Malnourished cirrhotic patient: what should we do?

Malnutrition and sarcopenia have a high prevalence in cirrhotic patients. Frailty generally overlaps with malnutrition and sarcopenia in cirrhosis, leading to increased morbidity and mortality. Rapid nutritional screening assessment should be performed in all patients with cirrhosis, and more specific tests for sarcopenia should be performed in those at high risk. The pathogenesis of malnutrition in cirrhosis is complex and multifactorial and it is not just due to reduction in protein and calorie intake. Nutritional management in malnourished patients with cirrhosis should be undertaken by a multidisciplinary team to achieve adequate protein/calorie intake. While the role of branched-chained amino acids remains somewhat contentious in achieving a global benefit of decreasing mortality- and liver-related events, these latter and vitamin supplements, are recommended for those with advanced liver disease. Novel strategies to reverse sarcopenia such as hormone supplementation, long-term ammonia-lowering agents and myostatin antagonists, are currently under investigation. Malnutrition, sarcopenia and frailty are unique, inter-related and multidimensional problems in cirrhosis which require special attention, prompt assessment and appropriate management as they significantly impact morbidity and mortality.

Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis.

BACKGROUND & AIMS: Wedge hepatic vein pressure (WHVP) accurately estimates portal pressure (PP) in alcohol- or viral hepatitis-related cirrhosis. Whether this also holds true in cirrhosis caused by non-alcoholic steatohepatitis (NASH) is unknown. We aimed to evaluate the agreement between WHVP and PP in patients with NASH cirrhosis in comparison to patients with alcohol- or HCV-related cirrhosis. METHODS: All consecutive patients with NASH cirrhosis treated with a transjugular intrahepatic portosystemic shunt (TIPS) in 3 European centres were included (NASH group; n = 40) and matched with 2 controls (1 with alcohol-related and 1 with HCV-related cirrhosis) treated with TIPS contemporaneously (control group; n = 80). Agreement was assessed by Pearson's correlation (R), intra-class correlation coefficient (ICC), and Bland-Altman method. Disagreement between WHVP and PP occurred when both pressures differed by >10% of PP value. A binary logistic regression analysis was performed to identify factors associated with this disagreement. RESULTS: Correlation between WHVP and PP was excellent in the control group (R 0.92; p <0.001; ICC 0.96; p <0.001) and moderate in the NASH group (R 0.61; p <0.001; ICC 0.74; p <0.001). Disagreement between WHVP and PP was more frequent in the NASH group (37.5% vs. 14%; p = 0.003) and was mainly because of PP underestimation. In uni- and multivariate analyses, only NASH aetiology was associated with disagreement between WHVP and PP (odds ratio 4.03; 95% CI 1.60-10.15; p = 0.003). CONCLUSIONS: In patients with decompensated NASH cirrhosis, WHVP does not estimate PP as accurately as in patients with alcohol- or HCV-related cirrhosis, mainly because of PP underestimation. Further studies aimed to assess this agreement in patients with compensated NASH cirrhosis are needed. LAY SUMMARY: Portal pressure is usually assessed by measuring wedge hepatic vein pressure because of solid evidence demonstrating their excellent agreement in alcohol- and viral hepatitis-related cirrhosis. Our results show that in patients with decompensated cirrhosis caused by non-alcoholic steatohepatitis, wedge hepatic vein pressure estimates portal pressure with less accuracy than in patients with other aetiologies of cirrhosis, mainly because of portal pressure underestimation.

Current and future perspective on targeted agents and immunotherapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide. HCC occurs predominantly in patients with underlying chronic liver disease and cirrhosis, and it presents a poor prognosis in advanced stage. Since its approval, for the following 10 years, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced HCC. Recently, more drugs have been studied and several advances in first­line and second­line treatment options should yield significant improvements in survival. Lenvatinib, another tyrosine­kinase inhibitor, was found to be non-inferior to sorafenib in terms of overall survival (OS), with significantly better progression-free survival and objective response rate (ORR). The tyrosinekinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second­line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second­line setting among patients with AFP≥400 ng/dL. Moreover, good efficacy was seen in phase I/II trials of immune checkpoint inhibitors as monotherapy. Ongoing trials are evaluating combination immune checkpoint inhibitor and tyrosine­kinase inhibitors or VEGF inhibitors for increasing overall survival in this patient population with advanced HCC.

Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy.

Hepatitis B virus (HBV) is a major health problem worldwide, with approximatively 240 million people living with a chronic HBV infection. HBV chronic infection remains the major cause of hepatocellular carcinoma worldwide, with more than half of HCC patients being chronic HBV carriers, even if underlying mechanisms of tumorigenesis are not totally understood. HBV-related HCC can be prevented by reducing the exposure to HBV by vaccination or by treatment of CHB infection. Current treatment of CHB are Peg-IFN alpha and oral NUCs. Treating HBV infection, either with IFN or NUCs, substantially reduces the risk of HCC development, even if antiviral therapy fails to completely eliminate HCC risk. Among treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC. The reduction of the risk of developing HCC during antiviral therapy is largely dependent upon the maintenance of virological remission, since viral load is found to be the most important factor leading to cirrhosis and its complications, including liver cancer development. The question whether Peg-IFN-alpha is superior to NUCs and whether there is a superior agent among NUCs is still controversial. Several studies demonstrated that antiviral therapy with NUCs could reduce the risk of HCC recurrence after curative treatment of HBV-related HCC.

Drug induced liver injury: from pathogenesis to liver transplantation.

Drug induced liver injury (DILI) is a necro-inflammatory liver disease caused by several drugs commonly used in clinical practice, herbs and dietary supplements prescribed for medical purposes. Despite its rarity, it represents the major cause of acute liver failure (ALF) requiring liver transplantation in USA and its frequency is increasing in Europe too. Two types of drug induced liver injury have been recognized: intrinsic and idiosyncratic. Predisposing factors may be classified in environmental, drugs- and individual- related risk factors, with the latter further distinguished in genetics and non-genetics. The liver injury can present with a hepatocellular, cholestatic or mixed pattern of disease. A definitive diagnosis of DILI is, nowadays, one of the main challenging issue in the management of these patients. Diagnosis often is based on suspicion derived from clinical history, biochemical exams and eventually on histological examination from liver biopsy. Score system may be helpful in these setting and new markers are gaining more prominence. Evaluation for liver transplantation is indicated when spontaneous resolution does not occur or in cases of ALF. Overall, the 1-year survival rate following liver transplantation is lower than that seen in patients who have been transplanted for chronic liver failure; however long-term survival is higher compared to other indications.

Management of portal hypertension severe complications.

Portal hypertension is a clinical syndrome characterized by an increase in the portal pressure gradient, defined as the gradient between the portal vein at the site downstream of the site of obstruction and the inferior vena cava. The most frequent cause of portal hypertension is cirrhosis. In patients with cirrhosis, portal hypertension is the main driver of cirrhosis progression and development of hepatic decompensation (ascites, variceal hemorrhage and hepatic encephalopathy), which defines the transition from compensated to decompensated stage. In decompensated patients, treatments aim at lowering the risk of death by preventing further decompensation and/or development of acute-on-chronic liver failure. Decompensated patients often pose a complex challenge which typically requires a multidisciplinary approach. The aims of the present review were to discuss the current knowledge regarding interventional treatments for patients with portal hypertension complications as well as to highlight useful information to aid hepatologists in their clinical practice. Specifically, we discussed the indications and contraindications of transjugular intra-hepatic portosystemic shunt and for the treatment of gastro-esophageal variceal hemorrhage in patients with decompensated cirrhosis (first section); we reviewed the use of interventional treatments in patients with hepatic vein obstruction (Budd-Chiari Syndrome) and in those with portal vein thrombosis (second section); and we briefly comment on the most frequent applications of selective splenic embolization in patients with and without underlying cirrhosis (third section).

Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD. METHODS: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD. RESULTS: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL. DISCUSSION: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD.

Milestones in the discovery of Budd-Chiari syndrome.

In 1845, George Budd published a brief report regarding three patients who developed an obstruction of the hepatic veins. The condition has never been reported before, and was related to sepsis and alcoholism. Fifty-three years later, Hans Chiari postulated that syphilis was causing the obstruction of the hepatic veins, and enriched the debate with clinical and pathological correlations. Following the hypothesis on the 'phlebitis obliterans', several authors proposed other pathophysiological explanations including congenital causes, chronic trauma and exogenous toxins. RG Parker, in 1959, first recognized the relationship between obstruction of hepatic veins and thrombophilic conditions such as polycythaemia vera, pregnancy and hormonal therapy. Based on that, anticoagulant treatment was attempted, but with unsatisfactory outcome. We need to wait until the mid 1980s to see a widespread adoption of anticoagulants, with a consequent improvement of patients' survival. The fear of haemorrhagic events in patients with liver disease discouraged this therapeutic approach, and other surgical interventions (mainly port-systemic shunts) were conceived, but with high morbidity and mortality. The first liver transplantation in 1976 and the first trans-jugular intra-hepatic porto-systemic shunt in 1993 represented two major cornerstones in the management of Budd-Chiari syndrome (BCS). Such progresses allowed modifying the treatment of BCS until the modern concept of stepwise therapy. The present review thoroughly reviews the major landmarks in the discovery, treatment and clinical management of patients with BCS.