Hepatotoxicity

Certain medicinal agents, when taken in overdoses (e.g. acetaminophen, paracetamol) and sometimes even when introduced within therapeutic ranges (e.g. halothane), may injure the organ.

Hepatotoxicity and drug-induced liver injury also account for a substantial number of compound failures, highlighting the need for toxicity prediction models (e.g. DTI),[2] and drug screening assays, such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.

Carbon tetrachloride 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.

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.

In an overdose, a large amount of NAPQI is generated, which overwhelms the detoxification process and leads to liver cell damage.

Administration of Acetylcysteine, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI.

Those that develop acute liver failure can still recover spontaneously, but may require transplantation if poor prognostic signs such as encephalopathy or coagulopathy is present (see King's College Criteria).

[17] Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity.

[32][33] Chinese herbal remedies: Jin Bu Huan, Ephedra, Shou Wu Pian, Bai Xian Pi.

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 the spleen via portal veins that bring drugs and xenobiotics in near-undiluted form.

Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, proteins) and exogenous substances (e.g., drugs, alcohol).

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

These processes tend to increase water solubility of the drug and can generate metabolites that are more chemically active and/or potentially toxic.

[40][41] 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: 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.

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) Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity.

To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected.

In the past, glucocorticoids in allergic features and ursodeoxycholic acid in cholestatic cases had been used, but there is no good evidence to support their effectiveness.

[citation needed] An elevation in serum bilirubin level of more than 2 times ULN with associated transaminase rise is an ominous sign.

[51][52] The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity: Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and pemoline.

Paracetomol (3D structure) overdose is the most common cause of drug-induced liver disease
Drug metabolism in liver: transferases are: glutathione, sulfate, acetate, glucoronic acid. P-450 is cytochrome P-450. Different pathways are shown for Drugs A, B and C.
Algorithm for suspected drug-induced hepatic toxicity