Publications by authors named "Craig Lammert"

31 Publications

Behaviors, symptoms, and outcomes of North American patients with autoimmune hepatitis during the COVID-19 pandemic.

J Investig Med 2021 Jul 27. Epub 2021 Jul 27.

Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA

The management of patients with autoimmune hepatitis (AIH) in the era of SARS-CoV-2 is challenging given minimal published clinical data. We used a large cohort of patients with AIH across the USA to investigate the differences in known risk factors for severe SARS-CoV-2 and AIH characteristics among patients who experienced symptoms consistent with COVID-19 illness versus those who did not. Additionally, we explored the effect of living through the SARS-CoV-2 pandemic on the extrahepatic symptoms and behaviors of patients with AIH. An invitation to complete a COVID-19-specific questionnaire was publicized in well-established social media cohorts of patients with AIH. Eligibility criteria were age ≥18 years, US residency, and an AIH diagnosis by a physician. A total of 420 individuals were eligible for the study. Symptoms consistent with COVID-19 were reported in 11% (n=48) with 3 patients requiring hospitalizations. Body mass index (BMI) >40 kg/m (23% vs 10%, p0.01) and exposure to house (33% vs 3%, p=0.0001) or work (38% vs 17%, p0.02) contacts with COVID-19 were factors found higher in those with symptoms. Cirrhosis or steroid use or immunosuppression was not significantly different between symptomatic and non-symptomatic groups. Worsening fatigue (45% vs 30%, p=0.06), anxiety (89% vs 70%, p=0.08), and itch (40% vs 18%, p=0.03) were more common among those reporting COVID-19 symptoms compared with those without. BMI >40 kg/m and exposure to contacts with COVID-19 illness but not cirrhosis or immunosuppression were associated with increased risk of COVID-19 illness in patients with AIH.
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http://dx.doi.org/10.1136/jim-2021-001871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318716PMC
July 2021

Racial differences in primary sclerosing cholangitis mortality is associated with community socioeconomic status.

Liver Int 2021 Jul 9. Epub 2021 Jul 9.

Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.

Background And Aims: Natural history and outcomes data in PSC are mostly derived from cohorts where Blacks have been underrepresented. It is unknown if there are differences in mortality between Blacks and Whites with PSC.

Methods: PSC patients seen at our institution from June 1988 to Jan 2019 were identified by merging prospective ERCP hepatology-clinic databases and liver-transplant registry. Data on race, clinical events, and death was obtained through chart review. Data on community health were collected using indices from county health rankings. Cumulative incidence of death was calculated using liver transplant (LT) as a competing risk.

Results: Of 449 patients, 404 were White and 45 were Black. The median-duration of follow-up was 7 years (IQR:3, 13). Black patients were younger at presentation than White patients (36.3 vs 42.5 years., P = .013). Disease severity as indicated by Mayo Risk Score categories (low 27% vs 31%, intermediate 54% vs 49% and high 19% vs 19%, P = .690), comorbidity burden and frequency of cirrhosis (42% vs 35%, P = .411) were similar between Blacks and Whites. Cumulative incidence of liver-related death, with LT as a competing risk was significantly higher in Blacks compared to Whites (sHR 1.80, 95%CI 1.25, 2.61, P = .002). There was a significant interaction between race and community socioeconomic factors that attenuated the racial difference in mortality (sHR 1.01, 95%CI 0.99, 1.04, P = .345).

Conclusions: Blacks with PSC present at a younger age with a similar disease severity as Whites but have higher liver related mortality that is mediated in part through community health.
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http://dx.doi.org/10.1111/liv.15008DOI Listing
July 2021

Utilization and Impact of Complementary and Alternative Medicines in Symptomatic Autoimmune Hepatitis Patients.

Dig Dis Sci 2021 Jun 23. Epub 2021 Jun 23.

Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.

Background: Complementary and alternative medicine (CAM) use has become increasingly common. It is also prevalent in patients with chronic liver disease, but the scope, depth, and safety of use is not well known.

Aims: This study aimed to evaluate the prevalence and patterns of CAM use in autoimmune hepatitis (AIH) patients.

Methods: Electronic invitation to complete a 22 item CAM-specific questionnaire was posted weekly to well-established AIH Facebook communities (combined membership of 4700 individuals) during a 6-week study period. Age ≥ 18 years and AIH diagnosis made by a treating physician were the eligibility criteria.

Results: The prevalence of ever CAM use among participants was 56.4%, and nearly 42% used CAM after AIH diagnosis. Among those reporting CAM use after diagnosis, 53.7% (51/95) indicated CAM was used to mitigate AIH-related phenomenon, most often targeting liver inflammation/fibrosis (67.7%), fatigue (51%), joint pain (47.1%), and sleep issues (45.1%). Most frequent physical CAM strategies were exercise (49.5%) and yoga (34%), whereas most frequent consumable CAM included healthier eating (45.3%), cannabidiol preparations (45.3%), and probiotics (44.3%). Seventy-five percent reported that CAM improved AIH symptoms and no severe adverse events were reported.

Conclusions: CAM use in AIH patients is prevalent, yet providers have historically failed to document their patient's CAM strategies. Beyond inherent drug-induced liver injury risk, drug-drug interactions remain a concern and could alter baseline immunosuppression levels in AIH. Despite a majority found CAM approaches that improved targeted symptoms, all were unable to alter the course of chronically prescribed medications by physicians.
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http://dx.doi.org/10.1007/s10620-021-07112-0DOI Listing
June 2021

HLA-DR Mismatch and Black Race Are Associated With Recurrent Autoimmune Hepatitis After Liver Transplantation.

Transplant Direct 2021 Jul 10;7(7):e714. Epub 2021 Jun 10.

Department of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN.

The predictors of recurrent autoimmune hepatitis (R-AIH) after liver transplantation (LT) are heterogeneous with limited data to guide immunosuppression, with little data on impact of race.

Aims: To describe the incidence, predictors, and outcomes of R-AIH.

Methods: We studied patients undergoing LT for AIH during 2000-2017 at our center. Liver biopsies were performed for clinical indications. R-AIH was defined using clinical and histologic criteria.

Results: Among 75 patients undergoing LT for AIH (mean age 45 ± 16, 65% female individuals, 19% Black), 71 (95%) received antithymocyte globulin induction with tacrolimus-based immunosuppression. R-AIH developed in 20 (27%) patients at a median interval of 313 d (interquartile range, 155-1205). R-AIH was associated with level 2 HLA-DR mismatch (hazard ratio, 3.6; (95% confidence interval, 1.3-9.9;  = 0.01) and Black race (hazard ratio, 4.5; 95% confidence interval, 1.8-11.8;  = 0.002)] in the multivariable analysis. R-AIH developed in 62% of patients with level 2 HLA-DR mismatch on single-agent immunosuppression but in <20% of patients with no or 1 HLA-DR mismatch regardless of maintenance immunosuppression. R-AIH developed in 8 (57%) of 14 Black patients (71% on single-agent and 43% on dual-agent maintenance immunosuppression). Patient and graft survival were not impacted by R-AIH over a median follow-up of 8.3 y (interquartile range, 3-12).

Conclusions: High-level HLA-DR mismatch and Black recipient race are associated with an increased risk of R-AIH. Immunosuppression did not predict R-AIH, but higher rates of disease recurrence with single-agent maintenance immunosuppression with these risk factors were observed and may guide maintenance immunosuppression in LT for AIH.
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http://dx.doi.org/10.1097/TXD.0000000000001160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196096PMC
July 2021

Environmental risk factors are associated with autoimmune hepatitis.

Liver Int 2021 May 12. Epub 2021 May 12.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Background: Failure of immunologic homeostasis and resultant hepatocyte destruction in autoimmune hepatitis (AIH) is likely the result of environmental triggers within a permissive genetic architecture.

Aims: We aimed to identify risk factors associated with AIH in a well-phenotyped AIH cohort.

Methods: We prospectively collected environmental questionnaires from 358 AIH cases and 563 healthy controls. Response frequencies were compared using logistic regression, adjusting for age at recruitment, sex and education.

Results: AIH cases were more likely to ever have a urinary tract infection (UTI) (53.6% vs 33.9%, P < .001) and recurrent UTI (more than 1 per year) (23.5% vs 15.9%, P = .002) compared to controls. Female cases more frequently had ever used oral contraceptives (83.0% vs 73.7%, P = .006), fewer pregnancies (median = 1 vs 3, P < .001) and less often used hormone replacement therapy compared to controls (28.5% vs 60.1%, P < .001). Current smoking was more prevalent in cases (18.9% vs 7.4%, P = .022), yet no difference according to historical smoking behaviours was observed. Finally, cases were less likely to have history of mumps (32.4% vs 53.1%, P = .011) and rheumatic fever (1.1% vs 4.4%, P = .028), but reported higher vaccination frequency to chicken pox (38% vs 28.1%), measles (66.5% vs 39.3%), mumps (58.7% vs 34.6%), rubella (55.3% vs 32.7%), pertussis (59.8% vs 40.1%) and pneumococcus (47.2% VS 39.4%) (P < .002).

Conclusions: Environmental factors are important in AIH pathogenesis. Replication of these findings and prospective examination may provide new insight into AIH onset and outcomes.
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http://dx.doi.org/10.1111/liv.14944DOI Listing
May 2021

Patients with Autoimmune Hepatitis Report Lower Lifetime Coffee Consumption.

Dig Dis Sci 2021 Apr 30. Epub 2021 Apr 30.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Background: Coffee drinking has been associated with decreased risk of some autoimmune diseases as well liver disease and outcomes. Environmental factors, such as coffee consumption, are yet to be assessed among patients with autoimmune hepatitis (AIH).

Aim: We sought to investigate the relationship between coffee consumption and risk of AIH utilizing the Genetic Repository of Autoimmune Liver Disease and Contributing Exposures (GRACE) database.

Methods: Lifetime coffee drinking was collected from 358 AIH patients (cases) and 564 volunteers (controls) from primary care visits. Groups were compared utilizing the Wilcoxon rank sum test for continuous variables and the Chi-square test for discrete variables. Logistic regression was used to analyze the effects of different coffee parameters (time, frequency, and cups) after adjusting for age, sex, education, smoking status, BMI, and daily activity.

Results: 24.6% of AIH patients never drank coffee compared to 15.7% of controls (p < 0.001), and only 65.6% were current drinkers compared with 77% of controls (p < 0.001). Among "ever" coffee drinkers, AIH patients consumed fewer lifetime cups of coffee per month (45 vs. 47 for controls, p < 0.001) and spent less percentage of life drinking coffee (62.5% vs. 69.1% for controls, p < 0.001). Concurrent inflammatory bowel disease was higher among AIH patients than controls (5.7% vs. 1.2%, p < 0.001), yet did not significantly contribute to "never" coffee drinking status. The relationship between lower coffee consumption and AIH persisted even after controlling for covariates.

Conclusions: Coffee consumption is lower among patients with AIH compared to controls.
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http://dx.doi.org/10.1007/s10620-021-06989-1DOI Listing
April 2021

Short-chain fatty acid and fecal microbiota profiles are linked to fibrosis in primary biliary cholangitis.

FEMS Microbiol Lett 2021 04;368(6)

Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

The gut microbiota and metabolome could play a role in primary biliary cholangitis (PBC) progression. We aimed to assess fecal microbiota and fecal short-chain fatty acids (SCFAs) in PBC according to fibrosis. In a cross-sectional study of 23 PBC patients, fecal microbiota and SCFAs were determined using 16S rRNA sequencing and nuclear magnetic resonance spectroscopy, respectively. Fecal acetate and SCFAs were higher in advanced fibrosis. Advanced fibrosis microbiota exhibited decreased alpha diversity, increased Weisella and a distinct community composition. SCFAs correlated with individual taxa in non-advanced fibrosis. Fecal microbiota and SCFAs correspond to fibrosis in PBC.
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http://dx.doi.org/10.1093/femsle/fnab038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062329PMC
April 2021

Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study.

Hepatology 2021 06;73(6):2099-2109

Department of Gastroenterology, Medical Faculty, Uludag University, Bursa, Turkey.

Background And Aims: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking.

Approach And Results: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19.

Conclusions: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.
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http://dx.doi.org/10.1002/hep.31797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250536PMC
June 2021

Sex disparities in waitlisting and liver transplant for acute liver failure.

JHEP Rep 2021 Feb 1;3(1):100200. Epub 2020 Nov 1.

Division of Gastroenterology/Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Background & Aims: Sex disparities in liver transplantation (LT) for chronic liver disease have been described. It is unclear if similar disparities exist for acute liver failure (ALF).

Methods: Adults waitlisted for LT from 2002 to 2016 with ALF were investigated using the United Network of Organ Sharing database. Clinical characteristics and causative aetiologies were compared between men and women who were waitlisted Status-1. Differences in LT, waitlist removal, and 1-year post-transplant survival were explored.

Results: Of 8,408 patients waitlisted for LT with ALF, 41.3% of men and 63.9% of women were waitlisted Status-1 ( <0.001). Women had significantly higher international normalised ratio, higher frequency of grade 3-4 hepatic encephalopathy, and different aetiologies of ALF than men. On univariable analysis, women were less likely to undergo LT (subdistribution hazard ratio [SHR] 0.90; 95% CI 0.84-0.97) and were more likely to die or be removed from the waitlist as a result of clinical deterioration (SHR 1.14; 95% CI 1.002-1.30) than men. The disparities in LT (HR 0.95; 95% CI 0.87-1.03) and death/clinical deterioration (SHR 1.13; 95% CI 0.99-1.29) were no longer significant on multivariable analysis. On multivariable analysis, there was no difference in 1-year post-transplant survival between men and women.

Conclusions: Women with ALF are more likely to be waitlisted Status-1 than men. There were no clear disparities in LT or waitlist removal. Sex differences in LT and waitlist removal were attenuated on fully adjusted models, suggesting that these disparities may in part be mitigated by Status-1 listing.

Lay Summary: Women with acute liver failure appear to be sicker than men and more often require urgent Status-1 waitlisting. There were no sex disparities in waitlist removal because of clinical deterioration or liver transplantation. This is in contrast to chronic liver disease, where sex disparities exist. The Status-1 waitlisting that women with acute liver failure receive may in part mitigate sex disparities in liver transplantation.
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http://dx.doi.org/10.1016/j.jhepr.2020.100200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817503PMC
February 2021

Exploratory Study of Autoantibody Profiling in Drug-Induced Liver Injury with an Autoimmune Phenotype.

Hepatol Commun 2020 Nov 1;4(11):1651-1663. Epub 2020 Sep 1.

Department of Medicine Indiana University School of Medicine Indianapolis IN USA.

Drug-induced liver injury (DILI) sometimes presents with an autoimmune hepatitis-like phenotype (AI-DILI), and it is challenging to distinguish it from autoimmune hepatitis (AIH). We conducted a study to identify autoantibodies unique to AI-DILI by profiling serum autoantibodies. Autoantibodies were quantified using an autoantigen array containing 94 autoantigens from four groups: AI-DILI (n = 65), DILI controls (n = 67), AIH (n = 17), and healthy controls (HCs; n = 30). In 37 patients with AI-DILI, samples were also collected 6 months after presentation. AI-DILI and AIH had similar anti-neutrophil antibody and anti-smooth muscle antibody prevalence. Compared to HCs, AIH had an increase in many immunoglobulin G (IgG; 35 [46.1%]) and IgM (51 [70%]) autoantibodies, whereas AI-DILI had an increase of IgM (40 [54.8%]) but not IgG autoantibodies. DILI controls had a similar IgG and IgM profile compared to HCs. Comparing AIH to AI-DILI identified 18 (23.7%) elevated IgG but only one (1.4%) IgM autoantibodies, indicating the unique IgG autoantibody profile in AIH. Compared to DILI and HCs, increased IgM autoantibodies in AI-DILI and AIH were common; however, AI-DILI induced by different drugs showed different frequencies of IgM autoantibodies, with nitrofurantoin-related AI-DILI showing a higher number of increased IgM autoantibodies. AI-DILI autoantibody levels at diagnosis and at 6 months showed a significant decline in 37 IgM autoantibodies. A model with highly correlated IgG and IgM was fitted into multivariate logistic regression and revealed an area under the curve of 0.87 (95% confidence interval, 0.79-0.95) to distinguish AIH from AI-DILI. The unique IgG and IgM autoantibody signature appears to be a promising biomarker for distinguishing AI-DILI from AIH.
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http://dx.doi.org/10.1002/hep4.1582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603536PMC
November 2020

Hepatic steatosis is highly prevalent but is not correlated with stiffness in autoimmune hepatitis.

Medicine (Baltimore) 2020 Oct;99(42):e22805

Indiana University School of Medicine, Indianapolis, IN.

The prevalence and impact of hepatic steatosis among patients with autoimmune hepatitis (AIH) is not well described.We conducted a cross-sectional study to determine the prevalence of hepatic steatosis in AIH patients and examined its relationship with hepatic fibrosis using vibration controlled transient elastography. Liver stiffness measurement (LSM), controlled attenuation parameter (CAP), gender, current age, and body mass index (BMI) were collected from 277 AIH patients. Hepatic steatosis was defined as CAP >263 db/m.The study participants were mostly female (82%) with an average age of 49 years and BMI 29.7 kg/m. Mean LSM was 12.5 (standard deviation 13.5) kPa and CAP was 244 (standard deviation 63) db/m. The prevalence of coexisting steatosis was 33.2%, and steatosis did not correlate with LSM (r = 0.05, P = .46). In this study, only gender (females with 31% lower LSM on average compared to males, P = .001) and BMI (each unit increase of BMI resulted in a 1.48% increase on average LSM, P = .01) correlated with LSM. Male gender had significant association with increased LSM, after controlling for age, BMI, and CAP (P = .001).This exploratory study using noninvasive vibration controlled transient elastography revealed hepatic steatosis is highly prevalent in patients with AIH but not associated with liver fibrosis.
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http://dx.doi.org/10.1097/MD.0000000000022805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571921PMC
October 2020

An Outbreak Presents An Opportunity to Learn About A Rare Phenotype: Autoimmune Hepatitis After Acute Hepatitis A.

Ann Hepatol 2020 Nov - Dec;19(6):694-696. Epub 2020 Sep 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA. Electronic address:

There are rare instances where patients with acute hepatitis A virus infection subsequently developed autoimmune hepatitis. The diagnosis of autoimmune hepatitis in this setting is challenging. Furthermore, information on treatment with steroids or other immune suppressants, duration of therapy and possibility of treatment discontinuation is currently unclear. Here we report a case series of four patients with histology proven autoimmune hepatitis after hepatitis A virus infection. We describe the presenting features, diagnosis, treatment and long-term outcomes of these cases. This case series provides a insight into the clinical presentation and treatment of autoimmune hepatitis after hepatitis A infection with interesting take home points for clinical hepatologists.
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http://dx.doi.org/10.1016/j.aohep.2020.08.069DOI Listing
September 2020

Genetic and Environmental Risk Factors for Autoimmune Hepatitis.

Authors:
Craig Lammert

Clin Liver Dis (Hoboken) 2019 Jul 2;14(1):29-32. Epub 2019 Aug 2.

Department of Medicine Indiana University School of Medicine Indianapolis IN.

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http://dx.doi.org/10.1002/cld.798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677013PMC
July 2019

Cannabidiol (CBD) Consumption and Perceived Impact on Extrahepatic Symptoms in Patients with Autoimmune Hepatitis.

Dig Dis Sci 2020 01 30;65(1):322-328. Epub 2019 Jul 30.

Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.

Background And Aims: Utilization and safety of cannabidiol (CBD) in patients with autoimmune hepatitis (AIH) are currently unknown. We aimed to identify the frequency of CBD use, impact on symptoms, and safety profile.

Methods: An invitation to complete a CBD-specific questionnaire was posted every other day to well-established autoimmune hepatitis Facebook communities (combined membership of 2600 individuals) during a 10-day study period. Age ≥ 18 years and an AIH diagnosis by a physician were the eligibility criteria for participation in the survey.

Results: In total, 371 AIH patients (median age 49 years, 32% reported advanced fibrosis) completed the questionnaire. Respondents were 91% women, 89% Caucasian, and 89% from North America. Ninety-three (25%) respondents were ever CBD users, with 55 of them (15% of the survey responders) identified as current users. Among ever users, 45.7% reported their treating doctors were aware of their CBD use. The most common reason cited for CBD use was pain (68%), poor sleep (62%), and fatigue (38%). Most respondents using CBD for these symptoms reported a significant improvement in pain (82%), sleep (87%), and fatigue (61%). In ever CBD users, 17.3% were able to stop a prescription medication because of CBD use: pain medication (47%), immunosuppression (24%), and sleep aids (12%). Side effects attributed to CBD use were reported in 3% of CBD users, yet there were no reported emergency department visits or hospitalizations.

Conclusion: CBD use was not uncommon in patients with AIH, and its use was associated with reports of improvement in extrahepatic symptoms.
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http://dx.doi.org/10.1007/s10620-019-05756-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943405PMC
January 2020

Black Adult Patients With Acute Liver Failure Are Sicker and More Likely to Undergo Liver Transplantation Than White Patients.

Liver Transpl 2019 11 9;25(11):1634-1641. Epub 2019 Aug 9.

Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN.

Racial and ethnic differences in the presentation and outcomes of patients wait-listed with acute liver failure (ALF) have not been explored. Adult patients with ALF wait-listed for liver transplantation (LT) from 2002 to 2016 were investigated using the United Network for Organ Sharing database. Clinical characteristics and causative etiologies were compared between white, black, Hispanic, and Asian patients with ALF who were wait-listed as status 1. A competing risk analysis was used to explore differences in LT and wait-list removal rates. Kaplan-Meier survival curves were used to explore differences in 1-year posttransplant survival. There were 8208 patients wait-listed with a primary diagnosis of ALF; 4501 were wait-listed as status 1 (55.3% of whites, 64.4% of blacks, 51.6% of Hispanics, 40.7% of Asians; P < 0.001). Black patients had higher bilirubin and Model for End-Stage Liver Disease at wait-listing than other groups. White patients were the most likely to have acetaminophen toxicity as a causative etiology, whereas black patients were the most likely to have autoimmune liver disease. Black patients were significantly more likely to undergo LT than white patients (hazard ratio, 1.20; 95% confidence interval, 1.08-1.30). There was no difference in wait-list removal because of death or clinical deterioration among racial/ethnic groups. The 1-year posttransplant survival was lowest in black patients (79.6%) versus white (82.8%), Hispanic (83.9%), and Asian (89.3%) patients (P = 0.02). In conclusion, etiologies of ALF vary by race and ethnicity. Black patients with ALF were more likely to be wait-listed as status 1 and undergo LT than white patients, but they were sicker at presentation. The 1-year posttransplant survival rate was lowest among black patients.
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http://dx.doi.org/10.1002/lt.25594DOI Listing
November 2019

Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis.

Clin Transl Gastroenterol 2019 06;10(6):e00032

Division of Infectious Diseases, Vanderbilt University Medical Centre, Nashville, Tennessee, USA.

Introduction: HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist.

Methods: We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01.

Results: DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P = 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P = 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles.

Discussion: Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.
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http://dx.doi.org/10.14309/ctg.0000000000000032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613860PMC
June 2019

Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis.

Dig Dis Sci 2019 06 7;64(6):1705-1710. Epub 2019 Jan 7.

Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.

Background: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood.

Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design.

Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case.

Results: Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC.

Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC.
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http://dx.doi.org/10.1007/s10620-018-5441-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525055PMC
June 2019

Patients With Chronic Liver Disease Suggestive of Nonalcoholic Fatty Liver Disease May Be at Higher Risk for Drug-Induced Liver Injury.

Clin Gastroenterol Hepatol 2019 12 20;17(13):2814-2815. Epub 2018 Dec 20.

Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address:

To date, there have been no studies that systematically examined if individuals with nonalcoholic fatty liver disease (NAFLD) have an increased risk of drug-induced liver injury (DILI). We conducted a study to test if the frequency of suspected DILI from prescription agents is higher in individuals with chronic liver disease (CLD) suggestive of NAFLD.
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http://dx.doi.org/10.1016/j.cgh.2018.12.013DOI Listing
December 2019

Extrahepatic Autoimmune Diseases are Prevalent in Autoimmune Hepatitis Patients and Their First-Degree Relatives: Survey Study.

Interact J Med Res 2018 Dec 19;7(2):e18. Epub 2018 Dec 19.

Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States.

Background: Concurrent autoimmune illnesses contribute to increased medical burden and reduced quality of life in patients with autoimmune hepatitis (AIH). The frequency of coexisting autoimmune conditions among North American patients with AIH and their families remains incomplete. Challenges associated with disease capture in the electronic medical record, high study costs, and geographic spread of patients are formidable barriers to understanding the extent of concurrent autoimmune conditions in these groups.

Objective: This objective of this study was to examine the frequency of extrahepatic autoimmune diseases (EHAD) among AIH cases and healthy controls as well as their first-degree relatives using social networking sites (SNS).

Methods: We developed a 53-question survey detailing the history of autoimmune diseases. A survey link was posted at routine intervals within specific Web-based cohorts on SNS. Healthy controls, without self-reported autoimmune liver disease, were recruited from Amazon's Mechanical Turk. Continuous variables were summarized using medians and P values obtained with the Wilcoxon rank-sum test. Categorical variables were compared using the chi-square test.

Results: Compared with controls (n=1162), cases (n=306) were more likely to be older (median age: 49 vs 33 years), female (284/306, 92.81% vs 955/1162, 82.18%), and have an EHAD (128/306, 41.83% vs 218/1162, 18.76%; P=.001). The most frequent EHADs among cases were thyroid disease (49/306, 16.01% ), Sjögren syndrome (27/306, 8.82%), Raynaud phenomenon (23/306, 7.52%), and psoriasis (22/306, 7.19%). Overall, 55.88% (171/306) of cases and 35.71% (1601/4484) of controls reported at least 1 first-degree relative (FDR) with a history of EHAD (P=.001). Cases had a significantly higher risk of EHAD than controls after the adjustment for age, sex, race, and body mass index: odds ratio 2.46 (95% CI 1.8-3.3); P=.001.

Conclusions: Patients with AIH report higher prevalence of coexistent EHAD than healthy controls, and their FDRs are also more likely to have autoimmune disorders.
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http://dx.doi.org/10.2196/ijmr.9625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315230PMC
December 2018

Leveraging Social Networking Sites for an Autoimmune Hepatitis Genetic Repository: Pilot Study to Evaluate Feasibility.

J Med Internet Res 2018 01 18;20(1):e14. Epub 2018 Jan 18.

Division of Digestive and Liver Diseases, Indiana University School of Medicine, Indianapolis, IN, United States.

Background: Conventional approaches to participant recruitment are often inadequate in rare disease investigation. Social networking sites such as Facebook may provide a vehicle to circumvent common research limitations and pitfalls. We report our preliminary experience with Facebook-based methodology for participant recruitment and participation into an ongoing study of autoimmune hepatitis (AIH).

Objective: The goal of our research was to conduct a pilot study to assess whether a Facebook-based methodology is capable of recruiting geographically widespread participants into AIH patient-oriented research and obtaining quality phenotypic data.

Methods: We established a Facebook community, the Autoimmune Hepatitis Research Network (AHRN), in 2014 to provide a secure and reputable distillation of current literature and AIH research opportunities. Quarterly advertisements for our ongoing observational AIH study were posted on the AHRN over 2 years. Interested and self-reported AIH participants were subsequently enrolled after review of study materials and completion of an informed consent by our study coordinator. Participants returned completed study materials, including epidemiologic questionnaires and genetic material, to our facility via mail. Outside medical records were obtained and reviewed by a study physician.

Results: We successfully obtained all study materials from 29 participants with self-reported AIH within 2 years from 20 different states. Liver biopsy results were available for 90% (26/29) of participants, of which 81% (21/29) had findings consistent with AIH, 15% (4/29) were suggestive of AIH with features of primary biliary cholangitis (PBC), and 4% (1/29) had PBC alone. A total of 83% (24/29) had at least 2 of 3 proposed criteria: positive autoimmune markers, consistent histologic findings of AIH on liver biopsy, and reported treatment with immunosuppressant medications. Self-reported and physician records were discrepant for immunosuppressant medications or for AIH/PBC diagnoses in 4 patients.

Conclusions: Facebook can be an effective ancillary tool for facilitating patient-oriented research in rare diseases. A social media-based approach transcends established limitations in rare disease research and can further develop research communities.
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http://dx.doi.org/10.2196/jmir.7683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795096PMC
January 2018

A dedicated paracentesis clinic decreases healthcare utilization for serial paracenteses in decompensated cirrhosis.

Abdom Radiol (NY) 2018 08;43(8):2190-2197

Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.

Purpose: The purpose of the study is to describe the effect of a dedicated paracentesis clinic on healthcare utilization by patients with decompensated cirrhosis and refractory ascites.

Methods: This Institutional Review Board-approved retrospective study identified cirrhotic patients receiving paracenteses over a 6-month period before and after creating the paracentesis clinic. Patients were followed for 12 months to collect outcome data including characteristics of subsequent hospitalizations and paracenteses. Logistic regression was used to examine the association between the paracentesis clinic and outcomes.

Results: There were 183 patients and 1364 paracenteses performed during the study time period. Age, gender, cirrhosis etiology, MELD, Child-Pugh, and Charlson comorbidity index were comparable between the two groups. Rates of mortality, transplant, and hospitalization were also similar during 1 year follow-up. After establishment of the paracentesis clinic, median paracenteses per patient increased from 2 (IQR 1-7) to 4 (IQR 2-11) (P = 0.01); albumin replacement after paracenteses ≥ 5 L improved from 76.3% to 91.7% (P < 0.001); and the fraction of outpatient paracenteses performed in the emergency department decreased from 13.4% to 3.8% (P < 0.001). Major complications remained negligible at 0.81% across both time periods. While fewer patients were admitted for ascites after the paracentesis clinic (39.6% vs. 20.8%, P = 0.009), more patients had acute kidney injury (AKI) during follow-up (47.2% vs. 65.9%, P = 0.02), with a trend towards more AKI admissions (22.6% vs. 35.4%, P = 0.09).

Conclusion: A dedicated paracentesis clinic can improve access and wait times, while also reducing admissions for ascites and paracenteses performed in the emergency department.
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http://dx.doi.org/10.1007/s00261-017-1406-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975110PMC
August 2018

Digital Cohorts Within the Social Mediome: An Approach to Circumvent Conventional Research Challenges?

Clin Gastroenterol Hepatol 2017 05;15(5):614-618

Department of Digestive and Liver Diseases, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address:

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http://dx.doi.org/10.1016/j.cgh.2017.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407392PMC
May 2017

Management of Difficult Cases of Autoimmune Hepatitis.

Curr Gastroenterol Rep 2016 Feb;18(2)

Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.

Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients.
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http://dx.doi.org/10.1007/s11894-015-0484-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410647PMC
February 2016

Investigation Gone Viral: Application of the Social Mediasphere in Research.

Gastroenterology 2015 Oct 22;149(4):839-43. Epub 2015 Aug 22.

Department of Internal Medicine, Indianapolis, Indiana.

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http://dx.doi.org/10.1053/j.gastro.2015.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827767PMC
October 2015

Reduced coffee consumption among individuals with primary sclerosing cholangitis but not primary biliary cirrhosis.

Clin Gastroenterol Hepatol 2014 Sep 16;12(9):1562-8. Epub 2014 Jan 16.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota. Electronic address:

Background & Aims: Coffee consumption has been associated with decreased risk of liver disease and related outcomes. However, coffee drinking has not been investigated among patients with cholestatic autoimmune liver diseases, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). We investigated the relationship between coffee consumption and risk of PBC and PSC in a large North American cohort.

Methods: Lifetime coffee drinking habits were determined from responses to questionnaires from 606 patients with PBC, 480 with PSC, and 564 healthy volunteers (controls). Patients (those with PBC or PSC) were compared with controls by using the Wilcoxon rank sum test for continuous variables and c(2) method for discrete variables. Logistic regression was used to analyze the estimate of the effects of different coffee parameters (time, frequency, and type of coffee consumption) after adjusting for age, sex, smoking status, and education level.

Results: Patients with PBC and controls did not differ in coffee parameters. However, 24% of patients with PSC had never drunk coffee compared with 16% of controls (P < .05), and only 67% were current drinkers compared with 77% of controls (P < .05). Patients with PSC also consumed fewer lifetime cups per month (45 vs 47 for controls, P < .05) and spent a smaller percentage of their lifetime drinking coffee (46.6% vs 66.7% for controls, P < .05). These differences remained significant in a multivariate model. Among PSC patients with concurrent ulcerative colitis, coffee protected against proctocolectomy (hazard ratio, 0.34; P < .001).

Conclusions: Coffee consumption is lower among patients with PSC, but not PBC, compared with controls.
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http://dx.doi.org/10.1016/j.cgh.2013.12.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101072PMC
September 2014

Biochemical response to ursodeoxycholic acid predicts survival in a North American cohort of primary biliary cirrhosis patients.

J Gastroenterol 2014 Oct 8;49(10):1414-20. Epub 2013 Dec 8.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Biochemical response to ursodeoxycholic acid among patients with primary biliary cirrhosis remains variable, and there is no agreement of an ideal model. Novel assessment of response coupled to histologic progression was recently defined by the Toronto criteria. We retrospectively assessed transplant-free survival and clinical outcomes associated with ursodeoxycholic acid response to evaluate the Toronto criteria using a large North American cohort of PBC patients.

Methods: Three hundred and ninety-eight PBC patients from the Mayo Clinic PBC Genetic Epidemiology Registry were assessed for ursodeoxycholic acid treatment and biochemical response per the Toronto criteria. Responders were defined by reduction in alkaline phosphatase to less than or equal to 1.67 times the upper normal limit by 2 years of treatment, whereas non-responders had alkaline phosphatase values greater than 1.67 times the upper normal limit. Probability of survival was estimated using the Kaplan-Meier method.

Results: Three hundred and two (76 %) patients were responders and 96 (24 %) were non-responders. Significantly more non-responders developed adverse events related to chronic liver disease compared to responders (hazard ratio (HR) 2.77, P = 0.001). Biochemical responders and early-stage disease at treatment start was associated with improved overall transplant-free survival compared to non-responders (HR 1.9) and patients with late-stage disease (HR 2.7) after age and sex adjustment.

Conclusions: The Toronto criteria are capable of identifying ursodeoxycholic acid-treated primary biliary cirrhosis patients at risk of poor transplant-free survival and adverse clinical outcomes. Our data reveal that despite advanced disease at diagnosis, biochemical response per the Toronto criteria associates with improved overall transplant-free survival.
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http://dx.doi.org/10.1007/s00535-013-0903-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048793PMC
October 2014

Questionnaire based assessment of risk factors for primary biliary cirrhosis.

Dig Liver Dis 2013 Jul 11;45(7):589-94. Epub 2013 Mar 11.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Background: Primary biliary cirrhosis is a cholestatic liver disease characterized by immune-mediated destruction of bile ducts. Its pathogenesis is largely unknown, although complex interactions between environment and genetic predisposition are proposed.

Aims: Identify disease risk factors using a detailed patient questionnaire and compare study findings to 3 published reports.

Methods: Questionnaire data were prospectively collected from 522 cases and 616 controls of the Mayo Clinic Primary Biliary Cirrhosis Genetic Epidemiology Registry. Case and control responses were compared using logistic regression, adjusting for recruitment age, sex, and education level.

Results: Cases reported ever regularly smoking cigarettes more frequently than controls (P < 0.001). History of urinary tract infection was similar between groups; however, cases reported multiple urinary tract infections more commonly than controls (P < 0.001). Frequency of other autoimmune disease was higher in cases than controls (P < 0.001). As well, prevalence of primary biliary cirrhosis among first-degree relatives was higher in case families than control families (P < 0.001).

Conclusions: Our study confirms prior reported risk factors associated with disease risk. Given the potential importance of gene and environment interactions, further examination of environmental risk factors considering genetic background may provide new insight into primary biliary cirrhosis pathogenesis.
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http://dx.doi.org/10.1016/j.dld.2013.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686972PMC
July 2013

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

Hum Mol Genet 2012 Dec 29;21(23):5209-21. Epub 2012 Aug 29.

Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN, USA.

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
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http://dx.doi.org/10.1093/hmg/dds359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490520PMC
December 2012

Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation.

Liver Transpl 2012 Jul;18(7):803-10

William J. von Leibig Transplant Center, Mayo Clinic, Rochester, MN 55905, USA.

Drug-induced liver injury (DILI) is increasingly being recognized as a common cause of acute hepatitis. The clinical impact of DILI after liver transplantation (LT) is not known. The aim of this study was to describe the frequency, clinical presentation, and outcomes of DILI in LT recipients. LT recipients with possible DILI were identified with electronic pathology records and clinical note database retrieval tools. Diagnostic criteria were applied to identify cases of DILI. Twenty-nine of 1689 LT recipients (1.7%) were identified with DILI. The mean age was 52 years, and 52% were women. The major indications for LT were primary sclerosing cholangitis (28%), cholangiocarcinoma (14%), and hepatocellular carcinoma (14%). The severity of DILI was mild or moderate in 92% of the cases. Nausea or diarrhea (31%), jaundice (24%), and pruritus (10%) were the most common symptoms at the time of diagnosis. The mean biochemistry values were as follows: alanine aminotransferase, 204 ± 263 U/L; aspartate aminotransferase, 108 ± 237 U/L; alkaline phosphatase, 469 ± 689 U/L; and total bilirubin, 1.9 ± 10.3 mg/dL. The median duration of medication use until the diagnosis of DILI was 57 days, and the major agent classes were antibiotics (48%), immunosuppressive agents (14%), and antihyperlipidemic drugs (7%). Trimethoprim-sulfamethoxazole was the most common implicated agent (n = 11). Serum liver enzymes improved within a median time of 34 days (range = 5-246 days) after drug withdrawal. Hepatic retransplantation or death did not occur. Among the 50 cases with possible DILI explained by other causes, 13 individuals (26%) had no alternative diagnosis despite histological findings compatible with DILI. In conclusion, DILI is a rare yet underrecognized event among LT recipients. The majority of cases are not clinically severe, and they resolve after drug cessation without hepatic retransplantation or death.
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http://dx.doi.org/10.1002/lt.23424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396746PMC
July 2012

Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events.

Hepatology 2010 Feb;51(2):615-20

Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Unlabelled: Reactive metabolites generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury (DILI), but supporting data are limited. If this is true, then compounds with significant hepatic metabolism should cause more DILI than those without it. We conducted a study to examine the relationship between hepatic metabolism and DILI of prescription medications. We systematically extracted the metabolism characteristics of 207 of the most widely prescribed oral medications in the United States. Compounds with >50% hepatic metabolism were characterized as those with significant hepatic metabolism (n = 149). Hepatic adverse events of interest were alanine aminotransferase >3 times the upper limit of normal, jaundice, liver failure, liver transplantation, or fatal DILI. Compared with compounds with lesser hepatic metabolism, compounds belonging to the significant hepatic metabolism group had significantly higher frequency of alanine aminotransferase >3 times the upper limit of normal (35% versus 11%, P = 0.001), liver failure (28% versus 9%, P = 0.004), and fatal DILI (23% versus 4%, P = 0.001), but not jaundice (46% versus 35%, P = 0.2) or liver transplantation (9% versus 2%, P = 0.11). Twelve compounds with no hepatic metabolism had no reports of liver failure, liver transplantation, or fatal DILI. When the relationship between hepatic adverse events and combination of hepatic metabolism and daily dose was examined, compounds with both significant hepatic metabolism and daily dose >50 mg (n = 50) were significantly more hepatotoxic than compounds belonging to other groups. Compared with medications without biliary excretion, compounds with biliary excretion (n = 50) had significantly higher frequency of jaundice (74% versus 40%, P = 0.0001).

Conclusion: Our study finds an important relationship between a compound's metabolism profile and reports of hepatic adverse events.
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http://dx.doi.org/10.1002/hep.23317DOI Listing
February 2010
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