Nonalcoholic fatty liver disease (NAFLD), already the most common form of liver disease in the United States, can be expected to increase in prevalence and severity in parallel with national ...epidemics of obesity and type 2 diabetes. NAFLD is frequently associated with insulin resistance. While insulin resistance, and thereby hyperinsulinemia, are, in large part, metabolic consequences of obesity, the basis of diversity in severity and progression of inflammation and fibrosis is not known. Increased susceptibility to oxidative stress is likely to play a role. Several patient characteristics have been associated with more severe histological findings in patients with NAFLD, including type 2 diabetes, hypertension, age over 40 years, and higher transaminases. Liver biopsy is, however, required to accurately grade and stage NAFLD histologically. Although the natural history of NAFLD is relatively poorly defined, NAFLD is increasingly recognized as an important cause of decompensated liver disease. Weight reduction and improved insulin sensitivity are associated with improved biochemical and histological parameters of NAFLD. There are, however, no proven safe and efficacious pharmacological treatments for NAFLD.
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting immune checkpoint molecules. ICIs are an immunotherapy for the treatment of many advanced malignancies. The advent of ICIs has ...been a major breakthrough in the field of oncology, a fact recognized by the 2018 Nobel Prize in Physiology or Medicine being awarded for the discovery. The Food and Drug Administration approved the first ICI, ipilimumab, in 2011 for the treatment of metastatic melanoma. Seven ICIs are now used in clinical practice, including nivolumab and pembrolizumab for treatment of advanced hepatocellular carcinoma. ICIs are increasingly used across the spectrum of hepatobiliary neoplasia. The utility of ICI therapy has been limited by immune‐related adverse reactions (irAEs) affecting multiple organ systems. Hepatotoxicity is an important irAE, occurring in up to 16% of patients receiving ICIs. Optimizing outcomes in patients receiving ICI therapy requires awareness of and familiarity with diagnosing and management of ICI‐induced immune‐mediated hepatotoxicity (IMH), including approaches to treatment and ICI dose management. The aim of this review article is to (1) provide a comprehensive, evidence‐based review of IMH; (2) perform a systematic review of the management of IMH; and (3) present algorithms for the diagnosis and management of IMH.
Although hepatocellular carcinoma (HCC) is more common in the setting of cirrhosis, there is increasing evidence that it can develop in the setting of noncirrhotic nonalcoholic fatty liver disease ...(NAFLD)/nonalcoholic steatohepatitis (NASH) and that steatosis alone can promote carcinogenesis. In addition, obesity, diabetes, and metabolic syndrome are recognized risks for the development of HCC. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. The surveillance for HCC in the setting of noncirrhotic NAFLD/NASH, obesity, diabetes, and metabolic syndrome remains an area of uncertainty.
Branched‐chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low ratio of plasma BCAAs to aromatic amino acids is a physiological hallmark of ...liver cirrhosis, and BCAA supplementation was originally devised with the intention of normalizing amino acid profiles and nutritional status. However, recent studies on BCAAs have revealed that, in addition to their role as protein constituents, they may have a role as pharmacological nutrients for patients with chronic liver disease. Large‐scale, multicenter, randomized, double‐blinded, controlled trials on BCAA supplementation have been performed in Italy and Japan, and results demonstrate that BCAA supplementation improves not only nutritional status, but also prognosis and quality of life in patients with liver cirrhosis. Moreover, accumulating experimental evidence suggests that the favorable effects of BCAA supplementation on prognosis may be supported by unforeseen pharmacological actions of BCAAs. This review summarizes the possible effects of BCAAs on albumin synthesis and insulin resistance from clinical and basic viewpoints. We also review the newly discovered clinical impact of BCAAs on hepatocellular carcinoma and the prognosis and quality of life of patients with liver cirrhosis. (HEPATOLOGY 2011;)
Background & Aims Hepatocyte cellular dysfunction and death induced by lipids and macrophage-associated inflammation are characteristics of nonalcoholic steatohepatitis (NASH). The fatty acid ...palmitate can activate death receptor 5 (DR5) on hepatocytes, leading to their death, but little is known about how this process contributes to macrophage-associated inflammation. We investigated whether lipid-induced DR5 signaling results in the release of extracellular vesicles (EVs) from hepatocytes, and whether these can induce an inflammatory macrophage phenotype. Methods Primary mouse and human hepatocytes and Huh7 cells were incubated with palmitate, its metabolite lysophosphatidylcholine, or diluent (control). The released EV were isolated, characterized, quantified, and applied to macrophages. C57BL/6 mice were placed on chow or a diet high in fat, fructose, and cholesterol to induce NASH. Some mice also were given the ROCK1 inhibitor fasudil; 2 weeks later, serum EVs were isolated and characterized by immunoblot and nanoparticle-tracking analyses. Livers were collected and analyzed by histology, immunohistochemistry, and quantitative polymerase chain reaction. Results Incubation of primary hepatocytes and Huh7 cells with palmitate or lysophosphatidylcholine increased their release of EVs, compared with control cells. This release was reduced by inactivating mediators of the DR5 signaling pathway or rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) inhibition. Hepatocyte-derived EVs contained tumor necrosis factor-related apoptosis-inducing ligand and induced expression of interleukin 1β and interleukin 6 messenger RNAs in mouse bone marrow–derived macrophages. Activation of macrophages required DR5 and receptor-interacting protein kinase 1. Administration of the ROCK1 inhibitor fasudil to mice with NASH reduced serum levels of EVs; this reduction was associated with decreased liver injury, inflammation, and fibrosis. Conclusions Lipids, which stimulate DR5, induce release of hepatocyte EVs, which activate an inflammatory phenotype in macrophages. Strategies to inhibit ROCK1-dependent release of EVs by hepatocytes might be developed for the treatment of patients with NASH.
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