Fatty Liver Disease, Metabolism and Alcohol Interplay: A Comprehensive Review

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and its incidence has been increasing in recent years because of the high prevalence of obesity and metabolic syndrome in the Western population. Alcohol-related liver disease (ArLD) is the most common cause of cirrhosis and constitutes the leading cause of cirrhosis-related deaths worldwide. Both NAFLD and ArLD constitute well-known causes of liver damage, with some similarities in their pathophysiology. For this reason, they can lead to the progression of liver disease, being responsible for a high proportion of liver-related events and liver-related deaths. Whether ArLD impacts the prognosis and progression of liver damage in patients with NAFLD is still a matter of debate. Nowadays, the synergistic deleterious effect of obesity and diabetes is clearly established in patients with ArLD and heavy alcohol consumption. However, it is still unknown whether low to moderate amounts of alcohol are good or bad for liver health. The measurement and identification of the possible synergistic deleterious effect of alcohol consumption in the assessment of patients with NAFLD is crucial for clinicians, since early intervention, advising abstinence and controlling cardiovascular risk factors would improve the prognosis of patients with both comorbidities. This article seeks to perform a comprehensive review of the pathophysiology of both disorders and measure the impact of alcohol consumption in patients with NAFLD.

Keywords: alcohol-related liver disease; cirrhosis; hepatocellular carcinoma; non-alcoholic fatty liver disease.

Figure 1

The keys aspects of the pathophysiology of NAFLD. Several factors, such as obesity, high-fat diets and (epi)genetics, lead to adipose tissue inflammation and dysbiosis, increasing systemic inflammatory response and leading to the development of hepatic steatosis and steatohepatitis. This image has been created using BioRender.

Figure 2

The key aspects in the pathophysiology of ArLD. Heavy alcohol consumption exerts its deleterious effects through direct mitochondrial toxicity leading to oxidative stress and dysbiosis that favors development of liver steatosis and steatohepatitis. This image has been created using BioRender.

Figure 3

Overlapping in pathophysiology of liver damage in NAFLD and ArLD. Although specific pathways are involved in the development of both NAFLD and ArLD, this figure shows the common processes that lead to hepatic fat accumulation and inflammation. In both pathologies, genetic predisposition leads to the upregulation of several pathways that increase lipogenesis and oxidative stress. Moreover, gut synthesis of ethanol metabolites (by gut microbiome in the case of NAFLD or by alcohol intake in ArLD) leads to an increased intestinal permeability and translocation of PAMPs that activate systemic immune response, increasing the synthesis of several inflammation mediators. These molecules lead to hepatic fat accumulation and the apparition of an immune infiltrate that leads to progressive liver damage. Steatohepatitis also exerts positive feedback, stimulating immune response and increased systemic inflammation. The following abbreviations should be noted: FFA free fatty acid; IL: interleukin, PAMPs: pathogen-associated molecular patterns; PPAR: peroxisome proliferator-activated receptor; SREBP: sterol regulatory element binding protein; TNF: tumor necrosis factor. This image has been created using BioRender.