Alcohol or Not: A Review Comparing Initial Mechanisms, Contributing Factors, and Liver Transplantation Outcomes Between Alcoholic and Nonalcoholic Steatohepatitis

Chronic liver diseases take many forms; alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are two common illnesses that potentially lead to cirrhosis, liver failure, and liver cancer. It is estimated that a quarter of heavy drinkers develop ALD and the same portion of people without heavy drinking habits have NAFLD. Alcohol intake is regularly used to differentiate NAFLD from ALD; however, diagnosis based on the discrimination threshold may be suboptimal when facing an obese patient with a high level of alcohol exposure. Therefore, understanding the common and/or different mechanism(s) driving each disease is extremely important. The ‘two-hit’ or ‘multi-hit’ hypothesis is used to explain the pathogenesis of both diseases. The ‘first hit’ refers to developing steatosis, the accumulation of fat components in the liver, and the ‘second hits’ are factors leading to oxidative stress, inflammation, and fibrosis, such as metabolic syndromes (e.g., morbid obesity, hyperglycaemia, hyperlipidaemia, disturbed circadian cycles, and altered intestinal microbiota) and environmental toxins (e.g., cigarette smoke and pollutants). Heritable factors also affect the probability and disease progression of both ALD and NAFLD. Whereas PNPLA3 and TM6SF2 variants are influential genetic risk factors for the diseases, epigenetic factors, such as DNA methylation, post-translational histone modifications, and small non-coding RNA, are of paramount importance. Moreover, considering that both ALD and NAFLD patients may eventually develop end-stage liver disease and require liver transplantation, the authors extensively investigated the worldwide outcomes from original literature for these two aetiologies, and the results showed no obvious differences in post-transplantation survival between them. Precise percentage determination of these two aetiologies contributing to steatohepatitis and its secondary injuries in the future would allow for better strategies for therapeutic and preventive intervention.