Autoimmune Liver Diseases in Canterbury, New Zealand

Abstract

Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are progressive autoimmune liver diseases (AiLD) that can lead to liver cirrhosis, hepatic failure, the need for liver transplantation and death. Although it is believed that there is an autoimmune basis to their pathogenesis, the precise aetiologies of AiLD remain unknown. The epidemiology of AiLD has remained poorly defined, as population-based epidemiological data concerning AiLD are scarce. This thesis details the descriptive epidemiology, survival and cancer incidence in population-based AIH, PBC, and PSC cohorts in Canterbury. In addition, this work also investigates genetic risk loci and environmental risk factors, as well as identifies prognostic factors that determine outcomes in the population-based cohorts of AIH. The major findings of this work are:

1. The incidence and prevalence of AIH and PSC in Canterbury are among the highest reported worldwide. This could mean that Cantabrians are predisposed to inflammatory autoimmune diseases and/or that case recruitment methodology in these epidemiological studies is thorough.

2. The incidence and prevalence of PBC is surprisingly low in Canterbury when compared with studies performed in northern Europe and northern America. As the majority of our population are of Anglo-Celtic background with shared genetic background with some of these countries, this work provided support to the hypothesis that there may be a protective effect or lack of a risk factor for PBC in Canterbury.

3. This is the first population-based AIH study to confirm that AIH presents predominantly in older women, contrary to the classical description of the disease. Nearly three quarters of patients presented after the age of 40 years with a single peak age of presentation in the sixth decade of life. This finding indicates that AIH should therefore be considered more frequently in clinical practice as a treatable cause of hepatitis in the older age group.

4. PSC associated with inflammatory bowel disease (IBD) has a worse outcome than PSC without IBD. This is the first study to show that there are striking differences between PSC with and without IBD with regard to serious complications such as cancer, death and requirement for liver transplantation. These findings demonstrate that IBD is at least a major modifying factor in the disease manifestation of PSC.

5. The mortality for AIH, PBC and PSC is significantly increased compared to the Canterbury population. The excess mortality is due to liver related death, indicating the inadequacy of current management strategies, and the need for new effective treatments for these conditions.

6. Risks of both hepatic and extra-hepatic malignancy are significantly increased in AIH and PSC patients. Although an association between PSC and hepatic malignancy and CRC is well established, this work has demonstrated for the first time that non-melanoma skin cancer risk is also significantly increased in these patients. The current study is also only the second study to examine the risk of malignancy in AIH patients, demonstrating that the risk of hepatobiliary, skin (non-melanoma) and haematological cancers are significantly raised, confirming that these are real risks that should not be ignored.

7. Susceptibility to type 1 AIH in Canterbury is independently associated with HLA-DRB1*0301. Polymorphism in FAS is associated with more aggressive disease phenotypes.

8. Antibiotic use is an independent risk factor for the development of AIH, whereas alcohol consumption and living in a childhood home with wood heating are independent protective factors against the later development of AIH.

9. The prevalence of AIH in first degree relatives is low at 0.2%, emphasising the importance of environmental factors in the aetiology of AIH.

10. Incomplete normalisation of ALT at 6 months, low serum albumin concentration at diagnosis and age at presentation of ≤20 years or >60 years, are significant independent predictors of liver related death or requirement for liver transplantation. Histological cirrhosis at diagnosis is not associated with poor prognosis and did not influence the response to initial immunosuppressive treatment.

In this thesis, we have presented detailed descriptive population-based cohorts of AIH, PSC and PBC in Canterbury. Several novel findings of this work will make important contributions to the current understanding of these conditions and aid in devising better management strategies.