Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
damage. Drug-induced liver injury is a cause of acute and chronic
liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.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.
paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...
) and sometimes even when introduced within
therapeutic ranges (e.g.
halothane), may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals (e.g.,
microcystin
Microcystins—or cyanoginosins—are a class of toxins produced by certain freshwater cyanobacteria, commonly known as blue-green algae. Over 250 different microcystins have been discovered so far, of which microcystin-LR is the most common. C ...
s), and
herbal remedies (two prominent examples being
kava
Kava or kava kava ('' Piper methysticum'': Latin 'pepper' and Latinized Greek 'intoxicating') is a crop of the Pacific Islands. The name ''kava'' is from Tongan and Marquesan, meaning 'bitter'; other names for kava include ''ʻawa'' ( Hawai� ...
, mechanism unknown, and
comfrey
''Symphytum'' is a genus of flowering plants in the borage family, Boraginaceae, known by the common name comfrey (pronounced ). There are 59 recognized species.WFO (2022): Symphytum L. Published on the Internet; http://www.worldfloraonline.org/ ...
, through its pyrrolizidine alkaloid content) can also induce hepatotoxicity. Chemicals that cause liver injury are called
hepatotoxins.
More than 900 drugs have been implicated in causing liver injury
(see LiverTox, external link, below) 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 (e.g. DTI),
and drug screening assays, such as
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.
Chemicals often cause
subclinical
In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asym ...
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 failure
Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
s.
Causes
Adverse drug reaction
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...
s are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic). Type A drug reaction accounts for 80% of all toxicities.
Drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalati ...
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
paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...
overdose, this type of injury occurs shortly after some threshold for toxicity is reached.
Carbon tetrachloride
Carbon tetrachloride, also known by many other names (such as tetrachloromethane, also recognised by the IUPAC, carbon tet in the cleaning industry, Halon-104 in firefighting, and Refrigerant-10 in HVACR) is an organic compound with the chemi ...
is commonly used to induce acute type A liver injury in animal models.
Idiosyncratic
An idiosyncrasy is an unusual feature of a person (though there are also other uses, see below). It can also mean an odd habit. The term is often used to express eccentricity or peculiarity. A synonym may be "quirk".
Etymology
The term "idiosyncr ...
(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 (Rezulin)
and
trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins pulled from market.
The herb
kava
Kava or kava kava ('' Piper methysticum'': Latin 'pepper' and Latinized Greek 'intoxicating') is a crop of the Pacific Islands. The name ''kava'' is from Tongan and Marquesan, meaning 'bitter'; other names for kava include ''ʻawa'' ( Hawai� ...
has caused a number of cases of idiosyncratic liver injury, ranging everywhere from asymptomatic to fatal.
Oral use of the
antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...
ketoconazole
Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous ca ...
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.
Paracetamol
Paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...
also known as acetaminophen, and by the brand names of 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
Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
worldwide.
Damage to the liver is not due to the drug itself but to a toxic metabolite (''N''-acetyl-''p''-benzoquinone imine (NAPQI)) produced by cytochrome P-450 enzymes in the liver.
In normal circumstances, this metabolite is detoxified by conjugating with
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
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 (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ...
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
Acetylcysteine, also known as ''N''-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been us ...
, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. Those that develop
acute liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
can still recover spontaneously, but may require transplantation if poor
prognostic
Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stable ...
signs such as
encephalopathy
Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...
or
coagulopathy
Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding ( bleeding diathesis), which may occur s ...
is present (see
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 encephalop ...
).
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
Phenylbutazone, often referred to as "bute", is a nonsteroidal anti-inflammatory drug (NSAID) for the short-term treatment of pain and fever in animals.
In the United States and United Kingdom, it is no longer approved for human use (except in th ...
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
Pediatrics ( also spelled ''paediatrics'' or ''pædiatrics'') is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, paediatrics covers many of their youth until the ...
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.
Other hydrazine derivative drugs
There are also cases where other
hydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...
derivative drugs, such as the
MAOI antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...
iproniazid
Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later ...
, are associated with liver damage.
Phenelzine
Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is primarily used as an antidepressant and anxiolytic. Along with tranylcypromine an ...
has been associated with abnormal liver tests.
Toxic effects can develop from antibiotics.
Natural products
Examples include
alpha-Amanitin containing mushrooms, kava, and aflatoxin producing molds.
Pyrrolizidine alkaloid
Pyrrolizidine alkaloids (PAs), sometimes referred to as necine bases, are a group of naturally occurring alkaloids based on the structure of pyrrolizidine. Pyrrolizidine alkaloids are produced by plants as a defense mechanism against insect he ...
s, 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.
Alternative remedies
Examples include:
Ackee fruit,
Bajiaolian
''Podophyllum pleianthum'' (syn. ''Dysosma pleiantha''), the many-flowered Chinese mayapple, is a species of flowering plant in the genus ''Podophyllum'', native to south-central and southeast China, including Taiwan. Shade tolerant, and deer res ...
,
Camphor
Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel (''Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the k ...
,
Copaltra,
Cycasin,
Garcinia,
Kava
Kava or kava kava ('' Piper methysticum'': Latin 'pepper' and Latinized Greek 'intoxicating') is a crop of the Pacific Islands. The name ''kava'' is from Tongan and Marquesan, meaning 'bitter'; other names for kava include ''ʻawa'' ( Hawai� ...
leaves,
pyrrolizidine alkaloid
Pyrrolizidine alkaloids (PAs), sometimes referred to as necine bases, are a group of naturally occurring alkaloids based on the structure of pyrrolizidine. Pyrrolizidine alkaloids are produced by plants as a defense mechanism against insect he ...
s,
Horse chestnut leaves,
Valerian,
Comfrey
''Symphytum'' is a genus of flowering plants in the borage family, Boraginaceae, known by the common name comfrey (pronounced ). There are 59 recognized species.WFO (2022): Symphytum L. Published on the Internet; http://www.worldfloraonline.org/ ...
.
Chinese herbal remedies:
Jin Bu Huan
Jin is a toneless pinyin romanization of various Chinese names and words. These have also been romanized as Kin and Chin (Wade–Giles). "Jin" also occurs in Japanese and Korean.
It may refer to:
States Jìn 晉
* Jin (Chinese state) (晉國) ...
,
Ephedra,
Shou Wu Pian
''Reynoutria multiflora'' (syn. ''Fallopia multiflora'' and ''Polygonum multiflorum'') is a species of flowering plant in the buckwheat family Polygonaceae native to central and southern China. It is known by the English common names tuber flee ...
,
Bai Xian Pi.
Industrial toxin
Examples include
arsenic
Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, b ...
,
carbon tetrachloride
Carbon tetrachloride, also known by many other names (such as tetrachloromethane, also recognised by the IUPAC, carbon tet in the cleaning industry, Halon-104 in firefighting, and Refrigerant-10 in HVACR) is an organic compound with the chemi ...
, and
vinyl chloride
Vinyl chloride is an 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 (PVC ...
.
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 gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, 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 vein
The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approx ...
s 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
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
, 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
Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, inclu ...
also lead to oxidative stress.
Injury to
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
and
bile duct
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates.
Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. ...
cells lead to accumulation of
bile acid
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primar ...
inside the liver. This promotes further liver damage.
Non-
parenchyma
Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms.
Etymology
The term ''parenchyma'' is New Latin from the word � ...
l cells such as
Kupffer cells, collagen-producing
stellate cell
Stellate cells are neurons in the central nervous system, named for their star-like shape formed by dendritic processes radiating from the cell body. Many stellate cells are GABAergic and are located in the molecular layer of the cerebellum. Ste ...
s, and
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s (i.e.
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
and
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
) 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.
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
) 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 substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, ...
chemicals (e.g.,
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
, steroid hormones,
fatty acids
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
,
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
) and
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogen ...
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 is usually divided into two phases: ''phase 1'' and ''phase 2''. Phase 1 reaction is generally speaking to prepare a drug for phase 2. However, many compounds can be metabolized by phase 2 directly or be excreted without any phase 2 reactions occurring. Phase 1 reaction involves
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...
,
reduction,
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
,
hydration Hydration may refer to:
* Hydrate, a substance that contains water
* Hydration enthalpy, energy released through hydrating a substance
* Hydration reaction, a chemical addition reaction where a hydroxyl group and proton are added to a compound
* ...
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/or potentially toxic. Most of phase 2 reactions take place in
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
and involve conjugation with endogenous compounds via
transferase
A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds o ...
enzymes. Phase 1 are typically more suitable for elimination.
A group of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
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 not a single enzyme, but rather consists of a closely related family of 50
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
s; 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 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:
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 enzyme production, or, in the case of CYP2E1, preventing degradation in the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
. 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 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
Chemicals produce a wide variety of clinical and
pathological
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in th ...
hepatic injury. Biochemical markers (e.g.
alanine transferase
Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first character ...
,
alkaline phosphatase
The enzyme alkaline phosphatase (EC 3.1.3.1, alkaline phosphomonoesterase; phosphomonoesterase; glycerophosphatase; alkaline phosphohydrolase; alkaline phenyl phosphatase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), systematic ...
and
bilirubin
Bilirubin (BR) ( Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from t ...
) are often used to indicate liver damage. Liver injury is defined as a rise in either (a)
ALT
Alt or ALT may refer to:
Abbreviations for words
* Alt account, an alternative online identity also known as a sock puppet account
* Alternate character, in online gaming
* Alternate route, type of highway designation
* Alternating group, mathema ...
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.
Liver damage is further characterized into hepatocellular (predominantly initial
Alanine transferase
Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first character ...
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 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 () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...
where the injury is largely confined to a particular zone of the
liver lobule. It may manifest as a very high level of
ALT
Alt or ALT may refer to:
Abbreviations for words
* Alt account, an alternative online identity also known as a sock puppet account
* Alternate character, in online gaming
* Alternate route, type of highway designation
* Alternating group, mathema ...
and severe disturbance of liver function leading to
acute liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
.
:Causes include:
:
Paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...
,
carbon tetrachloride
Carbon tetrachloride, also known by many other names (such as tetrachloromethane, also recognised by the IUPAC, carbon tet in the cleaning industry, Halon-104 in firefighting, and Refrigerant-10 in HVACR) is an organic compound with the chemi ...
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
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adapt ...
infiltration. (C) chronic hepatitis is very similar to
autoimmune hepatitis
Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the live ...
clinically, serologically, and histologically.
:Causes:
:(a) Viral hepatitis:
Halothane,
isoniazid,
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
:(b) Focal hepatitis:
Aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
:(c) Chronic hepatitis:
Methyldopa
Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high bl ...
,
diclofenac
Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth or rectally in a suppository, used by injection, or ...
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
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).
:Causes:
:(a) Bland:
Oral contraceptive pills,
anabolic steroid
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects ...
,
androgens
:(b) Inflammatory:
Allopurinol
Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth ...
,
co-amoxiclav
Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections. It is a combination consisting of a ...
,
carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...
:(c) Ductal:
Chlorpromazine
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar di ...
,
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
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around three to six months of age, with the baby ...
)
:Causes:
:(a) Microvesicular:
Aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
(
Reye's syndrome
Reye syndrome is a rapidly worsening brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While liver toxicity typically occurs in the syndrome, jaundice usually doe ...
),
ketoprofen,
tetracycline
Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis.
Common side effects in ...
(especially if expired)
:(b) Macrovesicular:
Acetaminophen
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
,
methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
:(c) Phospholipidosis:
Amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibril ...
,
total parenteral nutrition
:(d)
Antiviral
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...
:
nucleoside analogues
:(e)
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are inv ...
:(f) Hormonal:
Tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
Granuloma
A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious o ...
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
Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth ...
,
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
,
isoniazid,
quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
,
penicillin
Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
,
quinidine
Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is the enantiomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...
Vascular lesions
These result from injury to the vascular endothelium.
:Causes:
:
Venoocclusive disease
Hepatic veno-occlusive disease (VOD) or veno-occlusive disease with immunodeficiency is a potentially life-threatening condition in which some of the small veins in the liver are obstructed. It is a complication of high-dose chemotherapy given bef ...
: Chemotherapeutic agents, bush tea
:
Peliosis hepatis
Peliosis hepatis is an uncommon vascular condition characterised by multiple, randomly distributed, blood-filled cavities throughout the liver. The size of the cavities usually ranges between a few millimetres and 3 cm in diameter. Chapter 80 ...
: Anabolic steroids
:
Hepatic vein thrombosis: Oral contraceptives
Neoplasm
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
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
Vinyl chloride is an 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 (PVC ...
,
combined oral contraceptive pill
The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: proges ...
,
anabolic steroid
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects ...
,
arsenic
Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, b ...
,
thorotrast
Diagnosis
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
CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage.
CIOMS/RUCAM scale involves a scoring system that 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 ).
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
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.
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 (
Hy's Law).
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
Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) ...
) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high
AST.
Drugs withdrawn
The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity:
Troglitazone,
bromfenac,
trovafloxacin,
ebrotidine,
nimesulide,
nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...
,
ximelagatran
Ximelagatran (Exanta or Exarta, H 376/95) 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 thera ...
and
pemoline
Pemoline, sold under the brand name Cylert among others, is a stimulant medication which has been used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. It has been discontinued in most countries to due to rare ...
.
See also
*
Hepatoprotection
Hepatoprotection or antihepatotoxicity is the ability of a chemical substance to prevent damage to the liver. This is opposite to hepatotoxicity.
Hepatoprotective molecules used in emergency medicine
* Acetylcysteine is considered the hepatopro ...
*
Reye's syndrome
Reye syndrome is a rapidly worsening brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While liver toxicity typically occurs in the syndrome, jaundice usually doe ...
References
External links
LiverToxat the United States
National Library of Medicine
The United States National Library of Medicine (NLM), operated by the United States federal government, is the world's largest medical library.
Located in Bethesda, Maryland, the NLM is an institute within the National Institutes of Health. Its ...
{{Authority control
Toxicology
Diseases of liver
Hepatology