Youngstein, Taryn Alessandra Beth; (2019) Phenotypic and clinical outcome studies in amyloidosis and associated autoinflammatory diseases. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Background: Systemic Amyloidosis results from the deposition of insoluble proteins as amyloid that disrupt organ function with time. Over 30 proteins are known to form amyloid and the identification of the precursor protein is essential as it guides treatment strategies. In AA amyloidosis, the precursor protein is Serum Amyloid A (SAA) which forms amyloid when raised in the blood over time. Thus, AA amyloidosis is a feared complication of the hereditary periodic fever syndromes and other autoinflammatory diseases. // Aims: (1.) To investigate transthyretin (TTR) amyloid and describe non-cardiac TTR deposition; (2.) To determine the role of carpal tunnel biopsy in diagnosis of TTR amyloid; (3.) Investigate and define the changing aetiology of AA amyloidosis; (4.) To investigate the safety of IL-1 antagonism for autoinflammatory disease in pregnancy; (5.) Delphi consensus study to define phenotype and management approaches in the autoinflammatory disease Deficiency of ADA2 (DADA2). // Results and Conclusions: (1.) Non-cardiac TTR deposits were identified in 25 biopsies from the tissues of the bladder, duodenum, bone marrow, carpal tunnel tenosynovium, colon, stomach, lung, prostate, muscle. 84% had concurrent evidence of cardiac amyloid and 64% fulfilled consensus criteria for cardiac amyloidosis at presentation. Those with no cardiac involvement did not develop cardiac amyloid or amyloidosis over time; (2.) 16.7% of 60 carpal tunnel biopsies from the general population contained evidence of amyloid. In those with amyloid mean age was 78.13 years vs. 58.40 years (p=0.0092). 11.67% biopsies demonstrated definitive staining with TTR, median age 81.9 years, 71% female; (3.) An increasingly prevalent cohort of AA amyloidosis of unknown aetiology was identified, with the novel finding that this group have a significantly 4 raised BMI (p<0.0001) suggesting that adipocyte production of pro-inflammatory cytokines may contribute to the raised circulating serum amyloid A levels. These findings suggest that AA amyloidosis may become another consequence of the global obesity epidemic; (4.) Data on 31 maternal-exposed pregnancies from seven countries was collected, including the first data on canakinumab-exposed pregnancies. The first data on paternal exposure is described with no negative outcomes. Fourteen infants were breast fed with no complications. There were no reports of developmental delay, with follow-up of up to 10 years (median 18 months); (5.) International expert consensus has been reached on the diagnosis and management of DADA2 but areas of contention, most notably regarding heterozygotes, remain and is the focus of ongoing further work.

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