Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published November 22, 2017


Nonalcoholic steatohepatitis, a type of liver damage that is strongly associated with visceral adiposity and the metabolic syndrome, has become a major cause of cirrhosis and liver cancer. A number of inherited and environmental factors increase the risk of nonalcoholic steatohepatitis and influence its progression. The pathogenic mechanisms are being unraveled; metabolic stress, inflammation, and fibrosis have been identified as key processes.  Read the latest NEJM Review Article.

Clinical Pearls

Q: What are some of the differences between isolated hepatic steatosis and nonalcoholic steatohepatitis?

A: A definitive diagnosis of nonalcoholic steatohepatitis is currently based on histologic evidence not only of fat accumulation (steatosis) in hepatocytes but also of liver-cell injury and death and accumulation of inflammatory cells. Because livers with nonalcoholic steatohepatitis are more damaged than livers with isolated steatosis, nonalcoholic steatohepatitis is more likely than isolated steatosis to lead to progressive liver fibrosis and eventual liver-related illness and death. Nonalcoholic steatohepatitis always develops in the context of hepatic steatosis, but isolated steatosis is three or four times as prevalent as nonalcoholic steatohepatitis.

Q: What percentage of American adults will develop cirrhosis related to nonalcoholic steatohepatitis?

A: Cirrhosis related to nonalcoholic steatohepatitis will develop in approximately 2% of American adults at some point in their lives. This information is derived from fibrosis-progression rates among patients with nonalcoholic fatty liver disease, as well as evidence that approximately 6% of the adult population has nonalcoholic steatohepatitis and that approximately 25% of affected patients have at least F2 fibrosis (portal fibrosis with few septa) at the time of diagnosis. Indeed, nonalcoholic steatohepatitis will most likely be the top reason for liver transplantation in the United States by 2020.

Morning Report Questions

Q: What are some of the factors linked to the pathogenesis of nonalcoholic steatohepatitis?

A: Hepatocyte injury and death are key features that differentiate nonalcoholic steatohepatitis from isolated steatosis. Whether hepatocyte injury is the primary cause or a secondary consequence of liver inflammation is debatable. Both are likely to be relevant to the pathogenesis of nonalcoholic steatohepatitis because injured hepatocytes release factors promoting the accumulation of immune cells that produce hepatotoxic substances and incite further injury and inflammation. Conversely, factors that promote inflammation (e.g., visceral adiposity, the metabolic syndrome, changes in intestinal microbiota, and circadian-rhythm disruption) increase hepatocyte exposure to cytokines, gut-derived products, and other inflammatory mediators that are hepatotoxic. Genomewide association studies indicate that polymorphisms in patatin-like phospholipase domain–containing 3 (PNPLA3) and transmembrane 6 superfamily, member 2 (TM6SF2) promote the development of nonalcoholic steatohepatitis and related liver damage (i.e., cirrhosis, primary liver cancer, or both). Modifiable risk factors that challenge systemic and hepatic energy homeostasis have been linked to nonalcoholic steatohepatitis, including shift work and alterations in commensal microbiota.

Q: What therapies are available for patients with nonalcoholic steatohepatitis?

A: Currently, lifestyle modifications are the main intervention for nonalcoholic steatohepatitis without fibrosis. Adjunctive treatment with vitamin E or pioglitazone, an insulin-sensitizing agent with antiinflammatory actions, might also be considered. The same lifestyle modifications are also recommended for patients with more severe fibrosis. Vigorous efforts to determine the most effective methods for management of the metabolic syndrome and for screening for cancer are important, since cardiovascular disease and cancer are the leading causes of death in patients with nonalcoholic steatohepatitis and cirrhosis. A number of large clinical trials designed to identify effective and safe treatments for nonalcoholic steatohepatitis and liver fibrosis are in progress. Efforts have focused on ameliorating the three general processes that drive the pathogenesis and progression of nonalcoholic steatohepatitis: metabolic stress, inflammation, and fibrosis. Results have been reported for several studies, but no agent has yet received approval by the Food and Drug Administration for the treatment of nonalcoholic steatohepatitis.

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