Sanjaya K. Satapathy

Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non‐alcoholic steatohepatitis

Background and Aim:  Inhibition of tumor necrosis factor (TNF)‐α is a logical approach to manage patients with non‐alcoholic steatohepatitis (NASH). Pentoxifylline reduces TNF‐α and alanine aminotransferase (ALT) levels in patients with NASH. The aim of the present paper was to study if pentoxifylline can improve histological injury in patients with NASH.

A randomized controlled trial of lamivudine to treat acute hepatitis B

The role of antivirals in patients with acute viral hepatitis B (AVH‐B) has not been evaluated in controlled trials. The aim of this study was to evaluate the efficacy of lamivudine in patients with AVH‐B. AVH‐B patients with serum bilirubin of more than 5 mg/dL were randomized to receive either 100 mg of lamivudine daily for 3 months (group 1, n = 31) or placebo (group 2, n = 40). Patients were considered to have severe AVH‐B if they fulfilled 2 of 3 criteria: (1) hepatic encephalopathy; (2) serum bilirubin ≥ 10.0 mg/dL; and (3) international normalized ratio (INR) ≥ 1.6. At week 4, HBV DNA levels were significantly lower (P = 0.037) in group 1 (median: 3.6721 log copies/mL) than group 2 (median: 4.2721 log copies/mL). Thereafter, HBV DNA levels were comparable in the 2 groups. The improvement in serum bilirubin, ALT, and INR values was similar in the 2 groups. Twenty‐two patients (71%) in group 1 and 25 patients (62.5%) in group 2 had severe AVH‐B. Results were similar when patients with severe AVH‐B were analyzed separately. After 12 and 18 months, 93.5% and 92.5%, respectively, of patients in the lamivudine group and 96.7% and 97.5%, respectively, of patients in the placebo group lost HBsAg. There were no deaths in either group. After 1 year, 21 patients (67.7%) in group 1 and 34 patients (85%) in group 2 developed protective anti‐HBs titers (P = 0.096). All HBeAg‐positive patients in both groups lost e antigen and anti‐HBe developed in 71% and 87.5% of patients in groups 1 and 2, respectively (P = 0.132). Conclusion: Though lamivudine causes a greater decrease in levels of HBV DNA, it does not cause significantly greater biochemical and clinical improvement as compared to placebo in patients with acute hepatitis B. HEPATOLOGY 2007;45:97–101.)

Epidemiology and Natural History of Nonalcoholic Fatty Liver Disease.

The epidemic of obesity has resulted in a parallel incremental burden of nonalcoholic fatty liver disease (NAFLD) worldwide. Nonalcoholic fatty liver disease includes a spectrum of liver disease that ranges from simple fat accumulation in the liver to necroinflammation, fibrosis, cirrhosis, and hepatocellular carcinoma, which in essence represent the stages of the natural history of NAFLD. The rising prevalence of NAFLD globally may be accounted for by changes in dietary habits and an increase in sedentary lifestyle. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, is currently the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. In the current review, the authors discuss the uncertainty around the progression from NAFL (steatosis) to NASH (steatohepatitis), the undisputed progression of NASH to cirrhosis, and the risk factors that predispose to such progression. The published literature on the long-term cardiovascular complications and liver-related mortality of NAFLD is also discussed.

Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice

Obesity, a serious and growing health threat, is associated with low-grade inflammation that plays a role in mediating its adverse consequences. Previously, we have discovered a role for neural cholinergic signaling in controlling inflammation, and demonstrated that the cholinergic agent galantamine suppresses excessive proinflammatory cytokine release. The main objective of this study was to examine the efficacy of galantamine, a clinically-approved drug, in alleviating obesity-related inflammation and associated complications. After 8 wks on a high-fat diet, C57BL/6J mice were treated with either galantamine (4 mg/kg, intraperitoneally (i.p.)) or saline for 4 wks in parallel with mice on a low-fat diet and treated with saline. Galantamine treatment of obese mice significantly reduced body weight, food intake, abdominal adiposity, plasma cytokine and adipokine levels, and significantly improved blood glucose, insulin resistance and hepatic steatosis. In addition, galantamine alleviated impaired insulin sensitivity and glucose intolerance significantly. These results indicate a previously unrecognized potential of galantamine in alleviating obesity, inflammation and other obesity-related complications in mice. These findings are of interest for studying the efficacy of this clinically-approved drug in the context of human obesity and metabolic syndrome.

Clinical characterization of patients developing histologically‐proven fibrosing cholestatic hepatitis C post‐liver transplantation

Aim:  Fibrosing cholestatic hepatitis C (FCH) post‐liver transplantation (LT) is an uncommon disorder with extremely poor outcome. Using stringent histological criteria, we sought to identify cases of FCH to better characterize its incidence, clinical features and outcomes.

Novel treatment modalities for nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease in the Western world. It can lead to cirrhosis and hepatocellular cancer, and is independently associated with an increased risk of death due to cardiovascular and liver diseases. Over the past 5 years, numerous advances in understanding its pathogenesis have been made, providing a rationale for translation of this information into clinical trials. Although the optimum therapy is still awaited, there is strong evidence to support the use of vitamin E in selected subjects. Many other potential therapeutic options are now available. In this paper, we review the status of both current and emerging therapeutic strategies for patients with NASH.

Equally poor outcomes to pegylated interferon-based therapy in African Americans and Hispanics with chronic hepatitis C infection.

Objectives Treatment response to pegylated interferon based regimen is different between African Americans and Whites, but little comparable data is available comparing Hispanics and African Americans. Patients We retrospectively evaluated the rate of success in the treatment completion and response to peginterferon α-2a or α-2b plus ribavirin in 103 (male:female-69:34) hepatitis C virus (HCV)-polymerase chain reaction positive patients that included 68 Hispanic and 35 African Americans. Methods Patients were treated with peginterferon α-2a 180 mcg/wk (n=25) or peginterferon α-2b 1.5 mcg/kg/wk (N=78) and ribavirin 1000 to 1200 mg/d for 24 weeks (genotype 2 and 3) or 48 weeks (genotype 1 and 4) based on the genotype of the patient. Treatment was discontinued if the patients failed to have a 2-log drop in viral load after 12 weeks of treatment. Primary aim of the study was to evaluate success in completing a scheduled duration of pegylated interferon and ribavirin treatment in patients with chronic HCV infection and the reasons for discontinuation of the treatment. The secondary aim was to look for the end of treatment virologic response and sustained virologic response. The analysis was conducted by intention-to-treat. Results Of the 103 patients included in the study, 50 (48.5%) patients dropped out of the treatment because of side effects of the drug or noncompliance to the treatment protocol or alternate reasons; 44 (42.7%) of them could not continue beyond 12 weeks of therapy. There were no significant differences in the drop out rate between the African American [15 (43%)] and Hispanic [35 (51.5%)] patients (P=0.41). Overall, 41% of the patients completed the scheduled 24 week or 48 week treatment. HCV genotype-1 was the most prevalent genotype in both African Americans and Hispanics (88.6% vs. 75%, P=0.10). Overall end of the treatment response (ETR) was 29.1% (30/103) and sustained virologic response (SVR) was 23.3% (24/103) in this population. No significant differences were noted in the ETR (20% vs. 34%, P=0.14) and the SVR (20% vs. 25%, P=0.57) between the African Americans and Hispanics. When data were analyzed by genotype, overall SVR rates were 14.6% (12/82) in genotype 1 versus 57% (12/21) in genotype 2/3/4 (P<0.0001). Both these ethnic groups had comparable response rates when only patients with genotype-1 were considered 5/31 (16.1%) versus 7/51 (13.7%, P=0.76). Conclusions A significant proportion of the African Americans and Hispanics referred for HCV treatment with pegylated interferon dropped out early in the therapy, suggesting possible racial, socioeconomic, and cultural barriers in successful treatment for chronic HCV infection. Overall, both groups had similar poor response rates, well below those reported for White patients. As is true for the general population, patients with nongenotype 1 infection had a significantly better ETR and SVR.

Beneficial Effects of Statins on the Rates of Hepatic Fibrosis, Hepatic Decompensation, and Mortality in Chronic Liver Disease: A Systematic Review and Meta-Analysis

Objectives:Statins may improve outcomes in patients with chronic liver disease (CLD). We conducted a systematic review and meta-analysis to evaluate the impact of statins in the setting of CLD.Methods:We searched several databases from inception to 17 October 2016 to identify comparative studies evaluating the role of statins in CLD. Outcomes of interest were the associations between statin use and progression of fibrosis, development of hepatic decompensation in cirrhosis, and mortality in CLD. Adjusted hazard ratios (HRs) were pooled and analyzed using a random effects model. Subgroup analyses were performed based on the method of detection for progression of hepatic fibrosis and quality of studies.Results:We included 10 studies (1 randomized controlled trial and 9 observational) with 259,453 patients (54,441 statin users and 205,012 nonusers). For progression of hepatic fibrosis, pooled HR (95% confidence interval) was 0.49 (0.39–0.62). On subgroup analysis of studies using ICD-9 (The International Classification of Diseases, Ninth Revision) coding and a second method to detect cirrhosis, pooled HR was 0.58 (0.51–0.65); pooled HR for studies using ICD-9 coding only was 0.36 (0.29–0.44). For progression of fibrosis in patients with hepatitis C virus (HCV) infection, pooled HR was 0.52 (0.37–0.73). For hepatic decompensation in cirrhosis, pooled HR was 0.54 (0.46–0.65). For mortality, pooled HR based on observational studies was 0.67 (0.46–0.98); in the randomized controlled trial, HR was 0.39 (0.15–0.99). However, the quality of evidence for these associations is low as most included studies were retrospective in nature and limited by residual confounding.Conclusions:Statins may retard the progression of hepatic fibrosis, may prevent hepatic decompensation in cirrhosis, and may reduce all-cause mortality in patients with CLD. As the quality (certainty) of evidence is low, further studies are needed before statins can be routinely recommended.

Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management

With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

Posttransplant metabolic syndrome: New evidence of an epidemic and recommendations for management †

The success of liver transplantation (LT) is one of the great achievements of modern medicine. Advances in medical management and surgical techniques have resulted in sequential improvements in outcomes, with overall 5-year survival rates approaching 70% (http:// www.unos.org). The last 2 decades have witnessed an evolution in the causes of death and graft loss after LT. Perhaps most impressively, step wise improvements in the efficacy and tolerability of immunosuppression have reduced chronic rejection to a relatively minor cause of graft loss. As the frequency of immunological causes of graft loss and mortality has declined, other causes have become increasingly important. Cardiovascular disease, renal insufficiency, and malignancies are among the emerging important causes of mortality and graft loss after LT. Metabolic syndrome (MS) is a common thread of risk for each of these. The prevalence and etiology of posttransplant metabolic syndrome (PTMS) are thus of increasing interest to the transplant community. The report by Laish et al. in this issue of Liver Transplantation is very welcome in this regard. Laish et al. studied the records of 252 transplant recipients (mean age 1⁄4 54.5 6 2.8 years, proportion of men 1⁄4 57.9%) for pretransplant and posttransplant clinical and laboratory parameters of MS. Among the primary observations was the fact that rates of obesity [body mass index (BMI) > 30 kg/m], hypertriglyceridemia (>150 mg/dL), high-density lipoprotein cholesterol levels less than 40 (men) or 50 mg/dL (women), hypertension, and diabetes were significantly higher after transplantation than before transplantation. Most striking, however, was the finding that PTMS was diagnosed in 5.4% of patients before transplantation and in 51.9% afterward. By and large, transplant recipients with PTMS had risk profiles similar to those of nontransplant patients: they were older and heavier than patients without PTMS. PTMS conveyed a greater than 3-fold increase in the relative risk of major vascular and cardiac events. Significant independent predictors of PTMS included age (odds ratio 1⁄4 1.04) and pretransplant nonalcoholic fatty liver disease (odds ratio 1⁄4 3.4). How do these findings compare to what is known about MS and LT? The prevalence of MS in the West is approximately 34%, and increases with advancing age and BMI. The prevalence of MS in patients with cirrhosis and end-stage liver disease is not well established and varies with the etiology of the underlying liver disease, with an increased prevalence reported among patients with cryptogenic cirrhosis. The associations of pretransplantation cryptogenic cirrhosis and hepatitis C virus (HCV) infection as etiologies of liver disease with the development of PTMS may not be entirely unexpected because both of these conditions are associated with MS in the nontransplant setting. In the same vein, an increase in the relative risk of mortality and heart disease in men with MS in a