Hepatotoxicity pathophysiology

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Hepatotoxicity is defined as injury to the liver that is associated with impaired liver function caused by exposure to a drug or another noninfectious agent.[1]


Drug Metabolism in Liver

Drug metabolism in liver: transferases are : glutathione, sulfate, acetate, glucoronic acid. P450 is cytochrome P450 enzymes. 3 different pathways are depicted for Drugs A, B and C.

The human body identifies almost all drugs as foreign substances (i.e. xenobiotics) and subjects them to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissue in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins), and exogenous substances (e.g. drugs).[2] The central role played by liver in the clearance and transformation of chemicals also makes it susceptible to drug induced injury.

Drug metabolism is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is thought to prepare a drug for phase 2. However many compounds can be metabolised by phase 2 directly. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites which are more chemically active and potentially toxic. Most of phase 2 reactions take place in cytosol and involve conjugation with endogenous compounds via transferase enzymes. Chemically active phase 1 products are rendered relatively inert and suitable for elimination by this step.

A group of enzymes located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is the terminal oxidase component of an electron transport chain. It is not a single enzyme, rather consists of a family of closely related 50 isoforms, six of them metabolize 90% of drugs.[3][4] 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 almost all drugs) in phase 1.

Three important characteristics of the P450 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 CYP450 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.

Cytochrome P-450 enzyme induction and inhibition[4][5][6]
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,

2. Change in enzyme activity: Many substances can influence P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways.[7] 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 its synthesis. Depending on inducing drug's half life, there is usually a delay before enzyme activity increases.[4]

3. Competitive inhibition: Some drugs may share the same P-450 specificity and thus competitively block their bio transformation. This may lead to accumulation of drugs metabolised by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic substrate.

Mechanism of Liver Damage

Factors influencing
drug induced hepatotoxicity[8]
  • Age
  • Ethnicity and race
  • Gender
  • Nutritional status
  • underlying liver disease
  • Renal function
  • Pregnancy
  • Duration and dosage of drug
  • Enzyme induction
  • Drug- 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 gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and then spleen via portal veins which bring drugs and xenobiotics in concentrated form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.

Many chemicals damage mitochondria, an intracellular organelle that produce energy. Its dysfunction releases excessive amount of oxidants which in turn injures hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress.[9] Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside liver. This promotes further liver damage.[10] Non-parenchymal cells such as Kupffer cells, fat storing stellate cells and leukocytes (i.e. neutrophil and monocyte) also have role in the mechanism.

Adverse Drug Reactions

Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic).[11] Type A drug reaction accounts for 80% of all toxicities.[12]

Drugs or toxins that have a pharmacological (type A) hepatotoxicity are those that have predictable dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity such as directly damaging liver tissue or blocking a metabolic process. As in the case of Acetaminophen overdose, this type of injury occurs shortly after some threshold for toxicity is reached.

Idiosyncratic (type B) injury occurs without warning; when agents cause non-predictable hepatotoxicity in susceptible individuals which is not related to dose and has variable latency period.[13] This type of injury does not have a clear dose-response or temporal relationship, and most often do 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) and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins.

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[14] Acetaminophen
Anabolic steroid
Hormonal contraception

Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (i.e. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP.[15][14] Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed type 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 necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as very high level of ALT and severe disturbance of liver function leading to acute liver failure.
Causes: Acetaminophen (Tylenol), 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 type picture is the commonest, where histological features are similar to acute viral hepatitis. (B) in the focal or non specific hepatitis scattered foci of cell necrosis may accompany lymphocytic infiltrate. (C) chronic hepatitis type is very similar to autoimmune hepatitis clinically, serologically as well as histologically.
(a) Viral hepatitis like: Halothane, isoniazid, phenytoin
(b) Focal hepatitis: Aspirin
(c) Chronic hepatitis: Methyldopa, diclofenac
  • Cholestasis: Liver injury leads to impairment of bile flow and clinical picture is predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland without any parenchymal inflammation. In rare occasions it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (Vanishing duct syndrome).
(a) Bland: Oral contraceptive pills, anabolic steroid, androgens
(b) Inflammatory: Allopurinol, 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 where phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g. Tay-Sachs disease)
(a) Microvesicular: Aspirin (Reye's syndrome), ketoprofen, tetracycline
(b) Macrovesicular: Acetamenophen, methotrexate
(c) Phospholipidosis: Amiodarone, total parenteral nutrition
  • 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.
Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine
  • Vascular lesions: They result from injury to the vascular endothelium.
(a) Venoocclusive disease: Chemotherapeutic agents, bush tea
(b) Peliosis hepatis: Anabolic steroid
(c) 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.
Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast


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  2. Donald Blumenthal; Laurence Brunton; Keith Parker; Lazo, John S.; Iain Buxton. Goodman and Gilman's Pharmacological Basis of Therapeutics Digital Edition. McGraw-Hill Professional. ISBN 0-07-146804-8.
  3. Skett, Paul; Gibson, G. Gordon (2001). Introduction to drug metabolism. Cheltenham, UK: Nelson Thornes Publishers. ISBN 0-7487-6011-3.
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  6. "P450 Table". Retrieved 2007-09-29.
  7. Michalets EL (1998). "Update: clinically significant cytochrome P-450 drug interactions". Pharmacotherapy. 18 (1): 84–112. PMID 9469685.
  8. Keeffe, Emmet B; Friedman, Lawrence M. (2004). Handbook of liver diseases. Edinburgh: Churchill Livingstone. pp. 104–123. ISBN 0-443-06633-7. |access-date= requires |url= (help)
  9. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ (2002). "Mechanisms of hepatotoxicity". Toxicol. Sci. 65 (2): 166–76. doi:10.1093/toxsci/65.2.166. PMID 11812920.
  10. Patel T, Roberts LR, Jones BA, Gores GJ (1998). "Dysregulation of apoptosis as a mechanism of liver disease: an overview". Semin. Liver Dis. 18 (2): 105–14. PMID 9606808.
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