Immunoallergic Drug-Induced Liver Injury in Humans

• ABSTRACT
• INVOVLEMENT OF THE IMMUNE SYSTEM IN IDIOSYNCRATIC DRUG REACTIONS
• Immune Idiosyncrasy versus Metabolic Idiosyncrasy
• CLINICAL CHARACTERISTICS OF DILI
• Time to Onset
• Time Required for Resolution of DILI
• Response to Rechallenge
• Variability in the Clinical Picture
• Interpretation of Clues Provided by Human Cases of DILI
• Commonality in the Drugs that Cause DILI and Autoimmunity
• POSSIBLE MECHANISMS FOR DRUGS CAUSING BOTH DILI AND AUTOIMMUNITY
• SUMMARY AND CONCLUSIONS
• i ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

No conclusive data exist that define the mechanisms of idiosyncratic drug-induced liver injury (DILI) in humans; therefore, we are forced to speculate based on their clinical characteristics. The major characteristics are most easily explained by an immune mechanism. Many cases of idiosyncratic DILI tend to have a longer delay in onset and sometimes do not occur rapidly on rechallenge. These instances of DILI have been attributed to metabolic idiosyncrasy. However, these characteristics may also reflect an autoimmune mechanism, and most drugs that cause idiosyncratic DILI are also associated with various types of other autoimmune reactions. A characteristic feature of the immune system is that different individuals respond differently to the same immunogen. In some cases, a drug can induce an immune response to a reactive metabolite acting as a hapten; in others, the response is against a native protein, which leads to an autoimmune reaction. This is likely responsible for the interindividual differences in susceptibility and outcome noted in human DILI.

Drugs have overtaken viral hepatitis as the leading cause of acute liver failure in the developed world.[1] Among drugs, acetaminophen is the most common cause of acute liver failure. In principle, acetaminophen-induced liver failure can be prevented because it is limited to cases of overdose, although recent studies suggest that even therapeutic doses of acetaminophen can cause mild drug-induced liver injury (DILI).[2] Most other cases of DILI are idiosyncratic in nature. These adverse reactions are currently impossible to predict or prevent, and idiosyncratic DILI causes more cases of drug withdrawal than any other type of idiosyncratic drug reaction. Although there are several hypotheses—all of which are difficult to study—for the mechanisms of idiosyncratic DILI, little definitive evidence exists that supports any hypothesis. Circumstantial evidence supports the hypothesis that most DILI is caused by reactive metabolites rather than by the parent drug[3] [4]; however, likely exceptions to the theory include ximelagatran and liver injury caused by biologicals such as interferons. The liver's very high capacity to metabolize drugs is presumably why it is a common target of idiosyncratic drug reactions. The characteristics of idiosyncratic DILI also suggest that most cases are immune-mediated; however, in general, the evidence is not definitive and not everyone accepts this hypothesis. Nonetheless, to deal effectively with idiosyncratic DILI, a clear mechanistic understanding is required.

INVOVLEMENT OF THE IMMUNE SYSTEM IN IDIOSYNCRATIC DRUG REACTIONS

Drug-induced liver injury is just one of many different types of idiosyncratic drug reactions that can involve virtually any organ. Most idiosyncratic drug reactions appear to be immune-mediated. By definition, the autoimmunity that resembles lupus and is caused by drugs such as procainamide and hydralazine is immune-mediated. Certainly, the immunoglobulin (Ig) E-mediated skin rashes caused by penicillin are immune-mediated, as demonstrated by skin tests in which IgE antibodies react with a synthetic polymer of penicillin bound to lysine. Most other drug-induced skin rashes are also immune-mediated.[5] [6] Drug-induced generalized hypersensitivity reactions, such as those caused by abacavir, involve several organs, including skin, liver, and bone marrow; they also appear to be immune-mediated based on characteristics such as a very rapid onset on rechallenge and major histocompatibility complex (MHC) dependence.[7] Most idiosyncratic hematological adverse reactions (e.g., heparin-induced thrombocytopenia[8] and α-methyldopa-induced hemolytic anemia)[9] are also immune-mediated. Involvement of the immune system in drug-induced aplastic anemia is a bit less certain. Its involvement, whether it is drug-induced or idiopathic, is strongly suggested, however, because aplastic anemia usually responds to immunosuppression and because specific cytotoxic T cells have been described with aplastic anemia.[10] The one idiosyncratic drug reaction for which involvement of the immune system is most hotly debated is DILI.[11]

Immune Idiosyncrasy versus Metabolic Idiosyncrasy

In some cases, such as halothane and tienilic acid hepatotoxicity, the presence of antidrug antibodies has led most people to believe that these idiosyncratic reactions are immune-mediated[12]; however, there is no evidence that these antibodies are pathogenic—they probably are not, although they may contribute to the liver injury—and not everyone is convinced that DILI caused by these drugs is immune-mediated. The liver injury caused by other drugs, including isoniazid and ketoconazole, has specifically been referred to as a “metabolic” idiosyncrasy as opposed to an immune idiosyncrasy.[12] However, although having low N-acetyltransferase activity confers an increased risk of isoniazid-induced liver injury,[13] the relative risk is much too small to explain the idiosyncratic nature of DILI caused by this drug. Even adding polymorphisms in cytochrome P450 (CYP)2E1 and glutathione transferases is insufficient to explain the idiosyncratic nature of isoniazid-induced liver injury. Furthermore, there are no examples that I know of where polymorphisms in drug-metabolizing pathways have been shown to explain the idiosyncratic nature of DILI. We simply do not have a clear mechanistic understanding of any DILI. Nonetheless, the clinical characteristics of idiosyncratic DILI cases can provide important clues to the pathogenic mechanisms involved.

CLINICAL CHARACTERISTICS OF DILI

Several characteristics are common to most DILI cases; however, these characteristics vary significantly from one drug to another and even from one patient to another for the same drug, as in the case of minocycline. Minocycline treatment is associated with two types of DILI: one occurs after a relatively short period of treatment (<35 days) and is associated with signs of hypersensitivity such as eosinophilia and skin rash; the other occurs after a long period of therapy (>1 year) and is associated with evidence of autoimmunity such as autoantibodies, arthritis, and histology consistent with autoimmune hepatitis.[14] Such differences in characteristics imply that there are differences in the mechanisms of DILI among drugs and even among patients that experience hepatotoxicity from the same drug. The defining characteristic of idiosyncratic DILI is its unpredictable nature—most patients do not develop liver injury when treated with a specific drug at any dose within the therapeutic range. Furthermore, we have not been able to develop animal models simply by treating animals with high doses of drugs that are associated with a relatively high incidence of DILI in humans. However, in contrast to the way it is often characterized, idiosyncratic DILI is not dose independent. Although the incidences of idiosyncratic DILI may not vary significantly within the therapeutic range of a drug, it is axiomatic that there will always be a dose below which no one will develop DILI.[15] In fact, with some drugs (e.g., pyrazinamide), the incidence of DILI does increase with a dose that is within the therapeutic range.[16]

The idiosyncratic nature of DILI is most easily explained by an immune mechanism. A characteristic feature of “allergy” is that some people are sensitive to a specific allergen and others are not. Most people react to some highly allergenic agents, such as 2,4-dinitrochlorobenzene, whereas some agents only rarely result in an immune response. Other possible explanations for the idiosyncratic nature of DILI include polymorphisms in a metabolic pathway leading to a reactive metabolite and detoxication of a reactive metabolite. However, as stated previously, no polymorphism has been found that explains the idiosyncratic nature of DILI. Specific human leukocyte antigen (HLA) genotypes are associated with the liver injury caused by amoxicillin/clavulanic acid and ximelagatran,[17] which suggests that they are immune-mediated, but data are limited, and there is no evidence that most idiosyncratic DILI is associated with a specific HLA genotype.[18] Other factors could also play a role.

It has been stated that preexisting liver disease is not a risk factor for idiosyncratic DILI,[12] and in the main that appears to be true, although some examples show that viral hepatitis appears to increase the risk of DILI.[19] However, it is also true that most patients who develop DILI do not have preexisting liver disease. Another hypothesis is that chance exposure to an inflammatory event during therapy with a drug is the factor that makes DILI idiosyncratic, not by helping to initiate an adaptive immune response but by potentiation of direct cytotoxicity or an innate immune mechanism.[11] However, in my opinion this does not fit the characteristics of most DILI, and the liver damage in the animal model is more likely to involve a combination of lipopolysaccharide (LPS) toxicity and drug/LPS-induced hepatic ischemia.

Time to Onset

Another important characteristic of idiosyncratic DILI is the time to onset. The typical time between starting a drug and the onset of DILI is ∼1 to 3 months; however, that time frame significantly varies among drugs and patients. This time to onset is similar to that of other idiosyncratic drug reactions, although most mild skin rashes have a bit shorter time to onset, and drug-induced autoimmunity usually occurs after a longer period of treatment. This delay in onset is consistent with an immune mechanism because it takes time for the few lymphocytes that recognize a specific immunogen to expand to sufficient numbers to produce a clinically evident response. It is likely that autoimmune reactions take more time to develop because high-affinity T cells for autoantigens are deleted in the thymus.

An exception to the typical time to onset is telithromycin-induced liver injury. In recent reports, the time to onset of telithromycin hepatotoxicity was very short, with some patients developing liver failure within 3 days.[20] Some cases of liver failure associated with ciprofloxacin also appear to have a very short time to onset.[21] This is incompatible with the development of an adaptive immune response to an agent on first exposure and suggests that the mechanism involves a direct cytotoxic mechanism similar to that induced by acetaminophen. If that is the case, the basis for the idiosyncratic nature of telithromycin is hard to explain. There are rare examples of preexisting immune sensitivity to an agent because of cross-reactivity to some other agent. An example is the acute thrombocytopenia that occurs on first exposure to eptifibatide and tirofiban, which is mediated by preexisting antibodies to the drugs.[22] It is possible that a similar mechanism is involved in telithromycin-induced liver injury, but there is no evidence to support this hypothesis.

At the other extreme is the autoimmune DILI associated with minocycline in which more than a year of minocycline treatment is usually required to induce liver injury.[14] Given the autoimmune features of minocycline-induced liver injury, including classic antinuclear autoantibodies, it is reasonable to conclude that this is an example of immune-mediated DILI. Many cases of DILI associated with nitrofurantoin also appear to have features of autoimmunity.[23] Minocycline is also associated with a more generalized type of autoimmunity that resembles lupus without significant liver involvement.[24] As previously mentioned, a long time to onset appears to be a characteristic of drug-induced autoimmunity, and the lupus-like syndrome caused by procainamide and hydralazine often require more than a year of treatment before the syndrome becomes clinically evident.[25]

The drugs causing liver injury that have been classified as metabolic idiosyncrasy are isoniazid, pyrazinamide, ketoconazole, troglitazone, and others. These often have to be given for a long time before the onset of liver damage, but the range of time to onset appears to be broader than for drugs that cause immune idiosyncrasy. One possible explanation for the wide range in time to onset with these drugs is that the mechanism can vary analogous to the differences observed with minocycline. In general, patients with a long delay in the onset of DILI have a poorer prognosis.[26] [27]

Time Required for Resolution of DILI

With most cases of DILI, the patient recovers rapidly when the drug is stopped. However, in some cases the liver damage continues for a week or more after the drug has been discontinued, and these cases usually have a poor prognosis. A possible explanation for the continuation of liver damage after the drug has been stopped is that the mechanism involves an autoimmune component, which could continue in the absence of the inciting drug. In addition, it was recently observed that several patients treated with ximelagatran had normal serum alanine aminotransferase (ALT) levels when the drug was stopped, but a month later they had an increase in ALT; in two cases this was associated with clinical symptoms of liver damage.[28] This is difficult to explain, but it is possible that it is the result of an autoimmune mechanism that was initiated by the drug and continued to develop even after the drug was discontinued. In the past, it was claimed that chloramphenicol-induced aplastic anemia often occurred more than a month after the drug was stopped, and the longer the time period between stopping the chloramphenicol and the onset of aplastic anemia, the worse the prognosis.[29] Aplastic anemia appears to represent an autoimmune reaction.[30] This may be a feature of several types of idiosyncratic drug reactions that has not received notice.

Response to Rechallenge

One important characteristic of most immune responses is an amnestic response on rechallenge. The amnestic response is mediated by memory T and B cells, which lead to a much shorter time to onset and often a more severe reaction. However, not all immune-mediated reactions are associated with an amnestic response. We noticed that the autoimmune syndrome that resembles lupus induced by penicillamine in Brown Norway rats or induced by propylthiouracil in cats does not occur more rapidly on rechallenge.[31] This may be a feature of autoimmune reactions. When procainamide is stopped because a patient has developed procainamide-induced lupus, the clinical manifestations of autoimmunity usually, although not always, resolve rapidly. By definition, in an autoimmune reaction, the autoantigen such as histone protein remains. This means that that the autoreactive T and/or B cells must be deleted or anergized, which would also eliminate immune memory. However, lack of immune memory is not universal for autoimmune reactions, and rechallenge with a drug that has induced autoimmunity can lead to a rapid return in symptoms of autoimmunity.[32]

A clinical example of an immune-mediated idiosyncratic drug reaction that is not associated with an amnestic response is heparin-induced antibody-mediated thrombocytopenia. When the heparin is stopped and after the pathogenic antibodies are no longer detectable, if heparin is restarted, there is usually no recurrence of thrombocytopenia. If it does recur, the time to onset is not shorter.[33] It is not clear to what degree this is an autoimmune reaction, but the pathogenic antibodies are specific for the heparin-platelet factor 4 complex, and both of these molecules are endogenous.

In the case of idiosyncratic DILI, rechallenge data are sparse. However, many isolated reports show that inadvertent rechallenge occurred and resulted in very rapid onset of DILI; this strongly suggests an immune mechanism. In the case of halothane-induced liver injury, idiosyncratic DILI usually occurs only after multiple exposures, presumably because the duration of exposure is brief.[12] This is likely to be an example of an amnestic immune response, especially because the time to DILI onset in these cases is very short. It was recently found that ximelagatran-induced liver injury did not usually recur on inadvertent rechallenge even though it appears to be an immune-mediated reaction associated with specific MHC II genotypes.[28]

In contrast to other drugs, rechallenge to isoniazid is common because there are not many options for the treatment of tuberculosis. The response to isoniazid rechallenge is quite variable. In one series of patients, one patient developed fever and a 10-fold increase in serum aspartate aminotransferase (AST) levels 4 hours after a single rechallenge dose of isoniazid.[34] This amnestic response strongly supports an immune mechanism. However, another patient in the same series was treated for 1 month with isoniazid before recurrence of DILI. In some cases, DILI does not recur on isoniazid rechallenge, and it is usually possible to use isoniazid in a patient with a past history of isoniazid-induced liver injury by using an escalating dose protocol.[35] It is also possible that some cases of isoniazid-induced hepatotoxicity involve direct cytotoxicity, whereas others are immune-mediated; however, an alternative explanation for this variable response to rechallenge is that it is based on a variable degree of the autoimmune component in the mechanism of isoniazid-induced liver injury.

Variability in the Clinical Picture

As discussed previously, the characteristics of idiosyncratic DILI vary from drug to drug and even among different patients given the same drug, which suggests differences in the mechanism in different patients. Furthermore, the same drug can cause totally different types of idiosyncratic drug reactions in different people. For example, felbamate can cause DILI in one patient and aplastic anemia in another.[36] Presumably, the same reactive metabolite, atropaldehyde, is responsible for both. If these idiosyncratic drug reactions are immune-mediated, and the reactive metabolite binds both in the liver and bone marrow, once immune tolerance has been breached, why would the immune response be limited to the liver in one patient and the bone marrow in another? Even if the idiosyncratic reactions were not immune-mediated, it is hard to understand why an adverse reaction would be limited to one organ in one patient and to another organ in another patient; this is not a feature of other types of toxicity. A likely explanation is that the immune response is not simply against the drug but includes components of the tissue-specific proteins involved (Fig. [1]). For example, halothane-induced liver injury is associated with the antibodies. Some of these antibodies are directed against trifluoroacetylated proteins, which are derived from the reactive metabolite of halothane, but others are pure autoantibodies that recognize native proteins.[37] [38] In addition, the protein specificity of the antibodies also varies from patient to patient: In one case, a major protein target can be CYP2E1; in another, the major protein target of the host immune system response is disulfide isomerase.

Even in the case of antibodies against reactive metabolite-modified protein, some are specific for the hapten portion of the molecule, whereas in others the protein makes up a significant portion of the epitope recognized by the antibody (Fig. [1]). The actual liver damage caused by halothane is more likely to be cell-mediated rather than antibody-mediated, although most immune responses involve multiple arms of the immune system. However, the presence of antibodies indicates activation of the immune system, and the specificity of the antibodies provides clues as to what the immune system is responding to. It suggests that the protein that is modified is important to the immune response, and the response can be different in different people.

The ability of the immune system to generate a very large number of T-cell receptors is achieved by random gene rearrangement; therefore, the repertoire of T-cell receptors is different for different individuals, even for identical twins. Thus, the specificity of the immune response may depend on the T-cell receptor repertoire in an individual, and this can lead to different types of immune responses with resultant differences in the features of the idiosyncratic reaction. If, by chance, the T-cell receptor that has the strongest affinity recognizes drug-modified or normal liver proteins, the patient will develop DILI. If, however, the strongest affinity is for drug-modified or normal proteins found in bone marrow precursor cells, the patient will develop aplastic anemia. If the major immune response is against the drug portion of the modified hepatic protein, the DILI episode will have more typical immune features, whereas if the major response is against a native hepatic protein, the DILI episode will have significant autoimmune characteristics that could lead to a mistaken classification of metabolic idiosyncrasy (Fig. [1]). The polymorphic response of the immune system is essential to our survival as a species because it means that even if a pathogen can kill some people, it will not kill everyone due to the interindividual differences in immune response.

Interpretation of Clues Provided by Human Cases of DILI

Although it is certainly open to debate, a plausible interpretation of the characteristics of idiosyncratic DILI is that most cases are immune-mediated and some have a significant autoimmune component. If a drug can cause idiosyncratic acute liver failure, the number of patients that develop an increase in serum ALT >3 times the upper limit of normal is much higher than those that develop liver failure, but the time course for this type of injury is similar to that of more severe toxicity. In most cases, the serum ALT returns to normal despite continued treatment with the drug. This is referred to as adaptation,[39] and an obvious question is what determines which patients adapt and which develop significant toxicity. A reasonable hypothesis for the mechanism of adaptation is immune tolerance, especially given the propensity of an immune response in the liver to result in immune tolerance.[40] As discussed in the previous section, in one patient a reactive metabolite may induce an immune response to a hepatic protein and cause DILI, whereas in another patient the same reactive metabolite may lead to an immune response to a different protein and result in an idiosyncratic reaction involving a different target organ. Furthermore, using the earlier example of isoniazid, the DILI event may occur relatively early (and occur very rapidly on rechallenge) in one patient, indicating a more typical adaptive immune response, and in another patient it may occur later, not have immune memory, and have a significant autoimmune component (Fig. [1]).

Even if many cases of DILI have a significant autoimmune component, the characteristics are usually not those of typical autoimmune hepatitis; they lack elevated levels of gamma globulin and the usual autoantibodies, which are: antinuclear antibodies, anti-smooth muscle antibody for type I autoimmune hepatitis, and anti-liver/kidney microsome-1 antibodies for type II autoimmune hepatitis.[41] However, no absolute diagnostic criteria for autoimmune hepatitis are known, and many cases of idiopathic autoimmune hepatitis do not fit a typical pattern.

Commonality in the Drugs that Cause DILI and Autoimmunity

It is striking that many, if not most, of the drugs that cause DILI are also associated with a relatively high incidence of autoimmune syndromes such as lupus-like syndrome, autoimmune hemolytic anemia, vasculitis, and autoimmune hepatitis (Table [1]). Many are also associated with agranulocytosis. A stark exception is procainamide, which is associated with a high incidence of a lupus-like autoimmune syndrome[25] as well as agranulocytosis, but is infrequently associated with DILI.[42] Conversely, some drugs associated with DILI are not associated with a significant incidence of autoimmunity. A good example is ketoconazole.[43] Other drugs that cause DILI but not autoimmunity include halothane, troglitazone, bromfenac, trovafloxacin, and telithromycin; however, these drugs may not have been on the market long enough or the usual duration of therapy may have been insufficient to detect their ability to cause autoimmunity. Nevirapine and felbamate cause other types of idiosyncratic drug reactions in addition to DILI that appear to be immune-mediated—in the case of nevirapine, severe skin rashes, and in the case of felbamate, aplastic anemia. This commonality between the drugs that cause idiosyncratic DILI and autoimmunity is consistent with the hypothesis that some DILI has an autoimmune component.

POSSIBLE MECHANISMS FOR DRUGS CAUSING BOTH DILI AND AUTOIMMUNITY

It is reasonable to assume that if a reactive metabolite is responsible for idiosyncratic DILI, in most cases it would be formed in the liver. The most common source of reactive metabolites is CYP, and some DILI—such as that associated with tienilic acid, dihydralazine, carbamazepine, and halothane—is associated with antibodies against the CYP that formed the reactive metabolite—CYP2C9, CYP1A2, CYP3A4, and CYP2E1, respectively.[81] However, we have shown that several of the drugs that cause autoimmunity are oxidized to reactive metabolites by the myeloperoxidase system in neutrophils and macrophages, including Kupffer cells.[82] In addition, perinuclear antineutrophil cytoplasmic antibodies, some of which are specific for myeloperoxidase, are found in many autoimmune diseases.[83] In the absence of inflammation, activation of CD8 T cells in the liver leads to their early death and tolerance to the antigen involved.[84]

It is possible that the formation of reactive metabolites by Kupffer cells, leading to their activation, could help to overcome immune tolerance. It has also been proposed that activation of T cells in lymph nodes outside the liver is usually required to achieve an effective immune response in the liver[84]; therefore, the ability of a drug to be activated by myeloperoxidase in macrophages outside of the liver may also play a role in the ability of that drug to cause DILI. This ability could also lead to the induction of an autoimmune response or agranulocytosis. An important question is by what mechanism does a drug induce autoimmunity. The answer is unknown, but there are several possibilities. One possibility is that the drug or reactive metabolite causes cell damage that activates the immune system—the danger hypothesis.[85] Activation of macrophages by macrophage-generated reactive metabolites and inhibition of DNA methylation are other possible mechanisms.[86]

We have tried to develop animal models of idiosyncratic DILI by treating rats or mice with drugs such as isoniazid, nevirapine, amodiaquine, minocycline, and felbamate along with agents to decrease detoxication of reactive metabolites (buthionine sulfoximine) and agents to stimulate the immune system, such as polyinosinic:polycytidylic acid (poly I:C) and LPS. Even when we are able to induce an increase in serum ALT, the levels revert to normal despite continued treatment. It appears that we are just not able to overcome immune tolerance, which is the dominant immune response in the liver.

The development of an animal model of autoimmune hepatitis has proved to be difficult.[87] Penicillamine-induced autoimmunity in the Brown Norway rat is similar to lupus but includes hepatic necrosis as one manifestation.[88] In preliminary experiments, we have found that there is an increase in T helper type 17 (Th₁₇) cells in ∼50% of animals that develop autoimmunity (unpublished observation). The Th₁₇ cells are a “new” type of helper T cell that has been shown to be an important element in the pathogenesis of various autoimmune diseases.[89] A characteristic cytokine produced by Th₁₇ cells is interleukin (IL)-17, and the production of Th₁₇ cells is promoted by IL-6.[90]

We performed a study of serum levels of IL-17 in patients with drug-induced liver failure to determine if some patients had evidence of Th₁₇-mediated autoimmunity. We found that most of the patients with idiosyncratic drug-induced liver failure did have elevated levels of IL-6 and IL-17; however, many of the patients with acetaminophen-induced liver failure also had elevated levels of IL-6 and IL-17 (unpublished observation). It is unlikely, given the acute nature of acetaminophen-induced liver failure, that it is mediated by the adaptive immune system, and more recently it was found that IL-17 production is not unique to Th₁₇ cells. Interleukin 17 is also produced by γδ-T cells, natural killer (NK) cells, NKT cells, and macrophages,[91] one or more of which is presumably the source of IL-17 in acetaminophen-induced liver failure. Therefore, serum IL-17 levels cannot be used as a marker for Th₁₇ cells and autoimmunity. If the hypothesis that Th₁₇ cells are involved in some cases of DILI is correct, a more specific method will be required to demonstrate the activation of Th₁₇ cells, such as double staining of lymphocytes for CD4 and IL-17.

SUMMARY AND CONCLUSIONS

The characteristics of idiosyncratic DILI suggest that most, if not virtually all, are immune-mediated; however, without definitive evidence or a clear mechanistic understanding, this hypothesis is open to dispute. The immune response is polymorphic and complex: Each individual has a somewhat different immune response to an immunogen, both in terms of what part of the immunogen is recognized and which mix of immune cells are involved in the response. The lack of fever, rash, eosinophilia, or other classic features of an “allergic” reaction does not represent significant evidence against an immune-mediated reaction. The lack of immune memory (i.e., lack of a rapid response on rechallenge) does not prove that a specific reaction is not immune-mediated because several immune-mediated reactions also lack immune memory. The presence of a very rapid response on rechallenge, however, does argue for an immune-mediated reaction.

The differences in the characteristics of DILI from patient to patient are what would be expected from an immune mechanism. At present, no clear data indicate which cells are responsible for DILI, and, in general, immune responses involve multiple types of cells and mediators acting as part of a complex network. Some of the characteristics that have led to cases of idiosyncratic DILI being classified as “metabolic idiosyncrasy” may be due to an autoimmune component. Testing this hypothesis has significant implications for the treatment of DILI and also for the prediction of which drug candidates are likely to cause an unacceptable incidence of DILI.

ACKNOWLEDGMENTS

The author holds the Canada Research Chair in Adverse Drug Reactions. The work is supported by grants from the Canadian Institutes of Health Research.

ABBREVIATIONS

• ALT alanine aminotransferase

• AST aspartate aminotransferase

• CYP cytochrome P450

• DILI drug-induced liver injury

• HLA human leukocyte antigen

• Ig immunoglobulin

• IL interleukin

• LPS lipopolysaccharide

• MHC major histocompatibility complex

• NK natural killer (cells)

• NKT natural killer T (cells)

• poly I:C polyinosinic:polycytidylic acid

• Th₁₇ T helper type 17 (cells)

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Jack UetrechtM.D. Ph.D. 

Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto

Ontario, Canada M5S 3M2

Email: jack.uetrecht@utoronto.ca

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Jack UetrechtM.D. Ph.D. 

Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto

Ontario, Canada M5S 3M2

Email: jack.uetrecht@utoronto.ca