Medications and the liver

The interaction between drugs and the liver can be divided into three aspects:

1. the impact of liver disease on drug metabolism,
2. toxic effects of drugs on the liver and
3. drug metabolism in the liver. The number of possible interactions is enormous.

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The Impact of Liver Disease on Drug Metabolism

Liver disease can have a complex effect on the elimination, biotransformation, and pharmacokinetics of drugs. These effects involve a variety of pathogenetic factors: intestinal absorption, plasma protein binding, hepatic elimination rate, intrahepatic blood flow and portosystemic shunting, bile secretion, hepatoenteric circulation, and renal clearance. The final effect of a drug is unpredictable and does not correlate with the nature of the liver injury, its severity, or the results of liver laboratory tests. Thus, there are no general rules governing changes in drug dosage in patients with liver disease.

The clinical effect may be altered independently of the bioavailability of the drug, especially in chronic liver disease; for example, the sensitivity of the brain to opiates and sedatives is often increased in patients with chronic liver disease; thus, relatively low doses of these drugs may accelerate the development of encephalopathy in patients with cirrhosis. The mechanism of this effect may be due to changes in drug receptors in the brain.

Drug-induced liver injury

The mechanisms underlying drug-induced liver injury are complex and often poorly understood. Some drugs are directly toxic, with frequent toxic effects, with onset of action within a few hours of administration, and with dose-related toxicity. Other drugs rarely cause problems and only in susceptible individuals; liver injury usually occurs within a few weeks of administration, but may sometimes be delayed for months. These injuries are independent of dosage. Such reactions are rarely allergic in nature; they are more accurately considered idiosyncratic. The distinction between direct toxicity and idiosyncrasy may not always be clear; for example, some drugs whose toxic effects are initially attributed to hypersensitivity may damage cell membranes through the direct toxic action of intermediate metabolites.

Although there is currently no classification system for drug-induced liver injury, acute reactions (hepatocellular necrosis), cholestasis (with or without inflammation), and mixed reactions can be distinguished. Some drugs can cause chronic injury, which in rare cases leads to tumor growth.

Common reactions to hepatotoxic drugs

Preparation	Reaction
Paracetamol	Acute direct hepatocellular toxicity; chronic toxicity
Allopurinol	Various acute reactions
White toadstool mushroom (Amanita)	Acute direct hepatocellular toxicity
Aminosalicylic acid	Various acute reactions
Amiodarone	Chronic toxicity
Antibiotics	Various acute reactions
Antitumor drugs	Mixed acute reactions
Arsenic derivatives	Chronic toxicity
Aspirin	Various acute reactions
C-17-alkylated steroids	Acute cholestasis, steroid type
Chlorpropamide	Acute cholestasis, phenothiazine type
Diclofenac	Acute idiosyncratic hepatocellular toxicity
Erythromycin estolate	Acute cholestasis, phenothiazine type
Halothane (anesthetic)	Acute idiosyncratic hepatocellular toxicity
Liver antitumor agents for intra-arterial administration	Chronic toxicity
HMGCoA reductase inhibitors	Various acute reactions
Hydrocarbonates	Acute direct hepatocellular toxicity
Indomethacin	Acute idiosyncratic hepatocellular toxicity
Iron	Acute direct hepatocellular toxicity
Isoniazid	Acute idiosyncratic hepatocellular toxicity; chronic toxicity
Methotrexate	Chronic toxicity
Methyldopa	Acute idiosyncratic hepatocellular toxicity; chronic toxicity
Methyltestosterone	Acute cholestasis, steroid type
Monoamine oxidase inhibitors	Acute idiosyncratic hepatocellular toxicity; chronic toxicity
Nicotinic acid	Chronic toxicity
Nitrofurantoin	Chronic toxicity
Phenothiazines (eg, chlorpromazine)	Acute cholestasis, phenothiazine type; chronic toxicity
Phenylbutazone	Acute cholestasis, phenothiazine type
Phenytoin	Acute idiosyncratic hepatocellular toxicity
Phosphorus	Acute direct hepatocellular toxicity
Propylthiouracil	Acute idiosyncratic hepatocellular toxicity
Quinidine	Mixed acute reactions
Sulfonamides	Mixed acute reactions
Tetracycline, high doses IV	Acute direct hepatocellular toxicity
Tricyclic antidepressants	Acute cholestasis, phenothiazine type
Valproate	Various acute reactions
Vitamin A	Chronic toxicity
Oral contraceptives	Acute cholestasis, steroid type

Hepatocellular necrosis

According to the mechanism of development, hepatocellular necrosis can be associated with direct toxic action and idiosyncrasy, although this distinction is somewhat artificial. The main symptom is an increase in the level of aminotransferases, often to extremely high values. Patients with mild or moderate hepatocellular necrosis may develop clinical manifestations of hepatitis (e.g., jaundice, malaise). Severe necrosis may occur as fulminant hepatitis (e.g., liver failure, portosystemic encephalopathy).

Direct toxicity. Most drugs with direct hepatotoxic action cause dose-dependent liver necrosis; other organs (eg, kidneys) are often affected as well.

Direct hepatotoxicity from prescribed drugs can be prevented or minimized by strictly following the maximum dose recommendations and monitoring the patient's condition. Poisoning with direct hepatotoxins (e.g., paracetamol, iron preparations, death cap) often results in gastroenteritis within a few hours. However, liver damage may not become apparent until 1-4 days later. Cocaine use occasionally causes acute hepatocellular necrosis, probably due to the development of hepatocellular ischemia.

Idiosyncrasy. Medicines can cause acute hepatocellular necrosis, which is difficult to differentiate from viral hepatitis even histologically. The mechanisms of its development are not completely clear and are probably different for different drugs. Isoniazid and halothane have been studied most thoroughly.

The mechanism of the rare halothane-induced hepatitis is unclear but may involve formation of reactive intermediates, cellular hypoxia, lipid peroxidation, and autoimmune injury. Risk factors include obesity (possibly due to deposition of halothane metabolites in adipose tissue) and repeated anesthesias over relatively short periods of time. Hepatitis usually develops several days (up to 2 weeks) after drug administration, presents with fever, and is often severe. Eosinophilia or skin rash is sometimes seen. Mortality rates reach 20-40% if severe jaundice develops, but survivors usually recover completely. Methoxyflurane and enflurane, anesthetics similar to halothane, can cause the same syndrome.

Cholestasis

Many drugs primarily cause a cholestatic reaction. The pathogenesis is not fully understood, but at least clinically and histologically, two forms of cholestasis are distinguished - phenothiazine and steroid types. Diagnostic examination usually includes noninvasive instrumental examination to exclude biliary obstruction. Further examination (e.g., magnetic resonance cholangiopancreatography, ERCP, liver biopsy) is necessary only if cholestasis persists despite drug withdrawal.

Phenothiazine-type cholestasis is a periportal inflammatory reaction. Immunologic mechanisms are supported by changes such as periodic eosinophilia or other manifestations of hypersensitivity, but toxic damage to the hepatic ducts is also possible. This type of cholestasis occurs in approximately 1% of patients taking chlorpromazine and less frequently with other phenothiazines. Cholestasis is usually acute and is accompanied by fever and high levels of aminotransferases and alkaline phosphatase. Differential diagnosis of cholestasis and extrahepatic obstruction can be difficult, even on the basis of liver biopsy. Discontinuation of the drug usually leads to complete resolution of the process, although in rare cases progression of chronic cholestasis with fibrosis is possible. Cholestasis with similar clinical manifestations is caused by tricyclic antidepressants, chlorpropamide, phenylbutazone, erythromycin estolate and many others; However, the possibility of chronic liver damage has not been fully established.

The steroid type of cholestasis results from an enhancement of the physiological effect of sex hormones on bile formation rather than from immunologic sensitivity or cytotoxic effects on cell membranes. Injury to the excretory ducts, microfilament dysfunction, altered membrane fluidity, and genetic factors may be involved. Hepatocellular inflammation may be mild or absent. The incidence varies among countries, but averages 1–2% in women taking oral contraceptives. The onset of cholestasis is gradual and asymptomatic. Alkaline phosphatase levels are elevated, but aminotransferase levels are usually not very high, and liver biopsy shows only central bile stasis with little portal or hepatocellular involvement. In most cases, complete reversal of cholestasis occurs after drug withdrawal, but a more protracted course is possible.

Cholestasis in pregnancy is closely related to steroid-induced cholestasis. Women with cholestasis in pregnancy may subsequently develop cholestasis when using oral contraceptives and vice versa.

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Various acute reactions

Some drugs cause mixed forms of liver dysfunction, granulomatous reactions (eg, quinidine, allopurinol, sulfonamides), or various types of liver injury that are difficult to classify. HMGCoA reductase inhibitors (statins) cause subclinical elevations in aminotransferases in 1% to 2% of patients, although clinically significant liver injury is rare. Many antineoplastic agents also cause liver injury; the mechanisms of liver injury are varied.

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Chronic liver diseases

Certain drugs may cause chronic liver disease. Isoniazid, methyldopa, and nitrofurantoin may cause chronic hepatitis. In the absence of fibrosis, reversal usually occurs. The disease may begin acutely or insidiously. It may progress to cirrhosis. Rarely, a histologic picture similar to chronic hepatitis with sclerosis has been reported in patients taking paracetamol for a long time at low doses, eg, 3 g daily, although higher doses are usually used. Alcohol abusers are more prone to chronic liver disease, the possibility of which should be considered when unusually high aminotransferase levels, especially AST, are found incidentally (raised to more than 300 IU in the presence of alcoholic hepatitis alone). Amiodarone occasionally causes chronic liver disease with Mallory bodies and histologic features resembling alcoholic liver disease; the pathogenesis is based on phospholipidosis of the cell membranes.

A sclerosing cholangitis-like syndrome may develop with intra-arterial hepatic chemotherapy, especially with floxuridine. Patients receiving long-term methotrexate (usually for psoriasis or rheumatoid arthritis) may insidiously develop progressive liver fibrosis, especially with alcohol abuse or daily drug administration; liver function tests are often unremarkable and liver biopsy is necessary. Although methotrexate-induced fibrosis is rarely clinically evident, most authors recommend liver biopsy when the total drug dose reaches 1.5–2 g and sometimes after completion of treatment of the primary disorder. Noncirrhotic liver fibrosis, which may lead to portal hypertension, may result from the use of arsenic-containing drugs, excessive doses of vitamin A (eg, more than 15,000 IU/day for several months), or niacin. In many tropical and subtropical countries, chronic liver disease and hepatocellular carcinoma are believed to be caused by the consumption of foods containing aflatoxins.

In addition to causing cholestasis, oral contraceptives may also occasionally cause the formation of benign liver adenomas; very rarely, hepatocellular carcinoma occurs. Adenomas are usually subclinical but may be complicated by sudden intraperitoneal rupture and bleeding, requiring emergency laparotomy. Most adenomas are asymptomatic and are diagnosed incidentally during instrumental examination. Since oral contraceptives cause hypercoagulability, they increase the risk of hepatic vein thrombosis (Budd-Chiari syndrome). The use of these drugs also increases the risk of gallstones, since the lithogenicity of bile increases.

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Diagnosis and treatment of drug effects on the liver

Drug-induced hepatotoxicity may be suspected if the patient has unusual clinical features of liver disease (e.g., mixed or atypical features of cholestasis and hepatitis); if hepatitis or cholestasis is present when underlying causes have been excluded; if the patient is being treated with a drug known to be hepatotoxic, even in the absence of symptoms or signs; or if liver biopsy reveals histologic changes suggestive of a drug-induced etiology. The development of drug-induced hemolytic jaundice may indicate hepatotoxicity, but in such cases there is hyperbilirubinemia due to indirect bilirubin and other liver function tests are normal.

No diagnostic tests can confirm that the liver injury is caused by the drug. The diagnosis requires exclusion of other possible causes (e.g., instrumental examination to exclude biliary obstruction in case of symptoms of cholestasis; serologic diagnostics in case of hepatitis) and a temporal relationship between the drug intake and the development of hepatotoxicity. Recurrence of clinical manifestations of hepatotoxicity after resumption of drug intake is the most important confirmation, but because of the risk of severe liver injury, the drug is usually not re-administered when hepatotoxicity is suspected. Sometimes a biopsy is necessary to exclude other treatable conditions. If the diagnosis remains unclear after examination, the drug can be discontinued, which will facilitate the diagnosis and provide a therapeutic effect.

For some drugs that are directly hepatotoxic (e.g., paracetamol), blood drug levels can be measured to assess the likelihood of liver injury. However, if tests are not performed promptly, drug levels may be low. Numerous over-the-counter herbal products have been associated with liver toxicity; a history of use of such drugs should be obtained in patients with unexplained liver injury.

Treatment of drug-induced liver injury consists primarily of drug withdrawal and supportive measures.

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