Hepatotoxicity

Hepatotoxicity
Other names	see below list
granulomata. Other causes were excluded with extensive investigations. Liver biopsy. H&E stain.
Specialty	Gastroenterology
Complications	Cirrhosis, liver failure

Synonyms
Drug-induced liver injury (DILI) Toxin-induced hepatitis Drug-induced hepatitis Drug-induced hepatic necrosis Drug-induced hepatic fibrosis Drug-induced hepatic granuloma Toxic liver disease with hepatitis Toxic liver disease with cholestasis Toxic hepatitis Toxic liver disease Toxin-induced liver disease Drug-induced liver disease Drug-induced liver damage Hepatogenous poisoning

Hepatotoxicity (from hepatic toxicity) implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.

The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses (e.g.

.

More than 900 drugs have been implicated in causing liver injury

.

Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.^[4][5]

Causes

Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic).^[6] Type A drug reaction accounts for 80% of all toxicities.^[7]

is commonly used to induce acute type A liver injury in animal models.

Idiosyncratic (type B) injury occurs without warning, when agents cause non-predictable hepatotoxicity in susceptible individuals, which is not related to dose and has a variable latency period.^[8] This type of injury does not have a clear dose-response nor temporal relationship, and most often does not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process; Troglitazone (Rezulin)^[2][9] and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins pulled from market.

The herb kava has caused a number of cases of idiosyncratic liver injury, ranging everywhere from asymptomatic to fatal.

Oral use of the antifungal ketoconazole has been associated with hepatic toxicity, including some fatalities;^[10] however, such effects appear to be limited to doses taken over a period longer than 7 days.^[11]

Paracetamol

Nonsteroidal anti-inflammatory drugs

Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose-dependent and idiosyncratic reactions have been documented.[18] Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.

Glucocorticoids

Isoniazid

Isoniazide (INH) is one of the most commonly used drugs for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients.[21]

Other hydrazine derivative drugs

There are also cases where other

Natural products

Examples include

Alternative remedies

Examples include:

Industrial toxin

Examples include arsenic, carbon tetrachloride, and vinyl chloride.^[36]

Mechanism

Factors influencing drug-induced hepatotoxicity[12]
Age Ethnicity and race Gender Nutritional status Underlying liver disease Renal function Pregnancy Duration and dosage of drug Enzyme induction Drug-to-drug interaction

Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the

that bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.

Many chemicals damage

) also have a role in the mechanism.

Drug metabolism in liver

The human body subjects most, but not all, compounds to various chemical processes (i.e.

The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.

enzymes. Phase 1 are typically more suitable for elimination.

A group of

There is a tremendous diversity of individual P-450 gene products, and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including most drugs) in phase 1. Three important characteristics of the P-450 system have roles in drug-induced toxicity:

1. Genetic diversity:

Each of the P-450 proteins is unique and accounts (to some extent) for the variation in drug metabolism between individuals. Genetic variations (polymorphism) in P-450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds.

2. Change in enzyme activity:

Potent inducers	Potent inhibitors	Substrates
Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, St John's wort,	Amiodarone, Cimetidine, Ciprofloxacin, Fluconazole, Fluoxetine, Erythromycin, Isoniazid, Diltiazem	Caffeine, Clozapine, Omeprazole, Losartan, Theophylline

Many substances can influence the P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways.^[44] Drugs that modify cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand, inducers increase P-450 activity by increasing enzyme production, or, in the case of CYP2E1, preventing degradation in the proteasome. There is usually a delay before enzyme activity increases.^[41]

3. Competitive inhibition:

Some drugs may share the same P-450 specificity and thus competitively block their biotransformation. This may lead to accumulation of drugs metabolized by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic metabolites.

Patterns of injury

Patterns of drug-induced liver disease

Type of injury:	Hepatocellular	Cholestatic	Mixed
ALT	≥ Twofold rise	Normal	≥ Twofold rise
ALP	Normal	≥ Twofold rise	≥ Twofold rise
ALT: ALP ratio	High, ≥5	Low, ≤2	2–5
Examples[45]	NSAID	Anabolic steroid Chlorpromazine Clopidogrel Erythromycin Hormonal contraception	Amitriptyline, Enalapril Carbamazepine Sulfonamide Phenytoin

Chemicals produce a wide variety of clinical and

(initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed types of injuries are often encountered.

Specific histo-pathological patterns of liver injury from drug-induced damage are discussed below.

Zonal Necrosis

This is the most common type of drug-induced liver cell

.

Causes include:

Paracetamol, carbon tetrachloride

Hepatitis

In this pattern, hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug-induced hepatitis. (A) viral hepatitis is the most common, where histological features are similar to acute viral hepatitis. (B) in focal or non-specific hepatitis, scattered foci of cell necrosis may accompany lymphocytic infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis clinically, serologically, and histologically.

Causes:

(a) Viral hepatitis: Halothane, isoniazid, phenytoin

(b) Focal hepatitis: Aspirin

(c) Chronic hepatitis: Methyldopa, diclofenac

Cholestasis

Liver injury leads to impairment of bile flow and cases are predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland (without any

).

Causes:

(a) Bland:

androgens

(b) Inflammatory:

co-amoxiclav, carbamazepine

(c) Ductal: Chlorpromazine, flucloxacillin

Steatosis

Hepatotoxicity may manifest as triglyceride accumulation, which leads to either small-droplet (microvesicular) or large-droplet (macrovesicular) fatty liver. There is a separate type of steatosis by which phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g., Tay–Sachs disease)

Causes:

(a) Microvesicular:

Reye's syndrome), ketoprofen, tetracycline

(especially if expired)

(b) Macrovesicular:

Acetaminophen, methotrexate

(c) Phospholipidosis:

total parenteral nutrition

(d)

Antiviral: nucleoside analogues

(e) Corticosteroid

(f) Hormonal: Tamoxifen

Granuloma

Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated.

Causes:

Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine

Vascular lesions

These result from injury to the vascular endothelium.

Causes:

Venoocclusive disease

: Chemotherapeutic agents, bush tea

Peliosis hepatis: Anabolic steroids

Hepatic vein thrombosis

: Oral contraceptives

Neoplasm

Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma, and liver adenomas are the ones usually reported.

Causes:

Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast

Diagnosis

This remains a challenge in clinical practice due to a lack of reliable markers.

Treatment

In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In

]

Prognosis

An elevation in serum bilirubin level of more than 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (

Drugs withdrawn

The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity: Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and pemoline.^[47][53][54]

See also

• Hepatoprotection
• Reye's syndrome

References

External links

• LiverTox at the United States
  National Library of Medicine