Smoking is a Risk Factor for Autoimmune Hepatitis: An English Registry-Based Case-Control Study.

Purpose: Smoking is a risk factor for some autoimmune diseases, but its association with autoimmune hepatitis remains unknown. We conducted a population-based matched case-control study to examine the association between tobacco smoking and the risk of autoimmune hepatitis in England. Patients and Methods: From the Clinical Practice Research Datalink and linked Hospital Episode Statistics, 2005-2017, we included 987 cases diagnosed with autoimmune hepatitis after age 18 years and up to 10 frequency-matched population controls per case. We used multiple logistic regression to estimate the odds ratio of autoimmune hepatitis in ever-smokers vs never-smokers, adjusting for sex, age, general practice, calendar time of registration with the general practice, and socioeconomic status. Results: The autoimmune hepatitis cases were more likely to be ever-smokers than the controls (44% vs 37%). The ever-smokers had an increased risk of autoimmune hepatitis compared with the never-smokers (adjusted odds ratio = 1.20, 95% confidence interval 1.03-1.39). Conclusion: Smoking was associated with an increased risk of autoimmune hepatitis.

Extrahepatic autoimmune diseases in autoimmune hepatitis: Effect on mortality.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with an increased prevalence of extrahepatic autoimmune diseases and an increased mortality compared with the general population. The contribution of extrahepatic autoimmune diseases to the increased mortality has not been clarified. Our aim was to determine the effect of extrahepatic autoimmune diseases on mortality in AIH patients. METHODS: This nationwide register-based cohort study included all Danish patients diagnosed with AIH between 1995 and 2019. We examined the presence of extrahepatic autoimmune diseases and compared the mortality between AIH patients with and without extrahepatic autoimmune diseases. We adjusted our analysis for age, sex, calendar year of AIH diagnosis, cirrhosis, cancer, chronic obstructive pulmonary disease and ischaemic heart disease. RESULTS: We included 2479 AIH patients of whom 19.8% had one extrahepatic autoimmune disease and 3.3% had multiple. The adjusted 10-year cumulative mortality was 27.2% (95% confidence interval [CI]: 25.2-29.4) for patients with extrahepatic autoimmune diseases and 21.6% (95% CI: 19.9-23.6) for patients without. The adjusted mortality hazard ratio was 1.30 (95% CI: 1.12-1.52) for AIH patients with versus without extrahepatic autoimmune diseases; it was 1.25 (95% CI: 1.06-1.48) for patients with one extrahepatic autoimmune disease and 1.54 (95% CI: 1.15-2.05) for those with more than one. CONCLUSIONS: Extrahepatic autoimmune diseases increased the mortality in patients with AIH. Patients with multiple extrahepatic autoimmune diseases had a higher mortality than patients with just one extrahepatic autoimmune disease.

Increased Cancer Risk in Autoimmune Hepatitis: A Danish Nationwide Cohort Study.

INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease and as such may increase the risk of cancer. We examined cancer risks in a nationwide cohort of patients with AIH. METHODS: This study was based on nationwide Danish healthcare registries. We identified all persons diagnosed with AIH between 1994 and 2018. We included 1805 patients with AIH and 16,617 age- and sex-matched population controls. We estimated cumulative risks of cancers and risk ratios (RRs) between patients and controls. Within the cohort of patients with AIH, we examined the impact of immunosuppressive treatment (IST) and cirrhosis on cancer risks. RESULTS: The 10-year risk of any cancer was 13.6% (95% confidence interval [CI] 11.7-15.6) in patients with AIH with an RR of 1.5 (95% CI 1.3-1.7) compared with controls. Patients with AIH had a 10-year risk of 0.5% (95% CI 0.2-1.1) for hepatocellular carcinoma. The 10-year risk was 1.6% (95% CI 1.0-2.5) for colorectal cancer (RR: 2.1 [95% CI 1.3-3.5]) and 4.0% (95% CI 3.0-5.3) for nonmelanoma skin cancer (RR: 1.8 [95% CI 1.3-2.5]). Among patients with AIH, the risk of cancer was higher for those with cirrhosis (hazard ratio: 1.3 [95% CI 1.0-1.7]), and it also increased 1.05-fold (95% CI 1.0-1.1) for every year the patient was on IST. DISCUSSION: AIH was associated with a 1.5-fold increased 10-year risk of cancer compared with age- and sex-matched controls. Among patients with AIH, the risk of cancer was higher for those with cirrhosis, and it also increased slightly with longer duration of IST.

Incidence, prevalence and mortality of autoimmune hepatitis in England 1997-2015. A population-based cohort study.

BACKGROUND & AIMS: There are few population-based studies of the incidence and mortality of autoimmune hepatitis. The burden of the disease and how it has changed over time have not been fully explored. We conducted a population-based cohort study on the incidence and mortality of autoimmune hepatitis in England, 1997-2015. METHODS: From the Clinical Practice Research Datalink we included 882 patients diagnosed with autoimmune hepatitis in England, 1997-2015. The patients were followed through 2015, and we calculated the sex- and age-standardized incidence and prevalence of autoimmune hepatitis. We examined variation in incidence by sex, age, calendar year, geographical region and socioeconomic status, and incidence rate ratios were calculated with Poisson regression. We calculated all-cause and cause-specific mortality. RESULTS: The overall standardized incidence rate of autoimmune hepatitis was 2.08 (95% confidence interval 1.94-2.22) per 100,000 population per year, higher in women, higher in older age and independent of region and socioeconomic status. From 1997 to 2015 the incidence doubled from 1.27 (95% confidence interval 0.51-2.02) to 2.56 (95% confidence interval 1.79-3.33) per 100,000 population per year. The 10-year cumulative all-cause mortality was 31.9% (95% confidence interval 27.6-36.5), and the 10-year cumulative liver-related mortality, including hepatocellular carcinoma was ~10.5%. CONCLUSIONS: This population-based study showed that the incidence of autoimmune hepatitis doubled over an eighteen-year period. The incidence was particularly high in older women and was similar across all regions of England and independent of socioeconomic status. Patients with autoimmune hepatitis had a high mortality.

Extrahepatic autoimmune diseases in patients with autoimmune hepatitis and their relatives: A Danish nationwide cohort study.

BACKGROUND & AIMS: It is widely accepted that patients with autoimmune hepatitis have an increased prevalence of extrahepatic autoimmune diseases. It is believed that the patients' relatives share this trait, but it has not been studied in a satisfactory setting. We conducted a nationwide registry-based cohort study on this issue. METHODS: From Danish healthcare registries 1994-2015, we included 2745 patients with autoimmune hepatitis, 17 812 of their first- and second-degree relatives and 27 450 general population controls matched with the patients for sex and age. We compared the sex- and age-specific prevalence of extrahepatic autoimmune diseases between the patients with autoimmune hepatitis, their relatives and the controls. We computed the prevalence ratio as a measure of the relative prevalence, using the controls as reference group. RESULTS: In the patients with autoimmune hepatitis, the prevalence ratio of extrahepatic autoimmune diseases ranged from 7 to 10 until age 30 years (prevalence ratio at age 20 = 9.92; 95% confidence interval 6.21-15.83), after which it gradually decreased to about 2 (prevalence ratio at age 80 = 2.37; 95% confidence interval 1.89-3.00). Neither first- nor second-degree relatives had an increased prevalence of extrahepatic autoimmune diseases (prevalence ratio for relatives at age 20 = 1.11; 95% confidence interval 0.72-1.70; prevalence ratio at age 80 = 0.96; 95% confidence interval 0.70-1.31). CONCLUSIONS: Danish patients with autoimmune hepatitis were highly prone to extrahepatic autoimmune diseases, but their relatives were not.

Pregnancy and birth outcomes in a Danish nationwide cohort of women with autoimmune hepatitis and matched population controls.

BACKGROUND: Many patients with autoimmune hepatitis are women of fertile age. Some concerns of these patients are related to pregnancy. AIM: To conduct a nationwide study on risk of miscarriage, birth rate, and birth outcomes in women with autoimmune hepatitis. METHODS: From Danish healthcare registries, 1994-2015, we identified 179 births in 103 women with autoimmune hepatitis, 70 of which were first-time singleton births, and 1623 births in 1051 age-matched women (population controls), 662 of which were first-time singleton births. We calculated the risk of miscarriage and the birth rate after autoimmune hepatitis diagnosis in women with autoimmune hepatitis and controls. We used logistic regression to compare the odds of adverse birth outcomes (preterm birth, small for gestational age, congenital malformations and stillbirth) between women with autoimmune hepatitis and controls, adjusting for maternal age and smoking habits. RESULTS: The risk of miscarriage was similar in women with autoimmune hepatitis and controls: risk ratio 1.17 (95% confidence interval 0.81-1.68). The first-time birth rate, including singleton and multiple births, per 1000 person-years in women with autoimmune hepatitis was 37 (95% confidence interval 29-46), in controls 32 (95% confidence interval 30-35). Age at first-births was similar in women with autoimmune hepatitis and controls. Women with autoimmune hepatitis had an increased risk of preterm birth (adjusted odds ratio 3.19, 95% confidence interval 1.53-6.64) and small for gestational age babies (adjusted odds ratio = 3.20, 95% confidence interval 0.33-31.29), but not of congenital malformations (adjusted odds ratio = 1.27, 95% confidence interval 0.48-3.34) or stillbirth. Birth outcomes did not differ in autoimmune hepatitis patients on or off immunosuppression, and with or without cirrhosis. CONCLUSIONS: In Danish women with autoimmune hepatitis, fertility was unaffected. They had an increased risk of preterm birth and small for gestational age children, but not of congenital malformations or stillbirth.

Family occurrence of autoimmune hepatitis: A Danish nationwide registry-based cohort study.

BACKGROUND & AIMS: It is widely believed that autoimmune hepatitis accumulates in families, but the degree of familial clustering has not been clarified. We conducted a population-based study on the family occurrence of autoimmune hepatitis. METHODS: Through Danish nationwide registries we identified 8,582 first-degree and 9,230 second-degree relatives of index patients diagnosed with autoimmune hepatitis in 1994-2015; and 64 co-twins of index patients diagnosed with autoimmune hepatitis in 1977-2011. For first- and second-degree relatives we calculated the sex- and age-adjusted standardized incidence ratio of autoimmune hepatitis relative to the general population, and we calculated the cumulative risk, i.e. the cumulative incidence, of developing autoimmune hepatitis from the time of the index patient's diagnosis. For co-twins, we estimated the standardized incidence ratio and the concordance rate of autoimmune hepatitis. RESULTS: In first-degree relatives, there were six incident autoimmune hepatitis diagnoses during 64,020 years of follow-up: the standardized incidence ratio was 4.9 (95% CI 1.8-10.7), and the 10-year cumulative risk was 0.10% (95% CI 0.04-0.23). In the second-degree relatives, there were no incident autoimmune hepatitis diagnoses (expected number assuming incidence rate as in the Danish general population = 0.8). In the co-twins, there was one incident autoimmune hepatitis diagnosis during 1,112 years of follow-up, and the standardized incidence ratio was 53.9 (95% CI 1.4-300.4). The probandwise concordance rate, a measure of heritability, was higher in monozygotic than in dizygotic twins (8.7% [95% CI 1.1-28.0] vs. 0%). CONCLUSIONS: This nationwide study indicates that only first-degree relatives of index patients with autoimmune hepatitis are at increased risk of autoimmune hepatitis from the time of the index patient's diagnosis, but the absolute risk is very low. LAY SUMMARY: Autoimmune hepatitis is a chronic liver disease caused by a dysfunctional immune system. It is widely believed that autoimmune hepatitis accumulates in families. We studied the family members of patients with autoimmune hepatitis from the entire Danish population. We found that autoimmune hepatitis does accumulate in families, but the risk of autoimmune hepatitis in the family members is very low.

Benzodiazepines and risk for hepatic encephalopathy in patients with cirrhosis and ascites.

BACKGROUND: There is limited evidence to support the belief that benzodiazepines increase cirrhosis patients' risk of hepatic encephalopathy (HE). OBJECTIVE: We aimed to examine the association between benzodiazepine use and HE development in cirrhosis patients. METHODS: We used data on 865 cirrhosis patients with ascites from three trials to study the effect of benzodiazepine use on development of first-time HE. For each patient, we classified periods of benzodiazepine use by the number of days since initiation. We used Cox regression to compare the risk of HE in current benzodiazepine users vs. non-users adjusting for confounders. RESULTS: Cirrhosis patients were not at increased risk of HE for the first two days of benzodiazepine use, but then faced a five-fold increased risk of HE during days 3 to 10 of benzodiazepine use. The risk of HE was not increased for those who had been using benzodiazepines for more than 28 days. CONCLUSION: Cirrhosis patients who had begun using benzodiazepines between 3 and 10 days previously had a markedly increased risk of developing first-time HE. Cirrhosis patients who had been using benzodiazepines for just one or two days or continued use for more than 28 days did not have such an excess risk.

Worldwide Incidence of Autoimmune Liver Disease.

BACKGROUND: The variation that occurs in the incidence patterns of autoimmune liver diseases may provide insight into the risk factors causing the diseases. We systematically reviewed studies on the incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and immunoglobulin G4-associated cholangitis (IAC) in general populations. KEY MESSAGES: We found relevant studies through Medline and Scopus, and we examined whether they were population-based; the way they found cases for inclusion and which diagnostic criteria they used; and whether they used standardization to facilitate comparison with other studies. The 55 identified studies varied greatly in their case-finding methods, and only 14 (25%) of them used a standard population. Reported incidence rates of AIH were around 1 per 100,000 population per year, possibly higher in Scandinavia than in other countries, and a Danish study of the 1994-2012 period found an increasing incidence. A majority of PBC studies found incidence rates of 1-2 per 100,000 population per year and an increasing time trend, but incidence was lower in the Netherlands and New Zealand and higher in North East England. Most studies of PSC found incidence rates around 1 per 100,000 population per year, but there were no incident cases among 100,000 Alaska natives during the period 1984-2000. The incidence of IAC remains unknown. CONCLUSIONS: The incidence of the autoimmune liver diseases is around 1-2 per 100,000 population per year for each disease. The variation in incidence over time and place suggests that there are differences in the prevalence of risk factors for the diseases, but the studies used different methods and so it is difficult to draw firm conclusions. We recommend that groups of investigators conduct multisite studies with identical case-finding methods, and that they use a standard population to account for differences in demographics.

Alcoholic Cirrhosis Increases Risk for Autoimmune Diseases: A Nationwide Registry-Based Cohort Study.

BACKGROUND & AIMS: Alcoholic cirrhosis is associated with hyperactivation and dysregulation of the immune system. In addition to its ability to increase risk for infections, it also may increase the risk for autoimmune diseases. We studied the incidence of autoimmune diseases among patients with alcoholic cirrhosis vs controls in Denmark. METHODS: We collected data from nationwide health care registries to identify and follow up all citizens of Denmark diagnosed with alcoholic cirrhosis from 1977 through 2010. Each patient was matched with 5 random individuals from the population (controls) of the same sex and age. The incidence rates of various autoimmune diseases were compared between patients with cirrhosis and controls and adjusted for the number of hospitalizations in the previous year (a marker for the frequency of clinical examination). RESULTS: Of the 24,679 patients diagnosed with alcoholic cirrhosis, 532 developed an autoimmune disease, yielding an overall increased adjusted incidence rate ratio (aIRR) of 1.36 (95% confidence interval [CI], 1.24-1.50). The strongest associations were with Addison's disease (aIRR, 2.47; 95% CI, 1.04-5.85), inflammatory bowel disease (aIRR, 1.56; 95% CI, 1.26-1.92), celiac disease (aIRR, 5.12; 95% CI, 2.58-10.16), pernicious anemia (aIRR, 2.35; 95% CI, 1.50-3.68), and psoriasis (aIRR, 4.06; 95% CI, 3.32-4.97). There was no increase in the incidence rate for rheumatoid arthritis (aIRR, 0.89; 95% CI, 0.69-1.15); the incidence rate for polymyalgia rheumatica decreased in patients with alcoholic cirrhosis compared with controls (aIRR, 0.47; 95% CI, 0.33-0.67). CONCLUSIONS: Based on a nationwide cohort study of patients in Denmark, alcoholic cirrhosis is a risk factor for several autoimmune diseases.

Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study.

BACKGROUND & AIMS: Population-based studies of the clinical course of autoimmune hepatitis are scarce. We conducted a nationwide study of incidence, prevalence, prognosis, and causes of death of autoimmune hepatitis in Denmark. METHODS: From nationwide healthcare registries we identified all Danish citizens diagnosed with autoimmune hepatitis in 1994-2012 and their liver biopsy data. We followed patients through January 2013 and examined age-standardized incidence and prevalence, mortality, prognostic factors, risk of hepatocellular carcinoma, and causes of death. We used Cox regression to compare patients' mortality relative to a gender- and age-matched general population sample. RESULTS: We included 1721 autoimmune hepatitis patients. The incidence rate was 1.68 (95% confidence interval 1.60 to 1.76) per 100,000 population per year, and it doubled during the study period. Of the 1318 patients who were biopsied at diagnosis, 28.3% had cirrhosis. The 10-year cumulative risk of hepatocellular carcinoma was 0.7% (95% confidence interval 0.3 to 1.5). Male gender and cirrhosis were associated with high mortality and development of hepatocellular carcinoma. In the first year after diagnosis, patients with autoimmune hepatitis had six-fold higher mortality than the general population; later, their mortality remained two-fold higher. Their 10-year cumulative mortality was 26.4% (95% confidence interval 23.7 to 29.1). 38.6% of deaths were liver-related including 3.6% from hepatocellular carcinoma. CONCLUSIONS: This nationwide population-based study of autoimmune hepatitis showed that the incidence increased during 1994-2012, and that the disease remains associated with a high mortality, particularly in the first year after diagnosis. Male gender and cirrhosis were adverse prognostic factors.