Gillmore, Julian David; (2001) Characterisation and treatment of hereditary and acquired systemic amyloidosis. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Amyloidosis is a heterogeneous disorder associated with deposition of protein in an abnormal fibrillar form. Serum amyloid P component (SAP) is a normal plasma protein that binds specifically to amyloid fibrils, and has been developed as a scintigraphic tracer for quantitatively imaging amyloid deposits. The natural history of systemic amyloidosis suggests that amyloid deposition is irreversible and inexorably progressive, but various case reports, lately verified by SAP scintigraphy, indicate that amyloid deposits can regress when underlying conditions remit. The hypothesis studied in this thesis is that amyloid exists in a state of dynamic turnover, and that measures which reduce fibril precursor protein production may decrease amyloid load and improve clinical outcome generally. This was systematically confirmed in 80 patients with AA amyloidosis in whom acute phase inflammatory activity was monitored intensively and controlled in many cases, and in 50 patients with AL amyloidosis who were the first such cases to undergo autologous stem cell transplantation in the UK. Organ function often improved even when amyloid load only stabilised, suggesting that active deposition is more damaging than mature steady deposits. The significance of characterising amyloid type was highlighted by reversal of amyloid following liver transplantation in patients with hereditary fibrinogen [alpha]-chain and apolipoprotein AI amyloidosis, establishing new indications for this procedure. The genotype:phenotype spectrum of variant transthyretin amyloidosis was extended. Familial Mediterranean fever (FMF) was associated with numerous mutations in the pyrin gene, including a novel variant in British Caucasians that was atypically associated with dominant inheritance. AA amyloidosis in 10 patients with FMF did not correlate with any particular pyrin genotype. The natural history of amyloidosis reflects the nature of the conditions that underlie it. Although amyloid deposits do turnover, the rate varies greatly between patients, but, nevertheless, the various observations reported here have encouraging implications for patient management.

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