Alcoholic Liver Disease (ALD)

I. EPIDEMIOLOGY.

The association of alcohol abuse and liver damage has been known since the time of the ancient Greeks. The availability of alcoholic beverages, licensing laws, and economic, cultural, and environmental conditions all influence both per capita alcohol consumption and mortality from alcohol-related liver disease. Alcoholism is, in part, inherited, and aberrant alcohol-drinking behavior is genetically influenced. The risk factors that may affect the susceptibility to development of alcoholic liver disease include genetic factors, malnutrition, female gender, and viral agents (hepatitis virus B, C, and D).

Ninety percent to 95% of people with chronic alcohol consumption develop fatty liver. In almost all instances, this lesion is thought to be reversible on cessation of alcohol intake. Ten percent to 30% of individuals go on to perivenular sclerosis (collagen deposition in and around central veins). Ten percent to 35% of chronic alcoholics, however, have acute liver injury that may become recurrent or chronic. Some of these patients recover, but 8% to 20% go on to sinusoidal, perivenular, and pericentral fibrosis and cirrhosis. Even during the inflammatory stage without the presence of cirrhosis, patients may have portal hypertension, ascites, and esophageal varices.

II. RELATION OF CIRRHOSIS TO ALCOHOL CONSUMPTION.

The alcohol content of various beverages is shown in Table 51-1. The development of alcoholic cirrhosis correlates with the quantity and duration of alcohol consumption. For men, the relative risk of cirrhosis has been estimated to be 6 times greater when consumption is 40 to 60 g of alcohol per day than when it is up to 20 g per day, and 14 times greater at 60 to 80 g per day. The average “cirrhogenic” dose has been calculated to be 40 to 80 g of ethanol per day consumed for approximately 10 to 12 years.

In a case-controlled study in men, the relative risk for cirrhosis was 1.83 for men consuming 40 to 60 g of absolute alcohol per day compared to men consuming fewer than 40 g per day. The relative risk rose to 100 for men consuming more than 80 g per day. The average cirrhogenic and threshold doses are lower in women than in men. Binge drinking compared to drinking with meals and beer and spirits compared to wine drinking increases the risk for ALD.

III. ETHANOL METABOLISM

A. Absorption, distribution, and elimination.

In a healthy man, about 100 mg of ethanol per kilogram of body weight is eliminated in an hour. Heavy alcohol consumption for years may increase the rate of ethanol elimination up to 100%.

Ethanol is absorbed from the gastrointestinal tract, especially the duodenum and jejunum (70%-80%), by simple diffusion because of its small molecular size and low solubility in lipids. The rate of absorption is decreased by delayed gastric emptying and by the presence of intestinal contents. Food delays gastric absorption, producing a slower rise and lower peak value of blood alcohol in fed than in fasting patients.

The systemic distribution of alcohol is very rapid. In organs with a rich blood supply, such as the brain, lungs, and liver, alcohol rapidly equilibrates with the blood. Alcohol is poorly lipid-soluble. At room temperature, tissue lipids take up only 4% of the quantity of alcohol dissolved in a corresponding volume of water. In an obese person, therefore, the same amount of alcohol per unit of weight gives a higher blood alcohol concentration than in a thin person. The mean volume of distribution of ethanol is less in women than in men, resulting in higher peak blood concentrations and greater mean areas under the ethanol concentration-time curves.

TABLE 51-1 Alcohol Content of Various Beverages

Beverage		*Alcohol concentration^ (g/100 mL)**	Alcohol in standard measures
Beer		3.9	13.3 g; 12-oz bottle/can
Red wine		9.5	11.0 g/glass; 71 g/bottle
Rosé		8.7	10.0 g/glass; 65 g/bottle
White wine, dry		9.1	10.0 g/glass; 64 g/bottle
White wine, medium		8.8	10.0 g/glass; 62 g/bottle
White wine, sweet		10.2	11.0 g/glass; 71 g/bottle
White wine, sparkling		9.9	11.0 g/glass; 74 g/bottle
Port		15.9	124 g/bottle
Sherry, dry		15.7	123 g/bottle
Sherry, medium		14.8	115 g/bottle
Sherry, sweet		15.6	122 g/bottle
Vermouth, dry		13.9	122 g/bottle
Vermouth, sweet		13.0	100 g/bottle
Cherry brandy		19.0	148 g/bottle
Hard liquor 70%		31.7	240 g/bottle; 7.5 g/single-shot
	(brandy, gin, whiskey)
^*Percentage alcohol × 0.078 = g alcohol/100 mL.
Key: 1 fl oz = 30 mL; 1 pint = 470 mL; 1 wine bottle = 757 mL.

In humans, less than 1% is excreted in the urine, 1% to 3% via the lungs, and 90% to 95% as carbon dioxide after it is oxidized in the liver.

B. Chemical metabolism

1. Alcohol dehydrogenase.

Although most of the ingested ethanol is metabolized by the liver, other tissues such as the stomach, intestines, kidney, and bone marrow cells oxidize ethanol to a small extent. There is an alcohol dehydrogenase (ADH) present in the mucosa of the stomach, jejunum, and ileum, which results in a considerable first-pass metabolism of alcohol. The gastric ADH activity is less in women than in men and decreases with chronic alcoholism.

In the liver, the main pathway for ethanol metabolism is by its oxidation to acetaldehyde by ADH. Alternative pathways of oxidation in other subcellular compartments are also present. Multiple molecular forms of ADH exist, and at least three different classes have been described on the basis of structure and function. Various ADH forms appear in different frequencies in different racial populations. This polymorphism may explain, in part, individual variation in the rate of acetaldehyde production and first-pass elimination.

The hepatic metabolism of ethanol proceeds in three basic steps. First, ethanol is oxidized within the hepatocyte cytosol to acetaldehyde. Second, acetaldehyde is oxidized to acetate via catalysis mainly by aldehyde dehydrogenase (ALDH) in the mitochondria. Third, acetate ALDH is released into blood and is oxidized by peripheral tissues to carbon dioxide and water.

When ethanol is oxidized to acetaldehyde via ADH, nicotinamide-adenine dinucleotide (NAD) is required as a cofactor and is reduced to NADH during the reaction, resulting in an increase in the liver of the NADH/ NAD ratio. This increase in the redox state of the liver has serious metabolic effects such as inhibition of hepatic gluconeogenesis, impairment of fatty acid oxidation, decrease in citric acid cycle activity, and increase in conversion of pyruvate to lactic acid resulting in lactic acidosis.

2. The microsomal ethanol oxidizing system (MEOS)

is located in the endoplasmic reticulum (ER) of the hepatocyte. It is a cytochrome P-450-, NADPH-(reduced nicotinamide-adenine-dinucleotide phosphate), and oxygen-dependent enzyme system that oxidizes ethanol to acetaldehyde. Because chronic consumption of ethanol leads to the proliferation of the ER, the activity of the MEOS is also increased (induction). However, its quantitative contribution to the total ethanol metabolism is still controversial. The current nomenclature for MEOS is P45011E1. In addition to ethanol, this enzyme system oxidizes other alcohols, carbon tetrachloride (CCl₄), and acetaminophen (Tylenol).

3. ALDH

rapidly metabolizes acetaldehyde to acetate. Multiple molecular forms of ALDH have been demonstrated. Two major hepatic ALDH isoenzymes (I and II) exist in humans. The mitochondrial isoenzyme (ALDH I) has been reported to be missing in about 50% of liver specimens in Japanese people. The deficiency of ALDH I in Asians has several metabolic and clinical consequences.

4. Change in hepatic redox state.

When ethanol is oxidized to acetaldehyde in the hepatocyte cytosol via ADH, NAD is required as a cofactor. NAD is reduced to NADH. Also, ALDH-mediated conversion of acetaldehyde to acetate requires NAD conversion of NADH in the mitochondria. Thus, both the cytosolic and mitochondrial redox states are altered. This effect is manifested by respective increases of both liver and blood lactate to pyruvate and of β-hydroxybutyrate to acetoacetate ratios. This state leads to inhibition of hepatic gluconeogenesis, fatty acid oxidation, and citric acid cycle activity, which may clinically exhibit as fatty liver, hypoglycemia, and lactic acidosis (Fig. 51-1).

5. Alterations in metabolism

of ethanol, acetaldehyde, and acetate during chronic alcohol consumption. Chronic ethanol consumption enhances ethanol clearance except in the presence of clinically significant liver damage or severe food restriction. This effect is attributed to increased ADH activity, MEOS activity, a hypermetabolic state in the liver, and possible increased mitochondrial reoxidation of NADH, which is the rate-limiting step in ethanol elimination and metabolism. The explanation for increased ethanol elimination by corticosteroids is the induced increase in NADH conversion to NAD as a result of steroid-induced gluconeogenesis.

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