Paolo Caraceni

Serum α-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease : influence of HBsAg and anti-HCV status

BACKGROUND It is not established whether virological status affects the efficiency of alpha-fetoprotein (AFP) as a hepatocellular carcinoma (HCC) marker among patients with chronic liver disease (CLD). METHODS We enrolled in a case-control study 170 HCC and 170 CLD patients, matched for age, sex, CLD and HBsAg/anti-HCV status. The AFP sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. PPV and NPV were evaluated for three additional HCC prevalences (5, 10, and 20%). RESULTS The best discriminating AFP value was 16 ng/ml. A value of 20 ng/ml (above which investigations for HCC are recommended) had equivalent sensitivity (60.0 vs. 62.4%) and specificity (90.6 vs. 89.4%). PPV of 20 ng/ml was 84.6% but decreased to 25.1% at 5% tumor prevalence. NPV was 69.4% and rose to 97.7% at 5% prevalence. In the different groups of infected patients PPV ranged from 80.0 to 90.9%, falling to 17.4-34.5% at 5% prevalence. In noninfected patients PPV was 100% at any HCC prevalence. NPV ranged from 59.0 to 73.0%, reaching 96.5-98.1% at 5% prevalence. CONCLUSIONS In CLD patients, AFP monitoring misses many HCCs and inappropriately arouses suspicion of malignancy in many patients. Its usefulness is barely affected by the infection responsible for CLD. An AFP elevation could be more indicative of HCC in non-infected patients.

Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. METHODS We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24weeks. Fifty-nine patients had previous HCC. RESULTS DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99-10.84): 17 of 59 patients (28.81%, 95% CI: 17.76-42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45-5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p=0.03, OR: 4.18, 95% CI: 1.17-14.8) and history of HCC (p<0.0001, OR: 12.0, 95% CI: 4.02-35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis. CONCLUSIONS In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy. LAY SUMMARY New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

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.

Effects of Fractionated Plasma Separation and Adsorption on Survival in Patients With Acute-on-Chronic Liver Failure

BACKGROUND & AIMS Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. METHODS Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n = 77) or only SMT (SMT group, n = 68). The Prometheus liver support system was used to provide 8 to 11 rounds of FPSA (minimum of 4 hours each) for 3 weeks. Primary end points were survival probabilities at days 28 and 90, irrespective of liver transplantation. RESULTS Baseline clinical parameters and number of transplant patients were similar between study arms. Serum bilirubin level decreased significantly in the FPSA group but not in the SMT group. In an intention-to-treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMT group (P = .70); on day 90, they were 47% and 38%, respectively (P = .35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the 2 groups in the incidence of side effects. CONCLUSIONS Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients.

Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites

Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites Paolo Angeli1,⇑, Pere Ginès, Florence Wong, Mauro Bernardi, Thomas D. Boyer, Alexander Gerbes, Richard Moreau, Rajiv Jalan, Shiv K. Sarin, Salvatore Piano, Kevin Moore, Samuel S. Lee, Francois Durand, Francesco Salerno, Paolo Caraceni, W. Ray Kim, Vicente Arroyo, Guadalupe Garcia-Tsao

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)

Albumin infusion in patients undergoing large‐volume paracentesis: A meta‐analysis of randomized trials

Albumin infusion reduces the incidence of postparacentesis circulatory dysfunction among patients with cirrhosis and tense ascites, as compared with no treatment. Treatment alternatives to albumin, such as artificial colloids and vasoconstrictors, have been widely investigated. The aim of this meta‐analysis was to determine whether morbidity and mortality differ between patients receiving albumin versus alternative treatments. The meta‐analysis included randomized trials evaluating albumin infusion in patients with tense ascites. Primary endpoints were postparacentesis circulatory dysfunction, hyponatremia, and mortality. Eligible trials were sought by multiple methods, including computer searches of bibliographic and abstract databases and the Cochrane Library. Results were quantitatively combined under a fixed‐effects model. Seventeen trials with 1,225 total patients were included. There was no evidence of heterogeneity or publication bias. Compared with alternative treatments, albumin reduced the incidence of postparacentesis circulatory dysfunction (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.27‐0.55). Significant reductions in that complication by albumin were also shown in subgroup analyses versus each of the other volume expanders tested (e.g., dextran, gelatin, hydroxyethyl starch, and hypertonic saline). The occurrence of hyponatremia was also decreased by albumin, compared with alternative treatments (OR, 0.58; 95% CI, 0.39‐0.87). In addition, mortality was lower in patients receiving albumin than alternative treatments (OR, 0.64; 95% CI, 0.41‐0.98). Conclusions: This meta‐analysis provides evidence that albumin reduces morbidity and mortality among patients with tense ascites undergoing large‐volume paracentesis, as compared with alternative treatments investigated thus far. (HEPATOLOGY 2012)

Albumin: Pathophysiologic basis of its role in the treatment of cirrhosis and its complications

Since the introduction of human serum albumin as a plasma expander in the 1940s, considerable research has allowed a better understanding of its biochemical properties and potential clinical benefits. Albumin has a complex structure, which is responsible for a variety of biological functions. In disease, the albumin molecule is susceptible to modifications that may alter its biological activity. During the last decades, different methods to measure albumin function have been developed. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver failure. This observation led to the concept of effective albumin concentration, which represents the fact that plasma albumin concentration does not reflect its function. Indeed, in liver disease albumin function is several times less than its concentration. In patients with cirrhosis, albumin infusion reduces mortality in patients with spontaneous bacterial peritonitis and improves outcome following large volume paracentesis. In combination with vasoconstrictors, albumin is useful in the management of patients with hepatorenal syndrome. Its role is being investigated in a large number of indications, which rely on its volume and nonvolume expansion functions such as stroke, severe sepsis, Alzheimers disease, malaria, burns, and ovarian hyperstimulation syndrome. This review explores the above concepts, reviews the available evidence for the use of albumin in liver diseases, defines therapeutic limitations, and explores the challenges that should be addressed in future research. (Hepatology 2013;58:1836–1846)

Liver Transplantation from Donors Aged 80 Years and Over: Pushing the Limit

Older donors are a growing part of the total donor pool but no definite consensus exists on the limit of age for their acceptance. From November 1998 to January 2003, in a retrospective case–control multicenter study, we compared the outcome of 30 orthotopic liver transplantations (OLTs) with octogenarian donors and of 60 chronologically correlated OLTs performed with donors <40 years. The percentage of refusal was greater among older than younger donors (48.2 vs. 14.3%; p < 0.001). Cold ischemia was significantly shorter in the older than younger groups. Recipients with hepatocarcinoma and older age received octogenarian grafts more frequently. No differences were seen in post‐operative complications and 6‐month graft and patient survival. However, long‐term survival was lower in patients transplanted with octogenarian donors (p = 0.04). Interestingly, the mortality related to hepatitis C recurrence was greater in patients with octogenarian donors. Accordingly, the long‐term survival of HCV‐positive patients who received older grafts was lower than those receiving younger grafts (p = 0.05). Octogenarian livers can be used safely but a careful donor evaluation and a short cold ischemia are required to prevent additional risk factors. However, hepatitis C recurrence is associated with a greater mortality in patients who received octogenarian grafts raising concerns whether to allocate these livers to HCV‐positive recipients.

Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites

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 …