Nonalcoholic fatty liver disease and alcohol-related liver disease: From clinical aspects to pathophysiological insights

Abstract

Two major causes of steatohepatitis are alcohol and metabolic syndrome. Although the underlying causes of alcoholrelated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) differ, there are certain similarities in terms of the mode of disease progression and underlying pathophysiological mechanisms. Further, excessive alcohol consumption is often seen in patients with metabolic syndrome, and alcoholic hepatitis exacerbation by comorbidity with metabolic syndrome is an emerging clinical problem. There are certain ethnic differences in the development of both NAFLD and ALD. Especially, Asian populations tend to be more susceptible to NAFLD, and genetic polymorphisms in patatin-like phospholipase domain-containing 3 (PNPLA3) play a key role in both NAFLD and ALD. From the viewpoint of pathophysiology, cellular stress responses, including autophagy and endoplasmic reticulum (ER) stress, are involved in the development of cellular injury in steatohepatitis. Further, gutderived bacterial products and innate immune responses in the liver most likely play a profound role in the pathogenesis of both ALD and NASH. Though the recent progress in the treatment of viral hepatitis has reduced the prevalence of viral-related development of hepatocellular carcinoma (HCC), non-viral HCC is increasing. Alcohol and metabolic syndrome synergistically exacerbate progression of steatohepatitis, resulting in carcinogenesis. The gut-liver axis is a potential therapeutic and prophylactic target for steatohepatitis and subsequent carcinogenesis.

Association between Fasting Ketonuria and Advanced Liver Fibrosis in Non-Alcoholic Fatty Liver Disease Patients without Prediabetes and Diabetes Mellitus

“…However, studies on nutritional ketosis in patients with NAFLD have been poorly characterized. As previously mentioned, NAFLD is closely related to DM and prediabetes because of the common mechanism of IR with compensatory hyperinsulinemia [17,32]. Exacerbation of IR induces excessive glucose production in the liver and hepatic delivery of non-esterified fatty acids (NEFA) in adipose tissue [17].…”

MAFLD enhances clinical practice for liver disease in the Asia-Pacific region

“…70 In addition, alcoholic liver disease is a common cause of chronic liver disease in the Asia-Pacific region. 71 Co-existing alcoholic liver disease and hyperalimentation-associated fatty liver shows synergistic interaction, resulting in the progression of liver disease. 72 These findings imply that assessment of fatty liver is important for the clinical management of patients with viral hepatitis and alcohol intake, especially in the Asia-Pacific region (Figure 2).…”

“…71 In this population, heterozygosity for the aldehyde dehydrogenase 2*2 allele, which results in lower enzymatic activity, is highly prevalent, with the incidence reaching 45% in East Asia. 71,83 Whereas, in India, 96.3% of patients with alcoholic liver disease have at least one component of metabolic syndrome and 53.0% has three or more components of metabolic syndrome, suggesting the high prevalence of co-existence of alcoholic liver disease and hyperalimentation-associated fatty liver. 84,85 Patients with both alcoholic and NAFLD have higher serum levels of aminotransferases and a high prevalence of advanced fibrosis than in patients with NAFLD.…”

The Current View of Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma

“…The hyperinsulinemia associated with insulin resistance may promote cell proliferation and trigger carcinogenesis. Cellular stress responses, including autophagy and endoplasmic reticulum-associated activity, may trigger NAFLD cytotoxicity [ 43 ]. In addition, innate immune reactions between the products of intestinal bacteria and the liver increase deoxycholic acid levels, triggering the senescence of hepatic stellate cells [ 44 ].…”