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Title: Immunosuppressive therapy in autoimmune hepatitis : efficacy and toxicity
Author: Dhaliwal, Harpreet K.
ISNI:       0000 0004 7225 8772
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Introduction: Autoimmune Hepatitis (AIH) is a chronic inflammatory disease of the liver that, if untreated, leads to cirrhosis and death from liver failure. The mainstay of treatment is with prednisolone and azathioprine. Evidence has recently emerged that long-term survival, even in treated AIH, is reduced, thus raising the possibility that the current standard regimen is not adequately controlling disease activity. Aims: The aim of this study was to firstly, assess the efficacy and toxicity of current immunosuppressive regimens with specific reference to induction of histological remission. Secondly, to study the clinical significance of azathioprine metabolites, TPMT and ITPA genetic polymorphisms, in an attempt to improve clinical efficacy of azathioprine. Thirdly, to study the efficacy of mycophenolate (MMF) as an alternative to azathioprine. Results: 46% of patients with treated AIH who achieved biochemical remission had persisting histological activity and these patients were at higher risk of death/transplantation compared to patients who achieved histological remission (SMR 1.4 vs. 0.7; p < 0.05). Adverse events with AZA occurred in 27% of patients, with drug withdrawal in 21%. TGN, the active AZA metabolite, accumulates gradually, takes eight weeks to achieve steady state and dose increase of AZA is associated with increase in TGN, but not in a predictable manner. TGN values of > 220 pmol/8x108 RBCs were significantly associated with AIH remission. There was no association observed between TPMT heterozygosity and the occurrence of AZA related adverse events. Patients with the ITPA variant alleles associated with severe ITPase deficiency were significantly more likely to develop AZA induced adverse events. Finally, for patients who are intolerant to AZA, MMF is a suitable alternative with comparable remission rates. Conclusion: The results suggest that the current immunosuppressive regimen is inadequately controlling disease activity in a significant number of patients. Measurement of AZA metabolites may be helpful in these patients.
Supervisor: Lennard, Lynne ; Gleeson, Dermot Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available