Abstract
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.
Highlights
Prion diseases are transmissible neurodegenerative disorders characterised by the accumulation of a diseaseassociated misfolded form of the normal cellular prion protein (PrPC) in the central nervous system (CNS), commonly referred to as PrPSc [24]
PRNP codon 129 genotype was available in 30 of these 35 human pituitary-derived growth hormone (hGH)-iatrogenic Creutzfeldt–Jakob disease (iCJD) cases and confirmed our earlier findings that the MV (15 cases) and VV (11 cases) codon 129 genotypes dominate in United Kingdom (UK) hGH-iCJD cases and that these tended to occur earlier in the hGH-iCJD epidemic than the MM PRNP codon 129 cases (4 cases) [57]
This study provides a detailed description of the pathological phenotype of the largest series of iCJD cases (35 cases) occurring in recipients of hGH in the UK
Summary
Prion diseases are transmissible neurodegenerative disorders characterised by the accumulation of a diseaseassociated misfolded form of the normal cellular prion protein (PrPC) in the central nervous system (CNS), commonly referred to as PrPSc [24]. Human prion diseases occur in sporadic, genetic and acquired forms [24]. The acquired forms of human prion disease include kuru, variant Creutzfeldt– Jakob disease (vCJD) and iatrogenic Creutzfeldt–Jakob disease (iCJD). One of the commonest causes of iCJD was treatment with human pituitary-derived growth. Treatment with hGH was first associated with iCJD in 1985, since when the use of hGH was banned in many countries and replacement therapy with biosynthetic growth hormone was instigated [19, 34, 54]. Since 1985, over 240 cases of iCJD in hGH recipients have been reported in several countries [8, 50], with the largest numbers of cases occurring in France (119 cases) and the United Kingdom (UK) (78 cases). The last case of hGH-iCJD in France occurred in 2009 [4], deaths from hGH-iCJD continue to occur in the UK, with the most recent death occurring in 2016, over 30 years since hGH therapy was banned in the UK [57, 59]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
