Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol is a leading cause of mental retardation and congenital malformation. The abnormalities that have been characterized as fetal alcohol syndrome include (1) intrauterine growth retardation, (2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region (appearing as a flattened face), and (5) minor joint anomalies. More severe cases may include congenital heart defects and mental retardation. Although the level of alcohol intake required to cause serious neurologic deficits appears quite high, the threshold for more subtle neurologic deficits is uncertain.
The mechanisms that underlie ethanol’s teratogenic effects are unknown. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely on maternal and placental enzymes for elimination of alcohol.
The neuropathologic abnormalities seen in humans and in animal models of fetal alcohol syndrome indicate that ethanol triggers apoptotic neurodegeneration and also causes aberrant neuronal and glial migration in the developing nervous system. In tissue culture systems, ethanol causes a striking reduction in neurite outgrowth.
G. Immune System
The effects of alcohol on the immune system are complex; immune function in some tissues is inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (eg, liver, pancreas). In addition, acute and chronic exposure to alcohol have widely different effects on immune function. The types of immunologic changes reported for the lung include suppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T cells. In the liver, there is enhanced function of key cells of the innate immune system (eg, Kupffer cells, hepatic stellate cells) and increased cytokine production. In addition to the inflammatory damage that chronic heavy alcohol use precipitates in the liver and pancreas, it predisposes to infections, especially of the lung, and worsens the morbidity and increases the mortality risk of patients with pneumonia.
H. Increased Risk of Cancer
Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver. Evidence also points to a small increase in the risk of breast cancer in women. A threshold level for alcohol consumption as it relates to cancer has not been determined. Alcohol itself does not appear to be a carcinogen in most test systems. However, its primary metabolite, acetaldehyde, can damage DNA, as can the reactive oxygen species produced by increased cytochrome P450 activity. Other factors implicated in the link between alcohol and cancer include changes in folate metabolism and the growth-promoting effects of chronic inflammation.
Interactions between ethanol and other drugs can have important clinical effects resulting from alterations in the pharmacokinetics or pharmacodynamics of the second drug.
The most common pharmacokinetic alcohol-drug interactions stem from alcohol-induced increases of drug-metabolizing enzymes, as described in Chapter 4. Thus, prolonged intake of alcohol without damage to the liver can enhance the metabolic biotransformation of other drugs. Ethanol-mediated induction of hepatic cytochrome P450 enzymes is particularly important with regard to acetaminophen. Chronic consumption of three or more drinks per day increases the risk of hepatotoxicity due to toxic or even high therapeutic levels of acetaminophen as a result of increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites (see Figure 4–5). Current US Food and Drug Administration (FDA) regulations require that over-the-counter products containing acetaminophen carry a warning about the relation between ethanol consumption and acetaminophen-induced hepatotoxicity.