Mahmood, AS; (2017) Amyloidosis: Diagnostic investigations, clinical categories, prognosis and management. Doctoral thesis , UCL (University College London).

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Abstract

BACKGROUND: Amyloidosis is a very rare disorder of protein misfolding characterised by the deposition of certain proteins in an abnormal fibrillary form within the extracellular space, which disrupts the normal structure and function of organs throughout the body. Amyloid deposition may be systemic or localised, though there have been few systematic clinical studies of the latter. Treatment depends on the respective amyloid fibril type, and comprises chemotherapy regimens derived from myeloma for the most prevalent systemic monoclonal immunoglobulin light chain (AL) type. The clinical features of systemic AL amyloidosis are protean, commonly including a variety of poorly understood coagulation abnormalities and fatigue symptoms of uncertain cause. Measurement of serum free light chains (FLC) has been a very important advance in guiding treatment of systemic AL amyloidosis. Novel treatment approaches include the serum amyloid P component (SAP) depleting drug ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2 carboxylic acid which has shown promise in a pilot study in patients with hereditary fibrinogen amyloidosis. AIMS: To compare the performance of two commercially available serum free light chain assays and study the prognostic utility of each in systemic AL amyloidosis. To investigate the underlying bleeding and coagulation abnormalities, associated prognostic implications, endothelial dysfunction and implications for the possibility of light chain toxicity. To explore the sleep disordered breathing morbidity in amyloidosis. To investigate the incidence, patient characteristics and survival outcomes in patients with localised AL amyloidosis. To explore a subgroup of localised amyloidosis: tracheobronchial and laryngeal amyloidosis from a clinical and proteomic perspective. To examine two types of treatment in systemic amyloidosis: the use of lenalidomide based chemotherapy with prior use of Thalidomide/Bortezomib treatment in systemic AL amyloidosis and CPHPC treatment. RESULTS AND CONCLUSIONS: Both FreeliteTM and N Latex assays have high sensitivity for detecting abnormal FLC in patients with systemic light chain amyloidosis, showing an excellent correlation between the assays for identifying the abnormal light chain subtype but with discordance in the absolute values. Coagulation abnormalities in systemic AL amyloidosis were frequent and included the following abnormalities: elevated concentration of fibrinogen in 42 (56.8%), elevated FVIII 67 (90.5%) and vWF Ag 67 (90.5%). Kaplan Meier estimates showed that vWF Ag (p=0.039) and FVIII (p=0.01) thresholds greater than 280IU associated with a significant survival disadvantage. A fall in the vWF Ag levels following chemotherapy in those achieving a clonal response suggests potential light chain toxicity implications. Albumin concentration lower than 25g/L correlated with coagulation factors which are prothrombotic, implying that anticoagulation may be an important consideration in newly diagnosed systemic AL. Thus these findings suggest the potential prognostic utility of vWF Ag levels and thrombotic risks associated with newly diagnosed systemic AL patients. Recurrent overnight oxygen desaturations proved to be frequent in patients with cardiac and/or soft tissue amyloidosis, although the occurrence of sleep disordered breathing (SDB) needs confirmation with formal polysomnography. Patients with poor right heart ventricular systolic function score high with SDB questionnaires, which was associated with adverse outcome in newly diagnosed cardiac AL amyloidosis. Localised AL amyloidosis is a very different disease from systemic AL amyloidosis, with a far superior prognosis. Local surgical resection is adequate in most patients with localised amyloidosis in whom treatment is needed, and radiotherapy can have a useful role in some patients whose disease cannot be controlled by local measures. Progression to systemic AL amyloidosis is extremely rare except among patients with lymph node involvement. Patients with lymph node involvement and those with isotypic specific circulating free light chains warrant closer follow up for development of systemic amyloidosis. Most patients with localised AL have excellent long term outcomes. Laryngeal and tracheobronchial amyloidosis is a subtype of localised amyloidosis, in which hoarseness and dyspnoea are the predominant symptoms, the 2 year OS 93% and 90% respectively. Proteomic analysis of amyloid dissected from biopsies showed the presence of the amyloid signature proteins, apolipoprotein A1 (in greater amounts protein) and insulin-like growth factor binding protein complex in all samples compared with patients with systemic AL or transthyretin amyloidosis. Of interest, apolipoprotein A1 has been described within the respiratory tract and insulin growth factor has been postulated to play a role in inflammation, which may be relevant with respect to the pathogenesis and effects of airways amyloidosis. Lenalidomide and dexamethasone combination treatment following prior proteasome inhibitor based therapy produced an overall haematologic response rate of 61%, including 20% complete responses. Renal responses among patients who received prolonged treatment were surprisingly frequent; twenty one out of 38 (55%) evaluable patients achieved a renal response (40% on an ITT basis) – 7 (18%) at 6 months, 7 (18%) at 12 months and an additional 7 (18%) patients at 18 months by long term follow up. This raises the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits. CPHPC depletes circulating Serum amyloid P (SAP) component as a treatment for systemic amyloidosis.1 Our study of 10 patients suggested a significant reduction in the natural progression of renal decline and renal survival along with an excellent safety profile; this was supported by our QoL assessments using SFv36 questionnaires. The work in this thesis has thus contributed to improved characterisation and clinical management of various types of amyloidosis, and has identified several avenues of therapy that merit further investigation in larger populations and randomised clinical trials.

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