DRUG INDUCED HEPATITIS

DR Muhammad Umer Draz.(House officer.MU-1)11/07/07

INTODUCTION

Drugs are an important cause of liver injury. More than 900 drugs, toxins, and herbs have been reported to cause liver injury, and drugs account for 20-40% of all instances of fulminant hepatic failure. Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death. The manifestations of drug-induced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. Knowledge of the commonly implicated agents and a high index of suspicion are essential in diagnosis.

Risk factors for drug-induced liver injury

Race: Some drugs appear to have different toxicities based on race. For example, blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under the control of P-450 enzymes and can vary from individual to individual.

Age: Apart from accidental exposure, hepatic drug reactions are rare in children. Elderly persons are at increased risk of hepatic injury because of decreased clearance, drug-to-drug interactions, reduced hepatic blood flow, variation in drug binding, and lower hepatic volume. In addition, poor diet, infections, and multiple hospitalizations are important reasons for drug-induced hepatotoxicity.

Sex: Although the reasons are unknown, hepatic drug reactions are more common in females.

Alcohol ingestion: Alcoholic persons are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity by drugs.

Liver disease: In general, patients with chronic liver disease are not uniformly at increased risk of hepatic injury. Although the total cytochrome P-450 is reduced, some may be affected more than others. The modification of doses in persons with liver disease should be based on the knowledge of the specific enzyme involved in the metabolism. Patients with HIV infection who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects when treated with antiretroviral therapy. Similarly, patients with cirrhosis are at increased risk of decompensation by toxic drugs.

Genetic factors: A unique gene encodes each P-450 protein. Genetic differences in the P-450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions. Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of abnormal expression of P-450-II-D6. This can be identified by polymerase chain reaction amplification of mutant genes. This has led to the possibility of future detection of persons who can have abnormal reactions to a drug.

Other comorbidities: Persons with AIDS, persons who are malnourished, and persons who are fasting may be susceptible to drug reactions because of low glutathione stores.

Drug formulation: Long-acting drugs may cause more injury than shorter-acting drugs.

Host factors that may enhance susceptibility to drugs, possibly inducing liver disease

Female - Halothane, nitrofurantoin, sulindac Male - Amoxicillin-clavulanic acid (Augmentin) Old age - Acetaminophen, halothane, INH, amoxicillin-clavulanic acid Young age - Salicylates, valproic acid Fasting or malnutrition - Acetaminophen Large body mass index/obesity - Halothane Diabetes mellitus - Methotrexate, niacin Renal failure - Tetracycline, allopurinol AIDS - Dapsone, trimethoprim-sulfamethoxazole Hepatitis C - Ibuprofen, ritonavir, flutamide Preexisting liver disease - Niacin, tetracycline, methotrexate

Pathophysiology and mechanisms of drug-induced liver injury

Pathophysiologic mechanisms: The pathophysiologic mechanisms of hepatotoxicity are still being explored and include both hepatocellular and extracellular mechanisms. The following are some of the mechanisms that have been described: Disruption of the hepatocyte: Covalent binding

of the drug to intracellular proteins can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane.

Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin, causing cholestasis.

Cytolytic T-cell activation: Covalent binding of a drug to the P-450 enzyme acts as an immunogen, activating T cells and cytokines and stimulating a multifaceted immune response.

Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in programmed cell death.

Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.

Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.

Drug toxicity mechanisms: The classic division of drug reactions is into at least 2

major groups, (1) drugs that directly affect the liver and (2) drugs that mediate an immune response.

Intrinsic or predictable drug reactions: Drugs that fall into this category cause reproducible injuries in animals, and the injury is dose related. The injury can be due to the drug itself or to a metabolite. Acetaminophen is a classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon tetrachloride.

Idiosyncratic drug reactions: Idiosyncratic drug reactions can be subdivided into those that are classified as hypersensitivity or immunoallergic and those that are metabolic-idiosyncratic.

Hypersensitivity: Phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is characterized by fever, rash, and eosinophilia and is an immune-related response with a typical short latency period of 1-4 weeks.

Metabolic-idiosyncratic: This type of reaction occurs through an indirect metabolite of the offending drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur within a week or up to one year later. It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are noted. INH toxicity is considered to fall into this class. Not all drugs fall neatly into one of these categories, and overlapping mechanisms may occur with some drugs (eg, halothane).

METABOLISM OF DRUGS The liver metabolizes virtually every drug

or toxin introduced in the body. Most drugs are lipophilic (fat soluble), enabling easy absorption across cell membranes. In the body, they are rendered hydrophilic (water soluble) by biochemical processes in the hepatocyte to enable inactivation and easy excretion. Metabolism of drugs occurs in 2 phases. In the phase 1 reaction, the drug is made polar by oxidation or hydroxylation. All drugs may not undergo this step, and some may directly undergo the phase 2 reaction.

CLINICAL AND PATHOLOGICAL MANIFESTATION OF DRUG INDUCED LIVER DIUSEASE

Clinical manifestations The manifestations of drug-induced hepatotoxicity are

highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. The injury may suggest a hepatocellular injury, with elevation of aminotransferase levels as the predominant symptom, or a cholestatic injury, with elevated alkaline phosphatase levels (with or without hyperbilirubinemia) being the main feature. In addition, drugs that cause mild aminotransferase elevations with subsequent adaptation are differentiated from those that result in true toxicity that require discontinuation.

Asymptomatic elevations in aminotransferase: Some drugs cause asymptomatic elevations of liver enzymes that do not progress despite continued use of the drug.

This tolerance is also observed in 25-50% of the patients taking drugs such as methyldopa or phenytoin, and it is especially well described with INH.

Other drugs include sulfonamides,salicylates,sulfonylureas and quinidine.

Elevated aminotransferase levels with acute hepatocellular injury: Drug-induced liver injury is designated hepatocellular if the ALT levels are increased to more than twice the upper limit of the reference range, with alkaline phosphatase levels that are within the reference range or are minimally elevated. Elevation of aspartate aminotransferase (AST) greater than ALT, especially if more than 2 times greater, suggests alcoholic hepatitis. Elevation of AST less than ALT is usually observed in persons with viral hepatitis. In viral and drug-induced hepatitis, the AST and ALT levels steadily increase and peak in the low thousands range within 7-14 days. Many medications can cause increases in AST, such as acetaminophen, NSAIDs, ACE inhibitors, nicotinic acid, INH, sulfonamides, erythromycin, and antifungal agents such as griseofulvin and fluconazole. In acetaminophen overdose, transaminase levels greater than 10,000 IU/L are also noted.

Elevated aminotransferase and bilirubin levels suggestive of subfulminant or fulminant necrosis

With increasing hepatocellular injury, bilirubin levels are invariably increased, suggesting a worse prognosis. Normally, the total bilirubin level is less than 1.1 mg/dL and approximately 70% is indirect (unconjugated) bilirubin. Unconjugated hyperbilirubinemia (>80% of the total bilirubin is indirect) suggests hemolysis or Gilbert syndrome. Conjugated hyperbilirubinemia (>50% of the total bilirubin is direct) suggests hepatocellular dysfunction or cholestasis. When the bilirubin level is above 25-30 mg/dL, extrahepatic cholestasis is an unlikely diagnosis; because the predominantly conjugated bilirubin is water soluble, it is easily excreted by the kidney in extrahepatic cholestasis.

Subfulminant hepatic failure most commonly results from acetaminophen, halothane, methoxyflurane, enflurane, trovafloxacin, troglitazone, ketoconazole, dihydralazine, tacrine, mushroom poisoning, ferrous sulfate poisoning, phosphorus poisoning, and cocaine toxicity. Drugs that result in massive necrosis are propylthiouracil, INH, phenytoin, phenelzine, sertraline, naproxen, diclofenac, kava kava, and ecstasy.

Elevated alkaline phosphatase (acute cholestatic injury) levels: Acute intrahepatic cholestasis is divisible into 2 broad categories, (1) cholestasis without hepatocellular injury (bland jaundice or pure cholestasis) and (2) cholestasis with variable hepatocyte injury.

The most common biochemical abnormality is elevation of the alkaline phosphate level, usually without hyperbilirubinemia. Men and older patients are more prone to these adverse effects. The interval of developments is usually less than 4 weeks and may be as long as 8 weeks. Fever, rash, and eosinophilia may be observed in as many as 30% of individuals, but these findings do not define the disorder.

Some common drugs associated with cholestatic injury include chlorpromazine, ciprofloxacin, ofloxacin, cimetidine, phenytoin, naproxen, captopril, erythromycin, azithromycin, and dicloxacillin. Amoxicillin-clavulanic acid is also an important cause of cholestatic jaundice. Extrahepatic cholestasis secondary to biliary sludge or calculi is caused by sulindac or octreotide.

Summary: Pathological manifestations of drug-induced hepatotoxicity are as follows Summary: Pathological manifestations of drug-

induced hepatotoxicity are as follows: Acute hepatocellular injury Acute viral hepatitis–like picture - INH, halothane,

diclofenac, troglitazone Mononucleosis like picture - Phenytoin, sulfonamides,

dapsone Chronic hepatocellular injury - Pemoline, methyldopa Massive necrosis - Acetaminophen, halothane,

diclofenac Steatosis

Macrovesicular steatosis - Alcohol, methotrexate, corticosteroids, minocycline, nifedipine, TPN

Microvesicular steatosis - Alcohol, valproic acid, tetracycline, piroxicam

Steatohepatitis - Amiodarone, nifedipine, synthetic estrogens, didanosine

Pseudoalcoholic injury - Amiodarone Acute cholestasis - Amoxicillin-clavulanic acid, erythromycin,

sulindac Chronic cholestasis - Chlorpromazine, sulfamethoxazole-

trimethoprim, tetracycline, ibuprofen Granulomatous hepatitis - Carbamazepine, allopurinol, hydralazine Vascular injury - Steroids Neoplasia - Contraceptives, anabolic steroids Adenoma - Steroids Angiosarcoma - Vinyl chloride Hepatocellular carcinoma - Anabolic steroids, aflatoxin, arsenic,

vinyl chloride

DIAGNOSIS When a single agent is involved, the diagnosis may be relatively simple, but

with multiple agents, implicating a specific agent as the cause is difficult. To facilitate the diagnosis of drug-induced hepatic injury, several clinical tools for causality assessment have been developed to assist the clinician.

History: History must include dose, route of administration, duration, previous administration, and use of any concomitant drugs, including over-the-counter medications and herbs. Knowing whether the patient was exposed to the same drug before may be helpful. The latency period of idiosyncratic drug reactions is highly variable; hence, obtaining a history of every drug ingested in the past 3 months is essential. Onset: The onset is usually within 5-90 days of starting the drug. Exclusion of other causes of liver injury/cholestasis: Excluding other causes of liver

injury is essential. Dechallenge: A positive dechallenge is a 50% fall in serum transaminase

levels within 8 days of stopping the drug. A positive dechallenge is very helpful in cases of use of multiple medications.

Track record of the drug: Previously documented reactions to a drug aid in diagnosis.

Rechallenge: Deliberate rechallenge in clinical situations is unethical and should not be attempted; however, inadvertent rechallenge in the past has provided valuable evidence that the drug was indeed hepatotoxic.

Differential diagnoses

Acute viral hepatitisAutoimmune hepatitisShock liverCholecystitisCholangitisBudd-Chiari syndromeAlcoholic liver diseaseCholestatic liver diseasePregnancy-related conditions of liverMalignancyWilson diseaseHemochromatosisCoagulation disorders

Hepatic function tests and their interpretations are as follows:

Bilirubin (total) - To diagnose jaundice and assess severity Bilirubin (unconjugated) - To assess for hemolysis Alkaline phosphatase - To diagnose cholestasis and infiltrative

disease AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose

hepatocellular disease and assess progression of disease ALT/serum glutamate pyruvate transaminase (SGPT) - ALT relatively lower

than AST in persons with alcoholism Albumin - To assess severity of liver injury (HIV infection and

malnutrition may confound this.) Gamma globulin - Large elevations suggestive of autoimmune

hepatitis, other typical increase observed in persons with cirrhosis Prothrombin time after vitamin K - To assess severity of liver disease Antimitochondrial antibody - To diagnose primary biliary cirrhosis ASMA - To diagnose primary sclerosing cholangitis

Imaging studies

Imaging studies are used to exclude causes of liver pathology, after which a diagnosis can be made.

Ultrasonography: Ultrasonography is inexpensive compared with CT scanning and MRI and is performed in only a few minutes. Ultrasonography is effective to evaluate the gall bladder, bile ducts, and hepatic tumors.

CT scanning: CT scanning can help detect focal hepatic lesions 1 cm or larger and some diffuse conditions. It can also be used to visualize adjacent structures in the abdomen.

MRI: MRI provides excellent contrast resolution. It can be used to detect cysts, hemangiomas, and primary and secondary tumors. The portal vein, hepatic veins, and biliary tract can be visualized without contrast injections.

Procedures

Liver biopsy: Histopathologic evaluation remains an important tool in diagnosis. A liver biopsy is not essential in every case, but a morphologic pattern consistent with the expected pattern provides supportive evidence.

TREATMENT Early recognition of drug-induced liver reactions is essential to

minimizing injury. Monitoring hepatic enzyme levels is appropriate and necessary with a number of agents, especially with those that lead to overt injury. For drugs that produce liver injury unpredictably, biochemical monitoring is less useful. ALT values are more specific than AST values. ALT values that are within the reference range at baseline and rise 2- to 3-fold should lead to enhanced vigilance in terms of more frequent monitoring. ALT values 4-5 times higher than the reference range should lead to prompt discontinuation of the drug.

No specific treatment is indicated for drug-induced hepatic disease. Treatment is largely supportive and based on symptomatology. The first step is to discontinue the suspected drug. Specific therapy against drug-induced liver injury is limited to the use of N-acetylcysteine in the early phases of acetaminophen toxicity. L-carnitine is potentially valuable in cases of valproate toxicity. In general, corticosteroids have no definitive role in treatment. They may suppress the systemic features associated with hypersensitivity or allergic reactions. Management of protracted drug-induced cholestasis is similar to that for primary biliary cirrhosis. Cholestyramine may be used for alleviation of pruritus. Ursodeoxycholic acid may be used. Lastly, consulting a hepatologist is also helpful.

Referral to liver transplantation center/surgical care

No specific antidote is available for the vast majority of hepatotoxic agents. Emergency liver transplantation has increasing utility in the setting of drug-induced fulminant hepatic injury. Considering early liver transplantation is important. The Model for End-Stage Liver Disease score can be used to evaluate short-term survival in an adult with end-stage liver disease. This can help stratify candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin, international normalized ratio, and the cause of the cirrhosis. Another criterion commonly used for liver transplantation is the Kings College criteria.

Kings College criteria for liver transplantation in cases of acetaminophen toxicity are as follows: pH less than 7.3 (irrespective of grade of encephalopathy) Prothrombin time (PT) greater than 100 seconds or international

normalized ratio greater than 7.7 Serum creatinine level greater than 3.4 mg/dL in patients with

grade III or IV encephalopathy

Measurement of lactate levels at 4 and 12 hours also helps in early identification of patients who require liver transplantation.

Kings College criteria for liver transplantation in other cases of drug-induced liver failure are as follows:

PT greater than 100 seconds (irrespective of grade of encephalopathy) or

Any 3 of the following criteria: Age younger than 10 years or older than 40 years Etiology of non-A/non-B hepatitis, halothane hepatitis, or

idiosyncratic drug reactions Duration of jaundice of more than 7 days before onset of

encephalopathy PT greater than 50 seconds Serum bilirubin level greater than 17 mg/dL

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