The Merck Manual of Diagnosis and Therapy
Section 4. Hepatic And Biliary Disorders
Chapter 40. Alcoholic Liver Disease
Topics
[General]

[General]

Alcoholic liver disease: A spectrum of clinical syndromes and pathologic changes in the liver caused by alcohol (ethanol).

Pathogenesis

The major factors are the quantity of alcohol consumed, the patient's nutritional status, and genetic and metabolic traits. A linear correlation generally exists between the dose and duration of alcohol abuse and the development of liver disease, although not all who overuse alcohol develop significant liver damage. The alcohol equivalent to 10 g is 30 mL of 40-proof whiskey, 100 mL of 12% wine, or 250 mL of 5% beer. As little as 20 g of alcohol in women or 60 g in men can produce liver injury when consumed daily for years. For example, ingestion of 150 to 200 g of alcohol for 10 to 12 days produces fatty liver even in otherwise healthy men. For alcoholic hepatitis, patients consume 80 g of alcohol daily for almost a decade, whereas the average threshold to develop cirrhosis is 160 g daily over 8 to 10 yr. Duration is important.

By providing empty calories, decreasing the appetite, and causing malabsorption through its toxic effects on the gut and pancreas, alcohol promotes malnutrition. Malnutrition alone does not cause cirrhosis, but a lack of one or more nutritional factors may hasten the effects of alcohol.

Alcohol is a hepatotoxin whose metabolism creates profound liver cell derangements. Apparent variations in susceptibility (only 10 to 15% of alcoholics develop cirrhosis) and the greater susceptibility of females (even when adjusting for smaller body size) to alcohol-induced liver disease suggest that other factors are also significant. One may be that females have decreased alcohol dehydrogenase in their gastric mucosa, lessening metabolism. Family clustering of alcoholic liver disease occurs frequently. Thus, genetic factors may also be involved in alcohol metabolism: some people may be deficient in oxidizing alcohol. Certain HLA histocompatibility types have also been associated with alcohol-induced liver disease. Immunologic status does not appear to help determine susceptibility to alcohol, but immunologic mechanisms (particularly cytokine mediators) may be important in the inflammatory response and in liver injury.

Metabolism of Alcohol

Alcohol is readily absorbed from the GI tract, and > 90% is metabolized by the liver through oxidative mechanisms involving mainly alcohol dehydrogenase and certain microsomal enzymes (microsomal ethanol oxidizing system). Alcohol cannot be stored and must be metabolized. Alcohol dehydrogenase produces acetaldehyde, the major catabolite, which is further oxidized to acetate. Acetaldehyde may be toxic to the liver and other organs. The conversion of alcohol to acetaldehyde and of the latter to either acetate or acetyl coenzyme A involves the generation of reduced nicotinamide adenine dinucleotide (NADH), which shuttles into mitochondria, increasing the NADH/nicotinamide adenine dinucleotide ratio and thus the redox state of the liver. Thus, alcohol metabolism promotes a reduced intracellular state that interferes with carbohydrate, lipid, and other aspects of intermediary metabolism. The oxidation of alcohol is coupled with the reduction of pyruvate to lactate, which promotes hyperuricemia, hypoglycemia, and acidosis. Alcohol oxidation also is coupled with the reduction of oxaloacetic acid to malate. This may explain the reduced activity of the citric acid cycle, reduced gluconeogenesis, and increased fatty acid synthesis associated with alcohol metabolism.

-Glycerophosphate increases after alcohol consumption; the glycerol produced promotes increased triglyceride synthesis and leads to hyperlipidemia. Although O₂ consumption is normal after alcohol ingestion, there is a metabolic shift from O₂ consumption during the breakdown of fatty acids to the oxidation of alcohol to acetate. This shift may explain the reduced lipid oxidation and increased ketone formation recorded after alcohol ingestion. Alcohol metabolism may also induce a local hypermetabolic state in the liver, promoting hypoxic damage in zone 3 (the area around the terminal hepatic venules). The net effect is a reduced redox state, inhibited protein synthesis, and increased lipid peroxidation.

Whether alcoholics metabolize alcohol differently from nonalcoholics is unknown. Clearly, chronic ingestion of alcohol leads to hepatic adaptation with hypertrophy of the smooth endoplasmic reticulum and increased activity of the hepatic drug-metabolizing enzymes. Alcohol induces the microsomal ethanol oxidizing system, which is responsible in part for alcohol metabolism. Alcohol also induces microsomal P-450, which is involved in drug metabolism. Thus, the alcohol abuser acquires an increased tolerance to alcohol and drugs (eg, sedatives, tranquilizers, antibiotics), and neurologic adaptation develops. The result is a complex interaction between drugs, other chemicals, and alcohol.

Pathology

The spectrum of hepatic pathology associated with prolonged alcohol consumption ranges from the simple accumulation of neutral fat in hepatocytes to cirrhosis and hepatocellular carcinoma. The widely accepted fatty liver-alcoholic hepatitis-cirrhosis spectrum is a concept of convenience. The findings usually overlap, and many patients present with features of the entire spectrum. The key lesion may be fibrosis around the terminal hepatic venules and perhaps also the perisinusoidal space. From the perspective of pathology, it is better to diagnose alcoholic liver disease and describe the specific findings in each patient.

Fatty liver or steatosis (see also Ch. 39) appears to be the initial change and is the most common response to alcohol ingestion. The liver is large; the cut surface, yellow. The increased liver fat is derived from the diet, from free fatty acids mobilized from adipose tissue, and from lipid synthesized in the liver and inadequately degraded or excreted. Fat droplets of varying size are found in most hepatocytes except in regenerating areas. The droplets tend to coalesce, forming large (macrovesicular) globules that frequently occupy the entire cytoplasm. Fat accumulates in zones 3 (centrizonal) and 2 (midzonal). Fatty cysts probably represent late stages of the fatty change. These cysts are usually located periportally and form through fusion of the fat content of several hepatocytes. Other features include hydropic change in early stages of alcoholic liver injury and giant spherical mitochondria. The former--swollen, balloonlike hepatocytes--result from impaired release of protein and lipoproteins. These cells degenerate and disintegrate.

Alcoholic hepatitis includes the macrovesicular fatty change plus a diffuse inflammatory response to injury and necrosis (often focal); established cirrhosis may also be present.

Mallory (alcoholic hyaline) bodies are fibrillar proteins of intracytoplasmic inclusions within swollen hepatocytes; these cells contain little or no fat. With hematoxylin and eosin stain, Mallory bodies appear as irregular aggregates of purplish red material. Although characteristic of alcoholic hepatitis, Mallory bodies are also found in some cases of Wilson's disease, Indian childhood cirrhosis, cirrhosis following small-bowel bypass surgery, primary biliary cirrhosis (or other causes of prolonged cholestasis), diabetes mellitus, morbid obesity, and hepatocellular carcinoma. A polymorphonuclear reaction develops locally in response to the Mallory-containing and necrotic liver cells. In zone 3 of the liver acinus, connective tissue is laid down in the sinusoids and around hepatocytes. Collagen fibers also creep into the space of Disse, developing into a continuous membrane under the sinusoidal endothelium. Venous lesions also develop, such as prominent sclerosis around the terminal hepatic venules, termed sclerosing hyaline necrosis or central hyaline sclerosis. This lesion can lead to portal hypertension before cirrhosis becomes established and may be the earliest manifestation of cirrhosis. Venous scarring alone (as it occurs in veno-occlusive disease) can lead to the development of portal hypertension without overt cirrhosis.

Alcoholic hepatitis, with its diffuse inflammatory cell infiltrate and necrosis, is often viewed as the intermediary step between fatty liver and cirrhosis. Cell necrosis and centrizonal (zone 3) hypoxia can stimulate collagen formation. Fibrosis, however, occurs from the transformation of fat-storing Ito cells into fibroblasts. Thus, fibrosis can proceed to cirrhosis without an intervening stage of alcoholic hepatitis. About 20% of heavy drinkers develop cirrhosis, in which the liver is finely nodular, with its architecture disorganized by fibrous septa and nodules. Although the inflammatory cell infiltrate and fatty liver are characteristic, occasionally the histology may resemble chronic active hepatitis. If drinking stops and the liver undergoes a constructive regenerative response, the clinical picture can be that of a mixed cirrhosis (see Ch. 41).

Increased liver iron occurs in alcoholics with normal, fatty, or cirrhotic livers, but the incidence is < 10%. Iron is deposited in parenchymal and Kupffer cells. There is no relationship with the amount of iron in the alcoholic beverage consumed or with the length of drinking history. Body iron stores are not significantly increased.

Alcoholic cirrhosis represents end-stage disease, developing in 10 to 20% of those who are chronically heavy drinkers. Micronodular cirrhosis is evident, although this may be a lingering feature of fatty liver and alcoholic hepatitis. Some regeneration occurs from the surviving liver cells. The cirrhosis may slowly progress to a nonspecific macronodular pattern. The liver shrinks and becomes small.

Symptoms, Signs, and Diagnosis

Variations in drinking patterns, individual susceptibility to hepatotoxic effects of alcohol, and the many kinds of tissue damage promote a highly variable clinical picture. For a long time, no manifestations may be referable to the liver. Symptoms generally can be related to the quantity of alcohol ingested and the overall duration of alcohol abuse. As a guideline, symptoms usually become apparent in patients during their 30s, and severe problems tend to appear in patients in their 40s.

Patients with a fatty liver are usually asymptomatic. In 33%, the liver is enlarged, smooth, and occasionally tender. Routine biochemical studies are often within normal limits; -glutamyl transpeptidase (GGT) is often elevated. Vascular spiders and features of hyperestrogenism and hypoandrogenism from the alcoholism per se may be evident.

Alcoholic hepatitis can be suspected clinically, but the diagnosis depends on examination of a biopsy sample. The histologic lesion can be found throughout the clinical spectrum of alcoholic liver disease. Patients with alcoholic hepatitis may present with fatigue, fever, jaundice, right upper quadrant pain, a hepatic bruit, tender hepatomegaly, and leukocytosis, but so may patients with sepsis, cholecystitis, or mechanical extrahepatic biliary obstruction.

Cirrhosis may also be relatively asymptomatic, have features of alcoholic hepatitis, or be dominated by complications: portal hypertension with splenomegaly, ascites, hepatorenal syndrome, hepatic encephalopathy, or even hepatocellular carcinoma.

Laboratory Findings

Although sometimes suggestive, routine blood and biochemical tests are nonspecific and do not permit a definitive diagnosis. In alcoholic liver disease, various abnormalities of RBC morphology can exist, including target cells, macrocytes, spur cells, and stomatocytes. An elevated MCV is usual and can be a useful marker of alcohol abuse because it gradually returns to normal after cessation of drinking. Thrombocytopenia is common, either from the direct toxic effects of alcohol on the bone marrow or secondary to hypersplenism.

In alcoholic hepatitis, transaminase levels are moderately raised (about 250 U/L). Conjugated bilirubinemia actually deepens in the hospital. The activity of serum ALT is depressed (caused by a depletion of pyridoxal 5´-phosphate) relative to that of serum AST (AST:ALT ratio > 2). The activity of the serum GGT may help detect alcohol consumption. The value of GGT lies not in its specificity but in its being markedly elevated in patients with excessive alcohol intake or alcoholic liver disease. MCV, GGT, and alkaline phosphatase are the best combination of routine tests to identify chronic alcohol abuse. Liver scans and ultrasound are sometimes helpful. Liver biopsy (see Ch. 37) is the only basis for a secure diagnosis, particularly in alcoholic hepatitis. Even in alcoholics, other forms of liver disease occur.

Prognosis and Treatment

With abstinence, nonfibrotic liver damage may be reversed, and the survival of patients with alcoholic hepatitis, fibrosis, and cirrhosis improves. The significance of alcoholic hepatitis appears to be determined by the degree of associated fibrosis and liver cell necrosis. The reversibility of sclerosing hyaline necrosis is unknown.

In theory, treatment of alcoholic liver disease is simple and straightforward; in practice, it is difficult: the patient must stop drinking alcohol. After severe bouts of illness, major adverse social consequences (eg, job loss, family unit breakdown), and a review of the facts by a physician with whom a rapport has been established, many patients stop drinking. It helps to point out to the patient that much of the damage caused by alcoholic liver disease is reversible. Otherwise, management focuses on nonspecific supportive care. Acute alcohol withdrawal requires supportive care, fluid and electrolyte balance, and sedatives (eg, benzodiazepines) carefully titrated to the severity of the withdrawal symptoms. Excessive sedation in patients with marked liver disease can precipitate hepatic encephalopathy. (See also Alcoholism in Ch. 195.)

Nutritional and general support is time-honored. The value of corticosteroids in alcoholic hepatitis is moot, perhaps showing greatest promise in more severe disease, especially with hepatic encephalopathy. Antifibrinogenic agents (eg, colchicine, penicillamine) have not proven effective, whereas propylthiouracil to treat the possible hypermetabolic state of the alcoholic liver provides some benefit but has never gained acceptance. Trauma, infection, GI bleeding, nutritional deficiencies, fluid retention, and hepatic encephalopathy require specific attention, as discussed elsewhere in The Manual.