The Clinical and Histological Features of Idiosyncratic Liver Injury: Dilemma in Diagnosis of Autoimmune Hepatitis
Ufuk Barış Kuzu1, Erkin Öztaş1, Nesrin Turhan2, Fatih Saygılı1, Nuretdin Suna1, Hakan Yıldız1, Mustafa Kaplan1, Muhammet Yener Akpınar1, Meral Akdoğan1, Sabite Kaçar1, Zeki Mesut Yalın Kılıç1, Aydın Şeref Köksal1, Bülent Ödemiş1, Ertuğrul Kayaçetin1
1
:Department of Gastroenterology, Turkiye Yuksek Ihtisas Education and Research Hospital
2
:Department of Pathology, Turkiye Yuksek Ihtisas Education and Research Hospital
Corresponding Author: Ufuk Barış KUZU, M.D. Turkiye Yuksek Ihtisas Training and Research Hospital, Department of Gastroenterology Atatürk Bulvarı Kızılay Sokak No:4 Sıhhiye - Ankara PC:06000 Tel:+ 903123061334 Fax : +90 312 3121002 E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12530
This article is protected by copyright. All rights reserved.
ABSTRACT Objectives: Drug-induced liver injury (DILI) is becoming a worldwide problem with its still unexplained properties. Methods: The data of patients who were diagnosed as DILI between January 2008 and December 2013 were assessed. Results: Five patients diagnosed as intrinsic and 82 patients diagnosed as idiosyncratic DILI. The most causative agents were antimicrobial drugs. The most common injury pattern was hepatocellular. When patients with bilirubin levels more than 5 mg/dl are divided into two groups according to having steroid therapy (n=11) or not (n=40), there was not any significant difference according to their clinical results (p>0.05). Five of idiosyncratic DILI patients were diagnosed as drug-induced autoimmune hepatitis (DI-AIH). In histopathological examination, hepatic rosette formation, and emperipolesis were observed to be more common among patients with DI-AIH when compared to ones that don’t have (p 8 points) and whose diagnosis was approved by 5 experienced hepatologists were diagnosed to have DILI. Liver damage was defined as elevation of ALT, ALP and total bilirubin levels more than twice upper normal limit. Damage pattern (R) was assessed according to CIOMS criteria [(ALT/ULN)/(ALP/ULN) ratio]. Damage pattern was named as hepatocellular (HC) when R≥5, cholestatic (C) when R ≤2 and mixed (M) when R was between 2 and 5. These biochemical levels were calculated according to the serum samples obtained just after the diagnosis of liver damage.15,16 Diagnosis of DI-AIH among patients with DILI was established according to following criteria: Patients that have a score before therapy between 10 and 15 according to International Autoimmune Hepatitis Scoring System (IAHSS), have supporting histopathological findings, recovery after withdrawal of the drug (with or without immunosuppressive therapy) and without any relapse during follow up. Patients with IAHSS scores more than 15, relapsing after immunosuppressive therapy or immunosuppressive dependent patients were considered to have AIH and they were excluded.17 Liver biopsy is performed in our clinic in case of suspicion about autoimmune liver disease, alcoholic liver disease, underlying chronic liver disease and systemic diseases that can effect liver. All liver biopsy specimens were re-evaluated by a single experienced pathologist. Histopathological findings were classified into 6 main groups;1- Necroinflammatory 2- Cholestatic 3- Steatotic 4- Vascular Dilatation 5- End-stage 6- Tumor.18 Necroinflammatory injury was mainly divided into two as acute and chronic hepatitic pattern. Cholestatic injury was classified as acute, chronic and mixed pattern (hepatocellular + cholestatic). Mixed pattern was defined as subgroups according to the dominant pattern. Patients with epitheloid granuloma and zonal necrosis which are common in DILI were also recorded.18 For all assessments, dominant leukocyte infiltration in portal area and intra-acinar region was considered. Staging of fibrosis was evaluated according to the scoring system developed by Ishak.19 Histological findings that suggest chronic AIH, like interface hepatitis, lymphoplasmacytic cell infiltration in portal area, hepatic rosette formation and emperipolesis were recorded. Additionally characteristics of acute inflammation (centrilobular necrosis or lobular inflammation; single cell necrosis, spotty necrosis and confluent necrosis) in the specimens were also recorded.20,21 Result after damage were assessed according to clinical, laboratory, imaging and histopathological findings. Recovery for all patterns was defined as the normalisation of liver biochemical tests within 6 months after withdrawal of the agent. Chronicity was assessed according to clinical, laboratory (sustained elevation in liver biochemical tests after 6 months), imaging and histopathological (if possible) findings.
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Statistical Analysis Statistical Analysis were performed with SPSS version 20 (SPSS Inc., Chicago, USA). Consistent data were shown as mean (±standard deviation SD), median, if needed (interquartile ranges, 25-75 percentiles) and categoric data were shown as numbers and percentage (n, %). Chi-square and Fischer exact Test were used for categoric variables. Student’s T test and Mann Whitney U test were used for consistent variables. Correlation between laboratory findings and recovery time was investigated with Spearman’s Rho test. Settings with the rate of type I error below 5% were considered to be statistically significant. RESULTS Total of 101 patients in 6 years with diagnosis of DILI were evaluated and 14 were excluded because of lacking follow up data or loss of communication. After exclusion, a total of 87 patients were diagnosed as DILI and included in the study. Intrinsic mechanism was responsible for liver damage in 5 (5.7%) cases. Fungal alkaloids and acetaminophen were responsible for 80% (n=4) and 20% (n=1) of these cases respectively. One patient with liver damage due to fungal alkaloids died, when three of these patients had recovery after penicillin therapy. Orthotopic liver transplantation form living donor was performed for the patient with acetaminophen toxicity which lead to fulminant liver failure. Data of remaining 82 patients with idiosyncratic hepatotoxicity were evaluated; the mean age was 49.4±14.3 years where 57.3% (n=47) of patients were female. The most common symptom at the time of diagnosis was jaundice (n=29, 45.4%). Mean duration of using the suspected agent and latent period, defined as the time between diagnosis of DILI and onset of suspected agent were 55.14±91.4 and 63.7±89.05 days respectively. Three patients had underlying Child-Pugh A liver failure, where one of them had chronic alcoholic liver disease and two had cryptogenic cirrhosis.Recovery was observed in all of these patients after withdrawal of the suspected agent. Five patients (5.7%) all of whom were male, had alcohol consumption and all of them were taking alcohol less than 30 g/day. Eleven patients had a history of diabetes mellitus. 80.4% (n=66) of patients were followed up in our inpatient clinic. Recovery was observed in 66 (80.5%) patients, however 12 (14.6%) patients had chronicity, 3 (3.7%) patients died and 1 (1.2%) patient underwent liver transplantation. Agents Considered to be Responsible for Idiosyncratic Liver Damage A single agent (prescribed medicine, diet product or alternative herbal products) was considered to be responsible in 68.3% (n=56) of patients. The most common agents among these are antimicrobial drugs n=19 (23.1%), NSAIDs; n=12 (14.6%) and herbal and diet products n=5 (6%). Amoxicillin-clavulanate (n=7/19) was the most common cause among antimicrobial drugs where the other agents were metronidazole, ornidazole, cefuroxime axetil, ampicillin, ciprofloxacin, terbinafine, clarithromycin and albendazole. Diklophenac sodium was the most common NSAID (n= 3/12). The most common combination was NSAID + antibiotics in 5 cases and amoxicillin + clarithromycin prescribed for Helicobacter pylori eradication in 2 cases among 26 patients (31.7%) who were considered to have more than one responsible agents. Herbal and weight loss products were Yarrow Tea (Achillea millefolium), panax (Tribulus terrestris and Ginseng), Rosemary tea (Rosmarinus officinalis), chromium picolinate and Garcinia Cambogia (hydroxycitric acid). Narcotics were synthetic
This article is protected by copyright. All rights reserved.
cannabinoids called blue dolphin and bonsai. Table 1 summarises the damage patterns and clinical aspects of main groups of agents considered to be responsible for DILI. Clinical and Demographical Aspects According to Liver Damage Pattern The most common pattern was HC, (67.1%, n=55/82) followed by C (19.5%, n=55) and M (13.4%, n=11). Comparison of clinical and demographical aspects according to damage patterns are shown on Table 2. 56.3% of patients (n=31/55) among cases with HC pattern had ALT levels more than 20 times of upper normal limit. There was not significant difference between damage patterns by means of demographic and clinical aspects. However as it can be expected, ALT levels were higher in HC type where ALP levels were higher in C type (p=0.001 and p=0.001 respectively). Treatment and Clinical Results All the patients received intravenous hydration and per oral UDCA and additionally 13 patients were observed to take steroid therapy. When patients with bilirubin levels more than 5 mg/dl are divided into two groups according to having steroid therapy (n=11) or not (n=40), there was not any significant difference in terms of demographic features and laboratory findings between the groups (p>0.05). Similarly there was not any significant difference when these groups are compared according to their clinical results (p>0.05). However there was not any death or need for transplantation in the group receiving steroids, where two deaths and one transplantation was observed in steroid free group (Table 3). Demographic features, laboratory and histopathological findings of recovery, chronicity and death/transplantation groups after DILI were compared. Female ratio was highly elevated (n=11/12, 91.7%) in the chronicity group when compared to others (p=0.01). INR level was significantly higher than the other groups in the death/transplantation group as it can be expected (p=0,022) (Table 4). In histopathological examination dominant leukocyte types in portal area and intra-acinar region were different between recovery and chronicity groups; number of patients underwent liver biopsy were 35 and 9 respectively. The most leukocyte types of portal area in recovery group was eosinophil (40%), lymphocyte/lymphoplasmacytic cell (22.9%), mix (20%) and in chronicity group was mix (44.5%), lymphocyte/lymphoplasmacytic cell (33.3%), eosinophil (11.1%). And dominant leukocyte types in intra-acinar region in recovery group were eosinophils (37.1%), mixed (25.7%), lymphocyte/lymphoplasmocytic cells (22.9%) and in chronic group they were listed as mixed (55.5%), lymphocyte/lymphoplasmacytic cells (22.2%), and eosinophils (11.1%). Additionally any correlation between recovery time and laboratory findings (ALT,AST, eosinophil rate, Immunoglobulin-G and total bilirubin) were investigated. There was only a slight correlation between recovery day and total bilirubin levels (r=0.245; p=0.047). Liver Biopsy Histopathological results of 46 (56%) patients who underwent liver biopsy were evaluated. Thirtynine(84.7%) of these patients had necroinflammatory damage, where 8 of them were pure hepatocellular and 31 of them were with other patterns. Cholestatic damage was accompanying with hepatocellular damage in 20 (64.5%) of patients with mixed pattern. Predominant damage was hepatocellular in 13 of them and it was
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cholestatic in 7. Thirty-one of patients with necroinflammatory damage had acute hepatitis pattern and 19 of them had chronic pattern. Cholestatic injury was observed in 32 (69.5%) of patients where only 3 (9.3%) of them was pure cholestatic. Cholestatic injury was majorly composed of acute cholestasis (62.5%). Vascular damage was observed in 11 (23.9%) patients where most of them were represented with sinusoidal dilatation. Only one patient had venoocclusive damage due to NSAIDs. Three (6.5%) patients had steatotic pattern, all of them were (macrovesicular steatosis) and none of them showed steatohepatitis. One (2.1%) patients had end stage pattern (cirrhosis). Additionally 22 of all patients had zonal necrosis (2 panaciner and 20 centrilobular) and 5 of them had epitheloid granuloma. Distracting the attention that 13 of 46 patients (28.2%) had pericellular fibrosis with masson trichrome staining. Agents that are related with pericellular fibrosis were: NSAİDs, ciprofloxacin, metothrexate, Yarrow Tea (Achillea millefolium), amoxicillin-clavulanate, tamoxifen and metformin. Figure 1 shows the examples of most common histopathological patterns. DILI-AIH Association Five of 82 (6%) idiosyncratic DILI patients were diagnosed as DI-AIH according to their laboratory, serological and histological findings. All of them were receiving UDCA. Additionally two of them were on step-down steroid therapy. During follow up none of them died or had need for transplantation and recovery was observed in all 5 patients (50-160 days). There was no elevation in liver tests during the follow up (10-42 months) of these patients. Baseline characteristic of the patients are summarised on Table 5. All the patients with diagnosis of DI-AIH (n=5) were female, where of the others (n=77) only 54.5% were female. However this did not reach statistical significance (p=0.056). Patients with DI-AIH or without diagnosis of DI-AIH (non-DI-AIH) did not show any difference in terms of biochemical damage pattern, duration of suspected agent use and latent period (p>0.05). Despite the lack of difference for clinical results between two groups, recovery time was observed to be longer in DI-AIH group (63 days) when compare to nonDI-AIH group (45 days) (p0.05). Acute hepatitis, chronic hepatitis and cholestatic types among DI-AIH and the other DILI patients were observed; 100%, 60%, 60% and 63.4%, 39.2%, 68.3% respectively. Histopathological assessment of these 5 acute hepatitis patients with DI-AIH revealed lobular inflammation in 3, centrilobular necrosis in 1 and centrilobular necrosis with lobular inflammation in 1 of them. Alike histopathological patterns, there was not significant difference between groups by means of Ishak fibrosis score (1.2 vs. 1.59). Lymphoplasmacytic cell infiltration in portal area and in intraacinar region were observed to be nearly doubled in DI-AIH group (60% and 60% respectively) when compared to non-DI-AIH group (29.2% and 26.8% respectively) however this did not reach statistical significance (p>0.05). Additionally occurrence of interphase hepatitis, hepatic rosette formation and emperipolesis which resemble idiopathic autoimmune hepatitis were higher in DI-AIH group. However only hepatic rosette formation and emperipolesis was found to be statistically significant ( p
Ufuk Barış Kuzu1, Erkin Öztaş1, Nesrin Turhan2, Fatih Saygılı1, Nuretdin Suna1, Hakan Yıldız1, Mustafa Kaplan1, Muhammet Yener Akpınar1, Meral Akdoğan1, Sabite Kaçar1, Zeki Mesut Yalın Kılıç1, Aydın Şeref Köksal1, Bülent Ödemiş1, Ertuğrul Kayaçetin1
1
:Department of Gastroenterology, Turkiye Yuksek Ihtisas Education and Research Hospital
2
:Department of Pathology, Turkiye Yuksek Ihtisas Education and Research Hospital
Corresponding Author: Ufuk Barış KUZU, M.D. Turkiye Yuksek Ihtisas Training and Research Hospital, Department of Gastroenterology Atatürk Bulvarı Kızılay Sokak No:4 Sıhhiye - Ankara PC:06000 Tel:+ 903123061334 Fax : +90 312 3121002 E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12530
This article is protected by copyright. All rights reserved.
ABSTRACT Objectives: Drug-induced liver injury (DILI) is becoming a worldwide problem with its still unexplained properties. Methods: The data of patients who were diagnosed as DILI between January 2008 and December 2013 were assessed. Results: Five patients diagnosed as intrinsic and 82 patients diagnosed as idiosyncratic DILI. The most causative agents were antimicrobial drugs. The most common injury pattern was hepatocellular. When patients with bilirubin levels more than 5 mg/dl are divided into two groups according to having steroid therapy (n=11) or not (n=40), there was not any significant difference according to their clinical results (p>0.05). Five of idiosyncratic DILI patients were diagnosed as drug-induced autoimmune hepatitis (DI-AIH). In histopathological examination, hepatic rosette formation, and emperipolesis were observed to be more common among patients with DI-AIH when compared to ones that don’t have (p 8 points) and whose diagnosis was approved by 5 experienced hepatologists were diagnosed to have DILI. Liver damage was defined as elevation of ALT, ALP and total bilirubin levels more than twice upper normal limit. Damage pattern (R) was assessed according to CIOMS criteria [(ALT/ULN)/(ALP/ULN) ratio]. Damage pattern was named as hepatocellular (HC) when R≥5, cholestatic (C) when R ≤2 and mixed (M) when R was between 2 and 5. These biochemical levels were calculated according to the serum samples obtained just after the diagnosis of liver damage.15,16 Diagnosis of DI-AIH among patients with DILI was established according to following criteria: Patients that have a score before therapy between 10 and 15 according to International Autoimmune Hepatitis Scoring System (IAHSS), have supporting histopathological findings, recovery after withdrawal of the drug (with or without immunosuppressive therapy) and without any relapse during follow up. Patients with IAHSS scores more than 15, relapsing after immunosuppressive therapy or immunosuppressive dependent patients were considered to have AIH and they were excluded.17 Liver biopsy is performed in our clinic in case of suspicion about autoimmune liver disease, alcoholic liver disease, underlying chronic liver disease and systemic diseases that can effect liver. All liver biopsy specimens were re-evaluated by a single experienced pathologist. Histopathological findings were classified into 6 main groups;1- Necroinflammatory 2- Cholestatic 3- Steatotic 4- Vascular Dilatation 5- End-stage 6- Tumor.18 Necroinflammatory injury was mainly divided into two as acute and chronic hepatitic pattern. Cholestatic injury was classified as acute, chronic and mixed pattern (hepatocellular + cholestatic). Mixed pattern was defined as subgroups according to the dominant pattern. Patients with epitheloid granuloma and zonal necrosis which are common in DILI were also recorded.18 For all assessments, dominant leukocyte infiltration in portal area and intra-acinar region was considered. Staging of fibrosis was evaluated according to the scoring system developed by Ishak.19 Histological findings that suggest chronic AIH, like interface hepatitis, lymphoplasmacytic cell infiltration in portal area, hepatic rosette formation and emperipolesis were recorded. Additionally characteristics of acute inflammation (centrilobular necrosis or lobular inflammation; single cell necrosis, spotty necrosis and confluent necrosis) in the specimens were also recorded.20,21 Result after damage were assessed according to clinical, laboratory, imaging and histopathological findings. Recovery for all patterns was defined as the normalisation of liver biochemical tests within 6 months after withdrawal of the agent. Chronicity was assessed according to clinical, laboratory (sustained elevation in liver biochemical tests after 6 months), imaging and histopathological (if possible) findings.
This article is protected by copyright. All rights reserved.
Statistical Analysis Statistical Analysis were performed with SPSS version 20 (SPSS Inc., Chicago, USA). Consistent data were shown as mean (±standard deviation SD), median, if needed (interquartile ranges, 25-75 percentiles) and categoric data were shown as numbers and percentage (n, %). Chi-square and Fischer exact Test were used for categoric variables. Student’s T test and Mann Whitney U test were used for consistent variables. Correlation between laboratory findings and recovery time was investigated with Spearman’s Rho test. Settings with the rate of type I error below 5% were considered to be statistically significant. RESULTS Total of 101 patients in 6 years with diagnosis of DILI were evaluated and 14 were excluded because of lacking follow up data or loss of communication. After exclusion, a total of 87 patients were diagnosed as DILI and included in the study. Intrinsic mechanism was responsible for liver damage in 5 (5.7%) cases. Fungal alkaloids and acetaminophen were responsible for 80% (n=4) and 20% (n=1) of these cases respectively. One patient with liver damage due to fungal alkaloids died, when three of these patients had recovery after penicillin therapy. Orthotopic liver transplantation form living donor was performed for the patient with acetaminophen toxicity which lead to fulminant liver failure. Data of remaining 82 patients with idiosyncratic hepatotoxicity were evaluated; the mean age was 49.4±14.3 years where 57.3% (n=47) of patients were female. The most common symptom at the time of diagnosis was jaundice (n=29, 45.4%). Mean duration of using the suspected agent and latent period, defined as the time between diagnosis of DILI and onset of suspected agent were 55.14±91.4 and 63.7±89.05 days respectively. Three patients had underlying Child-Pugh A liver failure, where one of them had chronic alcoholic liver disease and two had cryptogenic cirrhosis.Recovery was observed in all of these patients after withdrawal of the suspected agent. Five patients (5.7%) all of whom were male, had alcohol consumption and all of them were taking alcohol less than 30 g/day. Eleven patients had a history of diabetes mellitus. 80.4% (n=66) of patients were followed up in our inpatient clinic. Recovery was observed in 66 (80.5%) patients, however 12 (14.6%) patients had chronicity, 3 (3.7%) patients died and 1 (1.2%) patient underwent liver transplantation. Agents Considered to be Responsible for Idiosyncratic Liver Damage A single agent (prescribed medicine, diet product or alternative herbal products) was considered to be responsible in 68.3% (n=56) of patients. The most common agents among these are antimicrobial drugs n=19 (23.1%), NSAIDs; n=12 (14.6%) and herbal and diet products n=5 (6%). Amoxicillin-clavulanate (n=7/19) was the most common cause among antimicrobial drugs where the other agents were metronidazole, ornidazole, cefuroxime axetil, ampicillin, ciprofloxacin, terbinafine, clarithromycin and albendazole. Diklophenac sodium was the most common NSAID (n= 3/12). The most common combination was NSAID + antibiotics in 5 cases and amoxicillin + clarithromycin prescribed for Helicobacter pylori eradication in 2 cases among 26 patients (31.7%) who were considered to have more than one responsible agents. Herbal and weight loss products were Yarrow Tea (Achillea millefolium), panax (Tribulus terrestris and Ginseng), Rosemary tea (Rosmarinus officinalis), chromium picolinate and Garcinia Cambogia (hydroxycitric acid). Narcotics were synthetic
This article is protected by copyright. All rights reserved.
cannabinoids called blue dolphin and bonsai. Table 1 summarises the damage patterns and clinical aspects of main groups of agents considered to be responsible for DILI. Clinical and Demographical Aspects According to Liver Damage Pattern The most common pattern was HC, (67.1%, n=55/82) followed by C (19.5%, n=55) and M (13.4%, n=11). Comparison of clinical and demographical aspects according to damage patterns are shown on Table 2. 56.3% of patients (n=31/55) among cases with HC pattern had ALT levels more than 20 times of upper normal limit. There was not significant difference between damage patterns by means of demographic and clinical aspects. However as it can be expected, ALT levels were higher in HC type where ALP levels were higher in C type (p=0.001 and p=0.001 respectively). Treatment and Clinical Results All the patients received intravenous hydration and per oral UDCA and additionally 13 patients were observed to take steroid therapy. When patients with bilirubin levels more than 5 mg/dl are divided into two groups according to having steroid therapy (n=11) or not (n=40), there was not any significant difference in terms of demographic features and laboratory findings between the groups (p>0.05). Similarly there was not any significant difference when these groups are compared according to their clinical results (p>0.05). However there was not any death or need for transplantation in the group receiving steroids, where two deaths and one transplantation was observed in steroid free group (Table 3). Demographic features, laboratory and histopathological findings of recovery, chronicity and death/transplantation groups after DILI were compared. Female ratio was highly elevated (n=11/12, 91.7%) in the chronicity group when compared to others (p=0.01). INR level was significantly higher than the other groups in the death/transplantation group as it can be expected (p=0,022) (Table 4). In histopathological examination dominant leukocyte types in portal area and intra-acinar region were different between recovery and chronicity groups; number of patients underwent liver biopsy were 35 and 9 respectively. The most leukocyte types of portal area in recovery group was eosinophil (40%), lymphocyte/lymphoplasmacytic cell (22.9%), mix (20%) and in chronicity group was mix (44.5%), lymphocyte/lymphoplasmacytic cell (33.3%), eosinophil (11.1%). And dominant leukocyte types in intra-acinar region in recovery group were eosinophils (37.1%), mixed (25.7%), lymphocyte/lymphoplasmocytic cells (22.9%) and in chronic group they were listed as mixed (55.5%), lymphocyte/lymphoplasmacytic cells (22.2%), and eosinophils (11.1%). Additionally any correlation between recovery time and laboratory findings (ALT,AST, eosinophil rate, Immunoglobulin-G and total bilirubin) were investigated. There was only a slight correlation between recovery day and total bilirubin levels (r=0.245; p=0.047). Liver Biopsy Histopathological results of 46 (56%) patients who underwent liver biopsy were evaluated. Thirtynine(84.7%) of these patients had necroinflammatory damage, where 8 of them were pure hepatocellular and 31 of them were with other patterns. Cholestatic damage was accompanying with hepatocellular damage in 20 (64.5%) of patients with mixed pattern. Predominant damage was hepatocellular in 13 of them and it was
This article is protected by copyright. All rights reserved.
cholestatic in 7. Thirty-one of patients with necroinflammatory damage had acute hepatitis pattern and 19 of them had chronic pattern. Cholestatic injury was observed in 32 (69.5%) of patients where only 3 (9.3%) of them was pure cholestatic. Cholestatic injury was majorly composed of acute cholestasis (62.5%). Vascular damage was observed in 11 (23.9%) patients where most of them were represented with sinusoidal dilatation. Only one patient had venoocclusive damage due to NSAIDs. Three (6.5%) patients had steatotic pattern, all of them were (macrovesicular steatosis) and none of them showed steatohepatitis. One (2.1%) patients had end stage pattern (cirrhosis). Additionally 22 of all patients had zonal necrosis (2 panaciner and 20 centrilobular) and 5 of them had epitheloid granuloma. Distracting the attention that 13 of 46 patients (28.2%) had pericellular fibrosis with masson trichrome staining. Agents that are related with pericellular fibrosis were: NSAİDs, ciprofloxacin, metothrexate, Yarrow Tea (Achillea millefolium), amoxicillin-clavulanate, tamoxifen and metformin. Figure 1 shows the examples of most common histopathological patterns. DILI-AIH Association Five of 82 (6%) idiosyncratic DILI patients were diagnosed as DI-AIH according to their laboratory, serological and histological findings. All of them were receiving UDCA. Additionally two of them were on step-down steroid therapy. During follow up none of them died or had need for transplantation and recovery was observed in all 5 patients (50-160 days). There was no elevation in liver tests during the follow up (10-42 months) of these patients. Baseline characteristic of the patients are summarised on Table 5. All the patients with diagnosis of DI-AIH (n=5) were female, where of the others (n=77) only 54.5% were female. However this did not reach statistical significance (p=0.056). Patients with DI-AIH or without diagnosis of DI-AIH (non-DI-AIH) did not show any difference in terms of biochemical damage pattern, duration of suspected agent use and latent period (p>0.05). Despite the lack of difference for clinical results between two groups, recovery time was observed to be longer in DI-AIH group (63 days) when compare to nonDI-AIH group (45 days) (p0.05). Acute hepatitis, chronic hepatitis and cholestatic types among DI-AIH and the other DILI patients were observed; 100%, 60%, 60% and 63.4%, 39.2%, 68.3% respectively. Histopathological assessment of these 5 acute hepatitis patients with DI-AIH revealed lobular inflammation in 3, centrilobular necrosis in 1 and centrilobular necrosis with lobular inflammation in 1 of them. Alike histopathological patterns, there was not significant difference between groups by means of Ishak fibrosis score (1.2 vs. 1.59). Lymphoplasmacytic cell infiltration in portal area and in intraacinar region were observed to be nearly doubled in DI-AIH group (60% and 60% respectively) when compared to non-DI-AIH group (29.2% and 26.8% respectively) however this did not reach statistical significance (p>0.05). Additionally occurrence of interphase hepatitis, hepatic rosette formation and emperipolesis which resemble idiopathic autoimmune hepatitis were higher in DI-AIH group. However only hepatic rosette formation and emperipolesis was found to be statistically significant ( p
