Hepatotoxicity
| Subordinate terms |
| Toxic hepatitis 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 |
Hepatotoxicity implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease.
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 and sometimes even when introduced within therapeutic ranges, may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals and herbal remedies can also induce hepatotoxicity.Chemicals that cause liver injury are called hepatotoxins.
More than 900 drugs have been implicated in causing liver injury and it is the most common reason for a drug to be withdrawn from the market. Hepatotoxicity and drug-induced liver injury also account for a substantial number of compound failures, highlighting the need for toxicity prediction models, and drug screening assays, such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process. Chemicals often cause subclinical injury to the liver, which manifests only as abnormal liver enzyme tests.
Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.
Cause
s are classified as type A or type B. Type A drug reaction accounts for 80% of all toxicities.Drugs or toxins that have a pharmacological hepatotoxicity are those that have predictable dose-response curves 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 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. 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 and trovafloxacin are two prime examples of idiosyncratic hepatotoxins pulled from market.
Oral use of ketoconazole has been associated with hepatic toxicity, including some fatalities; however, such effects appear to be limited to doses taken over a period longer than 7 days.
Acetaminophen (Paracetamol)
, paracetamol, also known by the brand name Tylenol and Panadol, is usually well tolerated in prescribed dose, but overdose is the most common cause of drug-induced liver disease and acute liver failure worldwide. Damage to the liver is not due to the drug itself but to a toxic metabolite produced by cytochrome P-450 enzymes in the liver. In normal circumstances, this metabolite is detoxified by conjugating with glutathione in phase 2 reaction. In an overdose, a large amount of NAPQI is generated, which overwhelms the detoxification process and leads to liver cell damage. Nitric oxide also plays a role in inducing toxicity. The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other drug intake, interval between ingestion and antidote, etc. The dose toxic to the liver is quite variable from person to person and is often thought to be lower in chronic alcoholics. Measurement of blood level is important in assessing prognosis, higher levels predicting a worse prognosis. 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.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. Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.Glucocorticoids
Glucocorticoids are so named due to their effect on the carbohydrate mechanism. They promote glycogen storage in the liver. An enlarged liver is a rare side-effect of long-term steroid use in children. The classical effect of prolonged use both in adult and paediatric population is steatosis.Isoniazid
Isoniazide 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.Other hydrazine derivative drugs
There are also cases where other hydrazine derivative drugs, such as the MAOI antidepressant iproniazid, are associated with liver damage. Phenelzine has been associated with abnormal liver tests. Toxic effects can develop from antibiotics.Natural products
Examples include many amanita mushrooms, and aflatoxins. Pyrrolizidine alkaloids, which occur in some plants, can be toxic. Green tea extract is a growing cause of liver failure due to its inclusion in more products.Industrial toxin
Examples include arsenic, carbon tetrachloride, and vinyl chloride.Alternative remedies
Examples include: Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Garcinia, Kava leaves, pyrrolizidine alkaloids, Horse chestnut leaves, Valerian, Comfrey. Chinese herbal remedies: Jin Bu Huan, Ma-huang, Shou Wu Pian, Bai Xian Pi.Mechanism
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 the spleen via portal veins 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 mitochondria, an intracellular organelle that produces energy. Its dysfunction releases excessive amount of oxidants that, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress. Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside the liver. This promotes further liver damage. Non-parenchymal cells such as Kupffer cells, fat storing stellate cells, and leukocytes also have a role in the mechanism.
Drug metabolism in liver
The human body identifies almost all drugs as foreign substances and subjects them to various chemical processes to make them suitable for elimination. This involves chemical transformations to reduce fat solubility and to change biological activity. 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 and exogenous substances. The central role played by liver in the clearance and transformation of chemicals 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 metabolized 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 that 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, but rather consists of a closely related family of 50 isoforms; six of them metabolize 90% of drugs. 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 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 for the variation in drug metabolism between individuals. Genetic variations 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.
Many substances can influence the P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways. 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 the inducing drug's half life, there is usually a delay before enzyme activity increases.
Some drugs may share the same P-450 specificity and thus competitively block their bio transformation. 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 substrate.
Patterns of injury
Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers are often used to indicate liver damage. Liver injury is defined as a rise in either ALT level more than three times of upper limit of normal, ALP level more than twice ULN, or total bilirubin level more than twice ULN when associated with increased ALT or ALP. Liver damage is further characterized into hepatocellular and cholestatic 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.