DRUG INDUCED HEPATITIS
DR Muhammad Umer Draz.
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
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
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
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
mechanisms of drug-induced
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
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 betaoxidation 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
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
CLINICAL AND PATHOLOGICAL
MANIFESTATION OF DRUG INDUCED
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
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
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
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
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.
manifestations of drug-induced
hepatotoxicity are as follows
Summary: Pathological manifestations of druginduced hepatotoxicity are as follows:
Acute hepatocellular injury
Acute viral hepatitis–like picture - INH, halothane,
Mononucleosis like picture - Phenytoin, sulfonamides,
Chronic hepatocellular injury - Pemoline, methyldopa
Massive necrosis - Acetaminophen, halothane,
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 overthe-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
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.
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
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 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
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.
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
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 Nacetylcysteine in the early phases of acetaminophen toxicity. Lcarnitine 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
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 endstage 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
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
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
PT greater than 50 seconds
Serum bilirubin level greater than 17 mg/dL