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


The results of this study demonstrate the highest incidence and prevalence of AIH hereto in a population-based setting. AIH, as in other studies, was found to be predominantly a disease of middle-aged and older women although a bimodal age distribution in women was observed. Immunosuppressive therapy was very effective in achieving biochemical remission in the current cohort and short-term prognosis was very favourable. DIAIH seems to be an increasingly recognized condition which might contribute to increasing incidence of AIH overall. A vast majority of drug-induced cases were caused by biological drugs.

The mean annual incidence of AIH during the study period was 2.2 per 100 000 inhabitants. This is the highest incidence reported so far in a population-based study.[5–8,11,13,15–18] The only study reporting higher incidence was not population-based and consisted of only six patients.[14] The incidence reported in this study is very similar to that reported from another geographically isolated area in Canterbury, New Zealand.[17] Recent studies have described an annual incidence of 0.67–1.92 per 100 000 in European populations.[7–11,13,15,16,18] Some of these studies have used validated scoring systems whereas others include patients diagnosed clinically, as retrospective applications of these scoring systems often cannot be confirmed reliably. Furthermore, some of these studies,[7,9,11] in contrast to this study, excluded children under the age of 18. This might overestimate the incidence as AIH is more commonly diagnosed in the adult population. Arguably the inclusion of DIAIH cases in this study risks overestimating the incidence. However those cases did meet the new simplified criteria[4] and/or the revised original score of the IAIHG[3] and all but one required treatment with immunosuppressive therapy despite discontinuation of the offending drug; their management thus being similar to the classical form of AIH.

The annual incidence in our study was 3.8 and 0.6 per 100 000 for women and men respectively. These figures are somewhat higher than previously reported for women (1.2–2.40 per 100 000) but in line with previous rates for men (0.12–0.93).[8,9,13,15,16,18] As demonstrated in Table 1 the female predominance in this study is in line with others. Interestingly, a similar proportion of males and females in this study had the drug-induced subtype of AIH; 20% and 18% respectively.

Because of limited number of patients and the small population of Iceland, fluctuations in annual incidence rates were expected. As shown in Figure 2 the incidence was higher in the final 2 years of this study. The incidence for every year in this study was higher than described in the previous Icelandic study of chronic active hepatitis in the 1970's (0.83 per 100 000).[5] Patients in that study were identified based on patients undergoing liver biopsy, prior to steroid therapy and prior to improvement in serological markers for AIH.[5]

Other researchers have recently described increasing incidence of AIH in Danish,[8] Dutch[7] and Finnish[10] cohorts covering the years from 1994 to 2015. Whether this represents a true rise in incidence or increasing awareness and diagnostic accuracy is yet to be answered. It is not specified if patients with DIAIH were included in those reports.

The highest prevalence of AIH reported so far is 42.9 per 100 000 from a cohort of Alaska Natives but unfortunately no incidence was reported in that study.[12] The prevalence described in this study, 26.9 per 100 000, is similar to those reported in recent studies from Denmark[8] and New Zealand[17] but higher than in AIH cohorts from Norway,[11] Spain,[13,16] Israel,[18] Sweden,[9,15] the Netherlands[7] and Finland.[10] Whether those variations are because of different methods or represent a difference in risk factors is unclear. In this study, various case-finding methods were utilized, seemingly more thorough than in most other studies.[5–11,13–16] Similar extensive case-finding mechanisms were used in a study by Delgado et al[18] that reported considerably lower prevalence than in this study, but their analysis was based on different inclusion criteria.

The median age in the current AIH cohort was similar as shown in previous studies which have median age in the range of 43–68 years.[9–11,15] The bimodal age distribution among females with a small incidence peak in younger women has been previously described by some authors,[8,9,15,19] but not others.[10,17]

Histology is one of the four components of the new simplified criteria[4] for diagnosis of AIH and is considered a prerequisite by current guidelines for diagnosis of AIH.[34] In this study liver biopsy was obtained in 61 of 71 (86%) cases. All but one had histological features typical or compatible with AIH. Cirrhosis was present in 13% of patient biopsied at diagnosis. The single case with atypical histology had features suggestive of steatohepatitis but was diagnosed clinically with AIH and managed accordingly with both steroids and azathioprine. The percentage of patients undergoing biopsy in this study is very similar to a larger Dutch cohort, in which 79% of patients were biopsied.[7] A previous study from the Mayo clinic has suggested that patients with typical laboratory features of AIH are very likely to have compatible histology and in cases in where liver histology was atypical it did not alter patient management.[36]

Most patients (70%) in this study achieved a score suggestive of probable or definite AIH according to the new simplified criteria. The remaining group often had lacking data of one or more components of the score, such as immunoglobulins or histology. If only patients who had a full set of data available were considered, 80% of patients met the criteria for probable or definite AIH.[4] All patients in the current study who did not fulfill the simplified criteria had revised original score[3] of either probable or definite AIH. This is somewhat expected as the revised original scoring system has been shown to have greater sensitivity but a lesser specificity for the diagnosis of AIH compared to the simplified one.[37] Of patients in this study who did not meet the simplified criteria despite having all components of the score available at diagnosis, 4/10 (40%) had DIAIH and 2/10 (20%) had overlap syndrome with PBC. This is in line with other studies showing that the simplified criteria did not predict the requirement of steroids in patients with DIAIH[33] and a high number of patients with PBC overlap among those who fell short of the simplified criteria.[7]

The frequency of DIAIH is higher in our study than in a study from the Mayo clinic.[20] The proportion of DIAIH out of all AIH patients identified between 1997 and 2007 was 9%.[20] Overall 11/13 (85%) DIAIH patients in our study had DIAIH as a result of biological drugs whereas Nitrofurantoin and Minocycline were the main causes (92%) in the Mayo clinic study.[20] It is conceivable that wider use of biological drugs can in part explain the higher incidence of AIH recorded in our study compared to previous ones (Table 1). When compared to patients with classical AIH, patients with DIAIH were less likely to have IgG above upper normal limits, positive SMA and to be treated with azathioprine. A trial of treatment discontinuation was successful in all DIAIH patients compared with 47% of patients with the classical form of AIH, with the difference being statistically significant. This is in line with other studies where only about 40% of DIAIH patients had elevated IgG levels.[23] Trial of discontinuation of corticosteroids has previously been shown to be more likely to be successful in the drug-induced group.[20]

Frequencies of overlap syndromes vary as no standard definitions currently exist.[38] In this study, 8% of patients were diagnosed with overlap with PBC and 1% with PSC which is in agreement with other studies of predominantly European descended patients with AIH[9,15,17] but higher than in a study of Alaska natives.[12]

Immunosuppressive therapy was initiated in almost all (97%) patients in our cohort as in most other reports.[18,39] Initial biochemical remission, defined as normalization of ALT values, was achieved in most cases (93%) where treatment was initiated. Recently, impaired survival of AIH patients compared to the general population has been reported in studies from Scandinavia[8–10] all of which had a longer median follow-up time (5.9–11.3 years) than the current one. An overall survival rate of 90% after median follow-up of 5 years is in line with what has been described previously by some[10,18,39] investigators but not others.[8] Of interest, Danielsson et al[9] found that relative survival of an AIH cohort started to differ from the general population 4 years from diagnosis but that difference became more prominent in the second decade after diagnosis.[9] Impaired survival of AIH patients with cirrhosis in this study is in line with a recent study found survival to be significantly impaired in AIH patients with cirrhosis compared to general population but not in AIH patients without cirrhosis.[40]

None of the patient in the current study underwent liver transplantation whereas 2–5% of patients in other cohorts have undergone transplantation.[7–10,18,39] We do not have an explanation for this. This might be due to earlier diagnosis in the Icelandic patients in recent years preventing liver damage but relatively short follow-up in the current study might also be a contributing factor. This might also reflect a smaller cohort. Four Icelandic patients underwent liver transplantation as a result of AIH, all diagnosed prior to the start of this study, with one transplantation taking place during the study period (in 2010).[41] The cause of death was considered liver-related in a minority of our patients with similar findings described recently by Puustinen et al[10] whereas others[8,9,39] have described a majority of liver-related deaths.

The strength of our study is that it consists of a well-defined cohort from a geographically isolated area, with many different case-finding strategies. This study was nationwide thus limiting regional referral bias. We were able to scrutinize medical records in our cohort and are confident that most, if not all, cases of AIH diagnosed in Iceland during the study period were found. Our main limitation is that validated scoring criteria could not be applied reliably to all patients thereby increasing the risk of overestimating the incidence.

Summary; the incidence and prevalence of AIH in the Icelandic population is among the highest reported to date. The disease has a marked female predominance. Drug-induced cases contribute in part to increasing incidence which can probably be associated with wider use of biological drugs. Immunosuppressive treatment was very effective and short-term prognosis favourable.