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Title: Clinical, biochemical, haematological and molecular epidemiology of erythropoietic protoporphyria : a United Kingdom cross-sectional study
Author: Holme, Stephen Alexander
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2011
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Abstract:
This thesis concerns erythropoietic protoporphyria (EPP, MIM 177000), a rare photodermatosis with systemic complications which results from an inherited partial deficiency of ferrochelatase (FECH), the terminal enzyme of haem biosynthesis. Excessive formation of the substrate, protoporphyrin IX, results in protoporphyrinaemia and accumulation in erythrocytes, plasma, skin and liver, prior to excretion in the bile. Protoporphyrin can absorb light, damaging surrounding tissues through the generation of free radicals, and clinically manifesting as painful photosensitivity within minutes of skin exposure to sunlight. Microcytic anaemia occurs in 20 - 60% of patients. Liver dysfunction and liver failure occurs in up to 35% and 4% of patients respectively. Management of EPP is based mainly on minimising the effects of sunlight by use of visible light sunscreens, clothing and behavioural measures to avoid direct sunlight. Despite advances in the biochemistry and genetic inheritance, there remains a lack of prospective clinical data for EPP. Previous studies have been retrospective analyses, often from tertiary centres specialising in the treatment of liver disease. Such studies typically report subjects in common, many from large family pedigrees. These limitations of ascertainment, bias and small population size have restricted accurate investigation of fundamental clinical issues relating to EPP. This thesis describes a prospective cross-sectional study of United Kingdom patients with EPP, designed to describe in detail clinical features, assess liver and haematopoietic function and to characterise vitamin D status. Genotyping was additionally undertaken and statistical analysis of measured variables performed to identify significant associations which might predict clinical status. The study cohort included 223 patients from 193 families (114 females, 109 males median age 34 years; range 5-87 years) most of whom were white Caucasians apart from two. Of 178 patients with 'dominant EPP' (dEPP), 48% of women and 33% of men were anaemic. Iron stores were decreased by two-thirds but normal serum soluble transferrin receptor-1 and iron concentrations suggested that erythropoiesis was not limited by iron supply. Liver dysfunction was present in 25% dEPP and significantly associated with total erythrocyte protoporphyrin (TEP) concentration, male sex, age, anaemia and alcohol consumption, but not with genotype. Vitamin D deficiency and insufficiency was present in 17% and 91% of 201 subjects respectively seen over a seven-month period between January and July. Both insufficiency and deficiency were significantly associated with the TEP and inversely with the time in minutes to the onset of symptoms following sunlight exposure. A new clinical EPP subtype was identified of seasonal palmar keratoderma, characterised by low erythrocyte protoporphyrin concentrations and recessive inheritance. This condition may carry a lower risk of liver disease than other patients with recessively-inherited EPP. Investigation of individuals, clinically presenting as EPP, but in whom no FECH mutation was identifiable, has identified a new condition, X-linked dominant protoporphyria, which results from a gain-offunction mutation of the C-terminal of 5-amino levulinate synthase 2, the initial rateregulating enzyme of erythroid haem biosynthesis. X-linked dominant protoporphyria causes neither anaemia nor iron overload.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.771567  DOI: Not available
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