Drug Hepatotoxicity: Environmental Factors

Drug-induced liver injury presents as various forms of acute and chronic liver disease. There is wide geographic variation in the most commonly implicated agents. Smoking can induce cytochrome P450 enzymes but this does not necessarily translate into clinically relevant drug-induced liver injury. Excessive alcohol consumption is a clear risk factor for intrinsic hepatotoxicity from acetaminophen and may predispose to injury from antituberculosis medications. Understanding of the role of infection, proinflammatory states, disorders of coagulation, and the hepatic clock in predisposing patients to drug-induced liver injury is evolving. More study focusing specifically on environmental risk factors predisposing patients to drug-induced liver injury is needed

Advice Regarding Alcohol Use by Individuals With Nonalcoholic Fatty Liver Disease: Primum non nocere

Individuals with nonalcoholic fatty liver disease (NAFLD) often ask their health care providers about routinely consuming non‐heavy amounts of alcohol for pleasure and potential health benefits. According to the American Association for the Study of Liver Diseases (AASLD) Practice Guidance published in 2018, there are insufficient data to make a recommendation with regard to non‐heavy alcohol consumption by individuals with NAFLD.(1) Although several cross‐sectional studies have suggested that light alcohol consumption (on average, <1 drink per day) may have a beneficial effect on the presence and severity of NAFLD, a large meta‐regression analysis suggested that lower body mass index among light and moderate drinkers is a potential confounder and thus casts doubt on the rigor of those studies

Pharmacotherapy for Nonalcoholic Fatty Liver Disease

Lifestyle modifications and optimization of the management of cardiometabolic comorbidities are currently the mainstay of treatment for patients with nonalcoholic fatty liver disease. Pharmacotherapy to halt or reverse hepatic histological injury and prevent the development of end-stage liver disease is specifically offered to patients with nonalcoholic steatohepatitis (NASH) and those with advanced fibrosis. In this review, the authors discuss the state of the art of various pharmacological agents for NASH. The efficacy of vitamin E and pioglitazone is reasonably well established in a selected group of patients with NASH. Current data do not offer convincing evidence for efficacy of pentoxifylline, long-chain polyunsaturated fatty acids, angiotensin receptor blockers, metformin, or ursodeoxycholic acid. They also discuss the state of several emerging agents for treating NASH including the farsenoid X receptor ligand, obeticholic acid

Emerging Treatments for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

This review discusses completed phase II randomized clinical trials with high-quality published results for compounds that demonstrate effects on nonalcoholic steatohepatitis histology (obeticholic acid, elafibranor, and liraglutide). The authors also review the available preliminary data on cenicriviroc and selonsertib, with or without simtuzumab’s phase II studies. Finally, the authors briefly discuss compounds that have been tested but did not achieve the primary end point of histologic improvement and appeared in high-quality published articles (cysteamine bitartrate and long-chain polyunsaturated fatty acids)

Management of Dyslipidemia as a Cardiovascular Risk Factor in Individuals with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the United States and is associated with an increased risk of cardiovascular disease (CVD) and cardiovascular (CV) mortality, independent of traditional cardiovascular risk factors. CVD is one of the most common causes of death among individuals with NAFLD and management of NAFLD must extend beyond liver disease to include CVD risk modification. Clinicians should assess CVD risk with the Framingham Risk Score (FRS) and screen for CVD risk factors including dyslipidemia, diabetes mellitus (DM), hypertension, tobacco use and the metabolic syndrome (MetS). CVD risk factors, particularly dyslipidemia, require aggressive medical management to reduce the high risk of CVD events and death in individuals with NAFLD

Activated recombinant factor VIIa should not be used in patients with refractory variceal bleeding: it is mostly ineffective, is expensive, and may rarely cause serious adverse events

Activated Recombinant Factor VIIa Does Not Improve Mortality in Variceal Bleeding. Bendtsen F, D’Amico G, Rusch E, de Franchis R, Anderson PK, Lebrec D, et al. Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: An individual patient based meta-analysis of two controlled trials. J Hepatol 2014; 61: 252–259. (Reproduced with Permission) BACKGROUND & AIMS: Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. METHODS: The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. RESULTS: 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p = 0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p = 0.023). No significant treatment effect was found at 42 days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. CONCLUSIONS: The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1–5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment

Liver Stiffness Measurements in Patients with Non‐cirrhotic Portal Hypertension – The Devil is In the Details

Non‐cirrhotic portal hypertension (NCPH) is often a diagnostic challenge due to signs and symptoms of portal hypertension that overlap with cirrhosis. The etiology of NCPH is broadly classified as prehepatic, hepatic (pre‐sinusoidal and sinusoidal) and post‐hepatic.1 Some common etiologies of NCPH encountered in clinical practice include portal vein thrombosis (prehepatic) and nodular regenerative hyperplasia (NRH) (hepatic)

Febuxostat-induced acute liver injury

Febuxostat is a unique xanthine oxidase inhibitor that was approved for the prevention of gout in the United States in 2009. Unlike allopurinol, febuxostat is not a nucleoside analogue and has a higher specificity for xanthine oxidase. Although this drug has not been on the market for a long time, febuxostat may be safer than allopurinol. Importantly, febuxostat appears to be safer than allopurinol, which has been linked to many instances of severe hypersensitivity reactions, including skin rash with eosinophilia and systemic manifestations (DRESS syndrome), Stevens Johnson syndrome, acute nephritis, acute icteric hepatitis and acute liver failure. While febuxostat is not infrequently associated with serum enzyme elevations during treatment, it has yet to be linked to cases of clinically apparent acute liver injury. We report a case of acute liver injury with jaundice due to febuxostat and which was identified in a prospective study of drug-induced liver injury in the United States