Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

Rudge, Peter; Jaunmuktane, Zane; Adlard, P; Bjurstrom, N; Caine, Diana; Lowe, Jessica; Norsworthy, Penny J.; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D. F.; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

doi:10.1093/brain/awv235

Cited by 97 publications

(106 citation statements)

References 48 publications

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“…One form of UK pituitary-derived hGH, the modified Wilhelmi preparation, had been administered to all hGH recipients who had developed iCJD, albeit in varying quantities and over different time periods [59, 64]. All 35 hGH-iCJD patients in this study had received hGH produced by the modified Wilhelmi method for treatment periods of between 6 months and 8.2 years.…”

Section: Resultsmentioning

confidence: 99%

Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK

et al. 2017

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Human-to-human transmission of Creutzfeldt–Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aβ) protein associated with Alzheimer’s disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aβ accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aβ, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aβ seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aβ and give insights into the possibility of iatrogenic transmission of AD and CAA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1703-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK

et al. 2017

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“…It also provides a description of the leading edge, peak and tail of the epidemic, rather than focussing largely on the tail of the epidemic [31]. In doing so, this study provides a unique opportunity to investigate the molecular epidemiology of prion transmission within a species, but across PRNP codon 129 polymorphic barriers.…”

Section: Discussionmentioning

confidence: 99%

UK Iatrogenic Creutzfeldt–Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches

et al. 2016

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Creutzfeldt–Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1638-x) contains supplementary material, which is available to authorized users.

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“…Much later it was discovered that some batches of the hormone were contaminated with PrP prions, resulting in iatrogenic Creutzfeldt -Jakob disease (CJD) in a subset of patients (Rudge et al 2015). Recently, eight hormone recipients in Great Britain who died of CJD at ages ranging from 36 to 51 yr were examined for the co-presence of AD-type lesions.…”

Section: Evidence For the Prion-like Seeding Of Ab In Humansmentioning

confidence: 99%