Biological Links Between Alcohol Use and Liver Disease in Persons Living with HIV

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

Liver disease due to alcohol use or metabolic dysfunction, the leading cause of cirrhosis in the US, is on the rise. Unhealthy alcohol use and metabolic dysfunction (e.g., diabetes, obesity, dyslipidemia) can each cause fat deposition in the liver, termed liver steatosis. Steatosis can lead to steatohepatitis (i.e., fatty liver and inflammation with or without fibrosis), which can progress to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Previously, liver-related morbidity in persons living with HIV (PWH) was predominantly driven by coinfection with viral hepatitis. With the advent of effective antivirals for viral hepatitis, steatosis is now the most common liver disease in PWH. Until recently, however, alcohol and HIV were considered separate and unique causes of steatosis. Large longitudinal studies of metabolic liver disease excluded PWH and persons with unhealthy alcohol use, preventing evaluation of the combined effects of these factors on liver disease. HIV is independently associated with higher risk for steatohepatitis and fibrosis, possibly because of chronic immune activation and gut microbial translocation, which can also be caused by alcohol use. Thus, alcohol and HIV may have synergistic adverse effects on the liver. Some genes that exhibit aberrant DNA methylation in response to alcohol use exhibit similar changes in the setting of liver disease, but whether DNA methylation mediates alcohol's effects on liver disease is unknown. Prior analyses relied on self-reported alcohol use, but when measured by the biomarker phosphatidylethanol (PEth), alcohol use is more strongly associated with serum-based measures of liver fibrosis. We propose to assess the effects of alcohol use, HIV, the gut microbiome, and epigenetics on the development of steatohepatitis and fibrosis in a large longitudinal study of PWH and persons without HIV: the Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study (MWCCS). We will use longitudinal data from vibration-controlled transient elastography, a highly accurate bedside liver imaging test, to identify steatohepatitis and fibrosis in >3500 MWCCS participants, as well as PEth, DNA methylation, 16S gut microbiome and shotgun metagenomic sequencing. The cohort has high proportions of persons at risk for liver disease due to older age, high rates of obesity, diabetes, and unhealthy alcohol use. We propose the following aims: 1) determine the effect of alcohol consumption on risk of steatohepatitis and fibrosis and the role of HIV; 2) establish whether the microbial composition of the gut explains associations between alcohol consumption and steatohepatitis and fibrosis; and 3) identify DNA methylation marks associated with unhealthy alcohol consumption and steatohepatitis and fibrosis. Through our studies of liver disease and the microbiome and epigenome in PWH, we have the expertise to accomplish our aims. The results of the proposed studies will reveal the effects of various levels of objectively measured alcohol use on risk for liver disease in PWH, define host and gut microbial processes associated with liver disease, and guide clinical recommendations for treating PWH who are at high risk of poor liver outcomes.