Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. METHODS: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. RESULTS: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p = .001). DILI cases with autoimmune features had significantly longer time to onset (p < .001) and resolution time (p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. CONCLUSIONS: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries.

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96-760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57-141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis.

Neutropenic Enterocolitis: Case report and literature review

Typhlitis, is also known as neutropenic enterocolitis, affects the cecum and distal ileum. It was frequently encountered in pediatric patients who were undergoing treatment for leukemia. Nonetheless, it can affect adult patients, regardless of the cause of the immunosuppression. We report the case of a 20-year-old patient who was receiving chemotherapy for Osteosarcoma, who had a 6-day history of nausea and vomiting, fever sensation, diarrhea, and diffuse abdominal pain. Physical examination was relevant for hemodynamic instability, a distended and tender abdomen predominantly in the right iliac fossa. The laboratory workup showed severe neutropenia, thrombocytopenia, and electrolyte disturbances. The image studies evidenced edema of the ascending colon and cecum. Treatment was started with vasopressor support, correction of electrolyte alterations, blood cell and platelet transfusion, G-CSF, hydration, broad spectrum antibiotic therapy, initially with adequate clinical and laboratory response. After a few days, he presented lower gastrointestinal bleeding which was treated by conservative management. In conclusion, typhlitis must be suspected in every patient developing neutropenia as a reaction to chemotherapy and who also presents gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and intense abdominal pain.

La tiflitis o también denominada enterocolitis neutropénica afecta el ciego e íleon distal. Fue descrita comúnmente en pacientes pediátricos sometidos a tratamiento para leucemia; sin embargo, puede afectar al paciente adulto independiente de la causa que origine la inmunosupresión. Presentamos el caso de un paciente de 20 años con antecedente de osteosarcoma, quien acude con tiempo de enfermedad de 6 días caracterizado por náuseas y vómitos, sensación de alza térmica, diarrea y dolor abdominal difuso. Al examen físico se encuentra hemodinámicamente inestable, abdomen distendido y se corrobora el dolor abdominal a predominio en fosa iliaca derecha. Los exámenes de laboratorio mostraron neutropenia severa, trombocitopenia y alteraciones hidroelectrolíticas. En los estudios de imágenes la TC evidenció edema de asas delgadas, así como edema de pared del colon ascendente y ciego. Se inició tratamiento con soporte vasopresor, corrección de alteraciones hidroelectrolíticas, transfusión de paquetes globulares y plaquetas, G-CSF, hidratación, terapia antibiótica de amplio espectro, inicialmente con adecuada respuesta clínica y laboratorial. Al cabo de unos días presentó hemorragia digestiva baja como complicación que fue tratada mediante manejo conservador. En conclusión, la tiflitis debe sospecharse en todo paciente que desarrolla neutropenia luego de quimioterapia y que presenta síntomas gastrointestinales como náuseas, vómitos, diarrea y dolor abdominal intenso. El manejo conservador, en pacientes con hemorragia digestiva y tiflitis, que involucra corrección de coagulopatía, transfusión de paquetes globulares e hidratación, puede ser el adecuado en pacientes que no cursan con inestabilidad hemodinámica y logran controlar el sangrado.

The establishment of public health policies and the burden of non-alcoholic fatty liver disease in the Americas.

Non-alcoholic fatty liver disease (NAFLD) affects 20-25% of the general population and is associated with morbidity, increased mortality, and elevated health-care costs. Most NAFLD risk factors are modifiable and, therefore, potentially amenable to being reduced by public health policies. To date, there is no information about NAFLD-related public health policies in the Americas. In this study, we analysed data from 17 American countries and found that none have established national public health policies to decrease NAFLD-related burden. There is notable heterogeneity in the existence of public health policies to prevent NAFLD-related conditions. The most common public health policies were related to diabetes (15 [88%] countries), hypertension (14 [82%] countries), cardiovascular diseases (14 [82%] countries), obesity (nine [53%] countries), and dyslipidaemia (six [35%] of countries). Only seven (41%) countries had a registry of the burden of NAFLD, and efforts to raise awareness in the Americas were scarce. The implementation of public health policies are urgently needed in the Americas to decrease the burden of NAFLD.

Neutropenic Enterocolitis: Case report and literature review.

Typhlitis, is also known as neutropenic enterocolitis, affects the cecum and distal ileum. It was frequently encountered in pediatric patients who were undergoing treatment for leukemia. Nonetheless, it can affect adult patients, regardless of the cause of the immunosuppression. We report the case of a 20-year-old patient who was receiving chemotherapy for Osteosarcoma, who had a 6-day history of nausea and vomiting, fever sensation, diarrhea, and diffuse abdominal pain. Physical examination was relevant for hemodynamic instability, a distended and tender abdomen predominantly in the right iliac fossa. The laboratory workup showed severe neutropenia, thrombocytopenia, and electrolyte disturbances. The image studies evidenced edema of the ascending colon and cecum. Treatment was started with vasopressor support, correction of electrolyte alterations, blood cell and platelet transfusion, G-CSF, hydration, broad spectrum antibiotic therapy, initially with adequate clinical and laboratory response. After a few days, he presented lower gastrointestinal bleeding which was treated by conservative management. In conclusion, typhlitis must be suspected in every patient developing neutropenia as a reaction to chemotherapy and who also presents gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and intense abdominal pain.

Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

BACKGROUND: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. OBJECTIVES: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. METHODS: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. RESULTS: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). CONCLUSIONS: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Prevalencia del virus de hepatitis C en donantes de sangre en el Perú 2016 - 2017 / Prevalence of viral hepatitis type C in blood donors in Peru 2016 - 2017

RESUMEN Objetivos: Conocer la prevalencia actual de la infección por el virus de la hepatitis C a nivel nacional ha tomado una gran importancia en la actualidad debido a los nuevos avances en el tratamiento de la infección del virus de la hepatitis C en los que los nuevos antivirales de acción directa han demostrado una alta tasa de respuesta viral sostenida. Materiales y métodos: El presente es un estudio descriptivo basado en la detección del anti VHC en los bancos de sangre del Ministerio de Salud de acuerdo a la información obtenida del Programa Nacional de Hemoterapia y Bancos de Sangre. (PRONAHEBAS). Resultados: En nuestro estudio la prevalencia de anticuerpos contra el virus de hepatitis C en donantes de sangre a nivel nacional fue 0,428% en el año 2016 y 0,301% en el año 2017. Conclusiones: Conocer datos actualizados acerca de la prevalencia de la infección del virus hepatitis C en nuestra población constituye el primer paso para poder combatir la enfermedad y reducir drásticamente la tasa de infección de acuerdo a la meta de OMS, que consiste en erradicar las hepatitis virales para el año 2030.

ABSTRACT Objectives: Knowing the current prevalence of hepatitis C virus infection has taken great importance nowdays due to the new advances in the treatment of hepatitis C virus infection in which the new direct-acting antivirals have demonstrated a high rate of sustained viral response. Materials and methods: This is a descriptive study based on the detection of anti VHC in the blood banks of "Ministerio de Salud del Perú" according to the information obtained from "Programa Nacional de Hemoterapia y Bancos de Sangre" (PRONAHEBAS). Results: In our study, the prevalence of anti-hepatitis C antibodies in blood donors nationwide was 0.428% in 2016 and 0.301% in 2017. Conclusion: To know updated data about the prevalence of hepatitis C virus infection in our population. It is the first step to be able to treat the disease and drastically reduce the infection rate according to the WHO target for 2030.

Comparison of different prognostic scores for patients with cirrhosis hospitalized with SARS-CoV-2 infection.

INTRODUCTION AND OBJECTIVES: Viral infections have been described to increase the risk of decompensation in patients with cirrhosis. We aimed to determine the effect of SARS-CoV-2 infection on outcome of hospitalized patients with cirrhosis and to compare the performance of different prognostic models for predicting mortality. PATIENTS: We performed a prospective cohort study including 2211 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through October 1, 2020 in 38 Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters of patients with and without cirrhosis. All patients were followed until discharge or death. We evaluated the prognostic performance of different scoring systems to predict mortality in patients with cirrhosis using ROC curves. RESULTS: Overall, 4.6% (CI 3.7-5.6) subjects had cirrhosis (n = 96). Baseline Child-Turcotte-Pugh (CTP) class was assessed: CTP-A (23%), CTP-B (45%) and CTP-C (32%); median MELD-Na score was 19 (IQR 14-25). Mortality was 47% in patients with cirrhosis and 16% in patients without cirrhosis (P < .0001). Cirrhosis was independently associated with death [OR 3.1 (CI 1.9-4.8); P < .0001], adjusted by age, gender, and body mass index >30. The areas under the ROC curves for performance evaluation in predicting 28-days mortality for Chronic Liver Failure Consortium (CLIF-C), North American Consortium for the Study of End-Stage Liver Disease (NACSELD), CTP score and MELD-Na were 0.85, 0.75, 0.69, 0.67; respectively (P < .0001). CONCLUSIONS: SARS-CoV-2 infection is associated with elevated mortality in patients with cirrhosis. CLIF-C had better performance in predicting mortality than NACSELD, CTP and MELD-Na in patients with cirrhosis and SARS-CoV-2 infection. Clinicaltrials.gov:NCT04358380.

Drug-induced liver injury: A management position paper from the Latin American Association for Study of the liver.

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbs-induced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular.

[Prevalence of viral hepatitis type C in blood donors in Peru 2016 - 2017]. / Prevalencia del virus de hepatitis C en donantes de sangre en el Perú 2016 - 2017.

OBJECTIVES: Knowing the current prevalence of hepatitis C virus infection has taken great importance nowdays due to the new advances in the treatment of hepatitis C virus infection in which the new direct-acting antivirals have demonstrated a high rate of sustained viral response. MATERIALS AND METHODS: This is a descriptive study based on the detection of anti VHC in the blood banks of â€Å“Ministerio de Salud del Perú†according to the information obtained from â€Å“Programa Nacional de Hemoterapia y Bancos de Sangre†(PRONAHEBAS). RESULTS: In our study, the prevalence of anti-hepatitis C antibodies in blood donors nationwide was 0.428% in 2016 and 0.301% in 2017. CONCLUSION: To know updated data about the prevalence of hepatitis C virus infection in our population. It is the first step to be able to treat the disease and drastically reduce the infection rate according to the WHO target for 2030.

Prospective Latin American cohort evaluating outcomes of patients with COVID-19 and abnormal liver tests on admission.

INTRODUCTION & OBJECTIVES: The independent effect of liver biochemistries as a prognostic factor in patients with COVID-19 has not been completely addressed. We aimed to evaluate the prognostic value of abnormal liver tests on admission of hospitalized patients with COVID-19. MATERIALS & METHODS: We performed a prospective cohort study including 1611 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through July 31, 2020 in 38 different Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters, including liver function tests, on admission and during hospitalization. All patients were followed until discharge or death. We fit multivariable logistic regression models, further post-estimation effect through margins and inverse probability weighting. RESULTS: Overall, 57.8% of the patients were male with a mean age of 52.3 years, 8.5% had chronic liver disease and 3.4% had cirrhosis. Abnormal liver tests on admission were present on 45.2% (CI 42.7-47.7) of the cohort (n = 726). Overall, 15.1% (CI 13.4-16.9) of patients died (n = 244). Patients with abnormal liver tests on admission presented higher mortality 18.7% (CI 15.9-21.7), compared to those with normal liver biochemistries 12.2% (CI 10.1-14.6); P < .0001). After excluding patients with history of chronic liver disease, abnormal liver tests on admission were independently associated with death [OR 1.5 (CI 1.1-2.0); P = 0.01], and severe COVID-19 (2.6 [2.0-3.3], P < .0001), both adjusted by age, gender, diabetes, pneumonia and body mass index >30. CONCLUSIONS: The presence of abnormal liver tests on admission is independently associated with mortality and severe COVID-19 in hospitalized patients with COVID-19 infection and may be used as surrogate marker of inflammation. CLINICALTRIALS.GOV: NCT04358380.

Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.

Stress and a sedentary lifestyle are associated with irritable bowel syndrome in medical students from Peru: a cross-sectional study.

BACKGROUND: Previous studies suggest that medical students may have higher rates of irritable bowel syndrome as compared to the general population. We hypothesized lifestyle characteristics may be associated to irritable bowel syndrome. METHODS: A cross-sectional survey was conducted in 2015 among students in their fourth, fifth, sixth and seven years of a medical school in Peru. Volunteer participants responded to questions pertaining to demographics, surveys including the Rome III criteria and the Self-reported Stress questionnaire. Regression models were performed to establish variables independently associated with irritable bowel syndrome. RESULTS: Out of 452 students, 346 responded the survey (response rate: 76.5%; female rate: 47%; median age: 22 years). The irritable bowel syndrome prevalence in respondents was 9.5% (95% confidence interval: 6.7%-13.1%). On univariate analysis, being a senior medical student (odds ratio: 2.8; 95% confidence interval: 1.3-5.9; P < 0.01), mental illness (odds ratio: 3.3; 95% confidence interval: 1.6-6.8; P = 0.002), psychiatric medication use (odds ratio: 2.8; 95% confidence interval: 1.4-5.9; P = 0.005), sedentary lifestyle (odds ratio: 4.4; 95% confidence interval: 1.8-11; P = 0.001) and stress (odds ratio: 4.4; 95% confidence interval: 2.1-9.3; P < 0.001) were associated to irritable bowel syndrome. On a multivariate analysis, a sedentary lifestyle (odds ratio: 3.2; 95% confidence interval: 1.25-8.20; P = 0.01) and stress (odds ratio: 3.0; 95% confidence interval: 1.35-6.67; P < 0.01) were independently associated with irritable bowel syndrome. CONCLUSION: The prevalence of irritable bowel syndrome in medical students from Peru is slightly lower compared to the global prevalence of irritable bowel syndrome. Stress and a sedentary lifestyle were independent risk factors associated with irritable bowel syndrome. Our study suggests that lifestyle modifications and stress coping techniques could have an impact to reduce the rates of irritable bowel syndrome in medical students.

[Autoimmune hepatitis induced by isotretionine]. / Hepatitis autoinmune inducida por isotretionina.

We describe a case of a teenage patient with the diagnosis of drug induced autoimmune hepatitis. The patient is a 16 years old female, with the past medical history of Hashimoto’s hypothyroidism controlled with levothyroxine, who started treatment with Isotretionin (®Accutane) 20 mg q/12 hours for a total of 3 months for the treatment of severe acne. The physical examination was within normal limits and the results of the laboratory exams are: Baseline values of ALT 28 U/L, AST 28 U/L. Three months later: AST 756 U/L, ALT 1199U/L, alkaline phosphatase 114 U/L, with normal bilirrubin levels throughout the process. The serology studies were negative for all viral hepatitis; ANA titers were positive (1/160) and igG levels were also elevated. A liver biopsy was performed, and was compatible with the diagnosis of autoimmune hepatitis. Corticosteroid therapy was started with Prednisone 40 mg per day one week after stopping the treatment with isotretionin, observing an improvement in the laboratory values. We describe this case and review the world literature since there are no reported cases of Isotretinoin-induced autoimmune hepatitis.

Hepatitis autoinmune inducida por isotretionina / Autoimmune hepatitis induced by isotretionine

Se describe el caso de una paciente adolescente con el diagnóstico de hepatitis autoinmune asociada a isotretionina. Es una paciente de sexo femenino de 16 años, con antecedente de enfermedad de Hashimoto controlada con levotiroxina, que inicia tratamiento con isotretionina (Accutane) a una dosis de 20 mg c/ 12 horas por 3 meses para el tratamiento de acné severo. Al examen físico no se encuentran anormalidades y los exámenes de laboratorio fueron los siguientes: Al inicio del tratamiento AST 28 y ALT 28 U/L, y luego de los 3 meses, llega al máximo de: AST 756 U/L, ALT 1199 U/L, fosfatasa alcalina 114 U/L y presentando valores normales de bilirrubinas a lo largo del cuadro clínico. El estudio de serología fue negativo para todas las hepatitis virales, encontrándose ANA positivo (1/160) y niveles elevados de IgG. Una biopsia hepática practicada fue compatible con el diagnostico de hepatitis autoinmune. Se procede a iniciar corticoterapia con Prednisona a una dosis de 40 mg diarios una semana después de detener el tratamiento con isotretionina, observándose una mejoría en los valores de laboratorio. Describimos este caso y hacemos una revisión de la literatura mundial debido a que no se ha descrito aun un caso de hepatitis autoinmune inducida por isotretinoina...

We describe a case of a teenage patient with the diagnosis of drug induced autoimmune hepatitis. The patient is a 16 years old female, with the past medical history of HashimotoÆs hypothyroidism controlled with levothyroxine, who started treatment with Isotretionin (Accutane) 20 mg q/12 hours for a total of 3 months for the treatment of severe acne. The physical examination was within normal limits and the results of the laboratory exams are: Baseline values of ALT 28 U/L, AST 28 U/L. Three months later: AST 756 U/L, ALT 1199U/L, alkaline phosphatase 114 U/L, with normal bilirrubin levels throughout the process. The serology studies were negative for all viral hepatitis; ANA titers were positive (1/160) and igG levels were also elevated. A liver biopsy was performed, and was compatible with the diagnosis of autoimmune hepatitis. Corticosteroid therapy was started with Prednisone 40 mg per day one week after stopping the treatment with isotretionin, observing an improvement in the laboratory values. We describe this case and review the world literature since there are no reported cases of Isotretinoininduced autoimmune hepatitis...