A. Risso

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)

Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis

Objective 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). Design 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 enrolment and 48 h after enrolment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. Results 240 patients (47.1%) met the criteria of ACLF at enrolment, 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 enrolment. Conclusions ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

Prevention of paracentesis-induced circulatory dysfunction in cirrhosis: Standard vs half albumin doses. A prospective, randomized, unblinded pilot study

BACKGROUND Paracentesis-induced circulatory dysfunction is a well-known complication of large volume paracentesis. Albumin infusion (8g of albumin/L of ascites removed) is effective in preventing it, but high costs and scant availability limit its use. AIM To compare standard vs half albumin doses. METHODS Seventy cirrhotic patients treated with large volume paracentesis were randomized to receive intravenous albumin as prevention of paracentesis-induced circulatory dysfunction: group 1 (35 patients) received 4g/L of ascites removed, group 2 (35 patients) received 8g/L of ascites removed. RESULTS The incidence of paracentesis-induced circulatory dysfunction (14% vs 20% in group 1 and group 2, respectively; p=ns), hyponatremia (9% vs 6%, p=ns) and renal impairment (0% in both groups) on the 6th day from paracentesis was similar between the two groups. After 6 months of follow-up, rates of survival and of recurrence of ascites requiring large volume paracentesis were not different between the two groups. CONCLUSIONS This unblinded, randomized, pilot study suggests that treatment with half doses of albumin is effective in the prevention of paracentesis-induced circulatory dysfunction and its related clinical complications in cirrhotic patients with tense ascites treated by large volume paracentesis. If confirmed, these results could support a significant costs reduction in the management of ascites in cirrhotic patients.

Urine Monocyte Chemoattractant Protein-1 Is an Independent Predictive Factor of Hospital Readmission and Survival in Cirrhosis

MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis. AIM: To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis. METHODS: Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed. RESULTS: 69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27–2.1) and 2003 (705–4586) ug/g creat vs 0.47 (0.2–1.1) and 1188 (512–2958) ug/g creat, in patients with and without readmission, respectively; p<0.05; median (IQR)). Furthermore, urine levels of MCP-1 were significantly associated with mortality (1.01 (1–3.6) vs 0.5 (0.2–1.1) μg/g creat, in dead and alive patients at 3 months; p<0.05). Patients with higher levels of urine MCP-1 (above percentile 75th) had higher probability of development of hepatic encephalopathy, bacterial infections or AKI. Urine MCP-1 was an independent predictive factor of hospital readmission and combined end-point of readmission or dead at 3 months. Plasma levels of MCP-1 did not correlated with outcomes. CONCLUSION: Urine, but not plasma, MCP-1 levels are associated with hospital readmission, development of complications of cirrhosis, and mortality. These results suggest that in cirrhosis there is an inflammatory response that is associated with poor outcomes.

Adrenal function and microbial DNA in noninfected cirrhotic patients with ascites: Relationship and effect on survival.

BACKGROUND There are few data on clinical relevance of adrenal dysfunction and its relationship with occult microbial DNA in noninfected haemodynamically stable cirrhotic patients with ascites. AIMS The aim of this study was to evaluate prognostic role of adrenal dysfunction, microbial DNA, and their relationship. METHODS Adrenal function was assessed in 93 consecutive patients following a corticotropin stimulation test. Adrenal dysfunction was defined as: basal cortisol <10 μg/dl, delta cortisol <9 μg/dl, or peak cortisol <18 μg/dl. Microbial DNA was assessed in blood and ascites of 54 consecutive patients. Patients were followed up until liver transplantation or death. RESULTS Adrenal dysfunction was not significantly associated with mortality, while the risk of death rose significantly with an increase in basal cortisol values (HR 1.13 per 1-μl/dl increase; 95% CI 1.01-1.26). Microbial DNA was independently associated with reduced survival (HR 8.05, 95% CI 1.57-41.2). In microbial DNA-positive patients a significant correlation was found between Model for End-Stage Liver Disease (MELD) score and basal cortisol values (Pearsons r=0.5107; p=0.018). CONCLUSIONS Microbial DNA and MELD score, but not adrenal function, were the best independent predictors of mortality in noninfected cirrhotic patients with ascites. High serum cortisol levels may be a systemic reaction to microbial translocation, increasing in parallel with deterioration of liver function.

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