Alcoholic and non-alcoholic steatohepatitis

Abstract

This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Keywords: Alcoholic hepatitis; Alcoholic liver disease; CYP2E1; Hangover; Hepatocarcinogenesis; Human immunodeficiency virus; Immunohistochemistry; Laboratory markers; Mallory–Denk bodies; Methylation; Micronutrients; Mitochondrion; Nonalcoholic steatohepatitis; Viral hepatitis.

Fig. 1

A) SNIP of morphometric quantitative immunofluorescence of FITC labeled antibody to C1Q in a liver of a patient with alcoholic hepatitis. The scale on the left is in arbitrary units of intensity tracing (197 compared with the control (B) of 78 p < 0.01) along the yellow line/arrow x918. B) SNIP of morphometric semi quantitative immunofluorescence of FITC labeled antibody to C1Q in the liver of a control patient. The fluorescent intensity scale on the left is lower than that shown in panel A. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

A) Flow chart for TLR4/TLR3 in liver biopsies from patients with alcoholic hepatitis (ASH). B) Flow chart for TLR4/TLR3 in liver biopsies from patients with non-alcoholic hepatitis (NASH).

Fig. 3

Flow chart for FATylation, ubiquitylation and ufmylation in liver biopsies from patients with alcoholic hepatitis (AH) and non alcoholic hepatitis (NASH).

Fig. 4

Zinc therapy positively impacts multiple mechanisms of ALD.