently asymptomatic, accounts for both longer hospital stay and increased mortality.

Low serum sodium concentration is an independent predictor of mortality in patients with cirrhosis, but its prevalence and clinical significance is unclear. To evaluate prospectively the prevalence of low serum sodium concentration and the association between serum sodium levels and severity of ascites and complications of cirrhosis, prospective data were collected on 997 consecutive patients from 28 centers in Europe, North and South America, and Asia for a period of 28 days. The prevalence of low serum sodium concentration as defined by a serum sodium concentration < or =135 mmol/L, < or =130 mmol/L, < or =125 mmol/L, and < or =120 mmol/L was 49.4%, 21.6%, 5.7%, and 1.2%, respectively. The prevalence of low serum sodium levels (<135 mmol/L) was high in both inpatients and outpatients (57% and 40%, respectively). The existence of serum sodium <135 mmol/L was associated with severe ascites, as indicated by high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large-volume paracentesis, and impaired renal function, compared with normal serum sodium levels. Moreover, low serum sodium levels were also associated with greater frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome, but not gastrointestinal bleeding. Patients with serum sodium <130 mmol/L had the greatest frequency of these complications, but the frequency was also increased in patients with mild reduction in serum sodium levels (131-135 mmol/L). In conclusion, low serum sodium levels in cirrhosis are associated with severe ascites and high frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome.

Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue.We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794.From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events.In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis.Italian Medicine Agency.

Bacterial infections are common and life-threatening in patients with cirrhosis. Little is known about the epidemiology of bacterial infections in different regions. We performed a multicenter prospective intercontinental study to assess the prevalence and outcomes of bacterial and fungal infections in patients with cirrhosis.We collected data from 1302 hospitalized patients with cirrhosis and bacterial or fungal infections at 46 centers (15 in Asia, 15 in Europe, 11 in South America, and 5 in North America) from October 2015 through September 2016. We obtained demographic, clinical, microbiology, and treatment data at time of diagnosis of infection and during hospitalization. Patients were followed until death, liver transplantation, or discharge.The global prevalence of multidrug-resistant (MDR) bacteria was 34% (95% confidence interval 31%-37%). The prevalence of MDR bacteria differed significantly among geographic areas, with the greatest prevalence in Asia. Independent risk factors for infection with MDR bacteria were infection in Asia (particularly in India), use of antibiotics in the 3 months before hospitalization, prior health care exposure, and site of infection. Infections caused by MDR bacteria were associated with a lower rate of resolution of infection, a higher incidence of shock and new organ failures, and higher in-hospital mortality than those caused by non-MDR bacteria. Administration of adequate empirical antibiotic treatment was independently associated with improved in-hospital and 28-day survival.In a worldwide study of hospitalized patients, we found a high prevalence of infection with MDR bacteria in patients with cirrhosis. Differences in the prevalence of MDR bacterial infections in different global regions indicate the need for different empirical antibiotic strategies in different continents and countries. While we await new antibiotics, effort should be made to decrease the spread of MDR bacteria in patients with cirrhosis.

•Patients with acutely decompensated cirrhosis without ACLF develop 3 different clinical courses.•Patients with pre-ACLF develop ACLF within 90 days and have high systemic inflammation and mortality.•Patients with unstable decompensated cirrhosis suffer from complications of severe portal hypertension.•Patients with stable decompensated cirrhosis have less frequent complications and lower 1-year mortality risk. Background & AimsAcute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF.MethodsA total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded.ResultsThree groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC).ConclusionsAcute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge.ClinicalTrials.gov numberNCT03056612.Lay summaryHerein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death – termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD – patients in this group rarely require hospital admission and have a much lower 1-year mortality risk. Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge.

The aim of the study was to investigate the prevalence and clinical course of renal failure that was induced by the various types of bacterial infections in patients with cirrhosis and ascites. Three hundred and nine patients, who were consecutively admitted to the 3 major hospitals of Padova, Italy, during the first 6 months of 2005, were studied prospectively. Of these, 233 patients (75.4%) had evidence of ascites. In 104 patients with cirrhosis and ascites (44.6%) a bacterial infection was diagnosed. A bacterial infection-induced renal failure was observed in 35 of 104 patients (33.6%). The prevalence of renal failure was higher in biliary or gastrointestinal tract infections and in spontaneous bacterial peritonitis (SBP) and in than in other types of infections. In addition, the progressive form of renal failure was only precipitated by biliary or gastrointestinal tract infections, SBP, and urinary tract infections (UTI). In a multivariate analysis only MELD score (P = 0.001), the peak count of neutrophil leukocyte in blood (P = 0.04), and the lack of resolution of infection (P = 0.03) had an independent predictive value on the occurrence of renal failure.The results of the study show that the development of bacterial-induced renal failure in patients with cirrhosis and ascites is related to the MELD score, and to both the severity and the lack of resolution of the infection. A progressive form of renal failure occurs only as a consequence of biliary or gastrointestinal tract infections, SBP, and UTI.

<h2>Summary</h2> Renal dysfunction is a common, life-threatening complication occurring in patients with liver disease. Hepatorenal syndrome (HRS) has been defined as a purely "functional" type of renal failure that often occurs in patients with cirrhosis in the setting of marked abnormalities in arterial circulation, as well as overactivity of the endogenous vasoactive systems.^4,5 In 2007, the International Club of Ascites (ICA) classified HRS into types 1 and 2 (HRS-1 and HRS-2).⁵ HRS-1 is characterised by a rapid deterioration of renal function that often occurs because of a precipitating event, while HRS-2 is a moderate and stable or slowly progressive renal dysfunction that often occurs without an obvious precipitant. Clinically, HRS-1 is characterised by acute renal failure while HRS-2 is mainly characterised by refractory ascites. Nevertheless, after these two entities were first described, new concepts, definitions, and diagnostic criteria have been developed by nephrologists for renal dysfunction in the general population and hospitalised patients. In particular, the definitions and characterisation of acute kidney injury (AKI), acute kidney disease and chronic kidney disease have been introduced/refined.⁶ Accordingly, a debate among hepatologists of the ICA led to a complete revision of the nomenclature and diagnosistic criteria for HRS-1, which was renamed HRS-AKI.⁷ Additionally, over recent years, greater granularity has been gained regarding the pathogenesis of HRS; it is now increasingly recognised that it is not a purely "functional" entity with haemodynamic derangements, but that systemic inflammation, oxidative stress and bile salt-related tubular damage may contribute significantly to its development. That is, HRS has an additional structural component that would not only make traditional diagnostic criteria less reliable, but would explain the lack of response to pharmacological treatment with vasoconstrictors plus albumin that correlates with a progressive increase in inflammation. Because classification, nomenclature, diagnostic criteria and pathogenic theories have evolved over the years since the traditional classification of HRS-1 and HRS-2 was first described, it was considered that all these novel aspects be reviewed and summarised in a position paper. The aim of this position paper authored by two hepatologists (members of ICA) and two nephrologists involved in the study of renal dysfunction in cirrhosis, is to complete the re-classification of HRS initiated by the ICA in 2012 and to provide an update on the definition, classification, diagnosis, pathophysiology and treatment of HRS.

Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival.Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.

<h3>Background & Aims</h3> Cirrhotic patients with acute decompensation frequently develop acute-on-chronic liver failure (ACLF), which is associated with high mortality rates. Recently, a specific score for these patients has been developed using the CANONIC study database. The aims of this study were to develop and validate the CLIF-C AD score, a specific prognostic score for hospitalised cirrhotic patients with acute decompensation (AD), but without ACLF, and to compare this with the Child-Pugh, MELD, and MELD-Na scores. <h3>Methods</h3> The derivation set included 1016 CANONIC study patients without ACLF. Proportional hazards models considering liver transplantation as a competing risk were used to identify score parameters. Estimated coefficients were used as relative weights to compute the CLIF-C ADs. External validation was performed in 225 cirrhotic AD patients. CLIF-C ADs was also tested for sequential use. <h3>Results</h3> Age, serum sodium, white-cell count, creatinine and INR were selected as the best predictors of mortality. The C-index for prediction of mortality was better for CLIF-C ADs compared with Child-Pugh, MELD, and MELD-Nas at predicting 3- and 12-month mortality in the derivation, internal validation and the external dataset. CLIF-C ADs improved in its ability to predict 3-month mortality using data from days 2, 3–7, and 8–15 (C-index: 0.72, 0.75, and 0.77 respectively). <h3>Conclusions</h3> The new CLIF-C ADs is more accurate than other liver scores in predicting prognosis in hospitalised cirrhotic patients without ACLF. CLIF-C ADs therefore may be used to identify a high-risk cohort for intensive management and a low-risk group that may be discharged early.

Background & Aims In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies. Methods We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n = 406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n = 301). Results HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n = 174) and not associated (n = 286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade. Conclusions In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF. In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies. We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n = 406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n = 301). HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n = 174) and not associated (n = 286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade. In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF.

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

In patients with cirrhosis and hepatorenal syndrome (HRS), terlipressin has been used either as continuous intravenous infusion or as intravenous boluses. To date, these two approaches have never been compared. The goal of this study was to compare the administration of terlipressin as continuous intravenous infusion versus intravenous boluses in the treatment of type 1 HRS. Seventy‐eight patients were randomly assigned to receive either continuous intravenous infusion (TERLI‐INF group) at the initial dose of 2 mg/day or intravenous boluses of terlipressin (TERLI‐BOL group) at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups (1 g/kg of body weight at the first day followed by 20‐40 g/day). Complete response was defined by decrease of serum creatinine (sCr) from baseline to a final value ≤133 μmol/L, partial response by a decrease ≥50% of sCr from baseline to a final value &gt;133 μmol/L. The rate of adverse events was lower in the TERLI‐INF group (35.29%) than in the TERLI‐BOL group (62.16%, P &lt; 0.025). The rate of response to treatment, including both complete and partial response, was not significantly different between the two groups (76.47% versus 64.85%; P value not significant). The mean daily effective dose of terlipressin was lower in the TERLI‐INF group than in the TERLI‐BOL group (2.23 ± 0.65 versus 3.51 ± 1.77 mg/day; P &lt; 0.05). Conclusion : Terlipressin given by continuous intravenous infusion is better tolerated than intravenous boluses in the treatment of type 1 HRS. Moreover, it is effective at doses lower than those required for intravenous bolus administration. (H epatology 2016;63:983–992)

Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis.This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018.A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; p < 0.001), intensive care unit admission (OR 2.09; p = 0.02), and recent hospitalization (OR 1.93; p = 0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series.MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated.Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.

For several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) ≥ 50% to a final value of sCr>1.5mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3mg/dl or a percentage increase in sCr ≥ 50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr ≥ 0.3mg/dl or increase in sCr ≥ 1.5-fold to 2-fold from baseline. AKI diagnosed with the two different criteria was evaluated for the prediction of in-hospital mortality.Consecutive hospitalized patients with cirrhosis and ascites were included in the study and evaluated for the development of AKI.Conventional criterion was found to be more accurate than AKIN criteria in improving the prediction of in-hospital mortality in a model including age and Child-Turcotte-Pugh score. The addition of either progression of AKIN stage or a threshold value for sCr of 1.5mg/dl further improves the value of AKIN criteria in this model. More in detail, patients with AKIN stage 1 and sCr<1.5mg/dl had a lower mortality rate (p=0.03), a lower progression rate (p=0.01), and a higher improvement rate (p=0.025) than patients with AKIN stage 1 and sCr ≥ 1.5mg/dl.Conventional criterion is more accurate than AKIN criteria in the prediction of in-hospital mortality in patients with cirrhosis and ascites. The addition of either the progression of AKIN stage or the cut-off of sCr ≥ 1.5mg/dl to the AKIN criteria improves their prognostic accuracy.

Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF.We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals.Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins.In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures.Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.

Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.

The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections.We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study).Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines.In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

Spontaneous bacterial peritonitis (SBP) is a common, life-threatening complication of liver cirrhosis. Third-generation cephalosporins have been considered the first-line treatment of SBP. In 2014, a panel of experts suggested a broader spectrum antibiotic regimen for nosocomial SBP, according to the high rate of bacteria resistant to third-generation cephalosporins found in these patients. However, a broader-spectrum antibiotic regimen has never been compared to third-generation cephalosporins in the treatment of nosocomial SBP. The aim of our study was to compare meropenem plus daptomycin versus ceftazidime in the treatment of nosocomial SBP. Patients with cirrhosis and nosocomial SBP were randomized to receive meropenem (1 g/8 hours) plus daptomycin (6 mg/kg/day) or ceftazidime (2 g/8 hours). A paracentesis was performed after 48 hours of treatment. A reduction in ascitic fluid neutrophil count <25% of pretreatment value was considered a treatment failure. The primary outcome was the efficacy of treatment defined by the resolution of SBP after 7 days of treatment. Thirty-two patients were randomized and 31 were analyzed. The combination of meropenem plus daptomycin was significantly more effective than ceftazidime in the treatment of nosocomial SBP (86.7 vs. 25%; P < 0.001). Ninety-day transplant-free survival (TFS) was not significantly different between the two groups. In the multivariate analysis, ineffective response to first-line treatment (hazard ratio [HR]: 20.6; P = 0.01), development of acute kidney injury during hospitalization (HR: 23.2; P = 0.01), and baseline mean arterial pressure (HR: 0.92; P = 0.01) were found to be independent predictors of 90-day TFS.The combination of meropenem plus daptomycin is more effective than ceftazidime as empirical antibiotic treatment of nosocomial SBP. Efficacy of the empirical antibiotic treatment is a strong predictor of 90-day survival in patients with nosocomial SBP.

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes.The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome.Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality.This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis.Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosisJournal of HepatologyVol. 69Issue 2PreviewThe natural history of cirrhosis is characterised by an asymptomatic compensated phase followed by a decompensated phase, marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. The following Clinical Practice Guidelines (CPGs) represent the first CPGs on the management of decompensated cirrhosis. In this context, the panel of experts, having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, extended its work to all the complications of cirrhosis, which had not been covered by the European Association for the Study of the Liver guidelines, namely: ascites, refractory ascites, hyponatremia, gastrointestinal bleeding, bacterial infections, acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, relative adrenal failure, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and porto-pulmonary hypertension. Full-Text PDF It has come to our attention that there is an error in the original manuscript in the section entitled ‘Renal impairment’ on page 429. The sentence ‘Recent studies have suggested that in patients with cirrhosis, in AKI stage 1, SCr <1.5 mg/dl is associated with a worse outcome than an SCr ≥1.5 mg/dl.’ should read ‘Recent studies have suggested that in patients with cirrhosis, in AKI stage 1, SCr ≥1.5 mg/dl is associated with a worse outcome than an SCr <1.5 mg/dl’. We apologise for this mistake and any inconvenience caused.

Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs.The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days.Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment.These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors.Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.

In addition to lowering cholesterol levels, statins have pleiotropic effects, particularly anti-inflammatory, antiangiogenic, and antifibrotic, that may be beneficial in some chronic inflammatory conditions. Statins have only recently been investigated as a potential treatment option in chronic liver diseases because of concerns related to their safety in patients with impaired liver function. A number of experimental studies in animal models of liver diseases have shown that statins decrease hepatic inflammation, fibrogenesis and portal pressure. In addition, retrospective cohort studies in large populations of patients with cirrhosis and pre-cirrhotic conditions have shown that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma development, and death. These beneficial effects persisted after adjustment for disease severity and other potential confounders. Finally, a few randomised controlled trials have shown that treatment with simvastatin decreases portal pressure (two studies) and mortality (one study). Statin treatment was generally well tolerated but a few patients developed severe side effects, particularly rhabdomyolysis. Despite these promising beneficial effects, further randomised controlled trials in large series of patients with hard clinical endpoints should be performed before statins can be recommended for use in clinical practice.

The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a relevant threat for humans worldwide. Abnormality in liver function tests (LFTs) has been commonly observed in patients with COVID-19, but there is controversy on its clinical significance. The aim of this study was to assess the prevalence, the characteristics and the clinical impact of abnormal LFTs in hospitalized, non-critically ill patients with COVID-19.In this multicentre, retrospective study, we collected data about 565 inpatients with COVID-19. Data on LFTs were collected at admission and every 7 ± 2 days during the hospitalization. The primary outcome was a composite endpoint of death or transfer to intensive care unit (ICU).Upon admission 329 patients (58%) had LFTs abnormality. Patients with abnormal LFTs had more severe inflammation and higher degree of organ dysfunction than those without. During hospitalization, patients with abnormal LFTs had a higher rate of transfer to ICU (20% vs 8%; P < .001), acute kidney injury (22% vs 13%, P = .009), need for mechanical ventilation (14% vs 6%; P = .005) and mortality (21% vs 11%; P = .004) than those without. In multivariate analysis, patients with abnormal LFTs had a higher risk of the composite endpoint of death or transfer to ICU (OR = 3.53; P < .001). During the hospitalization, 86 patients developed de novo LFTs abnormality, which was associated with the use of tocilizumab, lopinavir/ritonavir and acetaminophen and not clearly associated with the composite endpoint.LFTs abnormality is common at admission in patients with COVID-19, is associated with systemic inflammation, organ dysfunction and is an independent predictor of transfer to ICU or death.

Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe.This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019.A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p <0.0001). The 1-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3.The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF.Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes.

Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital.This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death.A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p <0.001). Spontaneous bacterial peritonitis, pneumonia or infections caused by extensively drug resistant (XDR) bacteria were more frequently associated with ACLF development. More patients with ACLF had a positive quick sequential organ failure assessment score and septic shock, resulting in a lower infection resolution rate (all p <0.001).Bacterial infections, especially with XDR organisms, are associated with the highest risk of ACLF development, accounting for almost half of cases globally. Geographic differences result in variable epidemiology and clinical outcomes.Bacterial infections can trigger a sudden deterioration in an otherwise stable cirrhotic patient, a condition known as acute-on-chronic liver failure or ACLF. This study has found that the development of ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. The common infections that can trigger ACLF include infection of the abdominal fluid, known as spontaneous bacterial peritonitis, pneumonia and by bacteria that are resistant to multiple antibiotics. Patients who develop ACLF following a bacterial infection have high death rates and are frequently unable to clear the infection.

There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient prognosis and is therefore considered the most important stratification variable for the risk of death. However, this classification is an oversimplification, as it does not discriminate between the prognostic subgroups that characterise the course of decompensation, which depends on the type and number of decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided by observational studies characterising acute decompensation (AD), which occurs mostly in patients who have already experienced decompensating events. Decompensation presents as AD in a portion of patients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the first decompensation, AD mostly represents further decompensation.

Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence of organ system failure(s) and a high risk of short-term mortality. ACLF is caused by an excessive systemic inflammatory response triggered by precipitants that are clinically apparent (e.g., proven microbial infection with sepsis, severe alcohol-related hepatitis) or not. Since the description of ACLF, some important studies have suggested that patients with ACLF may benefit from liver transplantation and because of this, should be urgently stabilised for transplantation by receiving appropriate treatment of identified precipitants, and full general management, including support of organ systems in the intensive care unit (ICU). The objective of the present Clinical Practice Guidelines is to provide recommendations to help clinicians recognise ACLF, make triage decisions (ICU vs. no ICU), identify and manage acute precipitants, identify organ systems that require support or replacement, define potential criteria for futility of intensive care, and identify potential indications for liver transplantation. Based on an in-depth review of the relevant literature, we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with ACLF.

Acute kidney injury (AKI) commonly occurs in patients with decompensated cirrhosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) could help discriminate between different etiologies of AKI. The aim of this study was to investigate the use of uNGAL in (1) the differential diagnosis of AKI, (2) predicting the response to terlipressin and albumin in patients with hepatorenal syndrome-AKI (HRS-AKI), and (3) predicting in-hospital mortality in patients with AKI.One hundred sixty-two consecutive patients with cirrhosis and AKI were included from 2015 to 2020 and followed until transplant, death, or 90 days. Standard urinary markers and uNGAL were measured. Data on treatment, type, and resolution of AKI were collected. Thirty-five patients (21.6%) had prerenal AKI, 64 (39.5%) HRS-AKI, 27 (16.7%) acute tubular necrosis-AKI (ATN-AKI), and 36 (22.2%) a mixed form of AKI. Mean values of uNGAL were significantly higher in ATN-AKI than in other types of AKI (1162 ng/ml [95% CI 423-2105 ng/ml] vs. 109 ng/ml [95% CI 52-192 ng/ml]; p < 0.001). uNGAL showed a high discrimination ability in predicting ATN-AKI (area under the receiver operating characteristic curve, 0.854; 95% CI 0.767-0.941; p < 0.001). The best-performing threshold was found to be 220 ng/ml (sensitivity, 89%; specificity, 78%). The same threshold was independently associated with a higher risk of nonresponse (adjusted OR [aOR], 6.17; 95% CI 1.41-27.03; p = 0.016). In multivariable analysis (adjusted for age, Model for End-Stage Liver Disease, acute-on-chronic liver failure, leukocytes, and type of AKI), uNGAL was an independent predictor of in-hospital mortality (aOR, 1.74; 95% CI 1.26-2.38; p = 0.001).uNGAL is an adequate biomarker for making a differential diagnosis of AKI in cirrhosis and predicting the response to terlipressin and albumin in patients with HRS-AKI. In addition, it is an independent predictor of in-hospital mortality.

Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes.We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort).We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4.The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care.European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

The prognostic impact of acute decompensation (AD), i.e. the development of complications that require hospitalization, has recently been assessed. However, complications of cirrhosis do not necessarily require hospitalization and can develop progressively, as in the recently defined non-acute decompensation (NAD). Nevertheless, there is no data regarding the incidence and prognostic impact of NAD. The aim of the study was to evaluate the incidence and the prognostic impact of NAD and AD in outpatients with cirrhosis.A total of 617 outpatients with cirrhosis from two Italian tertiary centers (Padua and Milan) were enrolled from January 2003 to June 2021 and followed prospectively until the end of the study, death or liver transplantation. The complications registered during follow-up were considered as AD if they required hospitalization, or NAD if managed at the outpatient clinic.During follow-up, 154 patients (25.0% of total patients) developed complications, 69 patients (44.8%) developed NAD and 85 (55.2%) developed AD, while 29 patients with NAD (42.0%) developed a further episode of AD during follow-up. Sixty-month survival was significantly higher in patients with no decompensation than in patients with NAD or AD. On multivariable analysis, AD (hazard ratio [HR] 21.07, p <0.001), NAD (HR 7.13, p <0.001), the etiological cure of cirrhosis (HR 0.38, p <0.001) and model for end-stage liver disease score (HR 1.12, p = 0.003) were found to be independent predictors of mortality.The first decompensation is non-acute in almost 50% of outpatients, though such events are still associated with decreased survival compared to no decompensation. Patients who develop NAD must be treated with extreme care and monitored closely to prevent the development of AD.This multicenter study is the first to investigate the role of non-acute decompensation (NAD) in patients with cirrhosis. In fact, while the unfavorable impact of acute decompensation is well known, there is currently a dearth of evidence on NAD, despite it being a common occurrence in clinical practice. Our data show that almost half of decompensations in patients with cirrhosis can be considered NAD and that such events are associated with a higher risk of mortality than no decompensation. This study has important clinical implications because it highlights the need to carefully consider patients who develop NAD, in order to prevent further decompensation and reduce mortality.

Beta-blockers are extensively used to prevent variceal bleeding in patients with large esophageal varices. It is not established if beta-blockers delay the growth of small varices.A total of 161 patients with cirrhosis and small esophageal varices (F1 according to the classification of Beppu et al.) without previous bleeding were enrolled. A total of 83 patients were randomized to nadolol (dose adjusted to decrease resting heart rate by 25%; mean dose given, 62 +/- 25 mg/day) and 78 to placebo. The principal end point was occurrence of large esophageal varices (F2 or F3 according to the classification of Beppu et al.). Endoscopic examination was performed after 12, 24, 36, 48, and 60 months of follow-up. Mean follow-up was 36 months.The 2 groups were well matched for demographic and clinical characteristics. During the study period, 9 patients randomized to nadolol and 29 randomized to placebo had growth of esophageal varices. At the end of follow-up, the cumulative risk was 20% versus 51% (P < 0.001) (absolute risk difference, 31%; 95% confidence interval, 17%-45%). When possible confounding factors were taken into account, treatment was a significant factor predicting growth of varices (odds ratio, 4.0; 95% confidence interval, 1.95-8.4). The cumulative probability of variceal bleeding was also lower in patients randomized to nadolol (P = 0.02). Survival was not different (P = 0.33). Adverse effects resulting in withdrawal of drug occurred in 9 in the nadolol group and one in the placebo group (P = 0.01).This study suggests that beta-blocker prophylaxis of variceal bleeding in patients with compensated cirrhosis should be started when small esophageal varices are present.

Recently, we presented evidence for conventional, strand-coupled replication of mammalian mitochondrial DNA. Partially single-stranded replication intermediates detected in the same DNA preparations were assumed to derive from the previously described, strand-asymmetric mode of mitochondrial DNA replication. Here, we show that bona fide replication intermediates from highly purified mitochondria are essentially duplex throughout their length, but contain widespread regions of RNA:DNA hybrid, as a result of the incorporation of ribonucleotides on the light strand which are subsequently converted to DNA. Ribonucleotide-rich regions can be degraded to generate partially single-stranded molecules by RNase H treatment in vitro or during DNA extraction from crude mitochondria. Mammalian mitochondrial DNA replication thus proceeds mainly, or exclusively, by a strand-coupled mechanism.

Background & Aims: The clinical importance of portal hypertensive gastropathy (PHG) as a source of gastrointestinal bleeding in patients with cirrhosis is poorly defined. We investigated the natural history of this condition in a large series of patients. Methods: All patients with cirrhosis seen at 7 hospitals during June and July 1992 were followed up with clinical and endoscopic examinations every 6 months for up to 3 years. Gastropathy was classified according to the classification of the New Italian Endoscopic Club. Results: The prevalence of gastropathy was 80% and was correlated with the duration of disease, presence and size of esophagogastric varices, and a previous history of endoscopic variceal sclerotherapy. During 18 ± 8 months of follow-up, gastropathy was stable in 29% of patients, deteriorated in 23%, improved in 23%, and fluctuated with time in 25%. The evolution of gastropathy with time was identical in patients with and without previous or current sclerotherapy. Acute bleeding from gastropathy occurred in 8 of 315 patients (2.5%). The bleeding-related mortality rate was 12.5%. Chronic bleeding occurred in 34 patients (10.8%). Conclusions: PHG is common in patients with cirrhosis, and its prevalence parallels the severity of portal hypertension. Gastropathy can progress from mild to severe and vice versa or even disappear completely. Bleeding from this lesion is relatively uncommon and rarely severe. Sclerotherapy of esophageal varices does not seem to influence the natural history of this condition.GASTROENTEROLOGY 2000;119:181-187

HepatologyVolume 29, Issue 6 p. 1662-1667 Original ArticleFree Access Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests Piero Amodio M.D., Corresponding Author Piero Amodio M.D. [email protected] From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalyClinica Medica V, via Giustiniani, 2, 35128 Padova, Italy. fax: 049-8754179===Search for more papers by this authorFranco Del Piccolo, Franco Del Piccolo From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorPiergiorgio Marchetti, Piergiorgio Marchetti From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorPaolo Angeli, Paolo Angeli From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorRosamaria Iemmolo, Rosamaria Iemmolo From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorLorenza Caregaro, Lorenza Caregaro From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorCarlo Merkel, Carlo Merkel From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorGiorgio Gerunda, Giorgio Gerunda From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorAngelo Gatta, Angelo Gatta From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this author Piero Amodio M.D., Corresponding Author Piero Amodio M.D. [email protected] From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalyClinica Medica V, via Giustiniani, 2, 35128 Padova, Italy. fax: 049-8754179===Search for more papers by this authorFranco Del Piccolo, Franco Del Piccolo From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorPiergiorgio Marchetti, Piergiorgio Marchetti From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorPaolo Angeli, Paolo Angeli From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorRosamaria Iemmolo, Rosamaria Iemmolo From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorLorenza Caregaro, Lorenza Caregaro From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorCarlo Merkel, Carlo Merkel From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorGiorgio Gerunda, Giorgio Gerunda From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this authorAngelo Gatta, Angelo Gatta From Clinica Medica V, Department of Clinical and Experimental Medicine, University of Padova, ItalySearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510290619Citations: 191AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract The prevalence and the clinical implications of subclinical cognitive alterations in cirrhotic patients have not been well defined as yet. Therefore, we performed a study to assess the clinical features and the survival of cirrhotic patients with cognitive alterations detected by the number connection test (NCT) and a set of computerized psychometric tests (Scan, Choice1, and Choice2) measuring the reaction times and the percentage of errors in performing specific tasks. Ninety-four cirrhotic patients (aged 58 ± 9 years) without overt hepatic encephalopathy and 80 controls (aged 53 ± 15 years) were consecutively enrolled. The median follow-up in cirrhotic patients was 426 days (lower quartile = 213 days; upper quartile = 718 days). Results of the NCT, Scan test, and Choice2 test were significantly worse in cirrhotic patients, whereas Choice1 did not differ significantly from the controls. In cirrhotic patients, the prevalence of altered psychometric tests was 21% (CI95% = 14%-31%) by NCT, 23% (CI95% =15%-33%) by Scan test, and 20% (CI95% =16%-30%) by Choice2 test. The alterations of NCT, Scan, and Choice2 were found to be related to the severity of liver disease, independently of its etiology. Increased risk of death was found to be associated with altered Scan test (hazard ratio = 2.4; CI95% =1.1-5.3), or altered Choice2 test (hazard ratio = 2.8; CI95% = 1.2-6.3). Multivariate regression showed that Scan and Choice2 tests had prognostic value on survival, in addition to Child-Pugh classes in the first year of follow-up. References 1 Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. A comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double-blind controlled trial. Gastroenterology 1977; 72: 573– 583.MEDLINE 2 Weissenborn K. Diagnosis of encephalopathy. 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Self-terminating versus exhaustive processes in rapid visual and memory search: an evaluative review. Percept Psychophys 1984; 53: 563– 580. 30 Hyman R. Stimulus information as a determinant of reaction time. J Exp Psychol 1953; 45: 188– 196. 31 Zeneroli ML, Cioni G, Ventura P, Russo AM, Venturini I, Casalgrandi G, Ventura E. Interindividual variability of the Number Connection Test. J Hepatol 1992; 15: 263– 264.MEDLINE 32 Finlayson MAJ, Johnson KA, Reitan RM. Relationship of level of education to neuropsychological measures in brain-damaged and non brain-damaged adults. J Consult Clin Psychol 1977; 45: 536– 542.MEDLINE 33 Yang SS, Wu CH, Chen DS. Somatosensory evoked potentials in subclinical portosystemic encephalopathy: a comparison with psychometric tests. Hepatology 1998; 27: 357– 361.MEDLINE 34 Weissenborn K, Rückert N, Hecker H, Manns MP. The number connection tests A and B: interindividual variability and use for the assessment of early hepatic encephalopathy. 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Prognostic indicators of survival in patients with cirrhosis and esophageal varices, without previous bleeding. Am J Gastroenterol 1989; 84: 717– 722.MEDLINE Citing Literature Volume29, Issue6June 1999Pages 1662-1667 ReferencesRelatedInformation

The electroencephalogram (EEG) is frequently altered in cirrhotic patients. We, therefore, performed a study to ascertain the features and the prognosis of cirrhotic patients without current overt hepatic encephalopathy (OHE) who have EEG alterations.A series of 296 consecutive cirrhotic patients who had undergone quantified-EEG was studied. The median follow-up was 442 days, 128 patients had bouts of OHE and 78 patients died from liver-related causes. Another group of 124 cirrhotic patients with a median follow-up of 223 days was examined to validate the prognostic model.EEG alterations were detected in 38% of the patients. The prevalence of EEG alterations was associated with the severity of cirrhosis (class B: odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.2-4.7; class C: OR = 3.5, 95% CI = 1.6-7.7), but not with the aetiology (alcoholic vs. non-alcoholic: OR = 0.9; 95% CI = 0.5-1.5). The EEG predicted the occurrence of OHE (chi2 = 26; P < 0.001) and mortality (chi2 = 34; P < 0.001), also adjusting for Child-Pugh class by a multivariate analysis. In the patients with a Child-Pugh score of > or = 8, the EEG discriminated between those patients with a higher 1-year risk of OHE (hazard ratio (HR) = 3.3, 95% CI = 1.8-6.1) and death (HR = 3.1, 95% CI = 1.7-5.6).In conclusion, quantified-EEG had a prognostic value for the occurrence of bouts of OHE and mortality in cirrhotic patients.

Clinical and anamnestic data, Pugh score, and size of esophageal varices were obtained in 129 cirrhotics. Hepatic vein catheterization was performed to measure hepatic venous pressure gradient (HVPG), indocyanine green (ICG) intrinsic hepatic clearance, and hepatic plasma flow. During a follow-up period of up to 60 months, 44 patients experienced gastrointestinal bleeding and 54 died. Applying Cox regression analysis, ICG intrinsic hepatic clearance, Pugh score, previous variceal bleeding, and HVPG were the only significant prognostic determinants of survival. In addition, Cox's regression analysis showed that HVPG, Pugh score, size of varices, and previous variceal bleeding all contained significant prognostic information regarding risk of gastrointestinal bleeding. The models were validated using a split-sample technique, and prognostic indexes for death and gastrointestinal bleeding were calculated. The prognostic index predicting death had significantly improved prognostic accuracy over a prognostic index calculated excluding the data obtained from hepatic vein catheterization (P less than 0.05). In conclusion, prognostic accuracy in cirrhosis with portal hypertension is significantly improved by information obtained from hepatic vein catheterization.

Background/Aims Psychometric Hepatic Encephalopathy Score (PHES) and EEG are used to detect minimal hepatic encephalopathy (MHE). We aimed at standardizing PHES in Italy and comparing Italian, German and Spanish norms in EEG characterized cirrhotic patients. Methods PHES was standardized on 228 normal individuals. Repeatability was studied in 128 individuals. One hundred patients with liver cirrhosis underwent EEG and PHES which was computed on the Spanish, German and the Italian norms. Results Age and education levels were predictors of psychometric tests; therefore, adjusted Z scores were calculated. Practice effect (p < 0.01) was detected. In the patients, the Italian norms were closer to the Spanish norms (difference −0.14 ± 1.32, p = 0.29) than to the Germans ones (difference 1.97 ± 2.07, p < 0.001). The PHES calculated on the Italian norms was correlated with the EEG mean dominant frequency more closely than the ones calculated on the German and Spanish norms (r = 0.38, r = 0.31, r = 0.33, respectively – p < 0.01). The detection of MHE on the basis of PHES and EEG showed limited agreement (73%, Cohen’s K = 0.32). Conclusions (i) Valid norms for PHES were produced, (ii) clues for the use of common norms in Latin Countries were found, (iii) different findings between PHES and EEG possibly reflect various features of MHE. Psychometric Hepatic Encephalopathy Score (PHES) and EEG are used to detect minimal hepatic encephalopathy (MHE). We aimed at standardizing PHES in Italy and comparing Italian, German and Spanish norms in EEG characterized cirrhotic patients. PHES was standardized on 228 normal individuals. Repeatability was studied in 128 individuals. One hundred patients with liver cirrhosis underwent EEG and PHES which was computed on the Spanish, German and the Italian norms. Age and education levels were predictors of psychometric tests; therefore, adjusted Z scores were calculated. Practice effect (p < 0.01) was detected. In the patients, the Italian norms were closer to the Spanish norms (difference −0.14 ± 1.32, p = 0.29) than to the Germans ones (difference 1.97 ± 2.07, p < 0.001). The PHES calculated on the Italian norms was correlated with the EEG mean dominant frequency more closely than the ones calculated on the German and Spanish norms (r = 0.38, r = 0.31, r = 0.33, respectively – p < 0.01). The detection of MHE on the basis of PHES and EEG showed limited agreement (73%, Cohen’s K = 0.32). (i) Valid norms for PHES were produced, (ii) clues for the use of common norms in Latin Countries were found, (iii) different findings between PHES and EEG possibly reflect various features of MHE.

Ascites is a frequent complication of cirrhosis and portal hypertension, because of the increase of the sinusoidal hydrostatic pressure. Cirrhosis accounts for over 75% of episodes of ascites. Cirrhotic patients with ascites have marked alterations in the splanchnic and systemic haemodynamics, causing central hypovolaemia and arterial hypotension with consequent activation of the vasoconstrictor systems, renin–angiotensin and sympathetic systems, and with increased renal sodium re-absorption. One of the most serious complications in cirrhotic patients with ascites is the occurrence of refractoriness, that is the inability to resolve ascites by the standard medical treatment with low sodium diet and diuretic doses up to 160 mg/day of furosemide and 400 mg/day of spironolactone. Many patients with refractory ascites also have a chronic renal insufficiency that is called hepatorenal syndrome type-2. In these patients ascites may be treated with periodic paracentesis or with transjugular intrahepatic portosystemic shunt. However, only liver transplantation may improve the survival of such patients.

Background & Aims The development of ascites in patients with cirrhosis is associated with a high rate of health care utilization. New models of specialized caregiving support are necessary to optimize its management. The aim of the study was to evaluate the efficacy and financial sustainability of the “Care management check-up” as a new model of specialized caregiving support based on a series of diagnostic facilities performed in real time and on the integrated activity of consultant hepatologists at the hospital unit for outpatients, dedicated nurses, physicians in training and primary physicians, compared to standard care in outpatients with cirrhosis and ascites. Methods 100 cirrhotic patients admitted to our hospital were allocated, after discharge, to the “Care management check-up” group (group 1), or to the “Standard outpatient care” group (group 2), and followed prospectively as outpatients up to death or for at least 12 months. Patients of the two groups could also access to a “Day hospital” when an invasive procedure was required. In group 1, the “Care management check-up” and the “Day hospital” taken together defined the “Care management program”. Results Twelve-month mortality was higher in group 2 than in group 1 (45.7% vs. 23.1%, p <0.025). The rate of 30-day readmission was also higher in group 2 (42.4% vs. 15.4%, p <0.01). The global cost attributable to the management per patient-month of life was lower (1479.19 ± 2184.43 €) in group 1 than (2816.13 ± 3893.03 €) in group 2 (p <0.05). Conclusions The study suggests that this new model of specialized caregiving reduces 12-month mortality in patients with cirrhosis and ascites as well as the global health care costs for their management. The development of ascites in patients with cirrhosis is associated with a high rate of health care utilization. New models of specialized caregiving support are necessary to optimize its management. The aim of the study was to evaluate the efficacy and financial sustainability of the “Care management check-up” as a new model of specialized caregiving support based on a series of diagnostic facilities performed in real time and on the integrated activity of consultant hepatologists at the hospital unit for outpatients, dedicated nurses, physicians in training and primary physicians, compared to standard care in outpatients with cirrhosis and ascites. 100 cirrhotic patients admitted to our hospital were allocated, after discharge, to the “Care management check-up” group (group 1), or to the “Standard outpatient care” group (group 2), and followed prospectively as outpatients up to death or for at least 12 months. Patients of the two groups could also access to a “Day hospital” when an invasive procedure was required. In group 1, the “Care management check-up” and the “Day hospital” taken together defined the “Care management program”. Twelve-month mortality was higher in group 2 than in group 1 (45.7% vs. 23.1%, p <0.025). The rate of 30-day readmission was also higher in group 2 (42.4% vs. 15.4%, p <0.01). The global cost attributable to the management per patient-month of life was lower (1479.19 ± 2184.43 €) in group 1 than (2816.13 ± 3893.03 €) in group 2 (p <0.05). The study suggests that this new model of specialized caregiving reduces 12-month mortality in patients with cirrhosis and ascites as well as the global health care costs for their management.

Background Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. Methods A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patient's 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. Findings 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B–C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1·530 (95% CI 1·107–2·116) for BCLC A versus BCLC 0, 1·572 (1·350–1·830) for BCLC B–C versus BCLC A, and 1·470 (1·164–1·856) for BCLC D versus BCLC B–C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11·19 months (IQR 10·73–11·67) for BCLC 0, 13·49 months (11·51–15·57) for BCLC A, 17·36 months (15·06–19·28) for BCLC B–C, and 28·46 months (26·38–30·34) for BCLC D. Interpretation Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B–C), regardless of the nodule number–size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. Funding None.

Liver cirrhosis is one of the main causes of death and disability-adjusted life-years worldwide. Generally, cirrhosis develops after a long period of liver-cell injury that leads to the deposition of collagen, leading to progressive fibrosis and nodule formation in the liver tissue. Most patients are diagnosed in late stages when liver decompensation or liver cancer develops. The diagnosis is rarely made in early stages-when liver fibrosis is mild to moderate but cirrhosis is not yet established-because the disease is asymptomatic. No strategies for detection of liver fibrosis at these early stages have been developed, but therapies are more effective in early stages than late stages of chronic liver diseases, so enabling early detection is an important research topic. Non-invasive methods for assessing liver fibrosis have been developed, of which the most commonly used are transient elastography-which estimates liver fibrosis by measuring liver stiffness-and serum biomarkers of fibrosis. Studies have shown that 6-7% of the adult population without known liver disease have liver fibrosis, mostly associated with non-alcoholic fatty liver disease. These data suggest that programmes of screening for liver fibrosis in the general population should be assessed.

Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (minimal HE [MHE]/grade 1 HE) is important. We examined if the animal naming test (ANT 1 ) (maximum number of animals listed in 1 minute) is useful in this context. In total, 208 healthy controls, 40 controls with inflammatory bowel disease, and 327 consecutive patients with cirrhosis underwent the ANT 1 . Patients were tested for MHE by the psychometric HE score, and 146 were assessed by electroencephalography; 202 patients were followed up regarding the occurrence of overt HE and death. In the healthy controls, ANT 1 was influenced by limited education (&lt;8 years) and advanced age (&gt;80 years, P &lt; 0.001). Using an age and education adjusting procedure, the simplified ANT 1 (S‐ANT 1 ) was obtained. An S‐ANT 1 of &lt;10 animals was abnormal. Of the patients, 169 were considered unimpaired, 32 as having HE ≥grade 2, and 126 as having MHE/grade 1 HE. This group had lower S‐ANT 1 than unimpaired patients (12 ± 0.4 versus 16 ± 0.7, P &lt; 0.001) and higher S‐ANT 1 than those with HE ≥grade 2 (4 ± 0.9). In grade 1 HE the S‐ANT 1 was lower than in MHE. Following receiver operating characteristic analysis (Youden's index), 15 animals produced the best discrimination between unimpaired and MHE/grade 1 HE patients. Thus, a three‐level score (0 for S‐ANT 1 ≥15, 1 for 10 ≤ S‐ANT 1 &lt; 15, 2 for S‐ANT 1 &lt;10) was obtained. This score was correlated both to the psychometric HE score ( P &lt; 0.0001) and to electroencephalography ( P = 0.007). By sample random split validation, both S‐ANT 1 and its three‐level score showed prognostic value regarding the 1‐year risk of overt HE and death. No inflammatory bowel disease control had S‐ANT &lt;15. Conclusion : The S‐ANT 1 is an easily obtainable measure useful for the assessment of HE. (H epatology 2017;66:198–208).

<h3>Background & Aims</h3> Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality). <h3>Methods</h3> We performed a retrospective analysis of 4 different cohorts of consecutive patients with HRS treated with terlipressin and albumin from February 2007 through January 2016 at medical centers in Europe (total, 298 patients). We analyzed demographic, clinical, and laboratory data collected before and during treatment; patients were followed until death, liver transplantation, or 90 days after HRS diagnosis. <h3>Results</h3> Response to treatment was observed in 53% of patients. Of patients with grade 1 ACLF, 60% responded to treatment; among those with grade 2 ACLF, 48% responded, and among those with grade 3 ACLF, 29% responded (<i>P</i> < .001 for comparison between grades). In multivariate analysis, baseline serum level of creatinine (odds ratio, 0.23; <i>P</i> = .001) and ACLF grade (odds ratio, 0.63; <i>P</i> = .01) were independently associated with response to treatment. Patient age (hazard ratio [HR], 1.05; <i>P</i> < .001), white blood cell count (HR, 1.51; <i>P</i> = .006), ACLF grade (HR, 2.06; <i>P</i> < .001), and no response to treatment (HR, 0.41; <i>P</i> < .001) associated with 90-day mortality. <h3>Conclusion</h3> In a retrospective analysis of data from 4 cohorts of patients treated for type 1 HRS, we found ACLF grade to be the largest determinant of response to terlipressin and albumin. ACLF grade affects survival independently of response to treatment. New therapeutic strategies should be developed for patients with type 1 HRS and extrarenal organ failure.

In patients with cirrhosis of the liver, acute kidney injury (AKI) is classified into 3 stages. Recent studies indicate that there are 2 subgroups of stage 1 disease, associated with different outcomes and serum levels of creatinine (SCr): stage 1A (SCr <1.5 mg/dL) and stage 1B (SCr ≥1.5 mg/dL). We performed a prospective study to validate, in a large series of patients with cirrhosis, the association between this new description and patient outcomes, and assess the relationship between AKI stage and the presence of acute-on-chronic liver failure.We collected data from 547 consecutive patients admitted for cirrhosis with acute decompensation to 2 tertiary hospitals (Italy and Spain), from February 2011 through June 2015. A total of 290 patients had AKI (53%; 197 had stage 1 disease); AKI stages were determined based on levels of SCr at diagnosis. Patients were followed up until death, liver transplantation, or for 90 days. The primary outcome was 90-day survival; secondary outcomes were progression and resolution of AKI and association with acute-on-chronic liver failure.Based on level of sCr at diagnosis, 58 patients had stage 1A disease and 139 had stage 1B disease. Of patients with stage 1A disease, 82% survived for 90 days; of patients with stage 1B disease, 55% survived for 90 days (P = .001). Hepatorenal syndrome and acute tubular necrosis were the most common causes of stage 1B AKI, and hypovolemia was the most common cause of stage 1A AKI. AKI progressed in a higher proportion of patients with 1B than 1A AKI (31% vs 15%; P = .017) and resolved in a higher proportion of patients with 1A disease (90% vs 52% of patients with stage 1B; P < .001). Stage 1B disease, but not 1A, was an independent predictor of AKI progression and mortality. ACLF developed in a significantly greater proportion of patients with stage 1B disease (76%) than stage 1A disease (22%; P < .001), which could account for the poor outcomes of patients with stage 1B disease.In a large group of patients with decompensated cirrhosis, we validated the association between AKI stages IA and IB (based on level of sCR) with survival times and AKI progression. We also associated these subgroups of AKI with development of acute-on-chronic liver failure. These findings are important for management of patients with decompensated cirrhosis.

Background & Aims Preliminary data suggest that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in cirrhotic patients. We aimed to further investigate simple serum non-invasive markers for diagnosing and grading OV. Methods A retrospective set of 510 cirrhotics and a prospective set of 110 cirrhotics were enrolled consecutively in five centers. Platelets, AST-to-ALT ratio, AST-to-platelet-ratio index, Forns’ index, Lok index, Fib-4, and Fibroindex were measured within 2 months from upper endoscopy, taken as a gold standard. Performance was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC). Results A combination of Lok index (cutoff = 1.5) and Forns’ index (cutoff = 8.8) had 0.80 AUC (0.76–0.84, 95% CI), and high NPV (>90%) to exclude clinically relevant OV, defined as large OV or small OV with red signs or in Child–Pugh C cirrhosis. By applying this combination, upper endoscopy would have been avoided in 1/3 of our cirrhotics. Large OV could be excluded with 96% NPV by Lok index (cutoff = 1.5). A combination of Lok index (cutoff = 0.9) and Forns’ index (cutoff = 8.5) predicted presence of any grade OV with good performance: 0.82 AUC (0.76–0.88, 95% CI), 88% PPV. Conclusions Serum non-invasive markers may be useful as a first line tool to identify cirrhotic patients in which the risk of clinically relevant OV is trivial, and to reduce the number of upper endoscopies. However, we are still far from the possibility of replacing upper endoscopy by simple serum non-invasive markers in the vast majority of patients. Preliminary data suggest that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in cirrhotic patients. We aimed to further investigate simple serum non-invasive markers for diagnosing and grading OV. A retrospective set of 510 cirrhotics and a prospective set of 110 cirrhotics were enrolled consecutively in five centers. Platelets, AST-to-ALT ratio, AST-to-platelet-ratio index, Forns’ index, Lok index, Fib-4, and Fibroindex were measured within 2 months from upper endoscopy, taken as a gold standard. Performance was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC). A combination of Lok index (cutoff = 1.5) and Forns’ index (cutoff = 8.8) had 0.80 AUC (0.76–0.84, 95% CI), and high NPV (>90%) to exclude clinically relevant OV, defined as large OV or small OV with red signs or in Child–Pugh C cirrhosis. By applying this combination, upper endoscopy would have been avoided in 1/3 of our cirrhotics. Large OV could be excluded with 96% NPV by Lok index (cutoff = 1.5). A combination of Lok index (cutoff = 0.9) and Forns’ index (cutoff = 8.5) predicted presence of any grade OV with good performance: 0.82 AUC (0.76–0.88, 95% CI), 88% PPV. Serum non-invasive markers may be useful as a first line tool to identify cirrhotic patients in which the risk of clinically relevant OV is trivial, and to reduce the number of upper endoscopies. However, we are still far from the possibility of replacing upper endoscopy by simple serum non-invasive markers in the vast majority of patients.

Abstract Patients with cirrhosis have a high risk of bacterial infections. Bacterial infections induce systemic inflammation that may lead to organ failure and acute‐on‐chronic liver failure ( ACLF ) resulting in a high risk of short term mortality. The early diagnosis and treatment of bacterial infections is essential to improve the patient's prognosis. However, in recent years, the spread of multidrug resistant ( MDR ) bacterial infections has reduced the efficacy of commonly used antibiotics such as third generation cephalosporins. In patients at high risk of MDR bacteria, such as those with nosocomial infections, the early administration of broad spectrum antibiotics has been shown to improve the prognosis. However, early de‐escalation of antibiotics is recommended to reduce a further increase in antibiotic resistance. Strategies to prevent acute kidney injury and other organ failures should be implemented. Although prophylaxis of bacterial infections with antibiotics improves the prognosis in selected patients, their use should be limited to patients at high risk of developing infections. In this article, we review the pathogenesis and management of bacterial infections in patients with cirrhosis.

Background & Aims Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. Methods We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. Results Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35–400) vs. 29(12–73) μg/g creatinine; p <0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28 day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83–0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r = 0.79; p <0.001 and r = 0.67; p <0.001), MELD (r = 0.68; p <0.001) and Interleukin-6 (r = 0.65; p <0.001). Conclusions NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. Lay summary Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF. Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35–400) vs. 29(12–73) μg/g creatinine; p <0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28 day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83–0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r = 0.79; p <0.001 and r = 0.67; p <0.001), MELD (r = 0.68; p <0.001) and Interleukin-6 (r = 0.65; p <0.001). NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome.

The trans jugular intrahepatic Porto systemic shunt (TIPS) is no longer viewed as a salvage therapy or a bridge to liver transplantation and is currently indicated for a number of conditions related to portal hypertension with positive results in survival. Moreover, the availability of self-expandable polytetrafluoroethylene (PTFE)-covered endoprostheses has dramatically improved the long-term patency of TIPS. However, since the last updated International guidelines have been published (year 2009) new evidence have come, which have open the field to new indications and solved areas of uncertainty. On this basis, the Italian Association of the Study of the Liver (AISF), the Italian College of Interventional Radiology—Italian Society of Medical Radiology (ICIR-SIRM), and the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI) promoted a Consensus Conference on TIPS. Under the auspices of the three scientific societies, the consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Bergamo on June 4th and 5th, 2015. The final statements presented here were graded according to quality of evidence and strength of recommendations and were approved by an independent jury. By highlighting strengths and weaknesses of current indications to TIPS, the recommendations of AISF-ICIR-SIRM-SIAARTI may represent the starting point for further studies.

The aim of this study was to evaluate the effect and molecular mechanism of albumin infusion on cardiac contractility in experimental cirrhosis with ascites. Cardiac contractility was recorded ex vivo in rats with cirrhosis and ascites and in control rats after the injection in the caudal vein of albumin, saline, or hydroxyethyl starch (HES). Gene and protein expression of β-receptors and pathways involved in their intracellular signaling such as Gαi2 protein (Gαi2), adenylate cyclase 3 (Adcy3), protein expression of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS), were evaluated in cardiac tissue in both groups. Phosphorylation and membrane-translocation of the cytosolic components of nicotinamide adenine dinucleotide phosphate (NAD(P)H)-oxidase and translocation of nuclear factor kappa B (NF-κB) were also evaluated. After saline intravenous injection, cardiac contractility was significantly reduced in rats with cirrhosis as compared to control rats (P < 0.01). This was associated with: (1) increased expression of protein Gαi2 (P < 0.05), TNF-α (P < 0.05), iNOS (P < 0.05); (2) increased NAD(P)H-oxidase activity (P < 0.05); (3) increased nuclear translocation of NF-κB (P < 0.05); and (4) lower expression of Adcy 3 (P < 0.05) in cardiac tissue of rats with cirrhosis. After albumin injection cardiac contractility (P < 0.01), protein expression of TNF-α, iNOS, Gαi2, and Adcy3, NAD(P)H-oxidase activity and nuclear translocation of NF-κB in cardiac tissue of rats with cirrhosis were reversed to control levels (P < 0.05). HES injection did not modify cardiac contractility and nuclear translocation of NF-κB in cardiac tissue of rats with cirrhosis. Conclusion: Albumin exerts a positive cardiac inotropic effect in rats with cirrhosis and ascites counteracting the negative effects of oxidative stress- and TNF-α-induced activation of NF-κB-iNOS pathway and oxidative stress-induced alteration of β-receptor signaling. (HEPATOLOGY 2013)

Introduction Patients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) ≥2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure ≤100 mm Hg or respiratory rate ≥22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis-3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections. Methods 259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients). Results Sepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (p&lt;0.01 for both). Similar results were observed in the validation cohort. Sepsis-3 (subdistribution HR (sHR)=5.47; p=0.006), qSOFA (sHR=1.99; p=0.020), Chronic Liver Failure Consortium Acute Decompensation score (sHR=1.05; p=0.001) and C reactive protein (sHR=1.01;p=0.034) were found to be independent predictors of in-hospital mortality. Patients with Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3. Conclusions Sepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance.

•Optimal liver stiffness thresholds for community-based screening of at-risk patients are 9.1–9.5 kPa for fibrosis (stages ≥F2). •Transient elastography is a cost-effective intervention for identifying patients with liver fibrosis in primary care. •Between 2,500 to 6,500 PPP-adjusted euros are needed to gain an extra year of life, adjusted for quality of life. •The survival effect of screening is most pronounced for the identification of significant (≥F2) fibrosis. Background & Aims Non-alcoholic fatty liver disease and alcohol-related liver disease pose an important challenge to current clinical healthcare pathways because of the large number of at-risk patients. Therefore, we aimed to explore the cost-effectiveness of transient elastography (TE) as a screening method to detect liver fibrosis in a primary care pathway. Methods Cost-effectiveness analysis was performed using real-life individual patient data from 6 independent prospective cohorts (5 from Europe and 1 from Asia). A diagnostic algorithm with conditional inference trees was developed to explore the relationships between liver stiffness, socio-demographics, comorbidities, and hepatic fibrosis, the latter assessed by fibrosis scores (FIB-4, NFS) and liver biopsies in a subset of 352 patients. We compared the incremental cost-effectiveness of a screening strategy against standard of care alongside the numbers needed to screen to diagnose a patient with fibrosis stage ≥F2. Results The data set encompassed 6,295 participants (mean age 55 ± 12 years, BMI 27 ± 5 kg/m2, liver stiffness 5.6 ± 5.0 kPa). A 9.1 kPa TE cut-off provided the best accuracy for the diagnosis of significant fibrosis (≥F2) in general population settings, whereas a threshold of 9.5 kPa was optimal for populations at-risk of alcohol-related liver disease. TE with the proposed cut-offs outperformed fibrosis scores in terms of accuracy. Screening with TE was cost-effective with mean incremental cost-effectiveness ratios ranging from 2,570 €/QALY (95% CI 2,456–2,683) for a population at-risk of alcohol-related liver disease (age ≥45 years) to 6,217 €/QALY (95% CI 5,832–6,601) in the general population. Overall, there was a 12% chance of TE screening being cost saving across countries and populations. Conclusions Screening for liver fibrosis with TE in primary care is a cost-effective intervention for European and Asian populations and may even be cost saving. Lay summary The lack of optimized public health screening strategies for the detection of liver fibrosis in adults without known liver disease presents a major healthcare challenge. Analyses from 6 independent international cohorts, with transient elastography measurements, show that a community-based risk-stratification strategy for alcohol-related and non-alcoholic fatty liver diseases is cost-effective and potentially cost saving for our healthcare systems, as it leads to earlier identification of patients. Non-alcoholic fatty liver disease and alcohol-related liver disease pose an important challenge to current clinical healthcare pathways because of the large number of at-risk patients. Therefore, we aimed to explore the cost-effectiveness of transient elastography (TE) as a screening method to detect liver fibrosis in a primary care pathway. Cost-effectiveness analysis was performed using real-life individual patient data from 6 independent prospective cohorts (5 from Europe and 1 from Asia). A diagnostic algorithm with conditional inference trees was developed to explore the relationships between liver stiffness, socio-demographics, comorbidities, and hepatic fibrosis, the latter assessed by fibrosis scores (FIB-4, NFS) and liver biopsies in a subset of 352 patients. We compared the incremental cost-effectiveness of a screening strategy against standard of care alongside the numbers needed to screen to diagnose a patient with fibrosis stage ≥F2. The data set encompassed 6,295 participants (mean age 55 ± 12 years, BMI 27 ± 5 kg/m2, liver stiffness 5.6 ± 5.0 kPa). A 9.1 kPa TE cut-off provided the best accuracy for the diagnosis of significant fibrosis (≥F2) in general population settings, whereas a threshold of 9.5 kPa was optimal for populations at-risk of alcohol-related liver disease. TE with the proposed cut-offs outperformed fibrosis scores in terms of accuracy. Screening with TE was cost-effective with mean incremental cost-effectiveness ratios ranging from 2,570 €/QALY (95% CI 2,456–2,683) for a population at-risk of alcohol-related liver disease (age ≥45 years) to 6,217 €/QALY (95% CI 5,832–6,601) in the general population. Overall, there was a 12% chance of TE screening being cost saving across countries and populations. Screening for liver fibrosis with TE in primary care is a cost-effective intervention for European and Asian populations and may even be cost saving.

•ACLF is common in outpatients with cirrhosis and is associated with a high short-term mortality. •Anemia, hypotension, ascites and MELD score are predictors of ACLF at 12 months in these patients. •These variables may identify patients at high risk of developing ACLF enabling strategies of surveillance and prevention to be planned. •Anemia is a potential novel target for strategies of prevention of ACLF. Background & Aims Acute-on-chronic liver failure (ACLF) is the most life-threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. Methods A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45 ± 44 months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. Results During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1 year, 5 years, and 10 years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p = 0.012), ascites (HR 2.53; p = 0.019), model of end-stage liver disease score (HR 1.26; p <0.001) and baseline hemoglobin (HR 0.07; p = 0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. Conclusions Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients. Lay summary There is a need to identify predictors of acute-on-chronic liver failure (ACLF) in patients with cirrhosis in order to identify patients at high risk of developing ACLF and to plan strategies of prevention. In this study, we identified four simple predictors of ACLF: model of end-stage liver disease (MELD) score, ascites, mean arterial pressure and hemoglobin. These variables may help to identify patients with cirrhosis, at a high risk of developing ACLF, that are candidates for new strategies of surveillance and prevention. Anemia is a potential new target for treating these patients. Acute-on-chronic liver failure (ACLF) is the most life-threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45 ± 44 months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1 year, 5 years, and 10 years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p = 0.012), ascites (HR 2.53; p = 0.019), model of end-stage liver disease score (HR 1.26; p <0.001) and baseline hemoglobin (HR 0.07; p = 0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients.

Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3).The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria.240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment.ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

Abstract Background &amp; Aims In patients with cirrhosis, the clinical benefit of the treatment with human albumin for ascites is debated, and no data are available regarding refractory ascites. In this study, in patients with cirrhosis and refractory ascites, we assessed the effect of long‐term albumin administration on emergent hospitalization and mortality. Methods Seventy patients with cirrhosis and refractory ascites, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, were included into the study. Forty‐five patients were non‐randomly assigned to receive long‐term administration of human albumin at the doses of 20 g twice per week (n = 45), in addition to standard medical of care (SOC), and compared to those followed according to SOC. Patients were followed up to the end of the study, liver transplantation or death. Results The cumulative incidence of 24‐month mortality was significantly lower in patients treated with albumin than in the group of patients treated with SOC (41.6% vs 65.5%; P = 0.032). The period free of emergent hospitalization was significantly longer in patients treated with long‐term administration of albumin ( P = 0.008). Analysing separately the causes of inpatient admission, patients treated with albumin showed a reduction in the incidence of overt hepatic encephalopathy, ascites, spontaneous bacterial peritonitis (SBP) and non‐SBP infections. In addition, a non‐significant trend towards a reduced probability of hepatorenal syndrome was observed. Conclusion In patients with cirrhosis and refractory ascites, long‐term treatment with albumin improves survival and reduces the probability of emergent hospitalizations.

Patients with refractory ascites (RA) require repeated large volume paracenteses (LVP), which involves frequent hospital visits and is associated with a poor quality-of-life. This study assessed safety and efficacy of an automated, low-flow pump (alfapump® [AP]) compared with LVP standard of care [SoC].A randomized controlled trial, in seven centers, with six month patient observation was conducted. Primary outcome was time to first LVP. Secondary outcomes included paracentesis requirement, safety, health-related quality-of-life (HRQoL), and survival. Nutrition, hemodynamics, and renal injury biomarkers were assessed in a sub-study at three months.Sixty patients were randomized and 58 were analyzed (27 AP, 31 SoC, mean age 61.9years, mean MELD 11.7). Eighteen patients were included in the sub-study. Compared with SoC, median time to first LVP was not reached after six months in the AP group, meaning a significant reduction in LVP requirement for the AP patients (AP, median not reached; SoC, 15.0days (HR 0.13; 95%CI 13.0-22.0; p<0.001), and AP patients also showed significantly improved Chronic Liver Disease Questionnaire (CLDQ) scores compared with SoC patients (p<0.05 between treatment arms). Improvements in nutritional parameters were observed for hand-grip strength (p=0.044) and body mass index (p<0.001) in the sub-study. Compared with SoC, more AP patients reported adverse events (AEs; 96.3% vs. 77.4%, p=0.057) and serious AEs (85.2 vs. 45.2%, p=0.002). AEs consisted predominantly of acute kidney injury in the immediate post-operative period, and re-intervention for pump related issues, and were treatable in most cases. Survival was similar in AP and SoC.The AP system is effective for reducing the need for paracentesis and improving quality of life in cirrhotic patients with RA. Although the frequency of SAEs (and by inference hospitalizations) was significantly higher in the AP group, they were generally limited and did not impact survival. Lay summary: The alfapump® moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, the alfapump reduces the need for large volume paracentesis (manual fluid removal by needle) in patients with medically untreatable ascites. This can improve life quality for these patients. www.clinicaltrials.gov#NCT01528410.

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute‐on‐chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28‐day follow‐up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short‐term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow‐up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow‐up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow‐up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.

Background & AimsWe performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP).MethodsWe performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course.ResultsThere were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007).ConclusionsIn a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279. We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.

BackgroundStatins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis.MethodsWe did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459.FindingsThe study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST −14 IU/L [–91 to 64; p=0·728] and for ALT −8 IU/L [–49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [–804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study.InterpretationTreatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis.FundingHorizon 20/20 European programme.

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.

Although terlipressin and albumin are effective at treating acute kidney injury-hepatorenal syndrome (AKI-HRS), liver transplantation (LT) is the best treatment. However, it is unclear if an effective treatment with terlipressin and albumin improves post-LT outcomes in these patients. The aim of this study was to evaluate the impact of response to treatment with terlipressin and albumin on posttransplant outcomes in patients with AKI-HRS.We analyzed two cohorts of patients with cirrhosis listed for LT between 2012 and 2016: 82 patients who developed AKI-HRS before LT and were treated with terlipressin and albumin and 259 patients without AKI-HRS who received transplants during the study period (control group). After LT, patients were followed up until discharge, every month for the first 3 months, and every 3 months thereafter. Of the patients, 43 (52%) responded to terlipressin and albumin. Responders had a better 30-day transplant-free survival (60% vs. 33%, P = 0.006), longer LT waiting list time (37 vs. 17 days, P = 0.041), and lower Model for End-Stage Liver Disease score at the time of LT (23 vs. 29, P = 0.007). Among patients with AKI-HRS receiving transplant, nonresponders required renal replacement therapy (RRT) more frequently than responders (20% vs. 0%, P = 0.024). Nonresponders had a significantly higher incidence of chronic kidney disease (CKD) at 1 year after LT than responders (65% vs. 31%, P = 0.019). In multivariate analysis, nonresponse to terlipressin and albumin was found to be an independent predictor for CKD at 1 year after LT (subdistribution hazard ratio [SHR] = 2.76, P = 0.001), whereas responders did not have an increased risk (SHR = 1.53, P = 0.210).In patients with AKI-HRS, response to terlipressin and albumin reduces the need for RRT after LT and reduces the risk of CKD at 1 year after LT.

Systemic inflammation and organ failure(s) are the hallmarks of acute-on-chronic liver failure (ACLF), yet their pathogenesis remains uncertain. Herein, we aimed to assess the role of amino acids in these processes in patients with ACLF.The blood metabolomic database of the CANONIC study (comprising 137 metabolites, with 43% related to amino acids) - obtained in 181 patients with ACLF and 650 with acute decompensation without ACLF (AD) - was reanalyzed with a focus on amino acids, in particular 9 modules of co-regulated metabolites. We also compared blood metabolite levels between ACLF and AD.The main findings in ACLF were: i) Metabolite modules were increased in parallel with increased levels of markers of systemic inflammation and oxidative stress. ii) Seventy percent of proteinogenic amino acids were present and most were increased. iii) A metabolic network, comprising the amino acids aspartate, glutamate, the serine-glycine one-carbon metabolism (folate cycle), and methionine cycle, was activated, suggesting increased purine and pyrimidine nucleotide synthesis. iv) Cystathionine, L-cystine, glutamate and pyroglutamate, which are involved in the transsulfuration pathway (a methionine cycle branch) were increased, consistent with increased synthesis of the antioxidant glutathione. v) Intermediates of the catabolism of 5 out of the 6 ketogenic amino acids were increased. vi) The levels of spermidine (a polyamine inducer of autophagy with anti-inflammatory effects) were decreased.In ACLF, blood amino acids fueled protein and nucleotide synthesis required for the intense systemic inflammatory response. Ketogenic amino acids were extensively catabolized to produce energy substrates in peripheral organs, an effect that was insufficient because organs failed. Finally, the decrease in spermidine levels may cause a defect in autophagy contributing to the proinflammatory phenotype in ACLF.Systemic inflammation and organ failures are hallmarks of acute-on-chronic liver failure (ACLF). Herein, we aimed to characterize the role of amino acids in these processes. The blood metabolome of patients with acutely decompensated cirrhosis, and particularly those with ACLF, reveals evidence of intense skeletal muscle catabolism. Importantly, amino acids (along with glucose), are used for intense anabolic, energy-consuming metabolism in patients with ACLF, presumably to support de novo nucleotide and protein synthesis in the activated innate immune system.

The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy.Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score.Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5-4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal.Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin - 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration.The ANSWER study has shown that long-term albumin administration improves survival and prevents the occurrence of major complications in patients with cirrhosis and ascites. This study shows that the achievement of these beneficial effects is related to a significant increase in serum albumin concentration. Even though the best results follow the achievement of a serum albumin concentration of 4 g/dl, a survival benefit is also achieved in patients who fail to normalise serum albumin.

Traditionally, the complications of cirrhosis, namely variceal bleeding, ascites and hepatic encephalopathy, were thought to result predominantly from circulatory dysfunction and altered organ perfusion arising as a result of portal hypertension. Over the past 20 years, large, international prospective studies have indicated the importance of systemic inflammation and organ immunopathology as additional determinants of organ dysfunction in cirrhosis, which not only manifests in the liver, brain, circulation and the kidneys, but also the immune system, gut, muscles, adrenal glands, reproductive organs, heart and lungs. This review provides an overview of the traditional and emerging concepts around the initiation and maintenance of organ dysfunction in cirrhosis and proposes a new paradigm based upon a better understanding of acute decompensation of cirrhosis. The interaction between the traditional concepts and the emerging perspectives remains a matter of great interest and the basis for future research.

•We assessed alterations of hemostasis in patients with decompensated cirrhosis and infections.•Infections were associated with reduced platelet aggregation (pro-hemorrhagic) and lower anticoagulants (pro-thrombotic).•Bacterial infections impair hemostatic balance in patients with decompensated cirrhosis. Background & AimsBacterial infections in cirrhosis are associated with increased bleeding risk. To assess the factors responsible for bleeding tendency in patients with bacterial infections, we conducted a prospective study comparing all 3 aspects of hemostasis (platelets, coagulation, and fibrinolysis) in hospitalized patients with decompensated cirrhosis with vs. without bacterial infections.MethodsPrimary hemostasis assessment included whole blood platelet aggregation and von Willebrand factor (VWF). Coagulation assessment included procoagulant factors (fibrinogen, factor II, V, VII, VIII, IX, X, XI, XII, XIII), natural anticoagulants (protein C, protein S, antithrombin) and thrombomodulin-modified thrombin generation test. Fibrinolysis assessment included fibrinolytic factors (plasminogen, t-PA, PAI-1, α2-AP, TAFIa/ai) and plasmin-antiplasmin complex (PAP).ResultsEighty patients with decompensated cirrhosis were included (40 with and 40 without bacterial infections). Severity of cirrhosis and platelet count were comparable between groups. At baseline, patients with cirrhosis and bacterial infections had significantly lower whole blood platelet aggregation, without significant differences in VWF. Regarding coagulation, bacterial infections were associated with reduced procoagulant factors VII and XII, and a significant reduction of all natural anticoagulants. However, thrombomodulin-modified thrombin generation was comparable between the study groups. Finally, although mixed potentially hypo-fibrinolytic (lower plasminogen) and hyper-fibrinolytic (higher t-PA) changes were present in bacterial infections, a comparable level of PAP was detected in both groups. Upon resolution of infection (n = 29/40), platelet aggregation further deteriorated whereas coagulation and fibrinolysis factors returned to levels observed in patients without bacterial infections.ConclusionIn hospitalized patients with decompensated cirrhosis, bacterial infections are associated with reduced whole blood platelet aggregation and a significant decrease of all natural anticoagulants, which may unbalance hemostasis and potentially increase the risk of both bleeding and thrombosis.Lay summaryBacterial infections are a common issue in hospitalized patients with decompensated cirrhosis (i.e. patients hospitalized due to severe complications of advanced chronic liver disease). Patients with decompensated cirrhosis who acquire infections may be at increased risk of bleeding complications following invasive procedures (that is a procedure in which the body is penetrated or entered, for instance by a needle or a tube). As bleeding complications in decompensated cirrhosis are associated with a high risk of further decompensation and death, there is an urgent need to understand the factors responsible for such increased bleeding tendency. Herein, we investigated the alterations of hemostasis (that is the physiological process responsible for clot formation and stability) in patients with decompensated cirrhosis and bacterial infections. We found that development of bacterial infections in these patients is associated with alterations of hemostasis (particularly of platelets and clotting cascade) that may increase the risk of both bleeding and thrombotic complications. Bacterial infections in cirrhosis are associated with increased bleeding risk. To assess the factors responsible for bleeding tendency in patients with bacterial infections, we conducted a prospective study comparing all 3 aspects of hemostasis (platelets, coagulation, and fibrinolysis) in hospitalized patients with decompensated cirrhosis with vs. without bacterial infections. Primary hemostasis assessment included whole blood platelet aggregation and von Willebrand factor (VWF). Coagulation assessment included procoagulant factors (fibrinogen, factor II, V, VII, VIII, IX, X, XI, XII, XIII), natural anticoagulants (protein C, protein S, antithrombin) and thrombomodulin-modified thrombin generation test. Fibrinolysis assessment included fibrinolytic factors (plasminogen, t-PA, PAI-1, α2-AP, TAFIa/ai) and plasmin-antiplasmin complex (PAP). Eighty patients with decompensated cirrhosis were included (40 with and 40 without bacterial infections). Severity of cirrhosis and platelet count were comparable between groups. At baseline, patients with cirrhosis and bacterial infections had significantly lower whole blood platelet aggregation, without significant differences in VWF. Regarding coagulation, bacterial infections were associated with reduced procoagulant factors VII and XII, and a significant reduction of all natural anticoagulants. However, thrombomodulin-modified thrombin generation was comparable between the study groups. Finally, although mixed potentially hypo-fibrinolytic (lower plasminogen) and hyper-fibrinolytic (higher t-PA) changes were present in bacterial infections, a comparable level of PAP was detected in both groups. Upon resolution of infection (n = 29/40), platelet aggregation further deteriorated whereas coagulation and fibrinolysis factors returned to levels observed in patients without bacterial infections. In hospitalized patients with decompensated cirrhosis, bacterial infections are associated with reduced whole blood platelet aggregation and a significant decrease of all natural anticoagulants, which may unbalance hemostasis and potentially increase the risk of both bleeding and thrombosis.

Background and aims Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. Methods Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. Results Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. Conclusions Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.

Patients with cirrhosis are prone to develop acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Little information is available on hepatic arterial hemodynamics in cirrhosis because of the invasiveness of methods. Hepatic arterial resistance indexes were evaluated noninvasively by Doppler ultrasonography and were correlated with portal hemodynamics evaluated both noninvasively and invasively.Hepatic arterial resistance indexes, portal blood flow velocity and volume, and portal vein congestion index were evaluated in 31 controls and 171 cirrhotic patients with (n = 13) or without (n = 158) portal vein thrombosis. Resistance to portal blood flow was also calculated in 15 patients from hepatic venous pressure gradient, measured by hepatic vein catheterization, and portal blood flow.Resistance indexes were significantly higher in cirrhotics without portal thrombosis than in controls (pulsatility index, 1.30 +/- 0.29 vs. 0.89 +/- 0.09; P < 0.001; resistive index, 0.71 +/- 0.07 vs. 0.59 +/- 0.04; P < 0.001). In patients with portal thrombosis, the pulsatility index (1.86 +/- 0.39) and resistive index (0.81 +/- 0.06) were significantly higher than in controls (P < 0.001) and in patients without thrombosis (P < 0.001). Resistance indexes directly correlated with portal resistance (P < 0.01), the congestion index (P < 0.01), and the degree of esophageal varices (P < 0.01).Hepatic arterial resistance indexes increase in cirrhosis, particularly with portal vein thrombosis. The pathophysiology of the increase in hepatic arterial resistance seems to be parallel to that of portal resistance.

The aim of the study was to define the features, prevalence, and pathophysiology of therapy for muscle cramps in cirrhotic patients. The first protocol study included 294 cirrhotic patients and 194 age- and sex-matched controls. Controls were defined as inpatients or outpatients without any clinical and laboratory evidence of liver disease. Features and prevalence of muscle cramps were defined on the basis of a standard questionnaire. As far as the pathophysiological associations of muscle cramps were concerned, the following parameters were evaluated: mean arterial pressure (MAP), nutritional status, liver function tests, plasma volume (PV), plasma renin activity (PRA), and electrolyte, mineral, and acid-base status. The prevalence of cramps was higher in cirrhotic patients than in controls, and it was related to the duration of recognized cirrhosis and to the severity of liver function impairment. At a multiple regression analysis, the presence of ascites, low values of MAP, and high values of PRA were the independent predictive factors for the occurrence of cramps in cirrhosis. In the second protocol study, the effects of a sustained expansion of the effective circulating volume induced by intravenous infusion of human albumin were compared with those of a placebo in 12 cirrhotic patients with more than three cramp crises a week. Compared with the placebo, albumin reduced the cramp frequency (P < .01). In conclusion, an increased prevalence of true muscle cramps occurs in patients with cirrhosis. Our data indicate that the pathophysiological link between cirrhosis and cramps may be represented by the reduction of the effective circulating volume. They also indicate that weekly infusion of human albumin may be an effective treatment for cramps in cirrhosis.

Background: Left ventricular systolic abnormalities have been reported in liver cirrhosis (LC). Diastolic function in cirrhotics, on the contrary, does not seem to have been studied so far. Methods: Diastolic function was evaluated in 42 cirrhotic patients and in 16 controls by means of Doppler echocardiography. Results: Compared with the controls, cirrhotics had increased left ventricular end-diastolic and left atrial volume, stroke volume, late diastolic flow velocity (peak A) (71 ± 17 cm/sec versus 56 ± 18; p < 0.01), time from onset of mitral inflow to the early peak (time E) (86 ± 11 msec versus 72 ± 14; p < 0.003), and deceleration time (DT) (194 ± 40 msec versus 159 ± 27; p < 0.001) and decreased ratio of peak E to peak A filling velocities (1.02 ± 0.35 versus 1.22 ± 0.25; p < 0.02). Patients with tense ascites had a higher E/A ratio (p < 0.03) and a shorter DT (p < 0.03) than patients with mild or no ascites. Conclusions: The impaired left ventricular relaxation in the presence of high stroke volume suggests a myocardial involvement in LC. The pseudonormalization of the E/A ratio and DT in patients with tense ascites could reflect loading conditions masking the relaxation abnormality.

The best known indicator of risk for first bleeding in patients with cirrhosis without previous bleeding is the index devised by the North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices (NIEC index), which results from the combination of size of esophageal varices, severity of red wale marks, and Child-Pugh class. Its efficiency is far from optimal, and validation studies have reported sensitivities and specificities markedly lower than those reported in the original study. In the present study we analyzed the efficiency of NIEC index in a large series of cirrhotic patients with varices without previous bleeding. In addition, we tried to improve the effectiveness of the index by modifying it, and to validate the modifications in an independent group of patients.A total of 627 patients were enrolled and followed until either a variceal bleeding or for a maximum of 2 yr. During this time, 117 experienced a first varicealUsing Cox's regression analysis, size of varices, severity of red wale marks, and Child-Pugh score were significant and independent predictors of first bleeding, as already noted in the original report of the NIEC group. However, coefficients and standard errors were markedly different, and the importance of size of esophageal varices in the regression was much larger, whereas that of Child-Pugh score was much lower. According to these data, a revised index was developed (Rev-NIEC). Using receiver operating characteristic (ROC) curve analysis, the revised index showed a larger efficiency, and the area under the curve was significantly larger (0.80 +/- 0.02 vs 0.74 +/- 0.02; p < 0.01). In particular, the curve showed that for a specificity of 75%, the new index had a sensitivity of 72% compared to that of 55% of the NIEC index. Validation in an independent sample of 84 patients showed good agreement between predicted and observed risk for bleeding. Validation with the bootstrap technique also showed adequate stability of the results.The revised index seems to be superior to the traditional index, and may turn out to be more useful in the selection of patients for different therapeutic procedures and in the stratification of patients in clinical trials.

The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available α-mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance (SVR), left forearm blood flow (LFBF), left leg blood flow (LLBF), RPF, glomerular filtration rate (GFR), UNaV, plasma renin activity (PRA), plasma concentration of antidiuretic hormone (ADH), and the serum levels of nitrite and nitrate (NOx) were evaluated in 25 cirrhotic patients with ascites (17 without HRS and 8 with type 2 HRS) before and during the 6 hours following the oral administration of 15 mg of midodrine. During the first 3 hours after the drug administration, a significant increase in MAP (89.6 ± 1.7 vs. 81.80 ± 1.3 mm Hg; P < .0001) and SVR (1,313.9 ± 44.4 vs. 1,121.2 ± 60.1 dyn · sec · cm−5; P < .0001) accompanied by a decrease in HR (69 ± 2 vs. 77 ± 3 bpm; P < .005) and CI (2,932.7 ± 131.4 vs. 3,152.5 ± 131.4 mL · min−1 · m2 BSA; P < .0025) was observed in patients without HRS. No change was observed in LFBF and LLBF. The improvement in systemic hemodynamics, which was also maintained during the the 3- to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 ± 43.1 vs. 385.7 ± 39.9 mL · min−1; P < .005), GFR (93.1 ± 6.5 vs. 77.0 ± 6.7 mL · min−1; P < .025), and UNaV (92.7 ± 16.4 vs. 72.2 ± 10.7 μEq · min−1; P < .025). In addition, a decrease in PRA (5.33 ± 1.47 vs. 7.74 ± 2.17 ng · mL−1 · h; P < .05), ADH (1.4 ± 0.2 vs. 1.7 ± 0.2 pg · mL−1; P < .05), and NOx (33.4 ± 5.0 vs. 49.3 ± 7.3 μmol−1; P < .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 ± 3.70 vs. 20.70 ± 4.82 ng · mL−1 · h; P < .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function.

Background & Aims:Portal hypertension in cirrhosis is secondary to an increase in hepatic resistance that occurs mainly through collagen deposition. However, recent evidence points to a major contribution by other factors, such as an intrahepatic reduction in nitric oxide production. Akt is a major activator of the endothelial nitric oxide synthase (eNOS) enzyme, but its potential role in intrahepatic resistance in cirrhosis is unknown. For this reason the aims of the present study were to determine whether there is an impaired Akt activation in cirrhotic livers and how this phenomenon relates to the decrease in NO production associated with portal hypertension.Methods:Cirrhosis was induced in rats by carbon tetrachloride inhalation. Protein abundance and phosphorylation status of Akt and eNOS were examined by Western blotting. The role of Akt in the liver of cirrhotic rats was investigated through infection with adenoviruses encoding either β-galactosidase (β-gal) or constitutively active Akt (myr-Akt).Results:The liver of cirrhotic animals showed a significant reduction in Akt and eNOS phosphorylation. Adenoviral delivery of myr-Akt restored eNOS phosphorylation and increased the intrahepatic concentration of guanosine 3′,5′-cyclic monophosphate. These events were associated with normalization in portal pressure and a significant increase in mean arterial pressure after 3 days of adenoviral infection. In contrast, transduction of livers with β-gal did not produce any change in these hemodynamic parameters.Conclusions:myr-Akt gene therapy restored Akt activation and NO production in the cirrhotic liver, suggesting that this therapy may be useful for the treatment of portal hypertension.

This prospective study analyzed the dropout probability and intention-to-treat survival rates of patients with hepatocellular carcinoma (HCC) selected and treated according to our policy before liver transplantation (LT), with particular attention to those exceeding the Milan criteria. Exclusion criteria for LT were macroscopic vascular invasion, metastases, and poorly differentiated disease at percutaneous biopsy. A specific multi-modal adjuvant algorithm was used to treat HCC before LT. A total of 100 HCC patients were listed for LT: 40 exceeded the Milan criteria in terms of nodule size and number (MILAN OUT) either at listing or in list, while 60 patients continued to meet the criteria (MILAN IN). The Milan criteria did not prove to be a significant predictor of dropout probability or survival rates using Cox's analysis. Cumulative dropout probability at 6 and 12 months was 0% and 4% for MILAN OUT, and 6% and 11% for MILAN IN. The intention-to-treat survival rates at 1 and 3 years were 95% and 85% in MILAN OUT, and 84% and 69% in MILAN IN. None of the 68 transplanted patients had recurrent HCC after a median 16-month follow-up (0-69 months). In conclusion, LT may be effective for selected, aggressively-treated HCC patients exceeding the Milan criteria.

Hepatorenal syndrome is a severe complication of advanced liver cirrhosis, in patients with ascites and marked circulatory dysfunction. It is clearly established that it has a functional nature, and that it is related to intense renal vasoconstriction. Despite its functional origin, the prognosis is very poor. In the present review, the most recent advances in diagnosis, pathophysiology, and treatment are discussed. Recent developments in pathophysiology are the basis of the new therapeutic strategies, which are currently under evaluation in randomised clinical trials. Hepatorenal syndrome is a severe complication of advanced liver cirrhosis, in patients with ascites and marked circulatory dysfunction. It is clearly established that it has a functional nature, and that it is related to intense renal vasoconstriction. Despite its functional origin, the prognosis is very poor. In the present review, the most recent advances in diagnosis, pathophysiology, and treatment are discussed. Recent developments in pathophysiology are the basis of the new therapeutic strategies, which are currently under evaluation in randomised clinical trials. 1. IntroductionThe occurrence of liver failure in patients with cirrhosis was first described during the 19th century, but the term hepatorenal syndrome (HRS) was first introduced in 1932 by Helvig and Schutz [[1]Helvig F.C. Schutz C.B. A liver and kidney syndrome: clinical, pathological, and experimental studies.Surg Gynecol Obstet. 1932; 55: 570-582Google Scholar] to describe a condition of acute renal failure occurring after biliary tract surgery in patients who showed a pathological pattern of acute tubular necrosis or tubular interstitial nephritis. Later on, this term reached a very wide diffusion, and was generally used to describe any kind of simultaneous severe impairment of liver and renal function. When, in the middle of the century it became progressively understood that pathophysiology of acute renal failure is grossly divided into an organic and a functional form of disease, it was clearly shown that renal involvement in advanced liver disease was generally a functional form of renal failure [[2]Hecker R. Sherlock S. Electrolyte and circulatory changes in terminal liver failure.Lancet. 1956; 2: 1121-1129Abstract Scopus (135) Google Scholar].Further studies showed that functional renal failure in advanced cirrhosis may be further divided into two forms, a more frequent, easily reversible and less severe condition of pre-renal failure due to vascular underfilling (bleeding, diarrhoea, excessive use of diuretics, heart failure), and a more severe condition, which is characterized by intense renal vasoconstriction and is similar in pathophysiological characteristics to conventional pre-renal failure, but does not improve after correction of vascular underfilling. The term HRS was thus restricted to this form of unexplained pre-renal failure in the course of advanced liver disease [[3]Papper S. The hepato-renal syndrome.Clin Nephrol. 1975; 4: 41-54PubMed Google Scholar]. Around the same time, it was observed that kidneys of patients dying of HRS could be successfully transplanted to patients with organic renal failure [[4]Koppel M.H. Coburn J.W. Mims M.M. Goldstein H. Boyle J.D. Rubini M.E. Transplantation of cadaveric kidneys from patients with hepato-renal syndrome: evidence for the functional nature of renal failure in advanced liver disease.N Engl J Med. 1969; 280: 1367-1371Crossref PubMed Scopus (223) Google Scholar], and it was shown that the intense renal vasoconstriction, which is usually observed at renal arteriography in patients with HRS (Fig. 1), disappeared at post-mortem vascular injection [[5]Epstein M. Berk D.P. Hollenberg N.K. Adams D.F. Chalmers T.C. Abrams H.L. et al.Renal failure in the patient with cirrhosis. The role of active vasoconstriction.Am J Med. 1970; 49: 175-185Abstract Full Text PDF PubMed Scopus (381) Google Scholar], emphasizing the functional nature of such renal insufficiency.In the last few years, there has been an extensive debate on the optimal criteria to define HRS and the first consensus definition was agreed upon at the 1994 meeting of the International Ascites Club [[6]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar] (Table 1). With the extensive application of these diagnostic criteria, it soon became apparent that there were some ambiguities and pitfalls in the definition of HRS, and that new and more precise diagnostic criteria were required. These new criteria were developed by the International Ascites Club at a focused study group held in San Francisco in 2006, and reported in 2007 [[7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar] (Table 2). It is evident that this new definition is more precise (clear definition of the procedures requested to exclude a prerenal failure), but is less strict than the previous one, since patients with recent or present infections, in particularly spontaneous bacterial peritonitis (SBP), are not excluded from a diagnosis of HRS.Table 1International Ascites Club’s diagnostic criteria of hepatorenal syndrome (1996; Ref. [6]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar)Major criteria:-Chronic or acute liver disease with advanced hepatic failure and portal hypertension-Low glomerular filtration rate (s-creatinine >1.5 mg/dL or creatinine clearance <40 mL/min)-Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhoea) or renal fluid losses (weight loss >500 g/day in patients with ascites without peripheral edema or 1000 g/day in patients with peripheral edema)-No sustained improvement in renal function (decrease in s-creatinine to 1.5 mg/dL or less, or increase in creatinine clearance to 40/mL/min or more) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline-Proteinuria <500 mg/day nad no ultrasonographic evidence of obstructive uropathy or parenchymal renal diseaseAdditional criteria (not necessary for the diagnosis):-Urine volume <500 mL/day-Urine sodium <10 mEq/L-Urine osmolality greater than plasma osmolality-Urine red blood cells <50/HPF-Serum sodium concentration <130 mEq/L Open table in a new tab Table 2New International Ascites Club’s diagnostic criteria of hepatorenal syndrome (2007; Ref. [7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar)-Cirrhosis with ascites-Serum creatinine > 1.5 mg/dL-No improvement in serum creatinine (decrease to a level of <1.5 mg/dL) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day-Absence of shock-No current or recent treatment with nephrotoxic drugs-Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (<50 RBC/high power field) and/or abnormal renal ultrasonography Open table in a new tab Such changes should be taken into consideration when comparing treatment results of new studies with those obtained in the previous years, because changes in definitions may lead to a sort of stage migration, a phenomenon that is well known to bio-statisticians [[8]Feinstein A.R. Sosin D.M. Wells C.K. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.N Engl J Med. 1985; 312: 1604-1608Crossref PubMed Scopus (1278) Google Scholar], and is characterized by an improvement in outcome in both stages involved (Fig. 2). Indeed, if patients with infections unresponsive to a 2-day infusion of albumin have a mortality rate intermediate between classical HRS and pre-renal azotemia (with the values suggested in the figure), the migration of these patients towards the group of patients with HRS would decrease mortality in HRS from 80% to 65%, and that of pre-renal azotemia from 27.5% to 20%.Fig. 2Expected changes in mortality rate of HRS and of pre-renal failure according to the old (1996 – Ref. [[6]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar]) and new (2007- Ref. [[7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar]) definitions of HRS because of the stage-migration effect of patients with infections not responding to a 2-day course of albumin. Frequencies and mortality rates are approximate and only used for exemplifying purpose.View Large Image Figure ViewerDownload Hi-res image Download (PPT)2. Natural historyHRS is a potentially reversible form of renal failure that occurs in patients with cirrhosis and ascites as well as in patients with acute liver failure. In cirrhotic patients with ascites, pre-renal failure (42%) and acute tubular necrosis (ATN) (38%) represent the most common forms of acute renal failure while HRS [[9]Moreau R. Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.Hepatology. 2003; 37: 233-243Crossref PubMed Scopus (198) Google Scholar] is somewhat less frequent (20%) (Table 3). The incidence of HRS in patients with cirrhosis and ascites is equal to 18% after 1 year, and reaches 39% after 5 years [[10]Gines A. Escorsell A. Gines P. Salo J. Jimenez W. Inglada L. et al.Incidence, predictive factors and prognosis of the hepato-renal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar]. In almost half the cases of HRS, one or more precipitating factors may be identified, including bacterial infections (57%), gastrointestinal hemorrhage (36%), and large volume paracentesis (7%) [[10]Gines A. Escorsell A. Gines P. Salo J. Jimenez W. Inglada L. et al.Incidence, predictive factors and prognosis of the hepato-renal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar].Table 3Acute renal failure in patients with cirrhosis and ascites (Ref. [9]Moreau R. Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.Hepatology. 2003; 37: 233-243Crossref PubMed Scopus (198) Google Scholar)1.Acute tubular necrosis (41.7%)2.Pre-renal failure (38%)3.Hepatorenal syndrome (20%)4.Post-renal failure (0.3%) Open table in a new tab HRS is characterized by (a) marked renal vasoconstriction with a consequent reduction in renal plasma flow and glomerular filtration rate, (b) the absence of pathological changes in the renal tissue, and (c) preserved renal tubular function. HRS usually arises when the chronic liver disease is associated with a marked circulatory dysfunction with low values of arterial pressure despite an overactivity of the sympathetic nervous and renin–angiotensin systems, which, according to the “arterial vasodilation hypothesis” occurs as a consequence of a marked arterial vasodilation, mainly located in the splanchnic circulation [[11]Schrier R.W. Arroyo V. Bernardi M. Epstein M. Henriksen J.H. Rodes J. Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.Hepatology. 1988; 8: 1151-1157Crossref PubMed Scopus (1376) Google Scholar]. Until a few years ago, the prognosis of cirrhotic patients developing HRS was very poor with mortality reaching 100% in some series, and a median survival time of two weeks from diagnosis [[10]Gines A. Escorsell A. Gines P. Salo J. Jimenez W. Inglada L. et al.Incidence, predictive factors and prognosis of the hepato-renal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar]. Thereafter, some new promising treatments of HRS have been proposed, and improvement in survival has been observed in some studies.3. Diagnosis of HRSThe diagnostic criteria for a diagnosis of HRS have been reported above in the introduction (Table 1, Table 2). Within the diagnostic category of HRS, two different types of HRS can be distinguished (Table 4). Type-1 HRS is characterized by a rapid progression of renal failure; therefore the main clinical presentation is overt acute renal failure. By contrast, in patients with Type 2 HRS the degree of the impairment of renal failure is less severe and more stable over time. As a consequence, the main clinical problem in these patients is refractory ascites (Table 4). The two types of HRS substantially differ in prognosis, since median survival of type-1 HRS averages 2 weeks, whilst that of type 2 is generally around 4–6 months [[12]Gines P. Guevara M. Arroyo V. Rodes J. Hepato-renal syndrome.Lancet. 2003; 362: 1819-1827Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar]. Besides the obvious differences in the severity of renal function impairment, further pathophysiological differences between type-1 and type-2 HRS are not fully elucidated, and it is not clearly defined if the two types share all the same pathophysiological mechanisms; nevertheless, it may be observed that Type-1 HRS is often induced by a precipitating event (Table 5), in particular spontaneous bacterial peritonitis [13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar, 14Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar]. Almost one third of patients with spontaneous bacterial peritonitis develop a progressive form of renal failure [13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar, 14Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar] which in most cases fulfils the most recent diagnostic criteria of type 1 HRS [[14]Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar]. More recently it has been observed that renal failure can be precipitated in cirrhotic patients with ascites by all types of bacterial infections. In most cases renal failure is transient and recovers after the resolution of the infection. However, in some cases an acute renal failure with the hallmarks of type 1 HRS can also be precipitated by urinary, biliary, or intestinal infections [[15]Fasolato S. Angeli P. Dallagnese L. Maresio G. Zola E. Mazza E. et al.Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.Hepatology. 2007; 45: 223-229Crossref PubMed Scopus (238) Google Scholar]. The risk factors for the development of renal failure after bacterial infections are (a) the severity of infection, (b) the MELD score at the diagnosis of infection and (c) the persistence of infection despite antibiotic treatment [15Fasolato S. Angeli P. Dallagnese L. Maresio G. Zola E. Mazza E. et al.Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.Hepatology. 2007; 45: 223-229Crossref PubMed Scopus (238) Google Scholar, 16Terra C. Guevara M. Torre A. Gilabert R. Fernandez J. Martin-Llahi M. et al.Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.Gastroenterology. 2005; 129: 1944-1953Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar]. In addition, the risk of developing type-1 HRS following a bacterial infection is higher in patients with cirrhosis who already present a type-2 HRS [13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar, 14Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar]. There are some observations suggesting that type-1 HRS in this clinical situation may occur as a consequence of an abrupt and severe additional deterioration in circulatory dysfunction characterized by a further enhancement in splanchnic arterial vasodilation and a decrease in cardiac output.Table 4Clinical types of hepatorenal syndrome (Ref. [7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar)-Type-1 hepatorenal syndrome: rapidly progressive reduction of renal function as defined by doubling of the initial s-creatinine to a level >2.5 mg/dL (226 μM/L) in less than two weeksClinical pattern: acute renal failure-Type-2 hepatorenal syndrome: moderate renal failure (s-creatinine ranging from 1.25 to 2.5 mg/dL or 113–226 μM/L) with a steady or slowly progressive courseClinical pattern: refractory ascites Open table in a new tab Table 5Precipitating events of hepatorenal syndrome-Spontaneous bacterial peritonitis-Paracentesis without plasma expansion-Gastrointestinal hemorrhage-Alcoholic hepatitis Open table in a new tab 4. Pathophysiology of HRSThe causes of the intense renal vasoconstriction underlying the occurrence of HRS are not fully understood. Compared to control subjects or cirrhotic patients with ascites but without HRS, patients with HRS consistently show lower splanchnic vascular resistance. Renal vasoconstriction, which is the pathophysiological basis of HRS, therefore develops in a context of a marked reduction of effective circulating volume related to peripheral arterial vasodilation [6Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar, 13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar]. The involvement of endogenous vasoconstrictor systems induced by the reduction of effective circulating volume in the development of HRS is clearly shown in clinical [17Arroyo V. Planas R. Gaya J. Deulofeu J. Rimola A. Perez-Ayuso R.M. et al.Sympathetic nervous activity, renin–angiotensin system and renal excretion of prostaglandin E2 in cirrhosis. Relationship to functional renal failure and sodium and water excretion.Eur J Clin Invest. 1983; 13: 271-278Crossref PubMed Scopus (199) Google Scholar, 18Henriksen J.H. Ring-Larsen H. Hepato-renal disorders: role of the sympathetic nervous system.Sem Liver Dis. 1994; 14: 35-43Crossref PubMed Scopus (76) Google Scholar, 19Gentilini P. Romanelli R.G. La Villa G. Maggiore Q. Pesciullesi E. Cappelli G. et al.Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver.Gastroenterology. 1993; 104: 588-594Abstract PubMed Google Scholar] and experimental studies [[20]Solis-Herruzo J.A. Duran A. Favela V. Castellano G. Madrid J.L. Munoz-Yague M.T. et al.Effects of lumbar sympathetic block on kidney function in cirrhotic patients with hepato-renal syndrome.J Hepatol. 1987; 5: 167-173Abstract Full Text PDF PubMed Scopus (83) Google Scholar]. The most recent advances in our understanding of the pathogenesis of HRS have focused on mainly two new aspects. The first one is that the peripheral arterial vasodilation occurs mainly in the splanchnic arterial vascular bed and the second is that in patients with cirrhosis and HRS, the modulation of cardiac output is relatively unable to prevent the severe reduction of effective circulating volume due to the splanchnic arterial vasodilation.The first of these concepts has been formulated on the basis of the results of some clinical studies in which Doppler ultrasonography was used to evaluate regional blood flow in cirrhotic patients. These studies consistently demonstrated that arterial vasodilation occurs in the splanchnic circulation in patients with cirrhosis, while arterial vasoconstriction occurs in other vascular beds, including renal, brachial, femoral, and cerebral beds [21Piscaglia F. Zironi G. Gaiani S. Ferlito M. Rapezzi C. Siringo S. et al.Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity.Eur J Gastroenterol Hepatol. 1997; 9: 799-804Crossref PubMed Scopus (24) Google Scholar, 22Fernandez-Seara J. Prieto J. Quiroga J. Zozaia J.M. Cobos M.A. Rodriguez-Eire J.L. et al.Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure.Gastroenterology. 1989; 97: 1304-13012PubMed Google Scholar, 23Maroto A. Gines P. Arroyo V. Gines A. Salò J. Claria J. et al.Brachial and femoral artery blood flow in cirrhosis: relationship to kidney dysfunction.Hepatology. 1993; 17: 788-793PubMed Google Scholar, 24Sacerdoti D. Bolognesi M. Merkel C. Angeli P. Gatta A. Renal vasoconstriction in cirrhosis evaluated by duplex ultrasonography.Hepatology. 1993; 17: 219-224PubMed Google Scholar, 25Dillon J.F. Plevris J.N. Wong F.C. Chan K.H. Lo N.T. Miller J.D. et al.Middle cerebral artery blood flow velocity in patients with cirrhosis.Eur J Gastroenterol Hepatol. 1995; 7: 1087-1091Crossref PubMed Scopus (32) Google Scholar, 26Rivolta R. Maggi A. Cazzaniga M. Castagnone D. Panzeri A. Solenghi D. et al.Reduction of renal cortical blood flow assessed by Doppler in cirrhotic patients with refractory ascites.Hepatology. 1998; 28: 1235-1240Crossref PubMed Scopus (57) Google Scholar, 27Guevara M. Bru C. Gines P. Fernadez-Esparrach G. Sort P. Bataller R. et al.Increased cerebrovascular resistance in cirrhotic patients with ascites.Hepatology. 1998; 28: 39-44Crossref PubMed Scopus (134) Google Scholar, 28Sugano S. Yamamoto K. Atobe T. Watanabe M. Vakui N. Iwasaki N. et al.Postprandial middle cerebral arterial vasoconstriction in cirrhotic patients. A placebo controlled evaluation.J Hepatol. 2001; 34: 373-377Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. At the same time, clinical studies directed to assess tissue-related blood flows, such as cutaneous and muscular blood flows, gave contrasting results, ranging from low to normal or even increased values [[29]Moller S. Henriksen J. The systemic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. II ed. Blackwell Publ., 2005: 139-155Google Scholar]. These discrepancies were also dependent on the methods used to estimate blood flow, which included color Doppler ultrasonography [21Piscaglia F. Zironi G. Gaiani S. Ferlito M. Rapezzi C. Siringo S. et al.Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity.Eur J Gastroenterol Hepatol. 1997; 9: 799-804Crossref PubMed Scopus (24) Google Scholar, 30Luca A. Garcia-Pagan J.C. Feu F. Lopez-Talavera J.C. Fernandez M. Bru C. et al.Noninvasive measurement of femoral blood flow and portal pressure response to propranolol in patients with cirrhosis.Hepatology. 1995; 21: 83-88PubMed Google Scholar], nuclear medicine techniques [[31]Carella M. Hunter J.O. Fazio S. Dela Piano C. Bartoli G.C. Capillary blood flow in the skin of forearm in cirrhosis.Angiology. 1992; 43: 969-974Crossref PubMed Scopus (15) Google Scholar], and plethysmography [[32]Newby D.E. Jalan R. Masumori S. Hayes P.C. Boon N.A. Webb D.J. Peripheral vascular tone in patients with cirrhosis: role of the rennin–angiotensin and sympathetic nervous systems.Cardiovasc Res. 1998; 38: 223-228Google Scholar]. The main clinical problem related to abnormalities of muscle blood flow is the occurrence of muscle cramps, which may be improved by a chronic expansion of effective plasma volume by means of albumin administration [[33]Angeli P. Albino G. Carraro P. Dalla Pria M. Merkel C. Caregaro L. et al.Cirrhosis and muscle cramps: evidence of a causal relationship.Hepatology. 1996; 23: 264-273Crossref PubMed Google Scholar], a procedure which probably contributes to correct the abnormalities of muscle blood flow.Splanchnic arterial vasodilatation is thought to be the consequence of an increased release of endogenous vasodilators due to portal hypertension and/or hepatic failure. Among the endogenous vasodilators, nitric oxide [[34]Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (370) Google Scholar], carbon monoxide [[35]Bolognesi M. Sacerdoti D. Piva A. Di Pascoli M. Zampieri F. Quarta S. et al.Carbon monoxide-mediated activation of large conductance calcium-activated potassium channels contributes to mesenteric vasodilation in cirrhotic rats.J Pharmacol Exp Ther. 2007; 321: 187-194Crossref PubMed Scopus (55) Google Scholar], glucagon [[36]Sieber C.C. Mosca P.G. Groszmann R.J. Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertensive rats.Am J Physiol. 1992; 262: G274-G277PubMed Google Scholar], prostacyclin [[37]Fernandez M. Garcia-Pagan J.C. Casadevall M. Acute and chronic cyclooxygenase blockade in portal-hypertensive rats: influence on nitric oxide biosynthesis.Gastroenterology. 1998; 110: 1529-1535Abstract Full Text Full Text PDF Scopus (95) Google Scholar], adrenomedullin [[38]Guevara M. Gines P. Jimenez W. Sort P. Fernandez-Esparrach G. Escorsell A. et al.Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems.Gastroenterology. 1998; 114: 336-343Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar] and endogenous opiates [[39]Ros J. Claria J. To-Figueras J. Planagumà A. Cejudo-Martı`n P. Fernandez-Varo G. et al.Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.Gastroenterology. 2002; 122: 85-93Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar] seem to be the most clearly involved. A detailed analysis of all possible vasodilators involved in the pathogenesis of splanchnic arterial vasodilations goes beyond the purposes of this paper; however it is apparent that several endogenous vasodilators can contribute to splanchnic arterial vasodilation in every stage of progression of cirrhosis, and that the relative role of each of them can vary in the different stages of the liver disease [[40]Angeli P. Fernandez-Varo G. Dalla Libera V. Fasolato S. Galioto A. Arroyo V. et al.The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites.Liver. 2005; 29: 429-437Google Scholar]. Indeed, early in the course of the disease, the decrease in the systemic vascular resistance due to the arterial splanchnic vasodilation is compensated by the increase in heart rate and in cardiac output (the so-called “hyperdynamic circulation”). However, as the liver disease progresses leading to a further impairment in portal hypertension and hepatic failure, the hyperdynamic circulation is no longer adequate to compensate the severity of the reduction of the effective blood volume due to the splanchnic arterial vasodilation. This leads to a further activation of the systemic endogenous vasoconstrictor systems (the sympathetic nervous system, the renin–angiotensin system, a

The role of bridging therapies for patients with hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT) remains controversial. There is strong evidence to support the effectiveness of sorafenib in extending the time to progression of HCC. Using a Markov model, we compared two strategies: one using sorafenib as neoadjuvant therapy before LT (Strategy A), and the other using no bridging therapy in the first 6 months (Strategy B). Reference case: T2 HCC patient with compensated cirrhosis. The benefit of sorafenib in delaying time to HCC progression was expressed as the hazard ratio (HR) and taken from recently published randomized trials. The endpoints considered were: survival benefit measured in quality-adjusted life days (QALDs), transplant probability, costs (C) in euro, willingness to pay (WTP), and net health benefit (NHB), where NHB = survival benefit - C/WTP. The calculated WTP of sorafenib in Italy was 346 euro per QALD. Probabilistic sensitivity analysis showed a median survival benefit of 94 QALDs (10% percentile = 38, 90% percentile = 210). In the base-case scenario (HR = 0.47, monthly dropout probability = 5%, median time to LT = 3 months), the gain in LT probability due to sorafenib was 5% and it increased proportionally with increasing median times to LT and decreasing HR. In the cost-benefit analysis, the incremental NHB of Strategy A versus Strategy B was 37 QALDs; it increased as sorafenib HR decreased and when median times to LT were shorter than 6 months, whereas for longer times it gradually dropped, particularly when Strategy B included effective locoregional treatments.Sorafenib neoadjuvant therapy is cost-effective by comparison with no therapy for T2-HCC patients waiting for LT, particularly for median times to LT under 6 months.

Hepatorenal syndrome (HRS) is a severe complication of cirrhosis that is associated with poor survival. A rapid diagnosis of HRS and a prompt initiation of the treatment with terlipressin and albumin are mandatory because this leads to an improvement of prognosis.This review covers the predictive value of HRS on 3-month mortality beyond the MELD score and its consequential impact on the prioritization policy to liver transplantation (LT). Moreover, it analyzes the impact of the response to pharmacological treatment on the MELD score, its possible delaying effect on the timing of LT, and suggests a way of overcoming the paradoxical effect of terlipressin and albumin on the priority to LT in responders.Finally, the review discusses the appropriate use of combined liver–kidney transplantation (CLKT) in patients with HRS who do not respond to treatment with terlipressin and albumin.

Background & Aims Hepatorenal syndrome (HRS) is a severe complication of cirrhosis with ascites. The International Ascites Club recommended strict diagnostic criteria and treatment with vasoconstrictors and albumin. Aim of this prospective cohort study was to investigate the prevalence of HRS, diagnostic criteria, treatment and 3-month outcome in the daily-clinical-practice. Methods Two-hundred-fifty-three patients with cirrhosis and renal failure consecutively admitted to 21 Italian hospitals were recruited. Results The prevalence of HRS was 45.8% (30% type-1 and 15.8% type-2). In 36% of cases HRS was presumed because not all diagnostic criteria could be fulfilled. In 8% of cases HRS was superimposed on an organic nephropathy. Patients with HRS type-1 were younger and showed higher leukocyte count, higher respiratory rates, and worse liver function scores. Sixty-four patients with HRS type-1 received vasoconstrictors (40 terlipressin and 24 midodrine/octreotide). A complete response was obtained in 19 cases (30%) and a partial response in 13 (20%). Age was the only independent predictor of response (p = 0.033). Three-month survival of patients with HRS type-1 was 19.7%. Survival was better in patients who responded to therapy. Age (p= 0.017), bilirubin (p= 0.012), and creatinine increase after diagnostic volume expansion (p= 0.02) independently predicted death. The mortality rate was 97% among patients with at least two negative predictors. Conclusions The diagnostic criteria of HRS in our daily-clinical-practice could not be completely fulfilled in one third of cases. The treatment with vasoconstrictors and albumin was widely implemented. Mortality was strongly predicted by simple baseline variables. Hepatorenal syndrome (HRS) is a severe complication of cirrhosis with ascites. The International Ascites Club recommended strict diagnostic criteria and treatment with vasoconstrictors and albumin. Aim of this prospective cohort study was to investigate the prevalence of HRS, diagnostic criteria, treatment and 3-month outcome in the daily-clinical-practice. Two-hundred-fifty-three patients with cirrhosis and renal failure consecutively admitted to 21 Italian hospitals were recruited. The prevalence of HRS was 45.8% (30% type-1 and 15.8% type-2). In 36% of cases HRS was presumed because not all diagnostic criteria could be fulfilled. In 8% of cases HRS was superimposed on an organic nephropathy. Patients with HRS type-1 were younger and showed higher leukocyte count, higher respiratory rates, and worse liver function scores. Sixty-four patients with HRS type-1 received vasoconstrictors (40 terlipressin and 24 midodrine/octreotide). A complete response was obtained in 19 cases (30%) and a partial response in 13 (20%). Age was the only independent predictor of response (p = 0.033). Three-month survival of patients with HRS type-1 was 19.7%. Survival was better in patients who responded to therapy. Age (p= 0.017), bilirubin (p= 0.012), and creatinine increase after diagnostic volume expansion (p= 0.02) independently predicted death. The mortality rate was 97% among patients with at least two negative predictors. The diagnostic criteria of HRS in our daily-clinical-practice could not be completely fulfilled in one third of cases. The treatment with vasoconstrictors and albumin was widely implemented. Mortality was strongly predicted by simple baseline variables.

Quantification of the number of noninhibited responses (lures) in the inhibitory control task (ICT) has been proposed for the diagnosis of minimal hepatic encephalopathy (MHE). We assessed the efficacy of ICT compared with recommended diagnostic standards.We studied patients with cirrhosis and healthy individuals (controls) who underwent the ICT at 2 centers (center A: n=51 patients and 41 controls, center B: n=24 patients and 14 controls). Subjects were evaluated for MHE by psychometric hepatic encephalopathy score (PHES). Patients from center B also were assessed for MHE by critical flicker frequency and spectral electroencephalogram analyses.Patients with cirrhosis had higher ICT lures (23.2+/-12.8 vs 12.9+/-5.8, respectively, P<.01) and lower ICT target accuracy (0.88+/-0.17 vs 0.96+/-0.03, respectively, P<.01) compared with controls. However, lures were comparable (25.2+/-12.5 vs 21.4+/-13.9, respectively, P=.32) among patients with/without altered PHES (center A). There was a reverse, U-shaped relationship between ICT lure and target accuracy; a variable adjusting lures was devised based on target accuracy (weighted lures at center B). This variable differed between patients with and without MHE. The variable weighted lures was then validated from data collected at center A by receiver operator characteristic curve analysis; it discriminated between patients with and without PHES alterations (area under the curve=0.71+/-0.07). However, target accuracy alone was as effective as a stand-alone variable (area under the curve=0.81+/-0.06).The ICT is not useful for the diagnosis of MHE, unless adjusted by target accuracy. Testing inhibition (lures) does not seem to be superior to testing attention (target accuracy) for the detection of MHE.

Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V(2) receptor antagonist, satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia.One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg (n=39), 12.5mg (n=36), 25mg (n=40) of satavaptan or placebo (n=36) for 12 weeks. Their Child-Pugh scores were 9.2+/-1.3, 8.7+/-1.7, 8.8+/-1.3, and 9.0+/-1.5, respectively.Median time to first paracentesis was 23, 26, and 17 days with satavaptan 5, 12.5, and 25mg, respectively, versus 14 days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly (p<0.05) in all satavaptan groups versus placebo. Mean increase in ascites was 2.82+/-0.48 L/week for placebo versus 2.12+/-0.40, 2.14+/-0.33, and 2.06+/-0.40 L/week for the 5, 12.5, and 25mg of satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan.Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.

The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy-two patients and 14 healthy volunteers underwent EEG and paper-and-pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)α, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE-related hospitalizations. Thirty-three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 ± 22 vs 7 ± 6, P < 0.01), IL6 (32 ± 54 vs 12 ± 13, P < 0.05) and TNFα (17 ± 8 vs 11 ± 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 ± 270 vs 258 ± 255, P < 0.01) and ammonia (66 ± 35 vs 45 ± 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFα and IL6; EEG indices with ammonia and IL6. CRP and TNFα concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow-up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05). Conclusion: PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome. (HEPATOLOGY 2011;53:558-566)

Advanced cirrhosis is often complicated by a multi organ failure syndrome which involves many different organs besides the liver. The high morbidity and mortality secondary to this clinical setting is often related to renal dysfunction, either alone or, more frequently, in combination with other organ dysfunction. A clear definition of renal dysfunction, an accurate differential diagnostic process of its different phenotypes as well as of full understanding of its pathophysiological mechanisms are crucial to the development of strategies for the management of this complication. This article is based either on the more recent knowledge on renal dysfunction in advanced cirrhosis or current opinions among the members of the International Club of Ascites (ICA) on the management of this complication, obtained through a survey and discussed during the EASL-ICA Joint Meeting in Berlin in March 2011. It reviews critically our current knowledge and it outlines future perspectives, on the management of renal dysfunction in patients with cirrhosis.

Summary Background &amp; Aims A moderate sodium restriction diet should be indicated in patients with cirrhosis and ascites. Nevertheless, there is a lack of specific investigation on its correct application. To evaluate the adherence of patients with cirrhosis and ascites to a moderately low‐salt diet and the impact on intake of total calories and serum sodium concentration. Methods A total of 120 outpatients with cirrhosis and ascites were interviewed with a pre‐established questionnaire. A quantitative assessment of nutrient and salt intake was performed. Result A moderately low‐salt diet was followed by 37 patients (Group A). Of the 83 patients who did not follow the diet (Group B), 54 thought that they were following it. The mean daily sodium intake was 79.5 ± 5.5 mmol/day (Group A) and 205.9 ± 14.1 mmol/day (Group B), P &lt; 0.0001. The adherence to diet was related to the severity of cirrhosis, and was higher among candidates for liver transplantation and in patients followed through the Care Management Program. Patients of Group A had reduced the mean daily calorie intake by 20% compared with Group B patients ( P &lt; 0.0005), while there was no difference on the occurrence of hyponatraemia. Conclusions This study shows a poor adherence of patients with cirrhosis and ascites to a moderate dietary sodium restriction. Adherence to a diet seems to increase with the worsening of liver disease, probably because of the reduction of alternative therapeutic options. In addition, a deficiency in the educational process can lead the patient to follow a sodium‐reduced diet by means of dangerous tools, such as reducing the overall daily food intake.

The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function remained slightly worse; in contrast, EEGs normalized in both groups. Liver Transpl 20:977-986, 2014. © 2014 AASLD.

Abstract Background &amp; Aims Bacterial strains resistant to antibiotics are a serious clinical challenge. We assessed the antibiotic susceptibility of bacteria isolated from infections in patients with cirrhosis by a multicentre investigation. Results Three hundred and thirteen culture‐positive infections (173 community acquired [ CA ] and 140 hospital acquired [ HA ]) were identified in 308 patients. Urinary tract infections, spontaneous bacterial peritonitis and bacteremias were the most frequent. Quinolone‐resistant Gram‐negative isolates were 48%, 44% were extended‐spectrum beta‐lactamase producers and 9% carbapenem resistant. In 83/313 culture‐positive infections (27%), multidrug‐resistant agents ( MDRA ) were isolated. This prevalence did not differ between CA and HA infections. MDRA were identified in 17 of 37 patients on quinolone prophylaxis, and in 46 of 166 not on prophylaxis (45% vs 27%; P &lt;.03). In 287 cases an empiric antibiotic therapy was undertaken, in 37 (12.9%) this therapy failed. The in‐hospital mortality rate of this subset of patients was significantly higher compared to patients who received an effective broad(er)‐spectrum therapy ( P =.038). During a 3‐month follow‐up, 56/203 culture‐positive patients (27.6%) died, 24/63 who have had MDRA ‐related infections (38%) and 32/140 who have had antibiotic‐susceptible infections (22.8%) ( P =.025). Multivariate analysis disclosed MDRA infection, age, hepatocellular carcinoma, bilirubin, international normalized ratio and the occurrence of portal hypertension‐related complications independent predictors of death. Conclusions Infection by MDRA is frequent in patients with cirrhosis and the prognosis is severe, especially in patients unresponsive to empiric antibiotic therapy.

Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.