Hepatotoxicity
Encyclopedia
| Alternative names |
|---|
| Toxic liver disease Toxin induced liver disease Drug induced liver disease Drug induced liver damage Hepatogenous poisoning |
| 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 (from hepatic toxicity) implies chemical-driven liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
damage.
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
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals (e.g., microcystin
Microcystin
Microcystins are cyclic nonribosomal peptides produced by cyanobacteria . They are cyanotoxins and can be very toxic for plants and animals including humans. Their hepatotoxicity may cause serious damage to the liver. Microcystins can strongly inhibit protein phosphatases type 1 and 2A , and are...
s) and herbal remedies
Herbalism
Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also known as botanical medicine, medical herbalism, herbal medicine, herbology, herblore, and phytotherapy...
can also induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxin
Hepatotoxin
A hepatotoxin is a toxic chemical substance that damages the liver.It can be a side-effect of medication, or found naturally, as microcystins, or in laboratory environments....
s.
More than 900 drugs have been implicated in causing liver injury and it is the most common reason for a drug to be withdrawn from the market. Chemicals often cause subclinical injury to liver which manifests only as abnormal liver enzyme tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
. Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.
Drug metabolism in liver
The human body identifies almost all drugs as foreign substances (i.e. xenobiotics) and subjects them to various chemical processes (i.e. metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) 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
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
chemicals (e.g., cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, steroid hormones, fatty acids, proteins) and exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
substances (e.g., drugs, alcohol). The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.
Drug metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
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
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
, hydration
Hydration reaction
In organic chemistry, a hydration reaction is a chemical reaction in which a hydroxyl group and a hydrogen cation are added to the two carbon atoms bonded together in the carbon-carbon double bond which makes up an alkene functional group. The reaction usually runs in a strong acidic, aqueous...
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
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
and involve conjugation with endogenous compounds via transferase
Transferase
In biochemistry, a transferase is an enzyme that catalyzes the transfer of a functional group from one molecule to another . For example, an enzyme that catalyzed this reaction would be a transferase:In this example, A would be the donor, and B would be the acceptor...
enzymes. Chemically active phase 1 products are rendered relatively inert and suitable for elimination by this step.
A group of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s 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
Oxidase
An oxidase is any enzyme that catalyzes an oxidation-reduction reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
component of an electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. 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 (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
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
) 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.
| Potent inducers | |Substrates | |
|---|---|---|
| Rifampicin Rifampicin Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ... , Carbamazepine Carbamazepine Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia... , Phenobarbital Phenobarbital Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the... , Phenytoin Phenytoin Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels... , (St John's wort St John's wort St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed.... ), |
Amiodarone Amiodarone Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985... , cimetidine Cimetidine Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet... , ciprofloxacin Ciprofloxacin Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of... , fluconazole Fluconazole Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade... , fluoxetine Fluoxetine Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company... , erythromycin Erythromycin Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and... , isoniazid Isoniazid Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid... , diltiazem Diltiazem Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia.... |
Caffeine Caffeine Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants... , clozapine Clozapine Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew... , omeprazole Omeprazole Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome... , losartan Losartan Losartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar... , theophylline Theophylline Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it... |
- 2. Change in enzyme activity:
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.
- 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 metabolized 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 |
|---|
|
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
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, 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 vein
Hepatic portal vein
The hepatic portal vein is not a true vein, because it does not conduct blood directly to the heart. It is a vessel in the abdominal cavity that drains blood from the gastrointestinal tract and spleen to capillary beds in the liver...
s which 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 produce energy. Its dysfunction releases excessive amount of oxidants which, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1
CYP2E1
Cytochrome P450 2E1 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene...
also lead to oxidative stress. Injury to hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
and bile duct
Bile duct
A bile duct is any of a number of long tube-like structures that carry bile.Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine.The...
cells lead to accumulation of bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
inside liver
Cholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
. This promotes further liver damage. Non-parenchyma
Parenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...
l cells such as Kupffer cell
Kupffer cell
Kupffer cells, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system .-History:The cells were first observed by Karl Wilhelm von Kupffer in 1876...
s, fat storing stellate cell
Hepatic stellate cell
Hepatic stellate cells , also known as perisinusoidal cells or Ito cells , are pericytes found in the perisinusoidal space of the liver also known as the space of Disse...
s, and leukocytes (i.e. neutrophil and monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
) also have role in the mechanism.
Adverse drug reactions
Adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic). Type A drug reaction accounts for 80% of all toxicities.
Drugs
DRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...
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
Idiosyncratic drug reaction
Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known...
(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. 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
Troglitazone
Troglitazone is an anti-diabetic and antiinflammatory drug, and a member of the drug class of the thiazolidinediones. It was developed by Daiichi Sankyo Co.. In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an...
(Rezulin) and trovafloxacin
Trovafloxacin
Trovafloxacin is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity...
(Trovan) are two prime examples of idiosyncratic hepatotoxins pulled from market.
When used orally, ketoconazole has been associated with hepatic toxicity, including some fatalities.
Patterns of injury
| Type of injury: | |Cholestatic | ALT Alanine transaminase Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase .... |
≥ Twofold rise | Normal | ≥ Twofold rise |
|---|---|---|---|
| ALP Alkaline phosphatase Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation... |
Normal | ≥ Twofold rise | ≥ Twofold rise |
| ALT: ALP ratio | High, ≥5 | Low, ≤2 | 2-5 |
| Examples | Acetaminophen Allopurinol Allopurinol Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :... Amiodarone Amiodarone Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985... HAART NSAID |
Anabolic steroid Anabolic steroid Anabolic steroids, technically known as anabolic-androgen steroids or colloquially simply as "steroids", are drugs that mimic the effects of testosterone and dihydrotestosterone in the body. They increase protein synthesis within cells, which results in the buildup of cellular tissue ,... Chlorpromazine Chlorpromazine Chlorpromazine is a typical antipsychotic... Clopidogrel Clopidogrel Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly... Erythromycin Erythromycin Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and... Hormonal contraception Hormonal contraception Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive... |
Amitryptyline, Enalapril Enalapril Enalapril is an angiotensin converting enzyme inhibitor used in the treatment of hypertension and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in... Carbamazepine Carbamazepine Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia... Sulfonamide Sulfonamide (medicine) Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame... Phenytoin Phenytoin Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels... |
Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
and bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
) are often used to indicate liver damage. Liver injury is defined as a rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP. 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 types of injuries are often encountered.
Specific histo-pathological
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
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
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
where the injury is largely confined to a particular zone of the liver lobule. It may manifest as a very high level of ALT
Alanine transaminase
Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase ....
and severe disturbance of liver function leading to acute liver failure.
- Causes include:
- ParacetamolParacetamolParacetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
, carbon tetrachlorideCarbon tetrachlorideCarbon tetrachloride, also known by many other names is the organic compound with the formula CCl4. It was formerly widely used in fire extinguishers, as a precursor to refrigerants, and as a cleaning agent...
Hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
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
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis
Autoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
clinically, serologically, and histologically.
- Causes: Viral hepatitis: HalothaneHalothaneHalothane is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic agent containing a bromine atom; there are several other halogenated anesthesia agents which lack the bromine atom and do contain the fluorine and...
, isoniazidIsoniazidIsoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
, phenytoinPhenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
Focal hepatitis: AspirinAspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
Chronic hepatitis: MethyldopaMethyldopaMethyldopa is an alpha-adrenergic agonist psychoactive drug used as a sympatholytic or antihypertensive. Its use is now mostly deprecated following the introduction of alternative safer classes of agents...
, diclofenacDiclofenacDiclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
Cholestasis
Cholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
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 parenchymal inflammation). On rare occasions, it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (Vanishing duct syndrome
Vanishing bile duct syndrome
Vanishing bile duct syndrome is a loose collection of diseases which leads to of the injury to hepatic bile ducts and eventual ductopenia.-Congenital/Developmental:In fetal and neonatal life the ductal plates are remodeled...
).
- Causes: Bland: Oral contraceptive pills, anabolic steroidAnabolic steroidAnabolic steroids, technically known as anabolic-androgen steroids or colloquially simply as "steroids", are drugs that mimic the effects of testosterone and dihydrotestosterone in the body. They increase protein synthesis within cells, which results in the buildup of cellular tissue ,...
, androgens Inflammatory: AllopurinolAllopurinolAllopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
, co-amoxiclavCo-amoxiclavAmoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...
, carbamazepineCarbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
Ductal: ChlorpromazineChlorpromazineChlorpromazine is a typical antipsychotic...
, flucloxacillinFlucloxacillinFlucloxacillin or floxacillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible Gram-positive bacteria. Unlike other penicillins, flucloxacillin has activity against beta-lactamase-producing organisms such as Staphylococcus...
Steatosis
Steatosis
In cellular pathology, steatosis is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm...
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
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...
)
- Causes: Microvesicular: AspirinAspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
(Reye's syndromeReye's syndromeReye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
), ketoprofenKetoprofenKetoprofen, 2--propionic acid is one of the propionic acid class of non-steroidal anti-inflammatory drug with analgesic and antipyretic effects...
, tetracycline (especially if expired) Macrovesicular: Acetamenophen, methotrexateMethotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
Phospholipidosis: AmiodaroneAmiodaroneAmiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
, total parenteral nutritionTotal parenteral nutritionParenteral nutrition is feeding a person intravenously, bypassing the usual process of eating and digestion. The person receives nutritional formulae that contain nutrients such as glucose, amino acids, lipids and added vitamins and dietary minerals...
Granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...
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:
- AllopurinolAllopurinolAllopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
, phenytoinPhenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
, isoniazidIsoniazidIsoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
, quinineQuinineQuinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, penicillinPenicillinPenicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, quinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
Vascular lesions
These result from injury to the vascular endothelium.
- Causes:
- Venoocclusive disease: Chemotherapeutic agents, bush tea
- Peliosis hepatisPeliosis hepatisPeliosis Hepatis is an uncommon vascular condition characterised by randomly distributed multiple blood-filled cavities throughout the liver. The size of the cavities usually ranges between a few millimetres to 3 cm in diameter...
: Anabolic steroids - Hepatic vein thrombosisBudd-Chiari syndromeIn medicine , Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or...
: 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 chlorideVinyl chlorideVinyl chloride is the organochloride with the formula H2C:CHCl. It is also called vinyl chloride monomer, VCM or chloroethene. This colorless compound is an important industrial chemical chiefly used to produce the polymer polyvinyl chloride . At ambient pressure and temperature, vinyl chloride...
, combined oral contraceptive pill, anabolic steroidAnabolic steroidAnabolic steroids, technically known as anabolic-androgen steroids or colloquially simply as "steroids", are drugs that mimic the effects of testosterone and dihydrotestosterone in the body. They increase protein synthesis within cells, which results in the buildup of cellular tissue ,...
, arsenicArsenicArsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
, thorotrastThorotrastThorotrast is a suspension containing particles of the radioactive compound thorium dioxide, ThO2, used as a contrast medium in X-ray diagnostics in the 1930s and 40s ....
Clinical assessment
This remains a challenge in clinical practice due to a lack of reliable markers. Many other conditions lead to similar clinical as well as pathological pictures. 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. Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established, dose-dependent, pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMSCouncil for International Organizations of Medical Sciences
The Council for International Organizations of Medical Sciences is an international, nongovernmental, not-for-profit organization established jointly by WHO and UNESCO in 1949....
/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale
CIOMS/RUCAM scale
The CIOMS/RUCAM scale is a tool to predict whether liver damage can be attributed to a particular medication.-Hepatotoxicity:Determining hepatotoxicity remains a major challenge in clinical practice due to lack of reliable markers. Many other conditions lead to similar clinical as well as...
involves a scoring system which categorizes the suspicion into "definite or highly probable" (score > 8), “probable” (score 6-8), “possible” (score 3-5), “unlikely” (score 1-2) and “excluded” (score ≤ 0). In clinical practice, physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity (e.g., cholestatic damage in amoxycillin-clauvonic acid
Co-amoxiclav
Amoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...
).
Treatment and prognosis
In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. 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.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 (Hy's Law
Hy's law
Hy's law is a prognostic indicator that a pure drug-induced liver injury leading to jaundice, without a hepatic transplant, has a case fatality rate of 10% to 50%...
). This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST
Aspartate transaminase
Aspartate transaminase , also called aspartate aminotransferase or serum glutamic oxaloacetic transaminase , is a pyridoxal phosphate -dependent transaminase enzyme . AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in...
.
Drugs withdrawn for hepatotoxicity
The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity: TroglitazoneTroglitazone
Troglitazone is an anti-diabetic and antiinflammatory drug, and a member of the drug class of the thiazolidinediones. It was developed by Daiichi Sankyo Co.. In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an...
, bromfenac
Bromfenac
Bromfenac is a non-steroidal anti-inflammatory drug marketed in the US as an ophthalmic solution by ISTA Pharmaceuticals for short-term, local use...
, trovafloxacin
Trovafloxacin
Trovafloxacin is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity...
, ebrotidine
Ebrotidine
Ebrotidine is an H2 receptor antagonist with gastroprotective activity. It has a gastro-protective action against ethanol-, aspirin- or stress-induced gastric mucosal damage. The antisecretory properties of ebrotidine are similar to those of ranitidine, and approximately 10-fold greater than those...
, nimesulide
Nimesulide
Nimesulide is a relatively COX-2 selective, non-steroidal anti-inflammatory drug with analgesic and antipyretic properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old...
, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, ximelagatran
Ximelagatran
Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy...
and pemoline
Pemoline
Pemoline was first synthesized in 1913 but it's activity was not discovered until the 1930s. Under the names it was used as a medication used to treat attention-deficit hyperactivity disorder and narcolepsy. Under the Convention on Psychotropic Substances, it is a Schedule IV drug...
.
Acetaminophen
Acetaminophen (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 (N-acetyl-p-benzoquinone imine NAPQI, or NABQI) which is produced by cytochrome P-450 enzymes in the liver. In normal circumstances, this metabolite is detoxified by conjugating with glutathioneGlutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
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
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
also plays 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 smaller 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 who develop acute liver failure can still recover spontaneously, but may require transplantation if poor prognostic signs such as encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
or coagulopathy
Coagulopathy
Coagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...
is present (see King's College Criteria
King's College Criteria
The King's College Criteria or the King's College Hospital criteria were devised in 1989 to determine if there were any early indices of poor prognosis in patients with acute liver failure. Acute liver failure is defined as the onset of encephalopathy or coagulopathy within 26 weeks of a patient...
).
Nonsteroidal anti-inflammatory drugs (NSAIDs)
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 phenylbutazonePhenylbutazone
Phenylbutazone, often referred to as bute, is a non-steroidal anti-inflammatory drug for the short-term treatment of pain and fever in animals. In the United States, it is no longer approved for human use.-In humans:...
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 (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.Natural products
Examples include many amanitaAmanita
The genus Amanita contains about 600 species of agarics including some of the most toxic known mushrooms found worldwide. This genus is responsible for approximately 95% of the fatalities resulting from mushroom poisoning, with the death cap accounting for about 50% on its own...
mushrooms (particularly the destroying angel
Destroying angel
The name destroying angel applies to several similar, closely related species of deadly all-white mushrooms in the genus Amanita. They are Amanita bisporigera and A. ocreata in eastern and western North America, and A. virosa in Europe. Another very similar species, A. verna or fool's mushroom was...
s), and aflatoxins.
Industrial toxin
Examples include arsenicArsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
, carbon tetrachloride
Carbon tetrachloride
Carbon tetrachloride, also known by many other names is the organic compound with the formula CCl4. It was formerly widely used in fire extinguishers, as a precursor to refrigerants, and as a cleaning agent...
, and vinyl chloride
Vinyl chloride
Vinyl chloride is the organochloride with the formula H2C:CHCl. It is also called vinyl chloride monomer, VCM or chloroethene. This colorless compound is an important industrial chemical chiefly used to produce the polymer polyvinyl chloride . At ambient pressure and temperature, vinyl chloride...
.
Herbal and alternative remedies
Examples include Ackee fruit, Bajiaolian, Camphor, Copaltra???, Cycasin, KavaKava
Kava or kava-kava is a crop of the western Pacific....
, pyrrolizidine alkaloids, Horse chestnut leaf, Valerian, Comfrey.
- Chinese herbal remedies:
- Jin Bu Huan, Ma-huangEphedraEphedra refers to the plant Ephedra sinica. E. sinica, known in Chinese as ma huang , has been used in traditional Chinese medicine for 5,000 years for the treatment of asthma and hay fever, as well as for the common cold...
, Sho-wu-pian