Pathophysiology and Management of Alcoholic Liver Disease: Update 2016

Abstract

Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.

Keywords: Carcinoma, hepatocellular; Corticosteroid therapy; Hepatitis, alcoholic; Liver transplantation; Malnutrition; PNPLA3.

Fig. 1

The progression for alcoholic liver injury to steatosis with scarring, inflammation and architectural distortion leading to cirrhosis. As a complication of cirrhosis, hepatocellular carcinoma may occur. However, only a minority of patients with alcoholic steatosis progress to severe liver injury.

Fig. 2

Hepatic metabolism of ethanol by enzymes ADH, CYP2E1 and catalase. Each enzyme generates acetaldehyde, a toxic and mutagenic metabolite of ethanol. While ADH is metabolically stable regardless of the alcohol challenge and catalase is irrelevant with respect to its role in hepatic alcohol degradation, CYP2E1 is inducible and contributes most to acetaldehyde production during heavy alcohol consumption.

Fig. 3

Structural modifications at the PNPLA3 rs738409 locus (I148) affect the substrate binding groove rather than the catalytic center of the protein. Substituting methionine (Met) for isoleucine (Ile) at position 148 of the PNPLA3 protein reduces accessibility for substrates (e.g., triglycerides) and thus results in a loss of function.

Fig. 4

Typical appearance of alcoholic cirrhosis showing three prominent features of alcoholic liver disease, i.e., fibrosis (blue arrow), steatosis (red arrow) and ballooning (yellow arrow). Significant inflammation is often not seen but consists of neutrophilic and lymphocytic infiltrates when visible (chromotrope anilin-blue stain; magnification × 100).