ALCOHOLIC LIVER DISEASE

Disorders that occur in alcohol abusers, often in sequence, include

• Fatty liver (in > 90%)

• Alcoholic hepatitis (in 10 to 35%)

• Cirrhosis (in 10 to 20%)

Hepatocellular carcinoma may also develop, especially in association with iron accumulation.

Quantity of alcohol

Alcohol content is estimated to be the beverage volume (in mL) multiplied by its percentage of alcohol. For example, the alcohol content of 40 mL of an 80-proof (40% alcohol) beverage is 16 mL by volume. Each mL contains about 0.79 g of alcohol. Although values can vary, the percentage of alcohol averages 2 to 7% for most beers and 10 to 15% for most wines. Thus, a 12-oz glass of beer contains about 3 to 10 g of alcohol, and an 8-oz glass of wine contains about 10 to 15 g.

Risk increases markedly for men who drink > 40 g, particularly > 80 g, of alcohol/day for > 10 year (eg, 3 to 6 cans of beer, 3 to 6 shots of hard liquor, 4 to 8 glasses of wine). For cirrhosis to develop, consumption must usually be > 80 g/day for > 10 yr. If consumption exceeds 230 g/day for 20 yr, risk of cirrhosis is about 50%. But only some chronic alcohol abusers develop liver disease. Thus, variations in alcohol intake do not fully explain variations in susceptibility, indicating that other factors are involved.

Sex

Women are more susceptible to alcoholic liver disease, even after adjustment for body size. Women require only 20 to 40g of alcohol to be at risk, half of that for men. Risk in women may be increased because they have less alcohol dehydrogenase in their gastric mucosa; thus, first-pass oxidation of alcohol is decreased.

Genetic factors

Alcoholic liver disease often runs in families, suggesting genetic factors (eg, deficiency of cytoplasmic enzymes that eliminate alcohol).

Alcohol absorption and metabolism

Alcohol (Ethanol) is readily absorbed from the stomach, but most is absorbed from the small intestine. Alcohol cannot be stored. A small amount is degraded in transit through the gastric mucosa, but most is catabolized in the liver, primarily by Alcohol Dehydrogenase (ADH) but also by Cytochrome P-450 2E1 (CYP2E1) and the Microsomal Enzyme Oxidation System (MEOS)

Metabolism via the ADH pathway involves the following

• ADH, a cytoplasmic enzyme, oxidizes alcohol into Acetaldehyde. Genetic polymorphisms in ADH account for some individual differences in blood alcohol levels after the same alcohol intake but not in susceptibility to alcoholic liver disease.

• Acetaldehyde dehydrogenase (ALDH), a mitochondrial enzyme, then oxidizes acetaldehyde to Acetate. Chronic alcohol consumption enhances acetate formation. Asians, who have lower levels of ALDH, are more susceptible to toxic acetaldehyde effects (eg, flushing); the effects are similar to those of Disulfiram, which inhibits ALDH.

• These oxidative reactions generate hydrogen, which converts Nicotinamide-Adenine Dinucleotide (NAD) to its reduced form (NADH), increasing the redox potential (NADH/NAD) in the liver.

• The increased redox potential inhibits fatty acid oxidation and gluconeogenesis, promoting fat accumulation in the liver.

Chronic alcoholism induces the MEOS (mainly in endoplasmic reticulum), increasing its activity. The main enzyme involved is CYP2E1. When induced, the MEOS pathway can account for 20% of alcohol metabolism. This pathway generates harmful reactive O₂ species, increasing oxidative stress and formation of O₂-free radicals.

Alcohol and Liver

Hepatic fat accumulation

Fat (triglycerides) accumulates throughout the hepatocytes for the following reasons:

• Export of fat from the liver is decreased because hepatic fatty acid oxidation and lipoprotein production decrease.

• Input of fat is increased because the decrease in hepatic fat export increases peripheral lipolysis and triglyceride synthesis, resulting in hyperlipidemia.

Hepatic fat accumulation may predispose to subsequent oxidative damage

Endotoxins in the gut

Alcohol changes gut permeability, increasing absorption of endotoxins released by bacteria in the gut. In response to the endotoxins (which the impaired liver can no longer detoxify), liver macrophages (Kupffer cells) release free radicals, increasing oxidative damage

Oxidative damage

Oxidative stress is increased by

• Liver hypermetabolism, caused by alcohol consumption

• Free radical-induced lipid peroxidative damage

• Reduction in protective antioxidants (eg, glutathione, vitamins A and E), caused by alcohol-related undernutrition

• Binding of alcohol oxidation products, such as acetaldehyde, to liver cell proteins, forming neoantigens and resulting in inflammation

• Accumulation of neutrophils and other WBCs, which are attracted by lipid peroxidative damage and neoantigens

• Inflammatory cytokines secreted by WBCs

Accumulation of hepatic iron, if present, aggravates oxidative damage. Iron can accumulate in alcoholic liver disease through ingestion of iron-containing fortified wines; most often, the iron accumulation is modest. This condition must be differentiated from hereditary hemochromatosis

Resultant inflammation, cell death, and fibrosis

Cell necrosis and apoptosis result in hepatocyte loss, and subsequent attempts at regeneration result in fibrosis. Stellate (Ito) cells, which line blood channels (sinusoids) in the liver, proliferate and transform into myofibroblasts, producing an excess of type I collagen and extracellular matrix. It is normally in a quiescent state and serves as a storehouse for vitamin A. The cytokine tumour growth factor- beta (TGF-β) is a major stimulus for stellate cell activation and collagen production. Other cytokines, such as platelet derived growth factor; connective tissue growth factor and oxidative stress also stimulate stellate cells to produce fibrosis. As a result, the sinusoids narrow, limiting blood flow. Fibrosis narrows the terminal hepatic venules, compromising hepatic perfusion and thus contributing to portal hypertension. Extensive fibrosis is associated with an attempt at regeneration, resulting in liver nodules. This process culminates in cirrhosis

Pathology

Fatty liver, alcoholic hepatitis, and cirrhosis are often considered separate, progressive manifestations of alcoholic liver disease. However, their features often overlap.

Fatty liver (steatosis)
The initial and most common consequence of excessive alcohol consumption. Fatty liver is potentially reversible. Macrovesicular fat accumulates as large droplets of triglyceride and displaces the hepatocyte nucleus, most markedly in perivenular hepatocytes. The liver enlarges.

Alcoholic hepatitis (steatohepatitis)
A combination of fatty liver, diffuse liver inflammation, and liver necrosis (often focal); all in various degrees of severity. The damaged hepatocytes are swollen with a granular cytoplasm (balloon degeneration) or contain fibrillar protein in the cytoplasm (Mallory or alcoholic hyaline bodies). Severely damaged hepatocytes become necrotic. Sinusoids and terminal hepatic venules are narrowed. Cirrhosis may also be present.

Alcoholic cirrhosis
Advanced liver disease characterized by extensive fibrosis that disrupts the normal liver architecture. The amount of fat present varies. Alcoholic hepatitis may coexist. The feeble compensatory attempt at hepatic regeneration produces relatively small nodules (micronodular cirrhosis). As a result, the liver usually shrinks. In time, even with abstinence, fibrosis forms broad bands, separating liver tissue into large nodules (macro-nodular cirrhosis)

Symptoms and Signs

Symptoms usually become apparent in patients during their 30s or 40s; severe problems appear about a decade later.

Fatty liver
Often asymptomatic. In one third of patients, the liver is enlarged and smooth, but it is not usually tender.

Alcoholic hepatitis
Ranges from mild and reversible to life threatening. Most patients with moderate disease are undernourished and present with fatigue, fever, jaundice, right upper quadrant pain, tender hepatomegaly, and sometimes a hepatic bruit. About 40% deteriorate soon after hospitalization, with consequences ranging from mild (eg, increasing jaundice) to severe (eg, ascites, portal-systemic encephalopathy, variceal bleeding, liver failure with hypoglycemia, coagulopathy). Other manifestations of cirrhosis may be present.

Cirrhosis
If compensated, may be asymptomatic. The liver is usually small (Atrophy); when the liver is enlarged, fatty liver or hepatoma should be considered. Symptoms range from those of alcoholic hepatitis to the complications of end-stage liver disease, such as portal hypertension (often with esophageal varices and upper GI bleeding, splenomegaly, ascites, and portal-systemic encephalopathy). Portal hypertension may lead to intrapulmonary arteriovenous shunting with hypoxemia (hepatopulmonary syndrome), which may cause cyanosis and nail clubbing. Acute renal failure secondary to progressively decreasing renal blood flow (hepatorenal syndrome) may develop. Hepatocellular carcinoma develops in 10 to 15% of patients with alcoholic cirrhosis.

Chronic alcoholism
Rather than liver disease, causes Dupuytren's contracture of the palmar fascia, vascular spiders, and peripheral neuropathy. In men, chronic alcoholism causes signs of hypogonadism and feminization (eg, smooth skin, lack of male-pattern baldness, gynecomastia, testicular atrophy, changes in pubic hair). Undernutrition may lead to multiple vitamin deficiencies (eg, of folate and thiamin), enlarged parotid glands, and white nails. In alcoholics, Wernicke's encephalopathy and Korsakoff's psychosis result mainly from thiamin deficiency. Hepatitis C occurs in > 25% of alcoholics; this combination markedly worsens the progression of liver disease.

Rarely, patients with fatty liver or cirrhosis present with Zieve's syndrome (hyperlipidemia, hemolytic anemia, and jaundice).

Source: API-Textbook of Medicine

Source: API-Textbook of Medicine