Low socioeconomic status exacerbates unmet health-related needs in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Diminished quality of life has been well characterized in patients with autoimmune hepatitis (AIH); however, the full spectrum of unmet needs is unclear. We hypothesized that there is a high burden of health-related unmet needs in patients with AIH, and this burden differs by socioeconomic status (SES). METHODS: Members of the Autoimmune Hepatitis Association were invited online and by email to complete a modified version of the Systemic Lupus Erythematosus Patient Needs Questionnaire. Demographic and clinical data were also captured. Low SES was defined as annual household income <30 k, education level below high school, or moderate-high concern for transportation, food or housing. Multivariable logistic regression assessed the association between unmet health-related needs and SES. RESULTS: There were 433 participants; 89.8% identified as women, 16.2% lived outside the US, and 25.6% were classified as low SES. Over 70% of respondents reported at least one moderate-high need in the health-related unmet need domains. In multivariable logistic regression, patients in the low-SES group reported significantly higher odds of unmet needs compared to the moderate-high-SES group: for adequate information about side effects (OR 1.64, 95% CI 1.06-2.53, p = 0.026), opportunity to speak with others with AIH (OR 2.34, 95% CI 1.50-3.66, p < 0.001), healthcare professionals acknowledging patient emotions (OR 2.41, 95% CI 1.56-3.74, p < 0.001) and being taken seriously by medical providers (OR 2.09, 95% CI 1.34-3.28, p = 0.001). CONCLUSION: There is a high burden of health-related unmet needs in all patients with AIH that is exacerbated by low SES.

Autoimmune hepatitis: Current and future therapies.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it predominantly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge. Currently, the standard treatment for AIH comprises immunosuppressants; however, their long-term use is associated with adverse effects. The pathogenesis of AIH is complex, involving T cells, macrophages, and plasma cells that invade the periportal parenchyma and lead to an inflammatory cascade that can result in liver damage. Due to the complexity of AIH pathogenesis, treatment targets several inflammatory pathways. However, unlike other autoimmune diseases in which targeted treatments have been approved, there has been little progress made in advancing the treatment paradigm for AIH. Major obstacles to progress include challenges in conducting clinical trials, particularly patient recruitment and ensuring a diverse range of backgrounds; poorly defined outcomes to assess treatment response and improved quality of life; and a lack of study designs that account for the stage of disease and variations in treatment. A focus on individualized and steroid-free treatment approaches is needed to improve AIH prognosis and minimize steroid-associated adverse effects.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Primary Sclerosing Cholangitis Limited to Intrahepatic Bile Ducts Has Distinctly Better Prognosis.

BACKGROUND: There are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic). AIMS: This study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC. METHODS: Patients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement. RESULTS: Our cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age (mean 37.9 vs. 43.0 years, P = 0.045), the IIPSC group was not different from the extra/intrahepatic. The IIPSC group had longer transplant-free survival (log-rank P = 0.001) with a significantly lower risk for liver transplantation (12% vs. 34%, P < 0.001). The IIPSC group had a lower risk of death or transplantation than the extra/intrahepatic PSC group [HR: 0.34, 95% CI: 0.17-0.67, P < 0.001]. No bile duct or gallbladder cancers developed in patients with IIPSC, compared to 24 in the extra/intrahepatic group. The clinical characteristics and outcomes of IIPSC were similar to 23 individuals with small-duct PSC. CONCLUSIONS: Patients with IIPSC have a favorable prognosis similar to small-duct PSC. These data are important for counseling patients and designing therapeutic trials for PSC.

African American race does not confer an increased risk of clinical events in patients with primary sclerosing cholangitis.

BACKGROUND: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. METHODS: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. RESULTS: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models. CONCLUSIONS: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis.

BACKGROUND: 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.

PROMIS Profile-29 is a valid instrument with distinct advantages over legacy instruments for measuring the quality of life in chronic liver disease.

BACKGROUND AND AIMS: The Patient-Reported Outcomes Measurement Information System (PROMIS) is increasingly used to measure health-related quality of life, yet, it has not been well-studied in chronic liver disease (CLD). This study compares PROMIS Profile-29 to Short-Form Health Survey (SF-36) and Chronic Liver Disease Questionnaire (CLDQ) in patients with CLD. APPROACH AND RESULTS: In all, 204 adult outpatients with CLD completed PROMIS-29, CLDQ, SF-36 and usability questionnaires. Mean scores were compared between groups, the correlation between domain scores was assessed, and floor/ceiling effects were calculated. Etiologies of CLD were NAFLD (44%), hepatitis C (16%), and alcohol (16%). Fifty-three percent had cirrhosis and 33% were Child-Pugh B/C with a mean model for end-stage liver disease score of 12.0. In all 3 tools, the poorest scores were in physical function and fatigue. The presence of cirrhosis or complications was associated with worse scores in most PROMIS Profile-29 domains, indicating known group validity. Strong correlations ( r ≥ 0.7) were present between Profile-29 and SF-36 or CLDQ domains measuring similar concepts, indicating strong convergent validity. Profile-29 was completed faster than SF-36 and CLDQ (5.4 ± 3.0, 6.7 ± 3.3, 6.5 ± 5.2 min, p = 0.003) and rated equally on usability. All CLDQ and SF-36 domains reached the floor or ceiling, while none were noted for Profile-29. These floor/ceiling effects were magnified when assessed in those with and without cirrhosis, indicating the improved depth of measurement by Profile-29. CONCLUSIONS: Profile-29 is a valid, more efficient, well-received tool that provides an improved depth of measurement when compared to SF-36 and CLDQ and, therefore, an ideal tool to measure general health-related quality of life in CLD.

Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.

BACKGROUND & 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.

Overlooked Symptoms in Autoimmune Hepatitis Negatively Impact Many Facets of Life.

BACKGROUND: Significant reduction in quality of life among patients with autoimmune hepatitis (AIH) patients has been observed in several studies. While acute symptoms associated with AIH have been well described, little is known about the overall impact of living with AIH on patients' quality of life. The aim of this qualitative descriptive study was to describe the impact of AIH and associated symptoms on quality of life from the perspectives of patients living with AIH. METHODS: Patients from Autoimmune Hepatitis Association support groups were recruited to participate in one of five online focus groups conducted between August and September 2020. After enrollment, patients were asked to complete a brief demographic and disease history questionnaire. A single moderator conducted interviews with each group guided by seven questions focused on the impact of AIH on the participants' quality of life. Each session was recorded, transcribed, and verified. Content analysis was used to summarize the participants' responses. RESULTS: The participants' discussed three overarching topics: (a) symptoms of AIH and medication side effects, (b) the impact the disease and symptoms/side effects on five domains of quality of life (work life, relationships with friends and family, social life, leisure activities, and diet and exercise) and (c) interactions with healthcare providers and recommendations for future research. CONCLUSIONS: Living with AIH can have profound effects on patients' quality of life in several domains. Healthcare providers and the AIH research community should focus on developing further strategies that can improve the quality of life in persons suffering from AIH.

SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis.

BACKGROUND: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. PATIENTS AND METHODS: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. RESULTS: We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17-85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10-0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11-0.35). CONCLUSIONS: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.

Germline Mutations in CIDEB and Protection against Liver Disease.

BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).

Autoimmune hepatitis and metabolic syndrome-associated disease development: a U.S. cohort study.

BACKGROUND: Autoimmune hepatitis (AIH) may coexist with metabolic syndrome-associated diseases (MSADs) given patients' inherent need for corticosteroid therapy, as well as general population trends. AIM: To examine the impact of MSAD risk factors on AIH or its treatment, and vice versa METHODS: This was a multi-centre retrospective cohort study of 552 patients with AIH diagnosed between January 2000 and December 2019. Data relating to demographic factors, laboratory values, AIH medications and MSADs were collected at diagnosis and at 1- and 3-year follow-up. Statistical relationships were analysed and reported. RESULTS: We included 552 patients in the study cohort (median age 50 years, 76.1% female). All MSADs, including hypertension, dyslipidaemia, diabetes and a gain of BMI ≥3 kg/m2 , increased within the AIH cohort over time. Initial treatment regimen impacted de novo diabetes but not other MSAD development. AIH biochemical remission was less frequent at 3 years post-diagnosis among patients with ≥1 MSAD. The incidence of new MSADs could be predicted by baseline factors in certain cases. CONCLUSION: In the largest US-based cohort of patients newly diagnosed with AIH, there was a considerable burden of pre-existing and de novo MSADs that may affect AIH treatment outcomes. Identifying those at highest risk of co-morbid MSADs allows for an individualised approach to management to reduce its long-term sequelae in patients with AIH.

Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.

BACKGROUND AND AIMS: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. APPROACH AND RESULTS: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. CONCLUSIONS: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.

Large Hepatic Adenomas and Hepatic Adenomatosis: A Multicenter Study of Risk Factors, Interventions, and Complications.

INTRODUCTION: Beyond oral contraceptives (OCs), metabolic factors have been suggested to increase the risk of hepatocellular adenoma (HCA). The impact of risks remains poorly defined, particularly among men and those with adenomatosis. Thus, we aimed to examine HCA clinical and outcome characteristics through a large multicenter cohort. METHODS: HCA diagnosis was made based on a combination of clinical, radiologic, and histologic criteria. Patient and clinical data including follow-up imaging, complications, and interventions were collected between 2004 and 2018 from 3 large academic centers. RESULTS: Among 187 patients (163 female and 24 male) with HCA, 75 had solitary HCA, 58 had multiple HCAs, and 54 had adenomatosis. Over a median follow-up of 3.3 years (quartile 1: 1.2, quartile 3: 8.8), 34 patients (18%) had radiologic interventions, 41 (21%) had surgical resections, 10 (5%) developed tumoral hemorrhage, and 1 had malignant transformation. OC and corticosteroid use were present in 70% and 16%, respectively. Obesity (51%), type 2 diabetes (24%), hypertension (42%), and hypertriglyceridemia (21%) were also common. Metabolic comorbidities were more common in patients with large HCAs and adenomatosis. Compared with women, men had less hepatic steatosis (4% vs 27%), smaller HCAs (2.3 cm vs 4.4 cm), and more corticosteroid use (38% vs 11%) ( P < 0.05 for all). With OC cessation, 69% had a decrease in size of HCA, but 25% eventually required advanced interventions. DISCUSSION: In this large HCA cohort, obesity and metabolic comorbidities were important risk factors associated with large HCAs and adenomatosis. Long-term adverse outcomes were infrequent, 5% had tumor hemorrhage, and 1 patient exhibited malignant transformation.

Transcriptomic profiling of blood from autoimmune hepatitis patients reveals potential mechanisms with implications for management.

Autoimmune hepatitis (AIH) is a poorly understood, chronic disease, for which corticosteroids are still the mainstay of therapy and most patients undergo liver biopsy to obtain a diagnosis. We aimed to determine if there was a transcriptomic signature of AIH in the peripheral blood and investigate underlying biologic pathways revealed by gene expression analysis. Whole blood RNA from 75 AIH patients and 25 healthy volunteers was extracted and sequenced. Differential gene expression analysis revealed 249 genes that were significantly differentially expressed in AIH patients compared to controls. Using a random forest algorithm, we determined that less than 10 genes were sufficient to differentiate the two groups in our cohort. Interferon signaling was more active in AIH samples compared to controls, regardless of treatment status. Pegivirus sequences were detected in five AIH samples and 1 healthy sample. The gene expression data and clinical metadata were used to determine 12 genes that were significantly associated with advanced fibrosis in AIH. AIH patients with a partial response to therapy demonstrated decreased evidence of a CD8+ T cell gene expression signal. These findings represent progress in understanding a disease in need of better tests, therapies, and biomarkers.