Lachmann, Helen J.; (2003) Characterisation, monitoring and treatment of systemic amyloidosis. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Amyloidosis is a heterogeneous group of disorders caused by extracellular deposition of protein in a characteristic abnormal fibrillar form. The development of serum amyloid P component (SAP) scintigraphy has uniquely enabled non-invasive serial assessment of the amount and distribution of amyloid deposits in patients. The findings of SAP scintigraphy have refuted the traditional belief that amyloid deposition is both inexorably progressive and irreversible. In contrast, amyloid deposits exist in a state of dynamic equilibrium, and therefore may regress when underlying disorders can be treated. Unfortunately many treatments used in systemic amyloidosis carry considerable iatrogenic risks. The general hypothesis explored in this thesis is that the rationale for treatment and clinical outcome of patients with the various forms of amyloidosis can be improved by more precise characterisation and quantitative monitoring of the disease process that underlie amyloid deposition. Hereditary systemic amyloidosis has hitherto been considered to be exceptionally rare, but the finding described in this thesis that it actually accounts for about 10% of patients with apparent sporadic acquired systemic amyloidosis demonstrates the critical importance of accurate diagnosis. This finding has already spared many patients undergoing inappropriate and dangerous chemotherapy, and, in some cases, has enabled liver transplantation to be performed with the objective of correcting the inherited metabolic abnormality. It has also facilitated the detailed clinical characterisation of the hereditary fibrinogen A α-chain amyloidosis phenotype, and has led to the introduction of routine DNA analysis among NHS patients attending the National Amyloidosis Centre. Precise quantitative monitoring of circulating amyloid fibril precursor proteins enabled the relationship between monoclonal immunoglobulin production and clinical outcome to be evaluated for the first time in AL amyloidosis, and in AA amyloidosis confirmed efficacy of surgical and pharmacological treatments in patients with Castleman's disease and familial Mediterranean fever (FMF) respectively. It also revealed for the first time the pattern and substantial intensity of sub-clinical inflammation in familial Mediterranean fever, explaining the high incidence of AA amyloidosis in this disorder.

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