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Item Behaviors, symptoms, and outcomes of North American patients with autoimmune hepatitis during the COVID-19 pandemic(BMJ, 2021-12) Vuppalanchi, Vahin; Gelow, Kayla; Vuppalanchi, Raj; Lammert, Craig; Green, Kelsey; Medicine, School of MedicineThe 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/m2 (23% vs 10%, p=0.01) and exposure to house (33% vs 3%, p=0.0001) or work (38% vs 17%, p=0.02) 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/m2 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.Item Black Adult Patients With Acute Liver Failure Are Sicker and More Likely to Undergo Liver Transplantation Than White Patients(Wiley, 2019) Nephew, Lauren; Zia, Zahra; Ghabril, Marwan; Orman, Eric; Lammert, Craig; Chalasani, Naga; Medicine, School of MedicineRacial 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.Item Cannabidiol (CBD) Consumption and Perceived Impact on Extrahepatic Symptoms in Patients with Autoimmune Hepatitis(Springer, 2019-07-30) Mathur, Karan; Vuppalanchi, Vahin; Gelow, Kayla; Vuppalanchi, Raj; Lammert, Craig; Medicine, School of MedicineBackground 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.Item Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis(Wolters Kluwer, 2023-05-23) Chalasan, Naga; Vuppalanchi, Raj; Lammert, Craig; Gawrieh, Samer; Braun, Jerome V.; Zhuang, Jiali; Ibarra, Arkaitz; Ross, David A.; Nerenberg, Michael; Quake, Stephen R.; Sninsky, John J.; Toden, Shusuke; Medicine, School of MedicineBackground: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by multifocal bile duct strictures. To date, underlying molecular mechanisms of PSC remain unclear, and therapeutic options are limited. Methods: We performed cell-free messenger RNA (cf-mRNA) sequencing to characterize the circulating transcriptome of PSC and noninvasively investigate potentially bioactive signals that are associated with PSC. Serum cf-mRNA profiles were compared among 50 individuals with PSC, 20 healthy controls, and 235 individuals with NAFLD. Tissue and cell type-of-origin genes that are dysregulated in subjects with PSC were evaluated. Subsequently, diagnostic classifiers were developed using PSC dysregulated cf-mRNA genes. Results: Differential expression analysis of the cf-mRNA transcriptomes of PSC and healthy controls resulted in identification of 1407 dysregulated genes. Furthermore, differentially expressed genes between PSC and healthy controls or NAFLD shared common genes known to be involved in liver pathophysiology. In particular, genes from liver- and specific cell type-origin, including hepatocyte, HSCs, and KCs, were highly abundant in cf-mRNA of subjects with PSC. Gene cluster analysis revealed that liver-specific genes dysregulated in PSC form a distinct cluster, which corresponded to a subset of the PSC subject population. Finally, we developed a cf-mRNA diagnostic classifier using liver-specific genes that discriminated PSC from healthy control subjects using gene transcripts of liver origin. Conclusions: Blood-based whole-transcriptome cf-mRNA profiling revealed high abundance of liver-specific genes in sera of subjects with PSC, which may be used to diagnose patients with PSC. We identified several unique cf-mRNA profiles of subjects with PSC. These findings may also have utility for noninvasive molecular stratification of subjects with PSC for pharmacotherapy safety and response studies.Item Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury(Elsevier, 2023) Chalasani, Naga; Li, Yi-Ju; Dellinger, Andrew; Navarro, Victor; Bonkovsky, Herbert; Fontana, Robert J.; Gu, Jiezhun; Barnhart, Huiman; Phillips, Elizabeth; Lammert, Craig; Schwantes-An, Tae-Hwi; Nicoletti, Paola; Kleiner, David E.; Hoofnagle, Jay H.; Drug Induced Liver Injury Network; Medicine, School of MedicineBackground & aims: Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN). Methods: Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661). Results: Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10-4), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10-5), and non-NTF DILI (OR 3.34, p = 0.003). Conclusion: NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. Impact and implications: Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.Item A dedicated paracentesis clinic decreases healthcare utilization for serial paracenteses in decompensated cirrhosis(Springer Nature, 2018-08) Cheng, Yao-Wen; Sandrasegaran, Kumar; Cheng, Katherine; Shah, Angela; Ghabril, Marwan; Berry, William; Lammert, Craig; Chalasani, Naga; Orman, Eric S.; Radiology and Imaging Sciences, School of MedicinePURPOSE: 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.Item Digital Cohorts Within the Social Mediome: An Approach to Circumvent Conventional Research Challenges?(Elsevier, 2017-05) Kulanthaivel, Anand; Fogel, Rachel; Jones, Josette; Lammert, Craig; Biohealth Informatics, School of Informatics and ComputingItem Exploratory Study of Autoantibody Profiling in Drug‐Induced Liver Injury with an Autoimmune Phenotype(Wiley, 2020-09-01) Lammert, Craig; Zhu, Chengsong; Lian, Yun; Raman, Indu; Eckert, George; Li, Quan‐Zhen; Chalasani, Naga; Medicine, School of MedicineDrug‐induced liver injury (DILI) sometimes presents with an autoimmune hepatitis‐like phenotype (AI‐DILI), and it is challenging to distinguish it from de novo 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), de novo 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 de novo AIH had similar anti‐neutrophil antibody and anti‐smooth muscle antibody prevalence. Compared to HCs, de novo 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 de novo AIH to AI‐DILI identified 18 (23.7%) elevated IgG but only one (1.4%) IgM autoantibodies, indicating the unique IgG autoantibody profile in de novo AIH. Compared to DILI and HCs, increased IgM autoantibodies in AI‐DILI and de novo 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 de novo AIH from AI‐DILI. Conclusion: The unique IgG and IgM autoantibody signature appears to be a promising biomarker for distinguishing AI‐DILI from de novo AIH.Item Health-related quality of life is dynamic in alcohol hepatitis and responds to improvement in liver disease and alcohol consumption(Wiley, 2022) Madathanapalli, Abhishek; Tang, Qing; Lammert, Craig; Samala, Niharika; Shah, Vijay H.; Sanyal, Arun; Chalasani, Naga; Desai, Archita P.; Biostatistics, School of Public HealthBackground: The impact of alcoholic hepatitis (AH) on health-related quality of life (HRQOL) remains inadequately described. We aimed to characterize HRQOL in AH and heavy drinkers (HD), and its associations with clinical variables and outcomes. Methods: This is a post hoc analysis of participants in the Translational Research and Evolving Alcoholic Hepatitis Treatment 001 study (NCT02172898). HRQOL was measured using Short Form Health Survey (SF-36). Mean SF-36 scores were compared in AH and HD with two-sample t-tests. Associations among clinical characteristics, 30-day mortality, and SF-36 mental and physical component scores (MC, PC) were investigated with generalized linear and logistic multivariate regression models. Trends of MC and PC scores were analyzed using one-way ANOVA. Results: Participants with AH (n = 258) and HD (n = 181) were similar demographically. AH cases had a mean Model for End-stage Liver Disease (MELD) score of 23 (7). AH cases had lower PC scores [37 (10) vs. 48 (11), p < 0.001] but higher MC scores [37 (13) vs. 32 (13), p < 0.001]. MC scores were independently associated with age, male gender, and daily alcohol consumption; PC scores were independently associated with age, BMI, alanine aminotransferase concentration, alkaline phosphatase concentration, white blood cell counts, and the presence of ascites. With each 5-point decrease in the baseline PC score, the adjusted odds of dying within 30 days increased by 26.7% (95% CI 1% to 46%). Over time, HRQOL in AH improved (day 0 to day 180 delta PC score: 4.5 ± 1.7, p = 0.008; delta MC score: 9.8 ± 2.0, p < 0.001). Participants with a MELD score <15 by day 180 had greater increases in PC scores than those with MELD score ≥15 (delta PC score 7.1 ± 1.8 vs. -0.7 ± 2.3, p = 0.009), while those abstinent by day 180 had greater increases in MC scores than those who were not abstinent (delta MC score 9.1 ± 1.8 vs. 2.8 ± 2.4, p = 0.044). Conclusions: HRQOL is poor in AH and HD in a domain-specific pattern. Independent of MELD score, lower baseline HRQOL is associated with higher 30-day mortality. Over time, HRQOL improves with greater gains seen in individuals with improved MELD scores and those who were abstinent.Item Hepatic steatosis is highly prevalent but is not correlated with stiffness in autoimmune hepatitis(Wolters Kluwer, 2020-10-16) Chalasani, Sai; Mathur, Karan; Shammas, Nicole; Orman, Eric; Vuppalanchi, Raj; Lammert, Craig; Medicine, School of MedicineThe 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/m2. 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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