Download Drug-Induced Hepatotoxicity

Drug-Induced Hepatotoxicity
Background
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Most drugs and toxins enter the body through the gastrointestinal tract, with a
minority absorbed directly through the lungs or skin or by a parenteral route.
Each foreign compound is:
o Eliminated unchanged.
or
o Metabolized by enzymes.
o Undergoes a spontaneous chemical transformation.
or
o Simply not eliminated.
Most compounds are lipophilic, entering the body through the gastrointestinal tract
and hepatocyte membrane barriers.
Biotransformation is the process by which therapeutic agents are rendered more
hydrophilic so that they can be:
o Filtered by the glomerulus.
or
o Excreted in bile.
Metabolism of drugs
Hepatic Biotransformation
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Most drugs and xenobiotics are lipophilic, enabling them to cross the membranes of
intestinal cells.
Drugs are rendered more hydrophilic by biochemical processes in the hepatocyte →
water-soluble products → excreted in urine or bile.
This hepatic biotransformation involves oxidative pathways, primarily by way of the
cytochrome P-450 enzyme system.
After further metabolic steps, which usually include conjugation to a:
o Glucuronide.
or
o Sulfate.
or
o Glutathione.
---» the hydrophilic product is exported into plasma or bile by transport proteins
located on the hepatocyte membrane ---» excreted by the kidney or the
gastrointestinal tract.
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Biotransformations from a nonpolar to a polar compound takes place in several steps
grouped as:
o Phase 1 reaction.
o Phase 2 reactions.
Phase 1 Reaction (the drug is made polar by oxidation or hydroxylation)
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In the phase 1 reaction, oxidation or demethylation occurs, mediated by cytochrome
P450, a gene superfamily (CYP) that has nearly 300 members.
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All drugs may not undergo this step, and some may directly undergo the phase 2
reaction.
A typical reaction → generates a hydroxyl group → participate in phase 2 reactions.
These reactions may result in the formation of metabolites that are far more toxic than
the parent substrate and may result in liver injury.
As an example, the metabolite of acetaminophen is N-acetyl-p-benzoquinone-imine
(NAPQI) and is produced with ingestion of high doses.
The cytochrome P-450 enzymes catalyze phase 1 reactions.
Cytochrome P-450 enzymes
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Cytochrome P-450 enzymes are hemoproteins located in the smooth endoplasmic
reticulum of the liver.
 It is found also in other sites:
Gastrointestinal tract.
Brain.
Kidneys.
Other tissues.
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P450 enzymes are composed of a unique apoprotein and a heme prosthetic group ---»
binds oxygen after electron-transfer reactions from NADPH, resulting in:---»
o Aliphatic and aromatic hydroxylation.
o O-, N-, or S-dealkylation.
o Dehalogenation.
At least 50 enzymes have been identified, and based on structure, they are categorized
into 10 groups, with groups 1, 2, and 3 being the most important in drug metabolism.
Each P-450 enzyme can metabolize many drugs.
Drugs that share the same P-450 specificity for biotransformation → competitively
inhibit each other→ drug interactions.
Several drugs can induce and inhibit the P-450 enzyme.
Inducers
Anticonvulsive:
 Phenobarbital
 Phenytoin
 Carbamazepine
 Primidone
Antimalarial
 Quinine
Antibiotics
 Rifampin
Antifungal
 Griseofulvin
Antacids
 Omeprazole - Induces P-450 1A2
Others
 Ethanol
 Glucocorticoids
Inhibitors
Antiarrhythmic
 Amiodarone
 Quinidine
Antibiotics
 Metronidazole
 Sulfonamides
 Erythromycin
Antituberculous
 Isoniazid
Antifungal
 Ketoconazole
Antacids
 Cimetidine
 Omeprazole - Inhibits P-450 2C8
Grape fruit
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Phase 2 Reactions
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After a phase 1 reaction, most compounds are still not very water-soluble and require
further metabolism.
Phase 2 reactions may occur within or outside the liver.
They involve conjugation with a moiety (i.e., acetate, amino acid, sulfate, glucuronic
acid) → further increases solubility.
Subsequently, drugs with high molecular weight may be excreted in bile, while the
kidneys excrete the smaller molecules.
In a typical phase 2 reaction, a large, water-soluble polar group → attached to a
hydroxyl oxygen by glucuronidation or sulfation → ether or ester linkages.
Compounds requiring glucuronidation include:
Acetaminophen
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Morphine
Furosemide
Bilirubin
Sulfation is as important as glucuronidation, particularly for the metabolism of steroid
compounds and bile acids.
Although phase 2 reactions are usually accomplished without a detrimental effect,
they can occasionally lead to toxic or carcinogenic byproducts.
Glutathione Metabolism
 A third metabolic pathway for detoxifying many compounds involves glutathione:
---» A thiol-containing tripeptide capable of binding to potentially harmful
electrophilic compounds through glutathione S-transferase.
 Glutathione substrate is depleted in the process of detoxification and must be
replenished by:
o Sulfhydryl compounds from the diet.
or
o Cysteine-containing drugs such as N-acetylcysteine.
 The glutathione S-transferase reaction is therefore central to the detoxification of a
number of compounds, including acetaminophen.
 Other enzymes: alcohol dehydrogenase, are important for the elimination of a few
compounds.
Enzyme Polymorphism
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Most drugs cause toxic reactions only rarely and without a dose-related pattern.
Explanations for these rare toxic events include genetically variant P450 isozymes,
which contribute either to lack of metabolism of a given precursor or excess
formation of a toxic metabolite.
In such persons, any drug metabolized primarily by this enzyme will have a greatly
prolonged half-life.
Role of Physiologic Factors
Variables Affecting Drug Metabolism
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Age
Sex
Diet
- Micronutrients (Ca, Mg, Cu, Zn, Fe)
- Caffeine
- Vegetable enzyme inducers
- Lipids
- Ethanol
Drug-drug interference
Pregnancy
Diabetes
Hepatic diseases
Renal disease
Enzyme polymorphism
Immune stimuli
- Interferon
- Interleukin
Enzyme induction
Pathophysiology and mechanisms of drug-induced liver injury
Pathophysiologic mechanisms:
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The pathophysiologic mechanisms of hepatotoxicity are still being explored and
include:
o Hepatocellular mechanisms.
o Extracellular mechanisms.
At least six mechanisms that primarily involve the hepatocyte produce liver injury,
and the manner in which various intracellular organelles are affected defines the
pattern of disease.
Disruption of the
hepatocyte
Disruption of the
transport proteins
Cytolytic T-cell
activation
Apoptosis of
hepatocytes
Mitochondrial
disruption
Bile duct injury
Covalent binding of the drug to intracellular proteins ---»decrease in ATP levels---»
actin disruption the surface of the hepatocyte --» blebs and rupture of the membrane.
Drugs that affect transport proteins at the canalicular membrane ---» interrupt bile
flow---» Loss of villous processes and interruption of transport pumps such as
multidrug resistance–associated protein 3 ---»prevent the excretion of bilirubin---»
cholestasis.
Covalent binding of a drug to the P-450 enzyme acts as an immunogen---»activating T
cells and cytokines ---»stimulating a multifaceted immune response.
Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas
---»trigger the cascade of intercellular caspases---»programmed cell death.
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, ---»decreased ATP production.
Toxic metabolites excreted in bile ---»injury to the bile duct epithelium.
Drug toxicity mechanisms:
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The classic division of drug reactions is into at least 2 major groups,
o Drugs that directly affect the liver.
 Hepatocellular.
 Cholestatic.
 Mixed.
o Drugs that mediate an immune response.
Drugs that directly affect the liver
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Hepatocellular
 If high-energy reactions involving cytochrome P-450 enzymes ---» covalent binding
of drug to intracellular proteins---» intracellular dysfunction ---» loss of ionic
gradients---»decline in ATP levels---»actin disruption---» cell swelling, and cell
rupture.
Cholestatic (little cell injury occurs)
1. Drugs that affect transport proteins at the canalicular membrane → interrupt bile flow.
2. Certain drugs, for example, bind to or disable the bile salt export protein.
3. Genetic defects in transporters, as in the multidrug-resistance–associated protein 3, in
combination with hormones may promote cholestasis during pregnancy or during
treatment with estrogen-containing medications.
Mixed forms of hepatic injury
 The combined failure of canalicular pumps and other intracellular processes → toxic
bile acids accumulate → secondary injury to hepatocytes.
 If cells of the bile ducts are injured → protracted or permanent cholestasis, a disorder
that has been termed the "vanishing bile duct syndrome."
Most hepatotoxic effects involve hepatocyte necrosis.
Some drugs injure bile ducts or canaliculi---»cholestasis without marked damage of
hepatocytes.
Other therapeutic agents affect sinusoidal or endothelial cells ---»veno-occlusive disease
or fibrosis.
Agents affecting fat-storing into cells ---»vitamin A toxicity---»fibrosis.
Agents causing a particular pattern of liver injury ---»affecting multiple cell types.
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Hepatocyte necrosis:
The most common reaction leading to cell necrosis is the formation of covalent bonds
between a reactive metabolite of the parent compound and cell proteins or DNA.
Oxidation may go awry if a reactive electrophilic compound accumulates or if oxygen
intermediates (such as the superoxide anion or free radicals) are formed, which then
react with cellular components.
Types of Toxic Reactions Occurring in the Liver
Type of reaction
1. Direct Toxic Reactions
2. Idiosyncratic Reactions
Agents
Acetaminophen, Carbon tetrachloride, Mushroom, phosphorus
Isoniazid, disulfiram, propyl thiouracil
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3. Toxic-allergic Reactions
Halothane, isoflurane, ticrynafen
4. Allergic hepatitis
Phenytoin, Amoxicillin-clavulanate, sulfonamides
5. Cholestatic Reactions
Chlorpromazine, erythromycin estolate, estradiol, captopril,
sulfonamides
Diltiazem, Quinidine, Phenytoin, procainamide
6. Granulomatous
Reactions
7. Chronic Hepatitis
Nitrofurantoin, methyldopa, Isoniazid, trazodone
8. Alcoholic Hepatitis–
Like Reactions
Amiodarone, perhexiline maleate, valproic acid
9. Microvesicular steatosis
Tetracycline, aspirin, zidovudine, Didanosine, fialuridine
10. Fibrosis or cirrhosis
alone
Methotrexate, vitamin A, methyldopa
11. Ischemic damage
Cocaine, sustained release nicotinic acid, Methylenedioxymethamphetamine
Cyclophosphamide, other chemotherapeutic agents, herbal teas
12. Veno-occlusive disease
Direct Toxic Reactions (Acetaminophen)
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Although used universally for nonnarcotic pain relief, acetaminophen has a
predictable toxic effect if taken in quantities exceeding those recommended in the
package insert, causing dose-related centrilobular necrosis in the liver.
The metabolic pathway for acetaminophen involves:
o Phase 1 reaction.
 Metabolized by cytochrome P450 2E1 (in a phase 1 reaction) to Nacetyl-p-benzoquinoneimine (NAPQI) if the capacity of the phase 2
reactions is exceeded or if cytochrome P450 2E1 synthesis is induced.
o Phase 2 reactions
 Acetaminophen primarily undergoes sulfation and glucuronidation.
o Glutathione detoxification.
 Glutathione-S-transferase is capable of detoxifying NAPQI to yield
mercapturic acid and its derivatives, if glutathione is available.
o The formation of reactive intermediates, which disrupt cell macromolecules.
As a general rule, the capacity for glucuronidation is much greater than that typically
required each day; even patients with advanced liver disease continue to have
adequate glucuronidation.
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If the quantity of acetaminophen exceeds the capacity of these phase 2 enzymes→ an
avidly electrophilic compound, N-acetyl-p-benzoquinoneimine (NAPQI), is formed
through cytochrome P450 → bind covalently to cell macromolecules→ disrupting
mitochondrial and possibly nuclear function.
In the absence of glutathione substrate, covalent binding to cell proteins occurs.
Two clinical scenarios account for most cases of acetaminophen-related hepatic
necrosis:
o The intentional suicidal overdose.
o The "therapeutic misadventure."
In the latter scenario, an alcoholic takes acetaminophen for pain relief in doses that
exceed those recommended in the package insert (4 g per 24 hours).
The result is a direct toxic reaction due to:
o Enzyme-induction.
o Glutathione-depletion.
Factors predisposing to toxicity:
o Starvation and alcohol deplete mitochondrial glutathione.
 This alcohol–acetaminophen syndrome, which is often unrecognized,
may be the most common form of acute liver failure in the United
States and Australia.
o P450 isozyme (P450 2E1) inducers as ethanol.
o Advanced age.
o Renal insufficiency.
Factors protecting against toxicity:
o N-acetylcysteine replenishes glutathione stores.
o P450 isozyme (P450 2E1) inhibitors as cimetidine.
Diagnosis
 Extremely elevated serum ALT, AST (mean, approximately 9000 U per liter)
distinguish this condition from viral or alcoholic hepatitis, but very high levels are
also observed in patients who take an intentional overdose of acetaminophen.
 Even with the measurement of acetaminophen levels in the blood, it may be difficult
to predict the outcome in such patients.
Treatment
 If there is uncertainty about the dose or time of ingestion or if the dose appears to
have been excessive regardless of the blood acetaminophen level, N-acetylcysteine
should be given through a nasogastric tube immediately and for the ensuing 48 hours,
to provide glutathione substrate.
 The expected survival rate is higher than 80 percent, but liver transplantation is
occasionally necessary.
Idiosyncratic Reactions (Isoniazid)
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15 - 20 % of patients receiving isoniazid as a single agent for prophylaxis against
tuberculosis may have increased serum AST, ALT levels.
Only 1 % have hepatic necrosis severe enough to require the withdrawal of the drug.
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First, simultaneous use of alcohol or rifampin → augment the toxicity of isoniazid.
Second, elderly may be more likely to have toxic reactions than younger persons.
Third, genetic differences → persons who are capable of rapid acetylation of
isoniazid have an increased likelihood of toxic reactions resulting from the formation
of acetylhydrazine, which is then transformed by cytochrome P450 into a reactive
metabolite.
Persons with slow acetylation are at greater risk for a toxic reaction through a separate
pathway that leads to the formation of hydrazine, which itself may be toxic.
In most patients, there is no evidence of an allergic reaction, and the histologic picture
is virtually indistinguishable from that of viral hepatitis.
Diclofenac occasionally causes severe hepatotoxic reactions.
Idiosyncratic drug reactions and the cells that are affected
Type of reaction
Effect on cells
Hepatocellular
Direct effect leads to:
 Cell dysfunction
 Membrane dysfunction
 Cytotoxic T-cell response
Cholestasis
Injury to canalicular membrane and
transporters
Immuno-allergic
Granulomatous
Microvesicular fat
Steatohepatitis
Autoimmune
Enzyme drug adducts on cell surface
induce IgE response
Macrophages, lymphocytes
infiltrates hepatic lobule
Altered mitochondrial respiration
β-oxidation leads to lactic acidosis
and triglyceride accumulation
Multifactorial
Fibrosis
Cytotoxic lymphocyte response
directed at hepatocyte membrane
components
Activation of stellate cells
Vascular collapse
Causes ischemic or hypoxic injury
Oncogenesis
Encourages tumour formation
Mixed
Cytoplasmic and canalicular injury,
Direct damage to bile ducts.
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Example of drugs
 Isoniazid
 Trazodone
 Diclofenac
 Lovastatin
 Chlorpromazine
 Estrogen
 Erythromycin and its derivatives
 Halothane
 Phenytoin
 Diltiazem
 Sulfa drugs
 Quinidine
 Tetracycline
 Acetyl salicylic acid
 Valproic acid
 Amiodarone
 Tamoxifen
 Nitrofurantoin
 Methyldopa
 Lovastatin
 Methotrexate
 Excess vitamin A
 Nicotinic acid
 Cocaine
 Methamphetamine
 Oral contraceptives
 Androgens
 Amoxicillin-clavulanate
 Carbamazepine
 Herbs
Combined Toxic and Allergic Reactions (Halothane)
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An anesthetic agent that can induce a combination of toxic and allergic reactions
leading to liver injury.
Severe halothane-related hepatitis generally develops after multiple exposures to the
drug such as those that can occur on subspecialty surgical services.
Protein adducts formed from initial toxic reaction → provide hapten → formation of
antibodies, so with subsequent exposure → antibody and cellular recognition of the
halothane protein-adduct antigen on the hepatocyte surface→ cell lysis.
Clinically: fever, eosinophilia, jaundice, usually no rash.
Biochemically: initial elevations in serum ALT & AST are delayed, but the interval
between the administration of halothane and toxic reactions becomes shorter with
each exposure.
Liver biopsy similar to those seen with idiosyncratic reactions.
A similar process occurs with other halogenated, volatile anesthetic agents.
Allergic Hepatitis (Phenytoin)
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Drugs such as phenytoin can cause a systemic allergic reaction characterized by:
o Fever.
o Rash.
o Lymphadenopathy.
o Eosinophilia.
o Presence of eosinophils or granulomas in liver-biopsy specimens.
This allergic reaction is accompanied by both hepatocyte necrosis and cholestasis.
The slow resolution of the illness suggests that the allergen remains on the hepatocyte
surface for weeks or months.
This drug-induced hypersensitivity hepatitis syndrome results in a mononucleosislike illness that may be confused with a viral illness or streptococcal pharyngitis, so
that the agent is not withdrawn, despite signs of developing hepatitis.
The result is often a severe form of the Stevens–Johnson syndrome, with fever lasting
for weeks.
The substitution of phenobarbital for phenytoin occasionally results in cross-reactivity
and a similar hypersensitivity reaction.
Rapid recognition & discontinuation of the drug are keys to limiting hepatic damage.
Cholestatic Reactions (Estradiol)
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The drugs that mainly affect bile flow, causing cholestatic injury, include:
o Estradiol.
o Chlorpromazine.
o Trimethoprim–sulfamethoxazole.
o Rifampin.
o Erythromycin estolate.
o Nafcillin.
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o Captopril.
Jaundice appears early, with associated pruritus but little alteration in the patient's
general well-being.
A liver biopsy reveals engorgement of the canaliculi with bile and minimal
hepatocellular injury.
Eosinophils may be found in mildly inflamed portal tracts.
Estradiol and other estrogens → decrease bile flow and Na+/K+–ATPase, change
tight junctions between cells, and alter the fluidity of the hepatocyte membrane.
Granulomatous Reactions
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Noncaseating granulomas resembling sarcoidosis in the liver are caused by a variety
of drugs.
The clinical picture is the same as that of other forms of granulomatous hepatitis:
o Low-grade fever.
o Chronic fatigue.
o Jaundice only in rare cases.
Drugs Associated with Granulomatous Liver Disease
Sulfonamides, Cephalexin, Penicillin, Nitrofurantoin
Antibiotics
Aspirin, Allopurinol, Oxyphenbutazone
Antirhematics
Phenytoin, Procarbazine, Diazepam, Carbamazepine
Antiepileptics
Sulfonylureas
Antidiabetics
Isoniazid
Antituberculous
Methyldopa, Hydralazine, Diltiazem
Antihypertensive
Trichlormethiazide, Quinidine, Procainamide, Metolazone, Halothane
Others
Drug-Induced Chronic Hepatitis (Methyldopa)
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Methyldopa → indolent form of liver damage that closely resembles autoimmune
chronic active hepatitis.
Hyperglobulinemia may be present, with positive tests for antinuclear antibodies.
The classic agent producing this reaction is oxyphenisatin, a laxative that has been
withdrawn from the market.
Cirrhosis may develop before the hepatitis is diagnosed.
Identifying the drug or toxin that has caused the cirrhosis is difficult retrospectively if
the patient has been consuming alcohol or if unrecognized viral hepatitis is present.
Fatty Liver and Alcoholic Hepatitis–Like Reactions (Amiodarone)
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Although fatty liver is most commonly related to obesity, diabetes, alcoholism, or
corticosteroid therapy, amiodarone and several other drugs can cause a disorder
similar to alcoholic hepatitis, termed nonalcoholic steatohepatitis.
Amiodarone (and some related compounds) causes severe liver toxicity, in an acute or
chronic form, as part of a multisystem syndrome.
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Diagnosis
 Moderately elevated serum ALT and AST levels.
 Characteristic lesion of steatohepatitis and cirrhosis can develop in just a few months.
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Microvesicular steatosis: fine vesicles are associated with considerable cellular
dysfunction but without cell death.
o Pregnancy.
o High doses of tetracyclines.
o Reye's syndrome associated with aspirin.
o Didanosine.
o Fialuridine had severe or fatal lactic acidosis in association with
microvesicular steatosis after eight weeks of therapy due to a gradual
uncoupling of mitochondrial oxidative metabolism..
Macrovesicular steatosis
Macrovesicular and microvesicular steatosis
o Acquired immunodeficiency syndrome (AIDS).
o Use of zidovudine.
Indolent Cirrhosis (Methotrexate)
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A gradual progression to cirrhosis without any manifestation of clinical illness is most
frequently noticed with methotrexate.
Toxicity may develop over a period of several years without any symptoms or
evidence of hepatitis or other biochemical abnormalities.
A liver biopsy is the only sure way to establish the diagnosis of indolent cirrhosis
caused by a drug reaction.
A pretreatment biopsy is not indicated unless:
o Patient has abnormal liver-function values.
o Suspicion of alcoholism.
Many clinicians routinely perform a biopsy after administering a total dose of 2500
mg of methotrexate.
Veno-Occlusive Disease
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Intensive chemotherapy, usually including the agent cyclophosphamide, is most
closely associated with the development of a rapidly progressive, occlusive disease of
small hepatic venules due to endothelial-cell injury.
Diagnosis
o Abrupt onset of painful hepatomegaly.
o Ascites.
o Jaundice.
o Other symptoms of hepatic insufficiency.
It is the most common complication of bone marrow transplantation.
A similar syndrome is observed in persons who drink Jamaican "bush tea."
Other Factors in Drug-Induced Liver Disease
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Cocaine Abuse
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After the ingestion of cocaine, shock and disseminated intravascular coagulation may
develop, with evidence of myonecrosis.
The associated toxic effect on the liver is likely to be ischemic in nature, the result of
systemic hypotension induced by coronary (and systemic arterial) vasospasm with
congestive heart failure.
Herbs:
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The increasing use of alternative medicines has led to many reports of toxicity.
The spectrum of liver disease is wide with these medicines.
o Senecio/crotalaria (Bush teas) can cause venoocclusive disease.
o Germander in teas is used for its anticholinergic and antiseptic properties.
 Jaundice with high transaminase levels may occur after 2 months of
use, but it disappears after stopping the drug.
o Chaparral is used for a variety of conditions, including weight loss, cancer,
and skin conditions.
 It may cause jaundice and fulminant hepatic failure.
o Chinese herbs (Jin bu huan [Lycopodium serratum], Inchin-ko-to [TJ-135],
Ma-huang [Ephedra equisetina]) have been associated with hepatotoxicity.
Table-2: Effects of Increased or Cumulative Doses of Drugs
Drug
Dose effect
Acetaminophen
Increased dose: Hepatocyte necrosis - Apoptosis
Amiodarone
Cumulative dose:
Steatohepatitis
Bromfenac
Cumulative dose: Hepatocyte necrosis
Cocaine, phencyclidine
Increased dose: Ischemic necrosis
Cyclophosphamide
Increased dose:
Hepatocyte necrosis (worse with increased
aminotransferase levels)
Cyclosporine
Increased dose:
Cholestatic injury
Methotrexate
Increased or Cumulative dose: Hepatocyte necrosis - Fibrogenesis
Niacin
Increased dose: Ischemic necrosis
Oral contraceptives
Cumulative dose: Associated with hepatic adenomas
Diagnosis
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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.
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.
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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.
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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 hepatitis
Shock liver
Budd-Chiari syndrome
Cholestatic liver disease
Autoimmune hepatitis
Cholangitis
Alcoholic liver disease
Pregnancy-related conditions of liver
Treatment
General measures
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Early recognition of drug-induced liver reactions is essential to minimizing injury.
Monitoring hepatic enzyme levels is necessary with agents that lead to overt injury.
o ALT values are more specific than AST values.
o ALT rise 2- to 3-fold prompt more frequent monitoring.
o ALT rise 4-5 times should lead to prompt discontinuation of the drug.
No specific treatment and treatment is largely supportive based on symptomatology.
Specific measures
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N-acetylcysteine in the early phases of acetaminophen toxicity.
L-carnitine is potentially valuable in cases of valproate toxicity.
Corticosteroids suppress the systemic features associated with hypersensitivity or
allergic reactions.
Management of protracted drug-induced cholestasis is similar to that for PBC.
Cholestyramine may be used for alleviation of pruritus.
Ursodeoxycholic acid may be used.
Referral to liver transplantation center/surgical care
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Emergency liver transplantation has increasing utility in the setting of drug-induced
fulminant hepatic injury.
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The Model for End-Stage Liver Disease score can be used to evaluate short-term
survival in an adult with end-stage liver disease.
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:
o
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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
o 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:
o PT greater than 100 seconds (irrespective of grade of encephalopathy) or
o 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
Hepatotoxicity in Patients with Chronic Liver Disease
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Patients with liver disease are not uniformly at increased risk for hepatic injury due to
Diminished likelihood of toxic reactions as a result of decreased enzyme activity.
Rates of drug metabolism in patients with cirrhosis may be reduced as much as 50 %.
Changes resulting from the increased fibrosis along the hepatic sinusoids in patients
with cirrhosis further separate the bloodstream and hepatocyte.
Some exceptions do exist:
Many enzyme systems are preserved particularly those involved in conjugation
reactions.
Increased levels of cytochrome P-450 2E1 in nonalcoholic steatohepatitis → enhance
the toxicity of acetaminophen.
Patients with hepatitis C do appear to be at increased risk for veno-occlusive disease
after myeloablative therapy in preparation for bone marrow transplantation.
Patients infected with HIV who are being treated with highly active antiretroviral
therapy are at increased risk for hepatotoxic effects when they are coinfected with
underlying liver diseases such as hepatitis B and C.
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The use of toxic drugs in the patient with established cirrhosis increases the risk of
hepatic decompensation.
Monitoring and caution
Frequent monitoring may be valuable but has not been shown to be cost effective and
is often not performed.
Since patients with cirrhosis are also prone to renal injury, aminoglycosides,
radiocontrast agents, and prostaglandin inhibitors must be used with extreme caution
in this group.
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