Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties.

Liver cirrhosis is commonly associated with nutritional alterations, reported in 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Nutritional disturbances are associated with a worse prognosis and increased risk of complication. Serum levels of branched-chain amino acids (BCAAs) are decreased in patients with liver cirrhosis. The imbalance of amino acids levels has been suggested to be associated with the development of complications, such as hepatic encephalopathy and sarcopenia, and to affect the clinical presentation and prognosis of these patients. Several studies investigated the efficacy of BCAAs supplementation as a therapeutic option in liver cirrhosis, but uncertainties remain about the real efficacy, the best route of administration, and dosage.

A Role for the Biological Clock in Liver Cancer.

The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor for cancer and classified as a potential group 2A carcinogen to humans. Hepatocellular carcinoma (HCC) is the prevailing histological type of primary liver cancer, one of the most important causes of cancer-related death worldwide. HCC onset and progression is related to B and C viral hepatitis, alcoholic and especially non-alcoholic fatty liver disease (NAFLD)-related milieu of fibrosis, cirrhosis, and chronic inflammation. In this review, we recapitulate the state-of-the-art knowledge on the interplay between the biological clock and the oncogenic pathways and mechanisms involved in hepatocarcinogenesis. Finally, we propose how a deeper understanding of circadian clock circuitry-cancer pathways' crosstalk is promising for developing new strategies for HCC prevention and management.

Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease.

BACKGROUND: In non-alcoholic fatty liver disease (NAFLD), a high-fat or high-fructose diet increases intestinal permeability and promotes derangement of the gut-liver axis. We hypothesize that, diet could be able to modulate intestinal permeability in patients with NAFLD. AIM: To detect diet-induced modification of intestinal permeability in patients with NAFLD undergoing a Mediterranean diet or a low-fat diet. METHODS: The current study was a dietary intervention for non-diabetic, patients with biopsy-verified NAFLD and increased transaminases. A crossover design was employed: participants underwent 16 weeks of Mediterranean diet, 16 wk of free wash-out, and 16 weeks of low-fat diet. Both diets were hypocaloric and no consumption of supplements was allowed. All patients were followed bimonthly by a dietitian. Evaluations of clinical and metabolic parameters were completed at baseline and at the end of each dietary period. Intestinal permeability was assessed by chromium-51 ethylene diamine tetraacetate excretion testing (51Cr-EDTA). RESULTS: Twenty Caucasian patients, 90% male, median age 43 years, body mass index (BMI) 30.9, with biopsy-verified NAFLD were enrolled. At the end of 16 weeks of a Mediterranean diet, a significant reduction in mean body weight (-5.3 ± 4.1 kg, P = 0.003), mean waist circumference (-7.9 ± 4.9 cm, P = 0.001), and mean transaminase levels [alanine aminotransferase (ALT) -28.3 ± 11.9 IU/L, P = 0.0001; aspartate aminotransferase (AST) -6.4 ± 56.3 IU/L, P = 0.01] were observed. These benefits were maintained after 16 wk of wash-out and also after 16 wk of low-fat diet, without further improvements. Fourteen of the 20 patients had intestinal permeability alteration at baseline (mean percentage retention of 51Cr-EDTA = 5.4%), but no significant changes in intestinal permeability were observed at the end of the 16 wk of the Mediterranean diet or 16 wk of the low-fat diet. CONCLUSION: Mediterranean diet is an effective strategy for treating overweight, visceral obesity and serum transaminase in patients with NAFLD. If the Mediterranean diet can improve intestinal permeability in patients with NAFLD, it deserves further investigation.

Biology, Epidemiology, Clinical Aspects of Hepatocellular Carcinoma and the Role of Sorafenib.

Sorafenib is a small molecular inhibitor of intracellular tyrosine and serine/threonine protein kinases (VEGFR, PDGFR, CRAF and BRAF), and is thought also to induce autophagy, a chief mechanism influencing tumor growth. Sorafenib shows efficacy in the management of non-resectable hepatocellular carcinoma (HCC), which is refractory to other chemotherapeutic drugs. HCC represents a major end point of chronic liver diseases and the third leading cause of cancer-related death. In HCC patients Sorafenib increases overall survival compared to placebo. The most common chronic liver disease affecting up to 30% of the population in Western countries is non-alcoholic fatty liver disease (NAFLD), an intra-hepatic amassing of triglycerides deemed as the hepatic manifestation of insulin resistance and obesity. NAFLD encompasses a range of disorders with grades of liver damage varying from steatosis to non-alcoholic steatohepatitis (NASH), hallmarked by hepatocellular injury/inflammation in the presence or not of fibrosis. NAFLD patients progress to NASH in 10% of cases, which may progress to cirrhosis and HCC. Recent exciting studies uncovered a potential therapeutic role for Sorafenib that goes beyond HCC, and extends to cirrhotic portal hypertensive syndrome during cirrhosis, and to selective anti-fibrotic effects mediated through direct inhibition of activated hepatic stellate cells (HSC), the cellular mediators of intra-hepatic matrix deposition. The aim of this review is to concisely summarize our current knowledge of the biology, epidemiology and clinical aspects of HCC, as well as the previously under-appreciated therapeutic efficacy of Sorafenib beyond HCC. The review therefore utilizes data along the spectrum of liver diseases, including from experimental via pre-clinical to clinical.

Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma.

UNLABELLED: The purpose was to assess the cost-effectiveness of sorafenib in the treatment of hepatocellular carcinoma (HCC) patients incorporating current prices and the results of the recent published field practice SOraFenib Italian Assessment (SOFIA) study. We created a Markov Decision Model to evaluate, in a hypothetical cohort of Caucasian male patients, aged 67 years with Barcelona Clinic Liver Cancer (BCLC) C HCC, or BCLC B HCC who were unfit or failed to respond to locoregional therapies, well compensated cirrhosis, and with performance status 0-1 according to Eastern Cooperative Oncology Group (ECOG), the cost-effectiveness of the following strategies: (1) full or dose-adjusted sorafenib for BCLC B and C patients together; (2) full or dose-adjusted sorafenib for BCLC B patients; (3) full or dose-adjusted sorafenib for BCLC C patients. Outcomes include quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). In the base-case analysis dose-adjusted sorafenib was the most effective of the evaluated strategies. For dose-adjusted sorafenib, QALY was 0.44 for BCLC B and C patients together, 0.44 for BCLC C patients, and 0.38 for BCLC B patients. The ICER of dose-adjusted sorafenib compared with BSC was €34,534 per QALY gained for BCLC B and C patients together, €27,916 per QALY gained for BCLC C patients, and €54,881 per QALY gained for BCLC B patients. Results were sensitive to BSC survival rate, and sorafenib treatment duration. CONCLUSION: In daily practice dose-adjusted, but not full-dose, sorafenib is a cost-effective treatment compared to BSC in intermediate and advanced HCC.

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial.

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation.

Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.

UNLABELLED: A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. CONCLUSION: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.

Acute hepatitis caused by a natural lipid-lowering product: when "alternative" medicine is no "alternative" at all.

BACKGROUND/AIMS: The general public's growing mistrust of the pharmaceutical industry and its perception of the lack of adverse effects of "natural" therapy have lead to the increasing use of "alternative drugs" for hypercholesterolemia. METHODS: A sixty-three year old woman presented with severe hypertransaminasemia that had developed progressively over a few weeks. For six months she had been taking Equisterol, an over-the-counter lipid-lowering product containing guggulsterol and red yeast rice extract. The product had been prescribed for hypercholesterolemia because the patient had developed hepatotoxicity while on lovastatin. RESULTS: Liver biopsy revealed severe lobular necroinflammatory changes with an eosinophilic infiltrate. The episode was regarded as an adverse drug reaction after exclusion of other possible causes of acute liver disease and the prompt normalization of liver function tests after Equisterol had been discontinued. Red yeast rice extract's cholesterol-lowering properties are largely due to fungal metabolites known as monacolins, one of which--monacolin K--is identical to lovastatin. CONCLUSIONS: The choice of an alternative medicine approach in this case subjected the patient to "re-challenge" with the official medicine agent that had previously caused mild hepatotoxicity. Physicians should keep in mind that "alternative" medicine is not always the safest alternative and sometimes it is not even "alternative."

[Oxidative stress in metabolic syndrome and nonalcoholic steatohepatitis. Is it possible a role for vitamins in clinical practice?]. / Lo stress ossidativo nella sindrome metabolica e nella steatoepatite non alcolica. E possibile un ruolo delle vitamine nella pratica clinica?

Metabolic syndrome (MS) is a worldwide medical problem characterized by a cluster of cardiovascular risk factors and metabolic modifications involving peripheral insulin resistance. Nonalcoholic steatohepatitis (NASH) represents the liver expression of this pathological condition. Both MS and NASH are characterized by proinflammatory status and increased oxidative stress. According this, we aimed to review the literature for considering a possible role for vitamins as therapeutical support in MS and NASH.