Influence of socioeconomic factors on liver transplant survival outcomes in patients with autoimmune liver disease in the United States.

INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILDs): autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) have different survival outcomes after liver transplant (LT). Outcomes are influenced by factors including disease burden, medical comorbidities, and socioeconomic variables. MATERIALS AND METHODS: Using the United Network for Organ Sharing database (UNOS), we identified 13,702 patients with AILDs listed for LT between 2002 and 2021. Outcomes of interest were waitlist removal, post-LT patient survival, and post- LT graft survival. A stepwise multivariate analysis was performed adjusting for transplant recipient gender, race, diabetes mellitus, model for end-stage liver disease (MELD) score, and additional social determinants including the presence of education, reliance on public insurance, working for income, and U.S. citizenship status. RESULTS: Lack of college education and having public insurance increased the risk of waitlist removal (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.09; 95 % CI, 1.00-1.18; respectively), and negatively influenced post-LT patient survival (HR, 1.16; 95 % CI, 1.06-1.26, and HR, 1.15; 95 % CI, 1.06-1.25; respectively) and graft survival (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.15; 95 % CI, 1.06-1.25; respectively). Not working for income proved to have the greatest detrimental impact on both patient survival (HR, 1.41; 95 % CI, 1.24-1.6) and graft survival (HR, 1.21; 95 % CI, 1.09-1.35). CONCLUSIONS: Our study highlights that lack of college education and public insurance have a detrimental impact on waitlist mortality, patient survival, and graft survival. Not working for income negatively affects post-LT survival outcomes. Not having U.S. citizenship does not affect survival outcomes in AILDs patients.

Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1.

BACKGROUND: No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. OBJECTIVE: The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. METHODS: The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. RESULTS: In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). CONCLUSIONS: A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated.

Autoimmune Hepatitis: Predictors of Native Liver Survival in Children and Adolescents.

OBJECTIVE: To determine predictors of native liver survival (NLS) in children and adolescents with autoimmune hepatitis (AIH). STUDY DESIGN: The medical records of children and adolescents with AIH were reviewed. A questionnaire was used to collect data on clinical presentation, biochemical and histologic findings, and treatment. RESULTS: A total of 819 patients were included, 89.6% with AIH-1 and 10.4% with AIH-2. The median age (months) at onset was 108 (min 6; max 210; IQR 59). The female sex was predominant (75.8%). The overall survival was 93.0%, with an NLS of 89.9%; 4.6% underwent liver transplantation. The risk of death or liver transplantation during follow-up was 3.2 times greater in patients with AIH-1 (P = .024). Greater levels of aspartate aminotransferase, alanine aminotransferase, serum albumin, platelet, and normal international normalized ratio at the initial presentation were associated with longer NLS (P = .046, P = .006, P < .001, P = .001, and P = .019, respectively). Normal C3 levels was associated with longer NLS (P = .017), with a chance of death or liver transplantation during follow-up being 3.4 times greater in patients with C3 below normal. Death or liver transplantation during follow-up was 2.8 times greater in patients with associated sclerosing cholangitis (P = .046). Complete remission favored NLS (P < .001), with a risk of death or liver transplantation 11.7 times greater for patients not achieving remission. CONCLUSIONS: The best predictors of NLS in children and adolescents with AIH were the AIH-2 subtype, a normal C3 at diagnosis, remission during treatment, and normal a cholangiogram during the disease course.

Early liver transplantation for corticosteroid non-responders with acute severe autoimmune hepatitis: The SURFASA score.

BACKGROUND & AIMS: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated. METHODS: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 µmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3-D0)/D0. RESULTS: A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC = 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%. CONCLUSION: In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort. LAY SUMMARY: The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.

SARS-CoV-2 infection in patients with autoimmune hepatitis.

BACKGROUND & AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH). METHODS: Data for patients with AIH and SARS-CoV-2 infection were combined from 3 international reporting registries and outcomes were compared to those in patients with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD). RESULTS: Between 25th March and 24th October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) patients with AIH were taking ≥1 immunosuppressive drug. There were no differences in rates of major outcomes between patients with AIH and non-AIH CLD, including hospitalization (76% vs. 85%; p = 0.06), intensive care unit admission (29% vs. 23%; p = 0.240), and death (23% vs. 20%; p = 0.643). Factors associated with death within the AIH cohort included age (odds ratio [OR] 2.16/10 years; 1.07-3.81), and Child-Pugh class B (OR 42.48; 4.40-409.53), and C (OR 69.30; 2.83-1694.50) cirrhosis, but not use of immunosuppression. Propensity score matched (PSM) analysis comparing patients with AIH with non-AIH CLD demonstrated no increased risk of adverse outcomes including death (+3.2%; -9.2%-15.7%). PSM analysis of patients with AIH vs. non-CLD (n = 769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6-31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%-15.6%). CONCLUSION: Patients with AIH were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease. LAY SUMMARY: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from 3 large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.

The impact of bariatric surgery on in-patient clinical outcomes among patients with autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a form of liver inflammation in which immune cells target hepatocytes, inducing chronic inflammatory states. Bariatric surgery (BS) was shown to reduce inflammation in severely obese patients. We hypothesize that obese patients with AIH and BS have lower prevalence of liver-related complications and in-patient mortality compared to those without BS.The National Inpatient Sample from 2007 to 2013 was queried for hospitalizations of adults over 18 years of age with a diagnosis of AIH. Of those, hospitalizations with BS were selected as cases and those with morbid obesity as controls. Case-control 1:2 matching was done based on sex, age, race, and comorbidities. Primary outcomes were prevalence of liver-related complications and in-patient mortality. Independent risk factors of in-patient clinical outcomes were identified using multivariate regression analysis.From 137,834 hospitalizations with a diagnosis of AIH, 688 with BS were selected as cases, and 1295 were matched as controls. The prevalence of ascites was higher in the BS group compared to the control (odds ratio 1.73, 95% confidence interval (CI) 1.27-2.36). The prevalence of cirrhosis (36.8% vs 33.2%), portal hypertension (7.4% vs 10.0%), hepatic encephalopathy (10.6% vs 8.7%), and varices and variceal bleeding (3.9% vs 5.5%) was not statistically different from case controls, (P > .05).BS was an independent risk factor for ascites (adjusted odds ratio (aOR) 1.87; 95% CI 1.36-2.56) and hepatic encephalopathy (aOR 1.42; 95% CI 1.03-1.97) but was an independent protective factor against in-patient mortality (aOR 0.21, 95% CI 0.08-0.55) once adjusted for age, sex, race, and comorbidities.

Normalization of serum immunoglobulin G levels is associated with improved transplant-free survival in patients with autoimmune hepatitis.

BACKGROUND: There is limited evidence linking achievement of biochemical response with outcomes in Autoimmune Hepatitis (AIH), and it is unclear whether normalization of serum immunoglobulin G (IgG) levels influences prognosis. AIMS: We aimed to investigate factors associated with death or liver transplantation in patients affected by AIH. METHODS: We undertook a retrospective analysis of all AIH patients attending a tertiary liver unit since 1980. Patients not meeting established diagnostic criteria for AIH or with a follow-up shorter than 18 months were excluded. RESULTS: 107 patients meeting inclusion criteria were included in the study. Mean age at diagnosis was 44 years, 29 patients (27.1%) had cirrhosis at baseline. Median follow-up was 79 months, and 70 patients (79.5%) reached biochemical response. Biochemical response was associated with reduced hazard of liver transplant or death (HR 0.07, 95% CI 0.01-0.46), whereas cirrhosis at diagnosis was an independent predictor of liver transplantation or death (Hazard ratio (HR) 11.8, 95%, confidence interval (CI) 1.18-117.4). Lack of normalization of serum IgG levels was associated with reduced 5-year transplant-free survival (95% in patients normalizing, compared to 86%, p = 0.02). CONCLUSION: Normalization of serum IgG levels alone translates in better transplant-free survival in patients with AIH and should be a treatment target along with transaminases.

Infectious complications and timing for liver transplantation in autoimmune acute liver failure in Japan: a subanalysis based on nationwide surveys between 2010 and 2015.

BACKGROUND: The prognosis of autoimmune acute liver failure (ALF) without liver transplantation (LT) is poor worldwide. We subanalyzed infectious complications of autoimmune ALF using data of nationwide surveys between 2010 and 2015 retrospectively and tried to determine when to evaluate the efficacy of corticosteroid (CS) treatment or abandon it for LT based on objective data. METHODS: One hundred and forty-four patients with autoimmune ALF, comprising 79 ALF with coma ≤ I, 52 ALF with coma ≥ II and 13 late onset hepatic failure (LOHF), were analyzed. RESULTS: CS was administered to 140 (97%) patients. Thirty-seven (26%) patients had infectious complications. Patients with infection revealed more advanced disease type (p < 0.001) and poorer spontaneous survival (p < 0.001) than those without infection. Median (interquartile range) duration between diagnosis of ALF and onset of infection was 18.5 (11-36) days, and that between introduction of CS and onset of infection was 17 (10.5-36) days. Seventy-nine (55%) recovered without LT, 14 (10%) received LT and 51 (35%) died without LT. Dead or transplanted patients were older (p = 0.0057), and revealed more advanced liver failure (p < 0.001) and more occurrence of infection (p < 0.001). CONCLUSIONS: A critical point for evaluating the efficacy of CS treatment and switching to LT is at most 2-week after diagnosis of ALF and introduction of CS. More important, we should accelerate the point and prepare for LT in cases of ALF with coma ≥ II and LOHF, and we should have performed LT by then at the latest in case of failure to improve.

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.

BACKGROUND: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. METHODS: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. RESULTS: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. CONCLUSIONS: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Association of Autoimmune Hepatitis and Cardiovascular Disease.

BACKGROUND: Autoimmune Hepatitis is a chronic liver disease while Cardiovascular Disease is seen in inflammatory states. This study sought to determine if Cardiovascular Disease was associated with Autoimmune Hepatitis. METHODS: The National Inpatient Sample selected patients with a primary diagnosis of Autoimmune Hepatitis and secondary diagnosis of Cardiovascular Disease in 2014. The primary outcome was the association of Autoimmune Hepatitis with Cardiovascular Disease. Secondary outcomes evaluated the hospital burden with Cardiovascular Disease. RESULTS: 16,375 patients with Autoimmune Hepatitis were included in the study. There was a decreased association between Autoimmune Hepatitis and Cardiovascular Disease (aOR 0.77, 95% CI 0.69-0.85, p < 0.00), Coronary Artery Disease, (aOR 0.75, 95% CI 0.67-0.85, p < 0.00), and Peripheral Vascular Disease (aOR 0.75, 95% CI 0.60-0.93, p = 0.01). Moreover, Coronary Artery Disease comprises 84% of the overall Cardiovascular Disease cohort and did not demonstrate significantly increased length of stay (aOR -0.53, 95% CI -1.16 to 0.12, p = 0.11) or hospitalization cost (aOR -6711, 95% CI -14336 to 912, p = 0.08). DISCUSSION: The decreased association between Autoimmune Hepatitis and Cardiovascular Disease is likely multifactorial in etiology. Consequently, this observation requires further examination with prospective trials.

Disease progression in paediatric- and adult-onset sclerosing cholangitis: Results from two independent Dutch registries.

BACKGROUND & AIMS: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. METHODS: Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. RESULTS: Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. CONCLUSION: Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.

Liver transplantation in adults with acute liver failure: Outcomes from the Argentinean Transplant Registry.

INTRODUCTION AND AIM: Liver transplantation (LT) for acute liver failure (ALF) still has a high early mortality. We aimed to evaluate changes occurring in recent years and identify risk factors for poor outcomes. MATERIAL AND METHODS: Data were retrospectively obtained from the Argentinean Transplant Registry from two time periods (1998-2005 and 2006-2016). We used survival analysis to evaluate risk of death. RESULTS: A total of 561 patients were listed for LT (69% female, mean age 39.5±16.4 years). Between early and later periods there was a reduction in wait-list mortality from 27% to 19% (p<0.02) and 1-month post-LT survival rates improved from 70% to 82% (p<0.01). Overall, 61% of the patients underwent LT and 22% died on the waiting list. Among those undergoing LT, Cox regression analysis identified prolonged cold ischemia time (HR 1.18 [1.02-1.36] and serum creatinine (HR 1.31 [1.01-1.71]) as independent risk factors of death post-LT. Etiologies of ALF were only available in the later period (N=363) with indeterminate and autoimmune hepatitis accounting for 28% and 26% of the cases, respectively. After adjusting for age, gender, private/public hospital, INR, creatinine and bilirubin, and considering LT as the competing event, indeterminate etiology was significantly associated with death (SHR 1.63 [1.06-2.51] and autoimmune hepatitis presented a trend to improved survival (SHR 0.61 [0.36-1.05]). CONCLUSIONS: Survival of patients with ALF on the waiting list and after LT has significantly improved in recent years. Indeterminate cause and autoimmune hepatitis were the most frequent etiologies of ALF in Argentina and were associated with mortality.

Acute onset autoimmune hepatitis: Clinical presentation and treatment outcomes.

INTRODUCTION AND AIM: Autoimmune hepatitis (AIH) may present acutely, which can rapidly progress to fulminant type. This pattern has been described worldwide but is generally under-reported. We aim to describe the clinical presentation and treatment outcomes of patients with acute onset AIH. MATERIALS AND METHODS: A multicenter retrospective cohort study of patients with acute onset AIH. Clinical, biochemical, and histological data were analyzed and the outcomes were reported. RESULTS: Seventy patients were included. The mean age was 33.8±1.5 years and 58.6% were female. Upon initial presentation, 94% had jaundice, 44% had fatigue, 31% had pruritus, and 29% had abdominal pain. Biochemical analysis revealed elevated alanine transaminase (733±463.6), aspartate transaminase (699±423), and total bilirubin (210±181.8). Antinuclear antibody (ANA) was positive in 61% of patients, anti-smooth muscle antibody (ASMA) in 69%, and both in 31%; immunoglobulin G (IgG) was elevated in 86% of patients. Advanced fibrosis was found in 39%. Complete remission was achieved in 74.3%, two patients required liver transplants and six died. No specific biomarkers were identified as predictive of remission; however, advanced age was associated with poor prognosis. CONCLUSION: Acute onset AIH is a disease that requires early diagnosis and management. We confirmed that elevated transaminases are the hallmark of biochemical presentation of acute AIH. High IgG, ANA and ASMA are typically present in such patients upon presentation, however, their absence does not totally exclude the diagnosis. Initial response to treatment was excellent; however, the long-term mortality was higher than the general patient population.

Long-term clinical outcomes in patients with autoimmune hepatitis according to treatment response in Asian country.

BACKGROUND & AIMS: As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long-term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain. METHODS: A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (<1year) and late CBR (≥1year) by the timing of remission. Liver-related adverse outcomes including liver-related death, liver transplantation and hepatocellular carcinoma were evaluated. RESULTS: With immunosuppressive treatment, 222 (76.3%) patients achieved CBR (early CBR: 168 and late CBR: 54). BR was achieved in 55 (18.9%) patients and 14 (4.8%) patients remained non-remission. With a median follow-up duration of 6.6 years, the risk of liver-related mortality was the lowest in patients with CBR, followed by patients with late CBR, BR and non-response. The cumulative risk of liver-related adverse outcomes was the highest in patients with non-response (8.51/100 person-years [PYs]), followed by BR (1.95/100 PYs), late CBR (1.89/100 PYs) and early CBR (0.75/100 PYs). By multivariable analysis, age, cirrhosis and treatment responses were independently associated with liver-related adverse outcomes. CONCLUSIONS: Patients with CBR within 1 year after treatment initiation had the lowest risk of liver-related adverse outcomes. Patients with late CBR and those with only BR had a comparable risk of long-term outcomes.

Incidence, prevalence, and causes of death of patients with autoimmune hepatitis: A nationwide register-based cohort study in Finland.

BACKGROUND: Epidemiological studies of autoimmune hepatitis are scarce and often based on single centre registries. AIMS: We conducted a nationwide register study of incidence, prevalence, survival, and causes of death of autoimmune hepatitis patients in Finland. METHODS: Autoimmune hepatitis cases 1995-2015 were retrieved from the national database of special reimbursements for drugs costs. Data on causes of death were retrieved from Statistics Finland. RESULTS: After incomplete registration of AIH during the first years, the incidence of autoimmune hepatitis stabilised to 1.1/100,000 person-years (1.6 in women and 0.52 in men) in 2008-2015. The prevalence of autoimmune hepatitis at the end of 2015 was 14.3/100,000, 23.0/100,000 in women and 6.6/100,000 in men. The all-cause standardized mortality ratio (SMR) of autoimmune hepatitis patients was 1.81 (95% confidence interval (CI) 1.47-2.20). The SMR was increased in all age groups and in both sexes. The SMR for hepatocellular carcinoma was 20.6 (95% CI 10.3-36.8), and for digestive diseases in overall 13.5 (95% CI 8.2-20.8), constituting mainly from autoimmune hepatitis and liver cirrhosis. CONCLUSION: Incidence of autoimmune hepatitis has remained stable, with clear female predominance. Autoimmune hepatitis is associated with a markedly increased risk of death with hepatocellular cancer forming the greatest risk.

Sex-related factors in autoimmune liver diseases.

Autoimmune diseases are a broad range of diseases in which the immune system produces an inappropriate response to self-antigens. This results in inflammation, damage, or dysfunction of tissues and/or organs. Many autoimmune diseases are more common in women and differences between female and male immune and autoimmune responses have been well documented. In general, most of the autoimmune diseases seem to affect more females, although there are exceptions. Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are considered to be autoimmune liver diseases (AILD). They all are rare diseases and they result in significant morbidity and mortality. The female predominance in PBC and AIH are among the strongest among autoimmune diseases. However, the mechanisms responsible for the sex differences in autoimmune liver diseases are largely unknown. In this review, we discuss the recent findings on the influence of sex-dependent mechanisms, which may contribute to differences in presentation, clinical characteristics, disease course, and complications observed between female and male patients with autoimmune liver disease.

Increased Mortality Among Patients With vs Without Cirrhosis and Autoimmune Hepatitis.

BACKGROUND & AIMS: There have been few reproducible studies of mortality in patients with autoimmune hepatitis (AIH) and its variants. We calculated mortality in a large national cohort of patients with AIH, with vs without cirrhosis, in the Netherlands. METHODS: We collected data from 449 patients with established AIH (77% female), from 6 academic and 10 non-academic hospitals in the Netherlands. We identified 29 patients with AIH and primary biliary cholangitis and 35 patients with AIH and primary sclerosing cholangitis (AIH-PSC). Mortality and liver transplantation data were assessed from August 1, 2006 through July 31, 2016. Standardized mortality ratios (SMR) were calculated using age-, sex-, and calendar year-matched mortality for the general Dutch population. RESULTS: During the 10-year follow-up period, 60 patients (13%) died (mean age, 71 years; range, 33-94 years). Twenty-six causes of death were liver related (43%), whereas the others could not be attributed to liver disease. Patients with AIH and cirrhosis had significantly higher mortality than the general population (SMR, 1.9; 95% CI, 1.2-3.4), whereas patients without cirrhosis did not (SMR, 1.2; 95% CI, 0.8-1.8). Patients with AIH-PSC had the largest increase in mortality, compared to the general population (SMR, 4.7; 95% CI, 1.5-14.6), of all groups analyzed. Mortality in patients with AIH and primary biliary cholangitis was not greater than the general population. Four or more relapses per decade or not achieving remission was associated with an increase in liver-related death or liver transplantation. Nine patients underwent liver transplantation; 2 died from non-liver related causes. Four of 9 patients on the waitlist for transplantation died before receiving a donated liver. CONCLUSION: In an analysis of data from a large national cohort of patients with AIH, we found increased mortality of patients with cirrhosis, but not of patients without cirrhosis, compared to the general Dutch population. Survival was significantly reduced in patients with AIH and features of concurrent PSC.

Waiting List Mortality and Transplant Rates for NASH Cirrhosis When Compared With Cryptogenic, Alcoholic, or AIH Cirrhosis.

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) cirrhosis have excellent postliver transplant survival despite having many comorbidities. We hypothesized that this could be due to a selection bias. METHODS: We analyzed the United Network for Organ Sharing data from 2002 to 2016 and compared postliver transplant survival of NASH (n = 7935) patients with cryptogenic cirrhosis (CC) (n = 6087), alcoholic cirrhosis (AC) (n = 16 810), and autoimmune hepatitis cirrhosis (AIH) (n = 2734). RESULTS: By 3 years of listing, the cumulative incidence (CI) of death or deterioration was 29% for NASH, 28% for CC and AC, and 24% for AIH, but when adjusted for risk factors, the CI was similar for NASH and AIH. The factors that increased the risk of waiting list removal due to death/deterioration were poor performance status, encephalopathy, diabetes, high Model for End-stage Liver Disease, Hispanic race, older age and a low serum albumin. Most patients were transplanted within the first year (median, 2 months; interquartile range, 1-7 months) of listing and by 5 years, the unadjusted CI of transplantation was 54% for NASH, 52% for CC, 51% for AIH, and 48% for AC. The adjusted CI of transplantation within 2 months of listing was higher for AC (subhazard ratio [SHR], 1.17), AIH (SHR, 1.17), and CC (SHR, 1.13) when compared with NASH, but after 2 months, adjusted transplantation rates decreased in AC (SHR, 0.6), AIH (SHR, 0.78), and CC (SHR, 0.95). The negative predictors of receiving a transplant were dialysis, female sex, nonwhite race, high albumin, and creatinine. CONCLUSIONS: Patients with NASH cirrhosis are not disadvantaged by higher waitlist removal or lower transplantation rates.

Corticosteroid Therapy Improves the Outcome of Autoimmune Hepatitis-Induced Acute Liver Failure.

BACKGROUND/AIMS: Autoimmune hepatitis (AIH) is a relatively rare cause of liver dysfunction and may lead in some cases to acute liver failure (ALF). The aim of our study was to evaluate the clinical course and outcome of patients with AIH-induced ALF. METHODS: We retrospectively enrolled 32 patients with AIH-induced ALF and 93 age- and sex-matched patients with chronic AIH (cAIH) who were enrolled at the University Clinic Essen from 1988 to 2014. All ALF patients were treated with corticosteroids after diagnosis. RESULTS: Overweight, higher γ-globulin levels, the absence of anti-smooth muscle antibodies and human leukocyte antigen (HLA) B8 and the presence of anti-mitochondrial antibodies and HLA DR7 were risk factors for an ALF vs chronic hepatitis manifestation of AIH. Liver histology was significantly more often typical for AIH in an ALF setting than in cAIH. The spontaneous survival rate was 91% and 97% in ALF and cAIH patients, respectively, at 6 months after diagnosis and only 1 patient in the ALF group developed sepsis under therapy. CONCLUSION: Liver biopsy in an AIH-mediated ALF setting was both safe and effective in diagnosing AIH. Corticosteroid therapy was not associated with high mortality or sepsis. Our findings suggest that corticosteroid treatment of AIH-mediated ALF may improve the outcome.