Drug induced liver injury and its relationship to autoimmune hepatitis

Recurrent Drug-Induced Liver Injury (DILI) with different drugs in the Spanish Registry: The dilemma of the relationship to autoimmune hepatitisJournal of HepatologyVol. 55Issue 4PreviewMultiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs. Full-Text PDF Drug-induced liver injury (DILI) is a leading cause of acute liver failure [[1]Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar] and is of major importance to the pharmaceutical industry, as it is the most frequent reason for withdrawal of substances from the market. More than 1000 different drugs and herbal remedies have been described to cause DILI. Some drugs cause a dose-dependent toxicity which can be anticipated – a well known example is acetaminophen. The vast majority of DILI cases cannot be foreseen and are, therefore, termed idiosyncratic. Oxidative stress, reactive metabolites, mitochondrial toxicity, modulation of drug metabolizing transporters, induction of apoptosis or necrosis, as well as immunoallergic reactions to protein adducts may all be involved in DILI, but for most of the drugs the specific mechanisms contributing to DILI are unknown [[2]Kaplowitz N. Idiosyncratic drug hepatotoxicity.Nat Rev Drug Discov. 2005; 4: 489-499Crossref PubMed Scopus (856) Google Scholar]. A classification of hepatocellular, mixed or cholestatic liver injury is used in the clinic to describe damage and severity of liver injury but its value in predicting the outcome of DILI is unclear. DILI can range from asymptomatic elevation of liver enzymes to fulminant hepatic failure [[1]Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar]. Its over-all mortality depends on the drug used, the timely detection of DILI including the appropriate action taken, as well as individual cofactors and comorbidities such as the presence of diabetes mellitus [[3]El-Serag H.B. Everhart J.E. Diabetes increases the risk of acute hepatic failure.Gastroenterology. 2002; 122: 1822-1828Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar]. Mortality rates of approximately 10% [[1]Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar] have been reported but may be highly overestimated since most mild drug reactions will not be registered. In most patients, DILI leads to a complete recovery. However, up to 1% of all patients with DILI may develop liver cirrhosis subsequently [[4]Bjornsson E. Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.J Hepatol. 2009; 50: 511-517Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar].DILI is a rare event with an estimated incidence of 1 per 10,000 to 1 per 100,000 treated patients [[5]Bjornsson E. Review article: drug-induced liver injury in clinical practice.Aliment Pharmacol Ther. 2010; 32: 3-13PubMed Google Scholar]. Some risk factors have been identified: the daily amount of the drug causing the reaction (intake of >50 mg daily increases risk), a predominantly hepatic metabolism of the drug (>50%) [[6]Lammert C. Bjornsson E. Niklasson A. Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events.Hepatology. 2010; 51: 615-620Crossref PubMed Scopus (201) Google Scholar], and mitochondrial dysfunction that may be the underlying cause of the increased risk of DILI in diabetes patients [[7]Boelsterli U.A. Lim P.L. Mitochondrial abnormalities – a link to idiosyncratic drug hepatotoxicity?.Toxicol Appl Pharmacol. 2007; 220: 92-107Crossref PubMed Scopus (178) Google Scholar]. Genetic polymorphisms within genes relevant to drug metabolism [[8]Lucena M.I. Andrade R.J. Martinez C. Ulzurrun E. Garcia-Martin E. Borraz Y. et al.Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.Hepatology. 2008; 48: 588-596Crossref PubMed Scopus (164) Google Scholar] are being identified and may be used to stratify the risk of DILI to certain drugs in the future.A question relevant to daily clinical practice is, if re-exposure to the same or to other drugs may cause a second DILI episode. Re-exposure to the same drug generally should be avoided due to the considerable mortality rate reported after re-exposure to drugs such as halothane (up to 50% due to a combination of mitochondrial and immune-mediated injury) [[9]Hunt C.M. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: a systematic review.Hepatology. 2010; 52: 2216-2222Crossref PubMed Scopus (28) Google Scholar]. Nonetheless, for drugs that are urgently needed in case of life threatening disease, such as in tuberculosis, careful re-exposure can be undertaken after the resolution of the first DILI episode with acceptable risk [[10]Sharma S.K. Singla R. Sarda P. Mohan A. Makharia G. Jayaswal A. et al.Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity.Clin Infect Dis. 2010; 50: 833-839Crossref PubMed Scopus (121) Google Scholar]. The risk of re-exposure to a different drug that may belong to the same class of drugs or be completely unrelated is not well studied. To this end, the study presented by Lucena et al. in this issue adds valuable and reassuring information [[11]Lucena M.I. Kaplowitz L. Hallal H. Castiella A. Garcia-Bengoecha M. Otazua P. et al.Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish registry.The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011; 55: 70-77Google Scholar]. In this study, the Spanish DILI registry of patients with probable or highly probable idiosyncratic DILI was searched for patients who suffered from a second DILI episode. Only a small number of patients (9 patients, 1.21%) from the cohort of patients with prior DILI developed a second episode of liver injury and none of the patients’ required liver transplantation or had a fatal outcome. Of particular interest, the majority of patients (8 out of 9) experiencing a second DILI episode had a similar (hepatocellular) damage pattern. The drugs responsible for the second DILI episode were structurally related to the drug of the first DILI episode in 4 out of 9 cases and, in 2 cases, the target of the drug was the same. This may point toward an immune-mediated drug injury directed against similar protein adducts forming haptens. Indeed, 4 out of the 9 patients (44%) were diagnosed with so called “autoimmune (AIH) DILI” since these patients fulfilled the criteria for probable or definite AIH, according to the revised and simplified score of the international autoimmune hepatitis study group [12Alvarez F. Berg P.A. Bianchi F.B. Bianchi L. Burroughs A.K. Cancado E.L. et al.International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis.J Hepatol. 1999; 31: 929-938Abstract Full Text Full Text PDF PubMed Scopus (2436) Google Scholar, 13Hennes E.M. Zeniya M. Czaja A.J. Pares A. Dalekos G.N. Krawitt E.L. et al.Simplified criteria for the diagnosis of autoimmune hepatitis.Hepatology. 2008; 48: 169-176Crossref PubMed Scopus (1242) Google Scholar]. This number was considerably higher than in patients with a first DILI episode, where only 12/733 (1.6%) patients were diagnosed with “AIH DILI” [[11]Lucena M.I. Kaplowitz L. Hallal H. Castiella A. Garcia-Bengoecha M. Otazua P. et al.Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish registry.The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011; 55: 70-77Google Scholar], suggesting that immune-mediated reactions become the main mechanisms leading to DILI after re-exposure to different drugs.There is no consensus on the nomenclature of immune-mediated DILI and we will propose some definitions and respective diagnoses at the end of this article. Until then, the diagnoses given in the publications cited will be used.In clinical practice, the differentiation between immune-mediated DILI and AIH may be challenging. There are no pathognomonic features of AIH and the diagnosis is made according to a clinical, biochemical, serological, and histological pattern which has to be confirmed by the response to immunosuppressive treatment [[14]Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1054) Google Scholar]. This difficulty in differentiating between AIH and drug induced immune-mediated liver injury has been recently highlighted by the study of Björnsson et al. [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar] demonstrating that in a large cohort of AIH patients, 9.2% suffered from “drug induced AIH”. There was no difference in or and treatment response was similar between AIH cases and “drug induced AIH”. However, were no in “drug induced in patients in was This in to the rate after withdrawal of in AIH in this which in most cases a [[14]Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1054) Google Scholar]. Of it has recently become that histological can be in DILI as well as in acute AIH [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar]. in AIH are in acute liver injury of and therefore, be with Y. J. Vergani D. The of and in acute liver a cohort Hepatol. 2007; Full Text Full Text PDF PubMed Scopus Google the we to of DILI and AIH and to appropriate diagnoses There are between DILI and and diagnoses and clinical in a The first is that a patient with known AIH DILI. this than in other patients is Liver will in these patients, which should be termed “AIH with second is that a patient has AIH that has not been diagnosed or the to AIH that is by DILI. The of hepatic and of these by may to a – – reaction in In a follow-up study of patients with DILI and from patients had been for liver and of these were diagnosed with AIH after a of [[4]Bjornsson E. Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.J Hepatol. 2009; 50: 511-517Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. mechanisms may be for drugs with such as C. T. E. S. Drug-induced autoimmune hepatitis by 2010; 52: PubMed Scopus (28) Google Scholar] or C. autoimmune treatment of – not only J 2008; Google Scholar]. In case and case of these patients developed AIH with a for these patients from AIH”. However, a of drug in a patient with unknown AIH cannot be out in these patients and in the of AIH may be the reason for the are a number of drugs that are well known to cause immune-mediated DILI. are patients with or mixed of damage that not after of the drug and but not with and patients may be from AIH by clinical, and histological and by response to immunosuppressive In may point toward DILI in these the drugs causing immune-mediated DILI are such as and [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar]. In these patients, the of treatment may be life Of particular in AIH, most of these patients not as have after the treatment [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar]. In with this have been identified for causing immune-mediated DILI, such as and A.K. J. J. M. et class in susceptibility and to liver Hepatol. 2010; Full Text Full Text PDF PubMed Scopus (121) Google Scholar], which are unrelated to the with these cases not develop AIH with a we to these and not to the we for patient A second DILI a different drug is a rare event but if it immune-mediated DILI is immune-mediated DILI from AIH is as the may be the same. Liver should be and may point toward DILI, cannot be used to the of treatment may be life in should be a complete has been This may be the only to between immune-mediated DILI and AIH, since the and a More treatment can be avoided in most patients with immune-mediated it to between AIH with DILI, drug induced AIH, and immune-mediated DILI features of since treatment and may of that not have to or of with to this Drug-induced liver injury (DILI) is a leading cause of acute liver failure [[1]Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar] and is of major importance to the pharmaceutical industry, as it is the most frequent reason for withdrawal of substances from the market. More than 1000 different drugs and herbal remedies have been described to cause DILI. Some drugs cause a dose-dependent toxicity which can be anticipated – a well known example is acetaminophen. The vast majority of DILI cases cannot be foreseen and are, therefore, termed idiosyncratic. Oxidative stress, reactive metabolites, mitochondrial toxicity, modulation of drug metabolizing transporters, induction of apoptosis or necrosis, as well as immunoallergic reactions to protein adducts may all be involved in DILI, but for most of the drugs the specific mechanisms contributing to DILI are unknown [[2]Kaplowitz N. Idiosyncratic drug hepatotoxicity.Nat Rev Drug Discov. 2005; 4: 489-499Crossref PubMed Scopus (856) Google Scholar]. A classification of hepatocellular, mixed or cholestatic liver injury is used in the clinic to describe damage and severity of liver injury but its value in predicting the outcome of DILI is unclear. DILI can range from asymptomatic elevation of liver enzymes to fulminant hepatic failure [[1]Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar]. Its over-all mortality depends on the drug used, the timely detection of DILI including the appropriate action taken, as well as individual cofactors and comorbidities such as the presence of diabetes mellitus [[3]El-Serag H.B. Everhart J.E. Diabetes increases the risk of acute hepatic failure.Gastroenterology. 2002; 122: 1822-1828Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar]. Mortality rates of approximately 10% [[1]Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar] have been reported but may be highly overestimated since most mild drug reactions will not be registered. In most patients, DILI leads to a complete recovery. However, up to 1% of all patients with DILI may develop liver cirrhosis subsequently [[4]Bjornsson E. Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.J Hepatol. 2009; 50: 511-517Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. DILI is a rare event with an estimated incidence of 1 per 10,000 to 1 per 100,000 treated patients [[5]Bjornsson E. Review article: drug-induced liver injury in clinical practice.Aliment Pharmacol Ther. 2010; 32: 3-13PubMed Google Scholar]. Some risk factors have been identified: the daily amount of the drug causing the reaction (intake of >50 mg daily increases risk), a predominantly hepatic metabolism of the drug (>50%) [[6]Lammert C. Bjornsson E. Niklasson A. Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events.Hepatology. 2010; 51: 615-620Crossref PubMed Scopus (201) Google Scholar], and mitochondrial dysfunction that may be the underlying cause of the increased risk of DILI in diabetes patients [[7]Boelsterli U.A. Lim P.L. Mitochondrial abnormalities – a link to idiosyncratic drug hepatotoxicity?.Toxicol Appl Pharmacol. 2007; 220: 92-107Crossref PubMed Scopus (178) Google Scholar]. Genetic polymorphisms within genes relevant to drug metabolism [[8]Lucena M.I. Andrade R.J. Martinez C. Ulzurrun E. Garcia-Martin E. Borraz Y. et al.Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.Hepatology. 2008; 48: 588-596Crossref PubMed Scopus (164) Google Scholar] are being identified and may be used to stratify the risk of DILI to certain drugs in the A question relevant to daily clinical practice is, if re-exposure to the same or to other drugs may cause a second DILI episode. Re-exposure to the same drug generally should be avoided due to the considerable mortality rate reported after re-exposure to drugs such as halothane (up to 50% due to a combination of mitochondrial and immune-mediated injury) [[9]Hunt C.M. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: a systematic review.Hepatology. 2010; 52: 2216-2222Crossref PubMed Scopus (28) Google Scholar]. Nonetheless, for drugs that are urgently needed in case of life threatening disease, such as in tuberculosis, careful re-exposure can be undertaken after the resolution of the first DILI episode with acceptable risk [[10]Sharma S.K. Singla R. Sarda P. Mohan A. Makharia G. Jayaswal A. et al.Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity.Clin Infect Dis. 2010; 50: 833-839Crossref PubMed Scopus (121) Google Scholar]. The risk of re-exposure to a different drug that may belong to the same class of drugs or be completely unrelated is not well studied. To this end, the study presented by Lucena et al. in this issue adds valuable and reassuring information [[11]Lucena M.I. Kaplowitz L. Hallal H. Castiella A. Garcia-Bengoecha M. Otazua P. et al.Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish registry.The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011; 55: 70-77Google Scholar]. In this study, the Spanish DILI registry of patients with probable or highly probable idiosyncratic DILI was searched for patients who suffered from a second DILI episode. Only a small number of patients (9 patients, 1.21%) from the cohort of patients with prior DILI developed a second episode of liver injury and none of the patients’ required liver transplantation or had a fatal outcome. Of particular interest, the majority of patients (8 out of 9) experiencing a second DILI episode had a similar (hepatocellular) damage pattern. The drugs responsible for the second DILI episode were structurally related to the drug of the first DILI episode in 4 out of 9 cases and, in 2 cases, the target of the drug was the same. This may point toward an immune-mediated drug injury directed against similar protein adducts forming haptens. Indeed, 4 out of the 9 patients (44%) were diagnosed with so called “autoimmune (AIH) DILI” since these patients fulfilled the criteria for probable or definite AIH, according to the revised and simplified score of the international autoimmune hepatitis study group [12Alvarez F. Berg P.A. Bianchi F.B. Bianchi L. Burroughs A.K. Cancado E.L. et al.International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis.J Hepatol. 1999; 31: 929-938Abstract Full Text Full Text PDF PubMed Scopus (2436) Google Scholar, 13Hennes E.M. Zeniya M. Czaja A.J. Pares A. Dalekos G.N. Krawitt E.L. et al.Simplified criteria for the diagnosis of autoimmune hepatitis.Hepatology. 2008; 48: 169-176Crossref PubMed Scopus (1242) Google Scholar]. This number was considerably higher than in patients with a first DILI episode, where only 12/733 (1.6%) patients were diagnosed with “AIH DILI” [[11]Lucena M.I. Kaplowitz L. Hallal H. Castiella A. Garcia-Bengoecha M. Otazua P. et al.Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish registry.The dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011; 55: 70-77Google Scholar], suggesting that immune-mediated reactions become the main mechanisms leading to DILI after re-exposure to different drugs. There is no consensus on the nomenclature of immune-mediated DILI and we will propose some definitions and respective diagnoses at the end of this article. Until then, the diagnoses given in the publications cited will be In clinical practice, the differentiation between immune-mediated DILI and AIH may be challenging. There are no pathognomonic features of AIH and the diagnosis is made according to a clinical, biochemical, serological, and histological pattern which has to be confirmed by the response to immunosuppressive treatment [[14]Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1054) Google Scholar]. This difficulty in differentiating between AIH and drug induced immune-mediated liver injury has been recently highlighted by the study of Björnsson et al. [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar] demonstrating that in a large cohort of AIH patients, 9.2% suffered from “drug induced AIH”. There was no difference in or and treatment response was similar between AIH cases and “drug induced AIH”. However, were no in “drug induced in patients in was This in to the rate after withdrawal of in AIH in this which in most cases a [[14]Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1054) Google Scholar]. Of it has recently become that histological can be in DILI as well as in acute AIH [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar]. in AIH are in acute liver injury of and therefore, be with Y. J. Vergani D. The of and in acute liver a cohort Hepatol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar]. In the we to of DILI and AIH and to appropriate diagnoses There are between DILI and The first is that a patient with known AIH DILI. this than in other patients is Liver will in these patients, which should be termed “AIH with The second is that a patient has AIH that has not been diagnosed or the to AIH that is by DILI. The of hepatic and of these by may to a – – reaction in In a follow-up study of patients with DILI and from patients had been for liver and of these were diagnosed with AIH after a of [[4]Bjornsson E. Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.J Hepatol. 2009; 50: 511-517Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. mechanisms may be for drugs with such as C. T. E. S. Drug-induced autoimmune hepatitis by 2010; 52: PubMed Scopus (28) Google Scholar] or C. autoimmune treatment of – not only J 2008; Google Scholar]. In case and case of these patients developed AIH with a for these patients from AIH”. However, a of drug in a patient with unknown AIH cannot be out in these patients and in the of AIH may be the reason for the are a number of drugs that are well known to cause immune-mediated DILI. are patients with or mixed of damage that not after of the drug and but not with and patients may be from AIH by clinical, and histological and by response to immunosuppressive In may point toward DILI in these the drugs causing immune-mediated DILI are such as and [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar]. In these patients, the of treatment may be life Of particular in AIH, most of these patients not as have after the treatment [[15]Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048Crossref PubMed Scopus (332) Google Scholar]. In with this have been identified for causing immune-mediated DILI, such as and A.K. J. J. M. et class in susceptibility and to liver Hepatol. 2010; Full Text Full Text PDF PubMed Scopus (121) Google Scholar], which are unrelated to the with these cases not develop AIH with a we to these and not to the we for patient A second DILI a different drug is a rare event but if it immune-mediated DILI is immune-mediated DILI from AIH is as the may be the same. Liver should be and may point toward DILI, cannot be used to the of treatment may be life in should be a complete has been This may be the only to between immune-mediated DILI and AIH, since the and a More treatment can be avoided in most patients with immune-mediated DILI. it to between AIH with DILI, drug induced AIH, and immune-mediated DILI features of since treatment and may of that not have to or of with to this The that not have to or of with to this