FRI0599 AA AMYLOIDOSIS IN RECIPIENTS OF CADAVERIC DERIVED PITUITARY GROWTH HORMONE – POTENTIAL EFFECT OF AN AMYLOID ENHANCING FACTOR?
Authors: Helen J. Lachmann, Dorota Rowczenio, Janet A. Gilbertson, Islam Noor, Hadija Trojer, Julian D. Gillmore, Ashutosh D. Wechalekar, Philip N. Hawkins
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The development of Creutzfeldt–Jakob disease (CJD) in individuals treated with human cadaveric pituitary-derived growth hormone (c-hGH) was reported in 1985 resulting in its immediate withdrawal(1). Amyloid-β protein (Aβ) deposits have been found at autopsy in individuals previously exposed to c-hGH and misfolded Aβ peptide was recently identified in archived vials of human c-hGH; this induced Aβ pathology in an experimental model(2). The suggestion that contaminants in c-hGH could seed protein misfolding is reminiscent of the concept of amyloid enhancing factor (AEF), in which administration of tiny amounts of amyloidotic material is associated with acceleration of experimentally induced murine AA amyloidosis(3). In humans AA amyloid is a rare complication of chronic inflammation in which the amyloid fibrils are derived from Serum Amyloid A protein (SAA), a circulating component of the acute phase response. <h3>Objectives</h3> To seek evidence of prior exposure to c-hGH in patients with AA amyloidosis. <h3>Methods</h3> A database of 782 patients with AA amyloidosis seen between 1990 &amp; 2017 was searched using: pituitary, craniopharyngioma &amp; growth hormone. Only patients exposed to GH prior to 1985 were included. <h3>Results</h3> 10 cases were identified; accounting for 8% of AA of unknown etiology. 8 were female, 9 north European, median age at diagnosis of amyloid 47.9 yr with a median time since starting c-hGH of 35 yr. The indications were: 4 craniopharyngioma, resection of ependymona, nasal pharyngeal tumour &amp; encephalocoele, 2 unexplained hypopituitarism. Chronic inflammation was assessed by serial blood tests after the diagnosis of amyloid; 1 had median SAA 131 mg/L; 4 had medians 20- 54 mg/L &amp; the others low level inflammation, median &lt; 20mg/L. No cause of inflammation was identified although 50% were obese. Genetic testing excluded systemic autoinflammatory disorders. 6 European patients were homozygous for SAA1.1 (66.7% compared to control frequency 29%)(4). 4 patients eventually required dialysis, 2 had renal transplants; median survival from diagnosis of amyloid was 132 mn &amp; 3 patients have died. <h3>Conclusion</h3> 2,000 UK children were exposed to c-hGH; the finding of AA amyloid of uncertein etiology in these 10 cases raises the possibility that contaminants in c-hGH potentially contribute to misfolding of SAA. 80% had at least one recognised additional modest risk factor for the development of AA amyloidosis in the form of SAA1.1 homozygosity or obesity suggesting that a combination of factors may contribute to amyloidogenesis in individuals who have low levels of circulating potentially amyloidogenic protein(4). <h3>References</h3> [1] Underwood LE, Fisher DA, Frasier DS, et al. Degenerative neurologic disease in patients formerly treated with human growth hormone: Report of the Committee on Growth Hormone Use of the Lawson Wilkins Pediatric Endocrine Society, May 1985. The Journal of Pediatrics. 1985;107(1):10-2. [2] Purro SA, Farrow MA, Lineham J, et al. Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone. Nature. 2018;564:415-9. [3] Lundmark K, Westermark GT, Nyström S, et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci U S A2002;99(10):6979-84. [4] Blank N, Hegenbart U, Dietrich S, et al. Obesity is a significant susceptibility factor for idiopathic AA amyloidosis. Amyloid. 2018;25(1):37-45. <h3>Disclosure of Interests</h3> Helen J. Lachmann Grant/research support from: SOBI, Novartis, Consultant for: Novartis, Takeda, Speakers bureau: SOBI. Novartis, Dorota Rowczenio: None declared, Janet A. Gilbertson: None declared, Islam Noor: None declared, Hadija Trojer: None declared, Julian D. Gillmore: None declared, Ashutosh D. Wechalekar: None declared, Philip N Hawkins: None declared