Porth's Essentials of Pathophysiology, 4e

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Disorders of Hepatobiliary and Exocrine Pancreas Function

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with half the cases reported to be unintentional over- doses. 24 Unintentional overdoses may occur when people unknowingly take several over-the-counter preparations that contain acetaminophen (e.g., an acetaminophen- containing cold preparation and acetaminophen pain medication). Numerous host factors contribute to the susceptibility to drug-induced liver disease, including genetic predisposition, age, underlying chronic liver dis- ease, diet and alcohol consumption, and the use of mul- tiple interacting drugs. Drugs and chemicals can exert their effects by caus- ing hepatocyte injury and death or by cholestatic liver damage due to injury of biliary drainage structures. Drug reactions can be acute or chronic, and predictable based on the drug’s chemical structure and metabolites or unpredictable (idiosyncratic) based on individual characteristics of the person receiving the drug. Direct Predictable Injury. Some drugs are known to have toxic effects on the liver. Examples are acetamino- phen, isoniazid, and phenytoin. Direct hepatic damage, which is often age and dose dependent, usually results from drug metabolism and the generation of toxic metabolites. Because of the greater activity of the drug- metabolizing enzymes in the central zones of the liver, these agents typically cause centrilobular necrosis. The injury is characterized by marked elevations in ALT and AST values with minimally elevated ALP. Bilirubin lev- els invariably are increased, and the prognosis often is worse when hepatocellular necrosis is accompanied by jaundice. Idiosyncratic Reactions. In contrast to direct pre- dictable drug reactions, idiosyncratic reactions are unpredictable, not related to dose, and sometimes accompanied by features suggesting an allergic reaction. Drugs are relatively small molecules and, therefore, unlikely to provoke an immune response. However, in the process of biotransformation, drugs may combine with enzymes, producing a compound large enough to serve as an antigen and induce the formation of anti- bodies or a direct cytotoxic T-cell response. In some cases, the reaction results directly from a metabolite that is produced only in certain persons based on a genetic predisposition. For example, certain people are capable of rapid acetylation of isoniazid, an antituber- culosis drug. Cholestatic Reactions. Cholestatic drug reactions result in decreased secretion of bile or obstruction of the biliary tree. Acute intrahepatic cholestasis is one of the most frequent types of idiosyncratic drug reactions. Among the drugs credited with causing cholestatic drug reactions are estradiol; chlorpromazine, an anti- psychotic drug; and some of the antibiotics, including amoxicillin/clavulanic acid, erythromycin, and nafcillin. Typically, cholestatic drug reactions are characterized by an early onset of jaundice and pruritus, with little altera- tion in the person’s general feeling of well-being. Most instances of acute drug-induced cholestasis subside once the drug is withdrawn.

These reactions, often referred to as biotransformations, are important considerations in drug therapy. Phase 1 reactions result in the chemical modification of reactive drug groups through oxidation, reduction, hydroxylation, or other chemical reactions. Many of these reactions involve drug-metabolizing enzymes that are located in the lipophilic endoplasmic reticulummem- branes of liver cells. One of the enzymes involved is the product of a gene superfamily called cytochrome P450 (abbreviated CYP or CYP P450). Multiple isoforms of the CYP enzyme have been identified and traced to the metabolism of specific drugs and to potential interac- tions among drugs. Of these isoforms, the CYP3A4 enzyme accounts for approximately 50% of the liver’s drug-metabolizing activity. 23 Many gene members of the CYP enzyme system can have their activity induced or suppressed as they undergo the task of metabolizing drugs. For example, drugs such as alcohol and barbiturates can induce cer- tain members to increase enzyme production, accelerat- ing drug metabolism and decreasing the pharmacologic action of the drug and of coadministered drugs that use the same member of the CYP system. In the case of drugs metabolically transformed to reactive intermedi- ates, enzyme induction may exacerbate drug-mediated tissue toxicity. Certain drugs can also inhibit enzymes in the CYP system. For example, the antibiotic erythromy- cin and the antifungal agents fluconazole, itraconazole, and ketoconazole inhibit CYP3A4 enzyme activity, as does grapefruit juice, thereby decreasing the metabolism of drugs that use this enzyme system. 23 Phase 2 reactions, which involve the conversion of lipid-soluble derivatives to water-soluble substances called conjugates , may follow phase 1 reactions or pro- ceed independently. Conjugation, a process that couples the drug with an activated endogenous compound such as glutathione, renders the drug more water soluble so it can be excreted in the bile or urine. Although many water-soluble drugs and endogenous substances are excreted unchanged in the urine or bile, lipid-soluble substances tend to accumulate in the body unless they are converted to less active compounds or water-soluble metabolites. Because the endogenous substrates used in the conjugation process are obtained from the diet, nutrition plays a critical role in phase 2 reactions. In addition to its role in metabolism of drugs and chemicals, the liver also is responsible for hormone inac- tivation or modification. Insulin and glucagon are inac- tivated by proteolysis or deamination. Thyroxine and triiodothyronine are metabolized by reactions involving deiodination. Steroid hormones such as the glucocorti- coids are first inactivated by a phase 1 reaction and then conjugated by phase 2 reactions. Drug-Induced Liver Disease Many widely used therapeutic drugs, including over- the-counter medications and “natural” products, can cause hepatic injury. 23 Hepatotoxicity is the lead- ing cause of acute liver failure in the United States. The drug most commonly involved is acetaminophen,