Increased Incidence of Autoimmune Hepatitis Is Associated With Wider Use of Biological Drugs

Kjartan B. Valgeirsson; Jóhann P. Hreinsson; Einar S. Björnsson


Liver International. 2019;39(12):2341-2349. 

In This Article


Study Population

A nationwide population-based study of all Icelanders diagnosed with AIH from 1 January 2006 to 31 December 2015.

Data Sources

Iceland is ideally seated as a venue for epidemiological studies because of geographical isolation. With a total population of approximately 340 000, about two thirds are in the primary catchment area of the National University Hospital of Iceland in Reykjavik's capital area with the remaining specialist care almost only provided in Akureyri Hospital with a primary catchment area of about 30 000. Patients from other parts of the country are referred to those hospitals. All Icelanders have access to public health services, but a part of outpatient services is privately managed. All Icelanders have a unique personal identification number assigned at birth or at immigration. Information regarding Icelandic population demographic was accessed from Statistics Iceland publicly available data ( The study protocol was approved by The Icelandic National Bioethics Committee (VSNb2010100016/03.7).

Patient Identification

We collected data of new diagnosis of AIH in Iceland (average population 319 403 during the study period) over a 10-year period from 2006 to 2015. Potential cases were identified through search of diagnostic codes (International Classification of Diseases tenth version) of chronic active hepatitis, AIH chronic hepatitis and unspecified AIH (K73.2, K75.4 and K73.9 respectively). Furthermore, we performed a text search for 'autoimmune hepatitis', 'AIH' and equivalent Icelandic translations in computerized medical records in both of the island's main hospitals. A list of all Icelandic patients referred for liver transplantations was acquired and reviewed. A request was sent to hepatologists, gastroenterologists and internal specialists in private practice and smaller regional hospitals for identification of known cases within their practice. A total of six physicians responded to our request.

Moreover, data of all SMA and liver kidney microsomal antibodies (LKMA) measurements for the study period were acquired from the National University Hospital of Iceland immunology department, the only immunology laboratory in the country performing analysis of SMA and LKMA. Some of the cases of DIAIH in this study have been included in previous studies from our group.[30–33] Medical records were reviewed, and patients included in the final analysis if they received the clinical diagnosis of AIH, marked by either ICD-10 codes for AIH and chronic active hepatitis (K75.4 and K73.2 respectively) or the clinical records clearly stating AIH as the primary diagnosis in cases where codification of records was incomplete. Furthermore, patients who were started on immunosuppressive therapy with either corticosteroids, azathioprine or both were included in the analysis if the records stated suspected AIH as the primary reason for treatment and evidence of exclusion of other liver disorders treated with corticosteroids, for example alcoholic hepatitis, were noted.

Data Collection

As mentioned above, retrospective search for cases with various case-finding methods and review of medical record was performed on patients fulfilling the inclusion criteria. We collected data about baseline characteristics of patients, serological markers, medications, histology, treatment methods and response, survival and liver transplantations. Antinuclear-, antimitochondrial and SMA were analysed using indirect immunofluorescence on rodent substrate with oesophageal, stomach, liver and kidney sections. Treatment response was defined as biochemical remission, further defined as alanine and aspartate transaminase (AST) values less than 1.5 times the upper limit of normal. Treatment response was defined using modification of current guidelines definition of biochemical remission,[34,35] as normalization of alanine transaminase (ALT) values. Treatment discontinuation was considered applicated if all immunosuppressive therapy was stopped. Relapse after treatment discontinuation was defined as requirement of immunosuppressive therapy because of increase of alanine aminotransferase values above upper limits of normal. DIAIH was defined according the criteria used in a recent single-centre study of the topic,[33] ie as a drug well documented as cause of DIAIH, with positive ANA and/or SMA antibodies, and/or elevated IgG; or requirement of corticosteroids, in patients without spontaneous recovery of liver tests despite discontinuation of the drug. Overlap syndrome with either primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) was documented if clinical records suggested such relationship based on results of laboratory analysis, autoantibodies, liver biopsy and/or imaging studies. Cirrhosis at diagnosis was noted if patients had histological features of cirrhosis according to their pathology report. Diagnostic score was calculated according to the new simplified criteria (NSC) of the International Autoimmune Hepatitis Group (IAIHG)[4] but the revised original score of the IAIHG[3] was calculated if patients did not fulfill the simplified criteria.

Statistical Analysis

Microsoft Office Excel 2016 (Microsoft) and R computer software, version 3.2.3 (The R foundation for Statistical Computing) were used for statistical analysis for all the clinical data obtained from medical records. Data are reported as medians and range/interquartile range (IQR) or as number and percentage, as appropriate. The Fisher exact test was used to compare groups with dichotomous variables and the Mann-Whitney U test, also known as Wilcoxon test, was used to compare groups with continuous variables. Survival among patients with and without cirrhosis at diagnosis was estimated using the Kaplan-Meier method and compared with the log rank test. The level of statistical significance was set at P < .05.

We tested for statistical significance of trends in AIH during the study period between 2006–2013 and 2014–2015 with log-linked Poisson regression analysis. In the statistical model, the number of cases was entered as a response variable, the time periods 2006–2013 and 2014–2015 were entered as a binomial explanatory variable, the annual population in Iceland was set as offset.