social and economic factors that influence alcohol consumption and thus the rates of mortality from cirrhosis. Early stages of alcoholic liver injury are reversible, but advanced stages are usually relentlessly progressive. The only known prevention for alcoholic cirrhosis is to limit consumption of alcohol.
For many years cirrhosis among alcoholics was attributed to nutritional deficiencies associated with alcoholism and not to the direct effects of alcohol on the liver. This belief was based on experiments in animals, principally in rats, in which cirrhosis could be produced by protein deficiency but not by alcohol alone (see Chapter 16) and on the frequent occurrence of nutritional deficiencies among alcoholics. However, more recent experiments have demonstrated that alcohol produces liver toxicity independently of the adverse effects of nutrient deficiencies, and cirrhosis has been reproduced in baboons by alcohol in the absence of nutrient deficiencies (Lieber et al., 1975; Popper and Lieber, 1980; see also Chapter 16).
It has long been known that alcoholism clusters in families, and rapidly accumulating evidence indicates that certain genotypes are more susceptible (see Chapters 4 and 16). A number of genetic markers have been associated with chronic alcoholism.
Most of these observations have been concerned with alcoholism and not specifically with cirrhosis. Since the major determinants of the effects of alcohol on tissue are the duration and intensity of exposure to alcohol and its metabolites, the genetic control of susceptibility to cirrhosis is probably associated with the alcohol-metabolizing enzymes of the liver (see Chapter 16). Therefore, both alcoholism and alcoholic cirrhosis are probably the results of genetic-environmental interactions.
There are two major varieties of gallstones: those composed primarily of cholesterol and those composed of heme pigments. Approximately 80% of the gallstones found in the U.S. population are composed of cholesterol. Therefore, the following discussion is limited to those. The prevalence of cholelithiasis in adults in industrialized countries, including the United States, is about 10%; the prevalence among women is about twice that among men (Strom and West, 1985). The prevalence of cholelithiasis is much higher in populations with American Indian ancestry, reaching up to 65% in some American Indian groups (Hesse, 1959). Cholelithiasis and associated cholecystitis are not frequent causes of death, but they are frequent causes of hospital admission and surgical intervention.
The physiological abnormality underlying the formation of gallstones is the accumulation of bile supersaturated with cholesterol. Supersaturation occurs when there is a high rate of cholesterol secretion, a low rate of bile acid secretion, a reduced bile acid pool, and low secretion of phospholipids.
Obesity increases risk of gallstones by increasing cholesterol secretion into bile. It seems logical that a high cholesterol intake would increase cholesterol secretion into the bile and increase the risk of gallstones, but there is no firm evidence from studies in humans that bile cholesterol saturation is increased by high intakes of cholesterol. Gastrointestinal disorders that impair the reabsorption of bile acids also may increase the risk of gallstone formation (reviewed by Bennion and Grundy, 1978a,b).
In general, dietary factors in gallstone formationexcept for those involved in obesityhave not been conclusively identified. There is conflicting and inconsistent evidence regarding the effects of polyunsaturated fats on bile cholesterol saturation and cholelithiasis (see Chapter 7). In some experiments in humans, very high intakes of polyunsaturated fatty acids increase the cholesterol saturation of bile and increase its lithogenicity. There is no evidence that PUFA intakes of up to 10% of total calories affect the lithogenicity of bile.
Several species of rodents are highly susceptible to the induction of gallstones when fed diets enriched with cholesterol and fats and are thus useful in studying the pathogenesis of gallstones. However, this susceptibility appears to be due to a genetic variation in their ability to metabolize cholesterol and bile salts, and their existence does not establish a causal relationship with dietary fats or cholesterol in humans (see Chapter 7).