Alcoholic Liver Disease

Alcohol causes a spectrum of liver injury that can progress from fatty liver to alcoholic hepatitis (often considered an intermediate stage) to cirrhosis.

Alcohol consumption is high in most Western countries. In the US, annual ingestion is estimated at 10 L of pure ethanol equivalent per person; 15 million people abuse or are dependent on alcohol. The male:female ratio is 11:4.

Risk Factors

The major causative factors in alcoholic liver disease are quantity of alcohol consumed, duration of alcohol abuse (usually > 8 yr), nutritional status, and genetic and metabolic traits. Among susceptible people, a linear correlation generally exists between the amount and duration of alcohol use and the development of liver disease. As little as 20 g of alcohol in women or 60 g in men can cause serious liver damage when consumed daily for several years. Consuming more than 60 g/day for 2 to 4 wk produces fatty liver even in otherwise healthy men; 80 g/day may lead to alcoholic hepatitis; and 160 g/day over a decade can lead to cirrhosis. Alcohol content is estimated to be the beverage volume (in mL) multiplied by its percentage of alcohol. For example, 16 mL of alcohol is contained in roughly 40 mL of an 80‑proof (40% alcohol) beverage. Each mL of alcohol contains about 0.79 g. Although values can vary, the percentage of alcohol is about 2 to 7% for most beers and 10 to 15% for most wines.

Only 10 to 20% of alcoholics develop cirrhosis. Women are more susceptible than men (even when adjusting for smaller body size), probably because women have less alcohol dehydrogenase in their gastric mucosa, which lessens the first-pass oxidation of alcohol. Alcoholic liver disease often runs in families, suggesting genetic factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol). Malnutrition, particularly protein-energy malnutrition, increases susceptibility. Other risk factors include a diet high in unsaturated fat, iron deposition in the liver, and concomitant hepatitis C virus infection.

Pathophysiology

Alcohol is readily absorbed from the stomach and small intestine. It cannot be stored; > 90% is metabolized through oxidation. The first breakdown product is acetaldehyde, which is produced by three enzymatic pathways: alcohol dehydrogenase (responsible for about 80% of metabolism), cytochrome P‑450 2E1 (CYP2E1), and catalase.

Acetaldehyde is converted to acetate by mitochondrial aldehyde dehydrogenase. Chronic alcohol consumption enhances acetate formation. The processes generate hydrogen, which converts nicotinamide-adenine dinucleotide (NAD) to its reduced form (NADH), increasing the redox potential in the liver. This replaces fatty acids as a fuel, lowers fatty acid oxidation, and allows triglycerides to accumulate, causing fatty liver and hyperlipidemia. The excess hydrogen also converts pyruvate to lactate, which decreases glucose production (hypoglycemia can result), causing renal acidosis, reduced urate excretion, hyperuricemia, and thus gout.

Alcohol metabolism may also make the liver hypermetabolic, causing hypoxia and free radical–induced lipid peroxidative damage. Alcohol and undernutrition deplete antioxidants, such as glutathione and vitamins A and E, which predispose to such damage.

Acetaldehyde initiates much of the inflammation and fibrosis of alcoholic hepatitis. It transforms the stellate (Ito) cells lining liver blood channels (sinusoids) into fibroblasts that develop myocontractile elements and actively produce collagen. The sinusoids narrow and fill, limiting transport and blood flow. Gut endotoxins, which the impaired liver can no longer detoxify, lead to production of inflammatory cytokines. Acetaldehyde and lipid peroxidation products recruit leukocytes, resulting in production of more inflammatory cytokines. This elicits a vicious circle of inflammation that culminates in fibrosis and loss of hepatocytes.

Fat is deposited throughout the hepatocytes, a result of increased input from peripheral adipose tissue, elevated triglyceride synthesis, decreased lipid oxidation, and reduced lipoprotein production that impairs fat export from the liver.