Immunogenetic and therapeutic aspects of Autoimmune Hepatitis

Only one study has examined the epidemiology of AIH in a population in which
hepatitis C infection was excluded. Boberg et al. found a mean annual incidence
of 1.9 cases of AIH per 100 000 and a point prevalence of 16.9 cases per 100
000 in a population in Norway. Autoimmune hepatitis is a progressive, chronic
hepatitis of unknown cause that occurs in people of both sexes and all age.
Like other autoimmune conditions, autoimmune hepatitis is a disease of unknown
cause that occurs in persons with a genetic predisposition. the search for
candidate genes has primarily focussed on genes encoding for antigen
presenting cells, human leukocyte antigens (HLA) lodging in major
histocompatibility complexes (MHC) and the T cell receptor (TCR)1. The
strongest association found until now is the association with the DR3 and DR4
alleles, that has been found in Caucasians in several studies. This association
has not been found in all AIH patients, which suggests the influence of
additional genes. Besides the presentation and recognition of antigens, genetic
changes in other steps of the immune response may be involved, such as
variations in the expression of co-stimulatory molecules. Another essential
prerequisite for the pathogenesis of all autoimmune diseases is the breakage of
immunological tolerance, which is the ability of an individual to differentiate
*self* from *non-self*. Like postulated in other autoimmune diseases, an
environmental trigger can lead to an avalanche of t-cell mediated events. The
nature of this trigger is unclear. The most plausible hypothesis is that
molecular mimicry by cross reactivity between epitopes of viruses and certain
liver antigens trigger the onset of disease. The short- and long-term efficacy
of immunosuppression with prednisolone or thiopurines in patients with
autoimmune hepatitis has been demonstrated unequivocally. In many cases,
however, patients are not treated or treatment is begun too late because the
diagnosis is missed. Therapy with thiopurines, a common therapeutic agent in
IBD, can have side effects that are usually caused by metabolites. It is
unknown if AIH has an influence on the transformation of AZA to 6-MP.

Primary Objective: To gain more insight in the genetic susceptibility for AIH.
For this we will study the presence of candidate genes in AIH patients, study
genetic similarities with other auto-immune diseases and perform a whole genome
association study
Secondary Objective(s):
To create a web-based Dutch registry to study the natural history,
(long term) effects of treatment of patients with autoimmune hepatitis.
* To facilitate sufficiently powered (clinical) studies in AIH.
* To update the current nationwide database on autoimmune hepatitis.
* To describe the demographic pattern of AIH in a well defined dutch
population
* To gain more insight in the nature of the immune response in AIH patients we
will perform a microarray analysis to determine expression of (inflammatory)
genes in AIH patients, compared to healthy controls.
* To gain more insight in the immunophenotype of the liver we will assess
leftover formalin fixed paraffin embedded liver tissue with immunohistochemical
staining.
* To describe pharmacokinetic and pharmacodynamic features of azathioprine in
patients starting azathioprine therapy.
* To study the association between thiopurine dosage, 6-MMP and 6-TGN levels
and clinical efficiacy
* To study the association of AZA,6MP,6TGN, 6MMP and TPMT levels and ALT, AST
and clinical condition in a dutch AIH population

Observational cohort study

AIH is a progressive, chronic hepatitis of unknown cause that occurs in people
of all ages. The diagnosis is based on characteristic clinical and biochemical
abnormalities, elevated levels of IgG and histologic characteristics. A
curative therapy for AIH is still not available, but appropriate management of
the disease can prolong survival, improve the quality of life, and avoid the
need for liver transplantation. An epidemiological study can provide clinicians
with valuable information and give direction to future research in aetiology
and therapy of the disease. Furthermore an insight in epidemiology can aid
health care officials in planning the future need for liver transplantations.
The immunogenetic research in this study can provide new insights in the
pathogenesis of the illness and thereby contribute to the development of
diagnostic tools and therapeutic agents. The risk and burden for the patient
is minimal. Participants will be asked to complete a short questionnaire and
an extra 17 ml blood will be drawn. No extra visits are scheduled.