Drugs are an important cause of liver damage. The mechanisms of drug-induced liver disease vary from drug to drug, are complex, and in most cases are not known. Some drugs have direct toxic effects and the liver damage caused by them is generally predictable, dose-dependent and specific to some drugs; others cause liver damage only occasionally in sensitive individuals, independent of the dose and unpredictable in occurrence. Such reactions in sensitive individuals are often referred to as allergic reactions, but the evidence is not sufficient for a true metabolic reaction, so it is better to refer to them as atopic reactions. The distinction between direct toxicity of drugs and idiosyncratic reactions is not as clear as previously thought; for example, some drugs previously considered allergens to susceptible individuals can directly damage cell membranes through their toxic intermediates.
The classification of drug-related liver damage is not entirely satisfactory, but most acute cases can still be classified as hepatocellular, cholestatic (with or without inflammation), or mixed. Some drugs can cause chronic liver damage, including tumors. Drug-induced hemolysis can cause unconjugated hyperbilirubinemia and mild jaundice without true liver injury, resulting in normal liver function tests.
Hepatocyte necrosis
Conceptually it can be divided into direct cytotoxicity and specific reactivity, but this classification is artificial.
Direct cytotoxicity Most drugs with direct hepatotoxicity can cause dose-related hepatic necrosis and damage to other organs (e.g., kidneys). These drugs cause several types of liver damage, for example, carbon tetrachloride and related hydrocarbons cause necrosis and fatty infiltration of hepatic alveolar zone 3 (central lobular zone); phosphorus causes necrosis mainly in hepatic alveolar zone 1 (periportal); ingestion of various species of mushrooms of the genus Trapdoor causes fatal hemorrhagic necrosis of the liver; high doses of intravenous tetracycline, especially in pregnant women, can cause diffuse fatty droplet infiltration of the liver with clinical manifestations The clinical picture resembles that of hepatitis.
Acute overdose of the non-narcotic analgesic paracetamol is an important cause of fulminant hepatic failure (see section 263 on paracetamol poisoning). In adults, paracetamol at doses >10-15g or >4g/d for several days can deplete glutathione in the liver. Under normal conditions, glutathione is detoxified by binding to potentially toxic intermediate metabolites. If this action is saturated, free intermediate metabolites can bind to large intrahepatic molecules, producing hepatic necrosis mainly in the hepatic alveolar zone 3. Microvascular damage is clearly an important mechanism of early liver damage.
Liver damage is often evident 2-5 days after paracetamol ingestion, when clinical and biochemical evidence of acute hepatocellular necrosis is also present. Mortality following paracetamol ingestion at doses >25 g is dramatically increased; very low doses can kill alcoholics because of increased formation of toxic intermediate metabolites following induction of P-450 enzymes by ethanol, leading to depletion of nutritional glutathione. Acetylcysteine replenishes glutathione, prevents hepatic necrosis, and can save the patient’s life if applied within 10-12 hours of intoxication; delayed doses up to 16-20 hours can be very ineffective. Acetylcysteine is not toxic and can be administered orally and intravenously. The oral dose is 140mg/kg for the first time and then 70mg/kg every 4 hours for 3 days. The intravenous dose is 300 mg/kg and the infusion is maintained for 20 hours, with half of the dose administered within 15 minutes. There is evidence that paracetamol may also cause chronic liver damage.
The drug may cause acute hepatocellular necrosis that is clinically, biochemically and histologically similar to viral hepatitis. This hepatocyte necrosis, unlike the toxic necrosis described above, is generally considered to be idiosyncratic, but the mechanism is unknown and may vary from drug to drug. There are many drugs that can cause atopic liver damage, including isoniazid, methyldopa, monoamine oxidase inhibitors, anti-inflammatory pain, propylthiouracil, phenytoin sodium, and the narcotic halothane. The most well-studied of these are isoniazid and halothane.
Isoniazid causes a mild but transient increase in transaminases in 20% of patients and symptomatic hepatitis in 1% to 2% of patients, and may be fatal. Patients over 30 years of age and those on rifampin appear to be more susceptible. The role of acetylation status is controversial, although the likelihood of hepatocellular toxicity is significantly increased in chronically acetylated individuals. Liver injury from isoniazid, unlike most other drug-induced hepatitis, may not develop until a year after dosing, unlike most other drug-induced hepatitis, and the association with isoniazid is often overlooked at this time. If the drug is not continued, chronic hepatitis and cirrhosis may develop. Whether isoniazid-induced liver damage is due to an allergic reaction or to the action of hepatotoxic products is unclear, but most evidence favors the latter (see Section 157).
Hepatitis associated with halothane is rare and occurs in patients who have received halothane anesthesia multiple times in a short period of time. Unexplained fever after halothane anesthesia is a warning sign. The mechanism of halothane-induced liver damage is unknown and may be related to the toxic effects of intermediate metabolites, cellular hypoxia, lipid peroxidation, and immune dysfunction. Obesity is a risk factor, because the metabolites of halothane can be stored in adipose tissue. In typical cases, severe hepatitis can occur days or weeks after surgery and is often heralded by fever. Fluorane-associated hepatitis has a short incubation period, negative serum markers for hepatitis B and C, occasional eosinophilia or rash, and sometimes subtle histologic differences that help differentiate it from post-transfusion hepatitis. The mortality rate of this hepatitis is high, but survivors often recover. The similar anesthetics methoxyflurane and fluoxymethoxyflurane can also cause this syndrome.
Cholestasis
Many drugs can cause a primary cholestatic reaction. The mechanism is often unclear, but clinically cholestasis can be divided into at least two types: phenothiazine and steroidal. Phenothiazine cholestasis is a periportal inflammatory reaction, often with an acute onset of fever and elevated transaminase and alkaline phosphatase levels. This cholestasis is difficult to distinguish from extrahepatic biliary obstruction, even by liver biopsy. This reaction may be individual specific, and thus in some cases eosinophilia and other allergic reactions may be present. However, other evidence suggests that this reaction is the result of a direct toxic effect on the small intrahepatic bile ducts due to interference with membrane ATPase activity. This type of cholestasis occurs in approximately 1% of patients taking chlorpromazine, whereas this type of liver damage rarely occurs in patients taking other phenothiazines. Patients usually recover completely after stopping the drug, but very few patients can develop chronic biliary cirrhosis even after stopping the drug. Other medications such as tricyclic antidepressants, chlorosulfonylurea, protamine and erythromycin can cause similar lesions, but it is not clear whether these medications will develop chronic liver disease.
Steroid cholestasis is a simple cholestatic reaction with very mild or no inflammatory response in the hepatocytes. The onset is usually slow and there are no systemic symptoms. Alkaline phosphatase is elevated, but transaminases are not significantly altered. Liver biopsy is only suggestive of cholestasis in the central region, with little portal reaction or hepatocellular disturbance. The patient may recover after discontinuation of the drug. Such cholestasis can be caused by oral contraceptives, methyltestosterone and related drugs, most of which are steroid hormones alkylated at the C-17 position. This syndrome occurs in approximately 1% to 2% of women taking oral contraceptives. The incidence of this syndrome varies from country to country, probably due to genetic factors. The drug reaction may be due to an overwhelming physiologic response to sex hormones that promote bile formation, rather than an immune allergic reaction or a membranotoxic effect. Although the exact mechanism by which these drugs cause bile transport dysfunction is not known, they severely affect fluid flow and ciliary motility in the bile ducts.
Steroidal cholestasis is closely related to cholestasis of pregnancy (see section 250). Women who have had gestational cholestasis often develop pharmacologic cholestasis when taking oral contraceptives, and similarly, women who take oral contraceptives and have pharmacologic cholestasis are susceptible to gestational cholestasis.
Mixed reactions
Some drugs can cause sarcoidosis or other difficult to classify liver damage, known as mixed liver dysfunction. These include aminosalicylic acid, sulfonamides, certain antibiotics, quinidine, allopurinol, valproic acid, and aspirin. Subclinical elevations of transaminases caused by lovastatin and related cholesterol-regulating drugs are not uncommon, but severe liver damage is rare. Many antineoplastic drugs can also cause this type of liver injury, and the mechanism varies from drug to drug.
Chronic liver disease
Progressive liver damage caused by isoniazid, methyldopa, and furantadine is difficult to distinguish from chronic hepatitis. Some patients have an acute onset of hepatitis, while others have an insidious onset that can eventually develop into cirrhosis. Chronic hepatitis with manifestations of liver fibrosis has been reported in patients taking paracetamol at doses below 3g per day for a long time. Alcoholics are particularly susceptible, and the presence of very high transaminase levels, especially AST (rarely exceeding 300 IU in simple alcoholic hepatitis), should be suspected in alcoholics. The cardiac drug amiodarone can also occasionally cause chronic liver injury with histological changes similar to alcoholic liver disease, including the presence of Mallory vesicles; membrane phospholipid deposition is one of the pathogenic mechanisms.
As mentioned above, chlorpromazine rarely causes chronic cholestasis with biliary fibrosis. Transhepatic arterial infusion of chemotherapeutic agents (especially fluorouracil) can cause sclerosing cholangitis-like lesions; long-term methotrexate (usually used to treat psoriasis or rheumatoid arthritis) can insidiously cause progressive liver fibrosis, which is usually unremarkable on liver function tests and requires a liver biopsy to confirm the diagnosis. Although methotrexate induced liver fibrosis is clinically uncommon, most authors recommend periodic liver biopsy if the cumulative dosage has reached 1.5-2 g. Arsenic agents can cause non-sclerotic liver fibrosis and portal hypertension, and chronic liver fibrosis occasionally occurs in healthy hobbyists who take large amounts of vitamin A or niacin. In many tropical and subtropical countries, consumption of moldy foods containing aflatoxins may be an important cause of chronic liver disease and hepatocellular carcinoma.
There is considerable evidence that oral contraceptives may occasionally cause benign hepatic adenomas and, rarely, hepatocellular carcinoma, in addition to the cholestasis described above (see Section 47, Primary Liver Cancer). In addition, oral contraceptives may increase the size of focal nodular hyperplastic lesions (adenomatous malformations) in the liver, but this correlation does not indicate that they are causative factors. Adenomas and focal nodular hyperplasia often have no clinical manifestations, but may present with sudden intra-abdominal rupture and bleeding requiring urgent laparotomy. Oral contraceptives also have a tendency to cause systemic hypercoagulability, and women taking oral contraceptives often develop hepatic vein thrombosis, which can lead to Budd-Chiari syndrome. In addition, these drugs can promote gallstone formation and increase the incidence of bile duct stones.