Dina Halegoua-De Marzio

Then and now: the progress in hepatitis B treatment over the past 20 years.

The ultimate goals of treating chronic hepatitis B (CHB) is prevention of hepatocellular carcinoma (HCC) and hepatic decompensation. Since the advent of effective antiviral drugs that appeared during the past two decades, considerable advances have been made not only in controlling hepatitis B virus (HBV) infection, but also in preventing and reducing the incidence of liver cirrhosis and HCC. Furthermore, several recent studies have suggested the possibility of reducing the incidence of recurrent or new HCC in patients even after they have developed HCC. Currently, six medications are available for HBV treatment including, interferon and five nucleoside/nucleotide analogues. In this review, we will examine the antiviral drugs and the progresses that have been made with antiviral treatments in the field of CHB.

Limited sampling estimates of epigallocatechin gallate exposures in cirrhotic and noncirrhotic patients with hepatitis C after single oral doses of green tea extract.

BACKGROUND Epigallocatechin-3-gallate (EGCG) has antiangiogenic, antioxidant, and antifibrotic properties that may have therapeutic potential for the treatment of cirrhosis induced by hepatitis C virus (HCV). However, cirrhosis might affect EGCG disposition and augment its reported dose-dependent hepatotoxic potential. OBJECTIVE The safety, tolerability, and disposition of a single oral dose of EGCG in cirrhotic patients with HCV were examined in an exploratory fashion. METHODS Eleven patients with hepatitis C and detectable viremia were enrolled. Four had Child-Pugh (CP) class A cirrhosis, 4 had Child-Pugh class B cirrhosis, and 3 were noncirrhotic. After a single oral dose of green tea extract 400 mg containing 94% pure EGCG, blood for EGCG levels and safety parameters was ascertained at 2, 4, and 10 hours. RESULTS C(max) and AUC to EGCG overlapped among the 3 groups, which suggests that the disposition of EGCG was not significantly altered in these patients with cirrhosis. CONCLUSIONS A single 400-mg oral dose of EGCG was safe and well tolerated by all of the patients in the study. These results provide guidance for the continued investigation of the long-term safety and antitumor potential of EGCG in cirrhotic patients with HCV.

Treatment of Severe Alcoholic Hepatitis With Corticosteroids and Pentoxifylline

Despite being the most frequently abused drug for centuries, alcohol was not recognized as a direct hepatotoxin until the 1960s.1 Alcohol abuse accounts for the third leading preventable cause of death and the second most common cause of cirrhosis after hepatitis C virus infection in the United States.2,3 Alcoholic hepatitis is a common complication of alcohol abuse; its severity can range from mild to severe liver inflammation and can lead to the development of jaundice, prolonged prothrombin time, and liver failure. When left untreated in its severe form, alcoholic hepatitis has an extremely high mortality rate of up to 40% within 6 months after onset of clinical symptoms.4 In addition to abstinence and nutritional support, corticosteroids have been the cornerstone of treatment for severe alcoholic hepatitis based on more than 3 decades of clinical data, although sometimes divergent, including clinical trials and meta-analyses.5-8 However, alcoholic hepatitis is responsive to corticosteroids in only approximately 40% of patients, and many patients have contraindications to corticosteroid therapy, such as active infection.4 For patients with contraindications to corticosteroids, use of pentoxifylline, a phosphodiesterase inhibitor and xanthine derivative, has shown reduced short-term mortality in several small studies among patients with severe alcoholic hepatitis.9-11 Use of other treatments beyond corticosteroids and pentoxifylline, including anti-tumor nec rosis factor ( TNF) agents 1 2 and S-adenosyl-L-methionine,13 has been disappointing, resulting in an important need for more effective therapies due to the persistently high mortality rate associated with severe alcoholic hepatitis.4 In this issue of JAMA, Mathurin and colleagues14 report the main findings of a randomized, multicenter, doubleblind, placebo-controlled study comparing the logical combination of prednisolone and pentoxifylline with prednisolone alone for the treatment of patients with severe alcoholic hepatitis. In this well-designed study spanning 2 countries and 24 hospitals, data were collected with the objective of determining whether the addition of pentoxifylline with prednisolone was more effective than prednisolone alone. Between 2007 and 2010, patients aged 18 to 70 years who were heavy drinkers (>40 g/d of alcohol for women and >50 g/d of alcohol for men) with biopsy-proven severe acute alcoholic hepatitis and a Maddrey discriminant function of at least 32 were enrolled. Patients (n = 270) were randomized to receive the allocated treatment (prednisolone and pentoxifylline vs prednisolone alone) for 28 days, regardless of treatment response evaluated by the Lille model on day 7, a well-accepted and validated tool to prognosticate response to corticosteroids in severe alcoholic hepatitis.15 The primary end point was 6-month survival. The secondary end points were the development of hepatorenal syndrome and response to therapy based on the Lille model, which defined treatment nonresponders after 7 days. The proposed mechanisms of the effects of corticosteroids and pentoxifylline in alcoholic hepatitis are thought to differ. Corticosteroids are thought to reverse hepatic inflammation by reducing the circulating levels of the proinflammatory cytokines, including IL-8 and TNF.16 Pentoxifylline, although its exact mechanism of action is not completely understood, is thought to benefit patients with severe alcoholic hepatitis due to a protective effect against hepatorenal syndrome, possibly by modulation of TNF transcription.17 Combination therapy with pentoxifylline and corticosteroids in severe alcoholic hepatitis is often used in clinical practice with the hope of synergistic action leading to improved patient survival. Although often prescribed, the combined use of corticosteroid and pentoxifylline has never been studied in a double-blind, placebo-controlled setting until this study by Mathurin and colleagues. Contrary to expected outcomes, Mathurin and colleagues reported the outcomes of a 4-week treatment with a combination of pentoxifylline and prednisolone, which did not improve 6-month survival compared with prednisolone treatment alone in patients with severe alcoholic hepatitis; both the pentoxifylline-prednisolone and placebo-prednisolone groups had a 6-month survival rate of approximately 69%. At day 7 of therapy, response to therapy was not significantly different as assessed by the Lille model. Of additional interest was the finding that the incidence of hepatorenal syndrome at 6 months was less in the pentoxifylline-prednisolone group than in the placebo-prednisolone group (8.4% vs 15.3%, P = .07), but failed to reach statistical significance. The study by Mathurin and colleagues14 is not the first study unable to demonstrate increased efficacy with the use of pentoxifylline in severe alcoholic hepatitis, but it is the largest and first fully randomized, placebo-controlled study of its kind. Although significant renal preservation was not observed in the pentoxifylline-prednisolone group, this study was only powered to detect survival as a primary outcome and may have been underpowered to detect a difference in the occurrence of hepatorenal syndrome. Nonetheless, an effect on early markers of recovery or decreased mortality from presumed preRelated article page 1033 Opinion

Spiral Enteroscopy Utilizing Capsule Location Index for Achieving High Diagnostic and Therapeutic Yield

Background and Aim. Spiral enteroscopy (SE) is a new small bowel endoscopic technique. Our aim is to review the diagnostic and therapeutic yield, safety of SE, and the predictive role of prior capsule endoscopy (CE) at an academic center. Methods. A retrospective review of patients undergoing SE after prior CE between 2008 and 2013 was performed. Capsule location index (CLI) was defined as the fraction of total small bowel transit time when the lesion was seen on CE. Results. A total of 174 SEs were performed: antegrade (147) and retrograde (27). Abnormalities on SE were detected in 65% patients. The procedure was safe in patients with surgically altered bowel anatomy (n = 12). The diagnostic yield of antegrade SE decreased with increasing CLI range. The diagnostic yield of retrograde SE decreased on decreasing CLI range. A CLI cutoff of 0.6 was derived that determined the initial route of SE. Vascular ectasias seen on CE were detected in 83% cases on SE; p < 0.01. Conclusions. SE is safe with a high diagnostic and therapeutic yield. CLI is predictive of the success of SE and determines the best route of SE. The type of small bowel pathology targeted by SE may affect its utility and yield.

Listing Practices for Morbidly Obese Patients at Liver Transplantation Centers in the United States.

OBJECTIVES The effect of morbid obesity on liver transplant outcomes has yielded mixed results. The aim of this study was to determine listing practices for morbidly obese patients at liver transplant centers in the United States. MATERIALS AND METHODS A 19-item survey was created to assess liver transplant evaluation and listing practices for morbidly obese patients. All adult liver transplant medical and surgical directors in the United States were contacted by e-mail, which provided an Internet link to an online survey. RESULTS We sent a total of 187 surveys by e-mail, with responses received from 46 physicians (24.7% response rate). A policy on evaluation and listing of obese patients was present at 70.5% of institutions, with most (54.5%) reporting that their body mass index cutoff for transplant was 40 kg/m2, but a range of 35 kg/m2 to unlimited was noted. Most respondents agreed that patients with high body mass index were less likely to be evaluated for transplant. Respondents reported increased complication rates among obese patients, with the most common being poor wound healing and increased infection rates. CONCLUSIONS Most medical and surgical liver transplant directors have a strong appreciation of the possible morbidity risks associated with performing liver transplants in morbidly obese patients and have policies in effect to minimize these risks.

Hepatotoxicity of Cardiovascular and Antidiabetic Drugs

With the increasing prevalence of cardiovascular disease and associated disorders globally, there has been a proliferation of medications for antiplatelet therapy, dyslipidemia, glycemic control, and hypertension. Liver injury of varying degrees, from asymptomatic elevation in liver enzymes to liver transplantation or death, has been reported to result from members of many drug classes. Statins offer the best example of a class of agents that may cause asymptomatic liver enzyme abnormalities that are likely to be of no clinical consequence. On the other hand, first generation thiazolidinediones and some of the antihypertensive agents are more prominently associated with a capacity to induce severe liver disease. It behooves the clinician to have a framework of understanding from which to base the diagnosis and management of hepatotoxicity attributable to drugs used to treat these common diseases. Thus, the goal of this chapter is to review the pertinent literature on hepatotoxicity associated with medications used for cardiovascular diseases and diabetes, including clinical presentation, histology, mechanisms of injury, and disease outcomes.

Training Directors Have Positive Perceptions of a Competency-Based Gastroenterology and Transplant Hepatology Fellowship Program

BACKGROUND & AIMS In 2012, the American Board of Internal Medicine approved a pilot competency-based transplant hepatology (TH) training program. This program allows gastroenterology (GI) and TH fellowships to be completed in 3 years. We investigated the perceptions and beliefs of GI and TH division and fellowship program directors on the competency-based TH training program. METHODS All current GI and TH division and fellowship program directors from the 162 fellowship programs accredited by the Accreditation Council for Graduate Medical Education were invited via e-mail to anonymously complete the online survey. The survey questioned their perceptions of the 3-year combined GI and TH training program. RESULTS A total of 116 participants completed the survey (∼38% response rate). Most respondents were GI fellowship directors (61%); 15% were GI and hepatology division directors, 19% were TH fellowship directors, 14% were TH division directors, and 5% were GI division directors. Most of the respondents were in favor of the pilot program (85%). Only 63% of all respondents believed that graduates of the pilot program would achieve the same level of competency in GI as those who completed the traditional program. Overall, 71% believed incorporation of the 3-year training model would increase interest and participation in TH fellowships. CONCLUSIONS Most of the academic GI and TH division and fellowship program directors embrace competency-based fellowship education and TH subspecialty training during the designated 3-year GI fellowship. Future studies will be needed to reevaluate these beliefs after several years.

Incidence, determinants and outcomes of pregnancy-associated hepatitis B flares: A regional hospital-based cohort study

There is limited knowledge about hepatitis B virus (HBV) flare among pregnant women. We evaluated the incidence, determinants and outcomes of HBV flare in a multicultural cohort of pregnant HBV‐infected women in the United States.

Complementary and alternative medications in hepatitis C infection.

Chronic hepatitis C (CHC) infection affects almost 3% of the global population and can lead to cirrhosis, liver failure, and hepatocellular carcinoma in a significant number of those infected. Until recently, the only treatments available were pegylated interferon and ribavirin, which traditionally were not very effective and have considerable side effects. For this reason, interest in complementary and alternative medications (CAM) in the management of hepatitis C has been investigated. Some CAM has demonstrated therapeutic potential in chronic hepatitis C treatment. Unfortunately, some CAM has been shown to have the potential to cause drug-induced liver injury. This article will review and evaluate many of the natural molecules that interact with the hepatitis C virus (HCV) life cycle and discuss their potential use and safety in HCV therapy, as well as highlight some important interactions between medical and complementary treatments.

Concepts and Treatment Approaches in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults and is the most common liver disease in Western nations. NAFLD is associated with central adiposity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and cardiovascular disease. It encompasses the entire spectrum of fatty liver diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with lobular/portal inflammation, hepatocellular necrosis, and fibrosis. Of those who develop NASH, 15–25% will progress to end stage liver disease and hepatocellular carcinoma over 10–20 years. Its pathogenesis is complex, and involves a state of lipid accumulation due to increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, and increased incidence of de novo lipogenesis. Plasma aminotransferases and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for definitive diagnosis. Many new plasma biomarkers and imaging techniques are now available that should improve the ability to diagnose NAFLD noninvasively Due to its complexity and extrahepatic complications, treatment of NAFLD requires a multidisciplinary approach with excellent preventative care, management, and treatment. This review will evaluate our current understanding of NAFLD, with a focus on existing therapeutic approaches and potential pharmacological developments.