Version May 2024
INTRODUCTION — Multiple drugs, both prescription and over-the-counter, herbal products, or toxins can cause hepatotoxicity through a variety of mechanisms [1,2]. A high index of suspicion is often necessary to expeditiously establish the diagnosis.
The hepatic metabolism of drugs and the mechanisms by which drugs might injure the liver will be reviewed here. The different clinical patterns of drug-induced hepatotoxicity and the use of medications in patients with liver disease are discussed separately. (See "Drug-induced liver injury" and "Overview of the management of chronic hepatitis C virus infection", section on 'Dose adjustments of medications' and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management'.)
EPIDEMIOLOGY — Drug-induced liver injury (DILI) and herbal-induced liver injury are well-recognized problems and symptomatically can mimic both acute and chronic liver diseases. Over 1000 medications and herbal products have been implicated in the development of DILI [3,4]. The probability of an individual drug causing liver injury ranges from 1 in 10,000 to 100,000, with some drugs reported as having an incidence of 100 in 100,000 (eg, chlorpromazine, isoniazid) [5,6]. DILI has a worldwide annual incidence ranging from 1.3 to 19.1 per 100,000 persons and 30 percent of cases will develop jaundice [6-16]. The prevalence and causes of DILI vary geographically [17]. DILI is the cause of acute jaundice in up to 50 percent of patients who present with new onset jaundice and accounts for 3 to 5 percent of hospital admissions for jaundice [8,9,13,18-23]. DILI accounts for up to half of the cases of acute liver failure in Western countries [24,25]. Finally, DILI was the most frequently cited reason for the withdrawal of medications from the marketplace (up to 32 percent) [26-33]. Following publication of the US Food and Drug Administration guidance statement for DILI in drug development, awareness of the issue increased and drug withdrawal subsequently decreased [6,34].
Database of drugs, herbs, and supplements associated with hepatotoxicity — The National Institutes of Health (NIH) maintains a searchable database of drugs, herbal medications, and dietary supplements that have been associated with DILI [35]. In addition, in 2004 the DILI Network initiated a prospective, observational, longitudinal study of individuals two years of age or older with suspected DILI [36]. The DILI Network continues to gather data and provide insight into the condition [37], and other DILI databases have been developed as well [30,38-40].
ROLE OF THE LIVER IN DRUG METABOLISM — The liver is responsible for the selective uptake, concentration, metabolism, and excretion of the majority of drugs and toxins that are introduced into the body. While some parent drugs can directly cause hepatotoxicity, it is generally the metabolites of these compounds that lead to drug-induced liver injury (DILI). These compounds are processed by a variety of soluble and membrane-bound enzymes, especially those related to the hepatocyte endoplasmic reticulum. Each drug has its specific enzyme disposal pathway(s) of biotransformation involving one or more of these enzyme systems. Genetic variation in drug metabolism is increasingly being recognized as a factor in the development of DILI [41]. Although less clear, environmental factors (eg, alcohol use) may also alter the processing of drugs and toxins.
The majority of drugs absorbed from the gastrointestinal tract are lipophilic and water-insoluble. They are rendered water-soluble via hepatic metabolism and thus, more easily excreted in the bile or renally filtered. Exogenous products are hepatically metabolized predominantly through two mechanisms: phase I and phase II reactions (figure 1) [42]. The subsequent products are then excreted via excretory transporters on either the canalicular or sinusoidal membranes (phase III reactions) [43].
Phase I reactions — Phase I reactions transform lipophilic molecules into more polar, hydrophilic molecules via oxidation, reduction, or hydrolysis. These reactions are catalyzed by the membrane-bound cytochrome P450 superfamily of mixed function oxidases (CYP) [44-47]. These hemoproteins are composed of an apoprotein and a heme prosthetic group (the oxidizing center).
Approximately 60 genes coding for CYP proteins have been identified in humans. These enzymes are organized into families (eg, CYP2) and subfamilies (eg, CYP2D), and further identified by the isoenzyme (eg, CYP2D6) [48,49]. The vast majority of these enzymes are located on the cytoplasmic side of the membrane of the endoplasmic reticulum (microsomal type) or the mitochondria (mitochondrial type) [48]. The microsomal type is responsible for phase I drug metabolism.
Hepatic metabolism of exogenous drugs and toxins is performed mainly by the CYP1, CYP2, and CYP3 families, with a smaller contribution from CYP4 [46,48,50,51]. Five isoenzymes are involved in 90 percent of all drug metabolism (CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2) [52,53]. The remaining families are often highly specific for the metabolism of endogenous compounds and are not inducible by exogenous compounds [48,54]. CYP3A is the major subfamily of hepatic CYP enzymes, and the most important drug metabolizing member is CYP3A4, comprising approximately 60 percent of all hepatic cytochromes and catalyzing the biotransformation of over 50 percent of commonly used drugs [48,55]. CYP2C9, 2C19, and 2D6 metabolize 37 percent of commonly used drugs [53]. Free radicals and toxic electrophilic compounds can be produced during this process. These reactive metabolites can then lead to cellular injury and are important to the development of idiosyncratic DILI [56,57].
CYP activity — Cytochrome activity varies considerably depending in part upon the concentration of the enzymes and the degree of induction by exogenous factors (table 1). (See 'Factors influencing drug metabolism and the risk of DILI' below.)
Factors that alter the activity of an enzyme have the potential to increase the toxicity of a compound (either by reducing its conversion to nontoxic metabolites or by increasing its conversion to toxic metabolites) or to decrease its therapeutic effectiveness (eg, by increasing the rate of metabolism of active drug).
In some cases, alternate detoxification routes may become overloaded, leading to the development of hepatotoxicity. This may in part explain why some drugs (such as acetaminophen) are not toxic in normal therapeutic doses but are toxic when increased amounts are ingested. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acetaminophen (paracetamol) poisoning: Management in adults and children".)
Phase II reactions — Phase II reactions occur either directly with a parent compound (rare) or with a metabolite formed by a phase I reaction that is still not adequately hydrophilic for excretion. These reactions conjugate the drug or metabolic byproducts to highly polar ligands such as glucuronate, sulfate, acetate, glycine, glutathione, or a methyl group (figure 1). As a general rule, phase II reactions result in the formation of readily excreted, nontoxic substances [42,50]. Phase II reactions occur predominantly within the hepatocyte cytoplasm via the uridine diphospho (UDP)-glucuronyl transferases (UGT), sulfotransferases, and glutathione S-transferases [58]. The UGT1 and UGT2 families are the most important in human glucuronidation [59]. Conjugation ordinarily leads to a decrease in pharmacologic activity with enhanced clearance of the compound (eg, acetaminophen, furosemide, and bilirubin), and these enzymes are rarely responsible for toxic metabolite formation. However, exceptions do occur [59], particularly with some cancer chemotherapeutic medications (eg, irinotecan). In some cases, conjugation leads to increased pharmacologic activity. For example, glucuronidation of morphine leads to increased analgesic potency and sulfation of minoxidil is required for its antihypertensive effect.
Phase III reactions — Phase III reactions lead to the transport of drugs and drug products across the canalicular membranes and into the bile. The biliary transporters are members of the adenosine triphosphate-binding cassette (ABC) superfamily and include multidrug resistant P-glycoprotein 1 (MDR1/ABCB1), MDR3 (ABCB4), multidrug resistant protein 2 (MRP2/ABCC2), and the bile salt export protein (BSEP/ABCB11) [60,61]. The predominant role of these transporters is that of regulation of bile formation and the excretion of xenobiotics [62]. Altered activity of these transporters may lead to hepatotoxicity [62-65].
Factors influencing drug metabolism and the risk of DILI — Several factors may alter the activity of any of these drug-metabolizing reactions and influence drug metabolism, contributing to hepatotoxicity [66]. These factors potentially alter the level of exposure to toxic drug products.
Genetics — Numerous genetic polymorphisms in the CYP isoenzymes, human leukocyte antigens (HLA) alleles, and other drug-processing enzymes have been identified and associated with DILI [46,54,67-76]. Genetic alterations may contribute to diminished metabolism, lack of metabolism, or excessive metabolism of a compound [77]. CYP polymorphisms have been shown to have five metabolic phenotypes: poor metabolizers, intermediate metabolizers, normal metabolizers, rapid metabolizers, and ultra-rapid metabolizers [78]. This has been particularly well studied in the alcohol-metabolizing CYP2E1 subfamily and in the CYP2D6 subfamily, which are responsible for the metabolism of drugs such as metoprolol, quinidine, and desipramine [1,79]. This genetic variability explains some of the individual hypersensitivity reactions to specific drugs.
Genetic polymorphisms in the phase II and the phase III enzymes also lead to both decreased and increased activity. This is seen in glutathione S-transferase, N-acetyltransferase 2, and UDP-glucuronosyltransferase B7, and has been associated with development of idiosyncratic DILI [59,80-86]. Certain genetic variations in the hepatobiliary transporters (BSEP, MDR3) may also predispose to drug-induced cholestasis or injury [62-64,87]. As an example, variable drug pharmacokinetics have been reported with digoxin and cyclosporine depending upon which genetic variant of the phase III hepatobiliary enzyme was present [60].
Another factor influencing the individual response to drugs is genetic polymorphisms of the major histocompatibility molecules (HLA), several of which have been identified [75,88-92]. Certain HLA types may favor presentation of the offending drug. As an example, a predominance of HLA-DR6 is seen in hepatitis caused by chlorpromazine, and a predominance of HLA-A11 is seen in hepatitis from tricyclic antidepressants [93]. In one study, patients with HLA B*5701 had an 80-fold increased risk of hepatotoxicity due to flucloxacillin [89]. There is a strong association of hepatotoxicity with HLA DRB1*07 and the use of ximelagatran. Multiple HLA haplotypes have been associated with amoxicillin-clavulanate-induced DILI (HLA-A*0201, HLA-B*1801, DRB1*1501, DRB5*0101, and DQB1*0602) [14,71,88,89,91,94,95]. HLA-A*3301 has been associated with all causes of DILI, particularly from terbinafine, fenofibrate, and ticlopidine [41,96]. Cholestatic DILI is more common in those with HLA DRB1*15 and HLA DQB1*06 [91,97,98].
Idiosyncratic DILI is most often immune-mediated [99-101]. The regulation of the immune response is genetically determined, which may play a role in an individual's susceptibility to hepatotoxicity. In addition, genetic alterations in the hepatocytes themselves may contribute to risk of injury [102].
Alcohol ingestion — The importance of alcohol in the development of DILI remains controversial [103-105]. Chronic alcohol ingestion increases CYP2E1 and CYP4A activity, an effect that lasts for up to 10 days following ingestion [103,106-110]. Alcohol also inhibits the rate of glutathione synthesis, leading to accelerated glutathione turnover, and it impairs mitochondrial transport of glutathione (with sequestration within the mitochondria) [103,106,111]. In a cohort study including 300 patients, any alcohol use within 12 months prior to the onset of DILI was a negative predictor of severe DILI [112]. Drugs that have been reported to have increased hepatotoxicity when associated with alcohol intake are acetaminophen, isoniazid, cocaine, methotrexate, and vitamin A [113].
Nutrition — Induction of CYP enzymes, particularly CYP1A2, has been observed with the ingestion of Brussels sprouts, cabbage, cruciferous vegetables (such as broccoli), and charcoal-broiled beef [48,114-116]. In contrast, grapefruit juice inhibits CYP3A activity, primarily acting on the intestinal form of the enzyme [117-119]. An excellent example is the interaction of grapefruit juice with the immunosuppressive agents cyclosporine or tacrolimus.
CYP activity may be increased by high-protein diets and reduced by low-protein diets and severe malnutrition [120-123]. Thus, states of severe malnutrition or chronic alcohol use disorder with poor nutrition may influence certain detoxifying cofactors such as glutathione.
Presence of other drugs — The concomitant use of two or more drugs may be one of the most important factors affecting components of the CYP system and influencing drug metabolism. A drug may act either as a cytochrome P450 inhibitor and slow another drug's metabolism, or it may induce CYP450 and enhance another drug's metabolism [48,53,124-126]. The adage that "alcohol and drugs do not mix" is based in part upon this phenomenon.
The list of drug interactions with the CYP system is vast. Even the aryl hydrocarbons in cigarette smoke can induce CYP1A2 [127]. Competitive inhibition of CYP can lead to clinically important drug interactions which are most pronounced when there is no alternative pathway for the metabolism of a potentially toxic drug or its metabolite. A striking example of this is the development of torsade de pointes during the administration of terfenadine or cisapride (both no longer available in the United States) to a patient taking a CYP3A4 inhibitor such as erythromycin or ketoconazole (table 1).
Drug-induced induction and inhibition of phase II enzymes are not uniformly seen [59]. However, reduced phase II reactions have been described with chlorpromazine and valproate use. There are many reports of both inhibition (eg, atorvastatin, carvedilol, clarithromycin, sertraline) and induction (eg, amiodarone, diltiazem, erythromycin, St. John's wort) of the phase III transporters [61]. These drug-drug interactions will significantly alter the transport and secretion activity of transport enzymes.
Patient demographics — An overall decrease in CYP activity has been reported to develop with increasing age [128-130]. Additionally, conjugation (phase II) reactions have been showed to be reduced in frail older adults, although this is not consistently seen [131].
It is therefore possible that older age increases the risk of developing DILI, but this is not uniformly supported by the data and appears to be drug-specific [11,12,97,132-134]. There still remain many interindividual differences that affect susceptibility, including genetic polymorphisms, biologic sex, volume of distribution, underlying liver disease, and nutritional status [134]. Older individuals do appear to have greater risk of toxicity from amoxicillin-clavulanate, isoniazid, and nitrofurantoin [12,135-137]. Older individuals are also more likely to develop cholestatic, rather than hepatocellular, DILI [12,97,132].
Infants may show considerable immaturity of the supply of drug-metabolizing CYP enzymes, which may be low to undetectable at birth and develop over time [138]. There are also major differences in the activity of the phase II enzymes in children when compared with adults [138]. Examples of medications that appear to have a greater risk of hepatotoxicity in children include acetylsalicylic acid and valproate [66]. There are no studies of the effects of aging on the hepatic phase III enzymes [129].
Women have been thought to be more susceptible to DILI than men [139]. Differences between men and women include a higher glucuronidation rate of acetaminophen in men and a greater expression of CYP3A4 in women [140,141]. Not all studies support a female preponderance and the increased susceptibility is most likely drug-specific. Drugs associated with DILI in woman include nitrofurantoin, erythromycin, flucloxacillin, minocycline, and isoniazid [96,142].
Racial differences in DILI presentation and prognosis have been reported. In one study of nearly 1000 patients with DILI, African American patients were more likely to have severe cutaneous reactions, severe liver injury, and worse outcomes (liver transplantation or liver-related death) compared with White patients [143]. This is attributed predominantly to variations in single nucleotide polymorphisms in different ethnic groups. A meta-analysis in patients treated for tuberculosis showed that in persons of East Asian and Middle Eastern descent, slow NAT2 genotype was associated with increased risk of DILI [144].
Underlying liver disease — Underlying liver disease and its role in DILI remains debated. Both acute and chronic liver diseases have a variable effect on the metabolism of many drugs [137,145]. Enzyme activities are generally reduced with increasing liver disease severity [145]. As a result, CYP activity may be increased (rare), unaltered, or in most cases reduced, or greatly reduced depending upon the severity of liver dysfunction [145,146]. The type of liver disease does not appear to be important. Reduction in the CYP activity leads to elevated plasma drug concentrations and increased risk of adverse drug reaction.
Phase II enzyme activity appears to be altered to a lesser degree [145,147,148]. The presence of cholestasis leads to decreased secretion (phase III) of both endogenous and exogenous substances [145]. This is seen not only in the setting of intrahepatic cholestasis but also secondary to biliary obstruction.
There has been considerable concern about the safety of statins in the setting of chronic liver disease. There are several trials that have confirmed their safety in this patient population [12,149-152]. However, there is more variation in serum levels of statins in the setting of cirrhosis; therefore, the drugs should be used more cautiously in this group [151]. (See "Statins: Actions, side effects, and administration", section on 'Chronic liver disease'.)
There is a growing body of evidence that nonalcohol-associated fatty liver disease may increase the risk or severity of DILI [153,154].
The data regarding the use of antituberculosis agents or antiretroviral agents used to treat HIV are more conflicting [66,149,150,155-157]. (See "Overview of antiretroviral agents used to treat HIV".)
Although patients with advanced liver disease are not generally felt to be at increased risk for all-cause DILI, those who develop DILI are more likely to have a worse outcome due to decreased functional hepatic reserve with mortality of 16 percent compared with 5.2 percent in those without chronic liver disease [11,12].
Dose — Liver damage from intrinsic hepatotoxins is clearly dose-related. While it has been thought that idiosyncratic DILI is dose-independent, this may not be entirely true [158-160]. There appears to be a threshold dose that may be necessary in most settings. Severe DILI rarely occurs from drugs taken at doses less than 10 mg, and drugs administered at daily doses of ≥50 mg are significantly more likely to cause DILI [25,66,97,99,126,160-165]. In addition, compounds are more likely to cause DILI if they are extensively hepatically metabolized when compared with drugs that have less extensive metabolism [160,161,166].
Drug lipophilicity — It has been shown that the lipophilicity of a drug/toxin is associated with increased risk for DILI [165,167]. The lipophilic nature of a drug affects its absorption, distribution, metabolism, and excretion. Medications at doses over 100 mg with high lipophilicity are significantly associated with severe DILI with an odds ratio of 14 [135,165,167].
MECHANISMS OF DRUG-INDUCED HEPATOTOXICITY — Drug-induced liver injury (DILI) is a complicated process involving the parent drug, its metabolites, and the host immune system [158]. Most hepatotoxic drug effects lead to hepatocyte necrosis or apoptosis and subsequent cell death. However, some drugs predominantly damage the bile ducts, biliary export proteins or bile canaliculi (cholestasis), vascular endothelial cells (sinusoidal obstruction syndrome), or the stellate cells. There may also be mixed patterns of injury (algorithm 1) [62,168-170]. (See "Drug-induced liver injury".)
Toxic hepatocellular injury may be classified by either clinical features (pattern of liver injury) or the underlying pathogenic mechanism (intrinsic hepatotoxins versus idiosyncratic reactions) (table 2). For the purposes of this review, we will use the pathogenic classification.
Direct Hepatotoxicity — Direct hepatotoxicity is caused by intrinsic hepatotoxins which reproducibly and predictably lead to dose-dependent hepatocellular necrosis ("toxic" hepatitis) in most mammalian species (algorithm 1). The latent period between the exposure and onset of hepatotoxicity is generally brief (ie, hours to a few days) and fairly consistent from person to person and among animal models. In addition to acute hepatitis, direct hepatotoxicity can lead to other forms of liver injury, including nodular regenerative hyperplasia, lactic acidosis and sinusoidal obstruction syndrome. (See "Drug-induced liver injury".)
In most instances, the drug itself or one of its active metabolites interacts with one or more cellular constituents (eg, proteins, lipids, DNA) to produce a sequence of events that often results in cell death [171]. Production of an active metabolite often yields free radicals, electrophilic radicals, or reactive oxygen species. Alternatively, covalent binding of the toxic metabolite to structures within the cell may interfere with their function or their regulation. These events may incite oxidative stress, glutathione depletion, redox changes, and/or lipid peroxidation, which may further affect cellular functions (eg, mitochondria, endoplasmic reticulum, cytoskeleton, etc) [43,172,173].
Drugs known to be intrinsically hepatotoxic are often removed from clinical use by regulatory agencies or fail to make it into the marketplace [30]. Examples include carbon tetrachloride, chloroform, and tannic acid [11]. However, some drugs with intrinsic hepatotoxic potential are still used clinically, either because they show hepatotoxicity only in large doses (eg, acetaminophen, niacin, iron sulfate), or because they show known dose-related toxicity (eg, ethanol, intravenous tetracycline, L-asparaginase, and phosphorus) [171]. Other direct hepatotoxins occur naturally, such as mushrooms (Amanita phalloides). (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acetaminophen (paracetamol) poisoning: Management in adults and children" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)
Acute hepatitis — The most common type of injury is acute hepatitis. Serum aminotransferases are typically 8 to 500 times normal. Serum alkaline phosphatase levels are only mildly elevated and jaundice is less common [113]. The risk of mortality is high in severe cases. Although hepatocellular damage may be the primary effect, some of these compounds can also damage other organs (especially the kidneys). (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Acute kidney injury (acute renal failure)'.)
The liver injury generally resolves when the drug is discontinued, or the dosage is decreased. Alternatively, adaptation can develop in which the injury resolves spontaneously despite continuation of the medication [174]. Severe cases will worsen despite drug discontinuation. This progression leads to acute liver failure, often necessitating liver transplantation [25,27].
Nodular regenerative hyperplasia — Nodular regenerative hyperplasia has been linked to chemotherapeutic agents and first-generation nucleoside antiretroviral agents. Its pathogenesis is poorly understood. However, it may be linked to chronic injury to the hepatic microvasculature [174].
Sinusoidal obstruction syndrome — Sinusoidal obstruction syndrome (SOS) was previously known as veno-occlusive disease. SOS develops following injury to the sinusoidal endothelial cells leading to extravasation of red cells and nonthrombotic obstruction of the sinusoids and central veins [175,176]. The most common drug-related cause of SOS is myeloablative-conditioning therapy in hematopoietic stem cell transplant. It can also be seen with immunosuppressive drugs (eg, azathioprine) or pyrrolizidine alkaloids [177].
Idiosyncratic hepatotoxicity — The majority of cases of DILI are related to idiosyncratic reactions (eg, amoxicillin-clavulanate, isoniazid, diclofenac, trimethoprim-sulfamethoxazole) [12]. These reactions occur in about 0.01 to 1 percent of individuals who are taking the drug (<1 to 100 of every 10,000 individuals exposed) [43,172,178]. Less than 1 percent of these drugs were associated with a predicted risk of developing DILI in preclinical or clinical trials [179]. The principal characteristic of this type of reaction is the apparent unpredictability of the liver injury in humans. The reactions tend to be species-specific and often cannot be reproduced experimentally in laboratory animals [172,173,178,180]. The latent period between exposure to the drug and the sensitivity reaction is highly variable; it may be one to three months, but reactions have been reported up to a year after starting the medication [101]. A threshold dose may be required. (See 'Dose' above.)
The individual's response to the drug/metabolite also contributes to the risk of DILI [165]. Although the parent compound may directly lead to idiosyncratic DILI, it is most often a toxic metabolite that is at fault [172,181]. Idiosyncratic drug toxicity may be either nonimmune (metabolic) or immune (allergic); however, overlap is believed to exist and leads to cellular injury [43,173,178].
In nonimmune injury, covalent binding of drug metabolites to cellular structures can incite cell death by interfering with protein/enzyme activity and disrupting critical cellular function. Immune-mediated idiosyncratic reactions depend upon a complex interaction of the drug and its metabolites with the host immune system, with resultant downstream effects that cause hepatocyte necrosis and/or apoptosis and unleash cytokines that can lead to secondary cell damage or have immune-modulating effects [43,100]. A comprehensive review of the biochemical and molecular mechanism of idiosyncratic DILI is beyond the scope of this review, and the reader is referred elsewhere [6].
Nonimmune — Nonimmune DILI is probably due to genetically determined aberrant metabolism of the drug in susceptible patients. The duration of exposure before the development of toxicity varies from weeks to one year, and reactions can develop several weeks after drug discontinuation. The injury may not recur or may recur many days to weeks after rechallenge. Features of an allergic or hypersensitivity reaction are absent. Drugs in this category include amiodarone, diclofenac, disulfiram, isoniazid, ketoconazole, troglitazone, and valproate. (See "Isoniazid hepatotoxicity" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)
Local accumulation of toxic metabolites (electrophilic species) results in covalent binding of the metabolite to cellular proteins, enzymes, lipids, and DNA. The hepatocyte undergoes significant oxidative stress, leading to redox changes and lipid peroxidation, which results in cellular necrosis [43,113]. As cellular stress worsens, the function of cellular structures such as mitochondria, receptor signaling, microtubules, and the endoplasmic reticulum is directly affected [172,173,182]. Drugs may also inhibit bile acid amidation and alter regulation of hepatic transporters (eg, bile salt export pump) that actively pump drug metabolites out of the hepatocytes [11,183,184]. This further increases the oxidative stress within the cell. Immunologic injury may play some role in metabolic DILI. Dead and dying hepatocytes can release endogenous damage-associated molecular patterns (DAMPs) [185]. DAMPs are recognized by the immune system, triggering or worsening sterile inflammation [185]. Neoantigens may also be formed by the reaction of the metabolite with the hepatocyte, leading to activation of the immune system [186].
Immune-mediated — Immune-mediated DILI is the least well understood form of DILI. It may be accompanied by clinical and histologic evidence of classic hypersensitivity. The duration of exposure is generally about one to eight weeks [172]. Rash, fever, joint pain and inflammation, lymphadenopathy, eosinophilic leukocytosis and, in severe cases, Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. However, these symptoms may be mild or absent. In some cases, the presentation may be similar to infectious mononucleosis (with atypical lymphocytes) (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis"). There is a prompt recurrence of symptoms in response to drug rechallenge of one or two doses [11,113,168]. This type of injury is believed to be a metabolite-initiated, immune-mediated attack on the liver [43]. Drugs that have been associated with this type of injury include amoxicillin-clavulanate, diclofenac, phenytoin, and allopurinol [142].
While cellular stress can activate an immune reaction to a drug, the drug can also directly lead to an immune response. The initial factor appears to be the modification of "self" proteins due to covalent binding of the active metabolite with host tissues (haptenization). These drug-protein products (adducts) can then cause direct toxicity or behave as neoantigens and trigger immune-mediated reactions [43,187]. The neoantigens are then presented by major histocompatibility complex class II, which leads to the activation of helper T-lymphocytes that subsequently recruit cytotoxic T-lymphocytes, natural killer cells, and B-cells [43,99,168,178,181]. Cytotoxic T-lymphocytes then mediate apoptosis via Fas ligand and granzyme B/porin [178]. The cells develop oxidative stress, which leads to the formation of reactive oxygen species that damage cellular DNA, proteins, and lipids [188]. This further induces immune-mediated liver damage. Mitochondrial dysfunction is seen and plays a pivotal role in the pathogenesis of DILI [164,170,188,189]. The drug or its reactive metabolite can also directly noncovalently bind to HLA alleles leading to immune system activation [190].
Haptenization alone does not appear to trigger immune-mediated responses, and the danger hypothesis has been proposed as an explanation for further injury. This hypothesis states that for the immune-mediated attack to develop, a second costimulatory factor must be present [99,191]. These factors appear to prime the immune system in susceptible individuals and may include infection or inflammatory conditions (eg, hepatitis B virus, hepatitis C virus, HIV infection), hepatocyte stress, or cellular damage (eg, DAMPs, heat shock proteins, S100 proteins) [43,185,192-194].
Neoantigens also prompt the development of autoantibodies against the cytochromes P450 (CYP), which can be identified in the serum, although it is unclear if these participate in the immune attack [43,172,187,195]. These autoantibodies are generally specific to the cytochrome that metabolizes the offending drug. The unique immunologic response of an individual to a drug and the specific T-cell receptor range may explain why hepatotoxicity occurs in some but not all individuals.
Both the innate/adaptive immune systems participate. Hepatocyte necrosis activates the innate system through proinflammatory mediators (eg, cytokines, chemokines, death signal pathways, etc) [187,196]. These mediators can be directly cytotoxic or lead to recruitment of cells of the innate immune system. The innate immune system may also have a role in recovery via anti-inflammatory components [43,187].
Idiosyncratic drug reactions of this type are becoming more frequently recognized, and the list of drugs implicated is sizable (eg, abacavir, nitrofurantoin, phenytoin, amoxicillin-clavulanate, dihydralazine, sulfonamides, minocycline, halothane, dapsone, diclofenac, carbamazepine, and sulindac) [11,197,198]. Liver biopsy often reveals eosinophilic or granulomatous inflammation of the liver with hepatocyte necrosis and cholestasis [199,200]. (See "Sulfonamide allergy in HIV-uninfected patients".)
Drug-induced autoimmune-like hepatitis — DILI can also present as an autoimmune-like hepatitis (DI-AIH) [142]. These patients generally have elevated levels of gamma globulins, antinuclear antibodies, and/or antismooth muscle antibodies. Drugs that have been associated with this pattern of injury include minocycline, nitrofurantoin, fluoroquinolones, and antitumor necrosis factor alpha inhibitors [201-204]. It can be difficult to differentiate DI-AIH from classic autoimmune hepatitis. However, it is imperative to distinguish DI-AIH from idiosyncratic DILI because DI-AIH responds to corticosteroid therapy. In addition, once it has resolved, there is no relapse after withdrawal of treatment [142]. This feature helps to differentiate it from classic AIH.
Indirect hepatotoxicity — Indirect hepatotoxicity has been proposed as a mechanism of drug injury in which the action of the drug leads to the hepatoxicity [174,205]. The drug induces or exacerbates liver disease. This type of injury is not dose-dependent and has a delayed latency (ie, generally months). The types of injury seen include fatty liver, acute hepatitis, immune-mediated hepatitis, and chronic hepatitis [174].
Examples of this would be the de novo development of fatty liver or its worsening with tamoxifen [206]. Glucocorticoids can lead to worsening of fatty liver secondary to their effect on insulin sensitivity. Antineoplastic agents can induce reactivation or worsening of viral hepatitis [207]. An immune-mediated response can be seen with tumor necrosis factor inhibitors, protein kinase inhibitors, and newer monoclonal antibodies (ie, checkpoint inhibitors) [203,208,209].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug-induced liver injury".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Drug-induced hepatitis (The Basics)")
SUMMARY
●Drug-induced liver injury (DILI) is a well-recognized problem and symptomatically can mimic acute and chronic liver diseases. Most patients with DILI will recover following withdrawal of the offending agent; however, in some cases, DILI can lead to liver transplantation or liver-related death. (See 'Epidemiology' above.)
●The liver is exposed to nearly all drugs absorbed from the intestinal tract and is the predominant site of drug metabolism. (See 'Role of the liver in drug metabolism' above.)
●Reactive drug metabolites, genetic susceptibility, and environmental factors all appear to play a role in development of DILI. (See 'Mechanisms of drug-induced hepatotoxicity' above.)
●Idiosyncratic hepatotoxicity is the most common type of DILI seen, accounting for >90 percent of cases. However, our understanding of the pathogenesis of DILI remains incomplete. (See 'Idiosyncratic hepatotoxicity' above.)
●A searchable database of drugs, herbal medications, and dietary supplements has been developed by the National Institutes of Health (NIH).
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