Carlo Alessandria

Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis

BACKGROUND & AIMS 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. METHODS 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%). RESULTS 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. CONCLUSIONS 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.

MELD score and clinical type predict prognosis in hepatorenal syndrome: Relevance to liver transplantation†

Important progress has been made recently regarding the pathogenesis and treatment of hepatorenal syndrome (HRS). However, scant information exists about factors predicting outcome in patients with cirrhosis and HRS. Moreover, the prognostic value of the model of end‐stage liver disease (MELD) score has not been validated in the setting of HRS. The current study was designed to assess the prognostic factors and outcome of patients with cirrhosis and HRS. The study included 105 consecutive patients with HRS. Forty‐one patients had type 1 HRS, while 64 patients had type 2 HRS. Patients with type 1 HRS not only had more severe liver and renal failure than type 2 patients, they also had greater impairment of circulatory function, as indicated by lower arterial pressure and higher activation of vasoconstrictor factors. In the whole series, the median survival was 3.3 months. In a multivariate analysis of survival, only HRS type and MELD score were associated with an independent prognostic value. All patients with type 1 HRS had a high MELD score (≥20) and showed an extremely poor outcome (median survival: 1 mo). By contrast, the survival of patients with type 2 HRS was longer and dependent on MELD score (≥20, median survival 3 mo; <20, median survival 11 mo; P < .002). In conclusion, the outcome of patients with cirrhosis and HRS can be estimated by using two easily available variables, HRS type and MELD score. These data can be useful in the management of patients with HRS, particularly for patients who are candidates for liver transplantation. (HEPATOLOGY 2005.)

Development and Validation of a Prognostic Score to Predict Mortality in Patients with Acute on Chronic Liver Failure.

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence

Hepatitis B virus (HBV) recurrence after liver transplantation is significantly reduced by prophylaxis with hepatitis B immune globulins (HBIG) or antiviral drugs in nonreplicating patients and by the combination of both drugs in replicating patients. However, the load of HBV DNA, which defines replicating status in patients undergoing liver transplantation, remains unclear. This study analyzes the correlation between the viral load, tested with a single amplified assay, at the time of liver transplantation, and the risk of hepatitis B recurrence in 177 HBV carriers who underwent transplantation in a single center from 1990 to 2002. Overall, HBV relapsed after surgery in 15 patients (8.5%) with a 5‐ and 8‐year actuarial rate of recurrence of 8% and 21%, respectively. After liver transplantation hepatitis B recurred in 9% of 98 selected subjects treated only with immune globulins and in 8% of 79 viremic patients who received immune globulins and lamivudine (P = NS). A linear correlation was observed between recurrence and viral load at the time of surgery. In transplant patients with HBV DNA higher than 100,000 copies/mL, 200–99,999 copies/mL, and DNA undetectable by amplified assay, hepatitis B recurred in 50%, 7.5%, and 0% of patients, respectively. Overall, a viral load higher than 100,000 copies/mL at the time of liver transplantation was significantly associated with hepatitis B recurrence (P = .0003). In conclusion, spontaneous or antiviral‐induced HBV DNA viral load at the time of surgery classifies the risk of HBV recurrence after liver transplantation and indicates the best prophylaxis strategy. (Liver Transpl 2005;11:402–409.)

Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.

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. Conclusions: 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. (Hepatology 2015;62:243‐252)

Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2

Objectives Renal failure secondary to hepatorenal syndrome or to organic renal disease occurs frequently in cirrhotic patients with portal hypertension. The present prospective study investigates the usefulness of terlipressin in both the diagnostic and the therapeutic approach to cirrhotics with renal failure. Patients and methods Sixteen patients were studied: 11 with hepatorenal syndrome type 2 (group 1) and five with organic renal disease (group 2). All received terlipressin (1 mg/4 h intravenously) for 7 days. Subsequently, 12 patients (nine from group 1 and three from group 2) underwent a transjugular intrahepatic portosystemic shunt. Results Terlipressin significantly improved renal function (serum creatinine, 1.8 ± 0.8 versus 2.4 ± 0.9 mg/dl; blood creatinine clearance, 53 ± 8 versus 21.3 ± 8.7 ml/min; P < 0.05) in group 1 [8/11 patients (73%) versus 1/5 (20%) of group 2; P < 0.05]. The only patient in group 2 who responded to terlipressin had a mixed renal dysfunction. Renal function improved significantly after transjugular portosystemic shunt in all patients who responded to terlipressin. Conclusions Terlipressin administration significantly improves renal function in cirrhotic patients with hepatorenal syndrome type 2 but not in organic kidney failure. By providing the critical information that a patients kidney function is (or is not) reversible, a trial with terlipressin may be useful when selecting cirrhotic patients with renal failure as candidates for a transjugular intrahepatic portosystemic shunt or liver transplantation.

Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis.

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo‐inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo‐osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by 1H–magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline‐containing compounds, creatine/phosphocreatine, and N‐acetyl‐aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients. (HEPATOLOGY 2004;39:1613‐1622.)

The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure

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. Conclusion: These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249‐1264).

Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites.

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 defintion 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.