NR APEA
AU Brown,P.
TI Update on iatrogenic Creutzfeldt-Jakob disease and lessons from the human growth hormone story
QU Workshop on TSE Risks in Relation to Source Material, Processing, and End-Product Use. June 8-9, 1998, College Park, MD
IA http://www.life.umd.edu/jifsan/tse/brown.htm funktioniert nicht mehr
PT Workshop
VT
The current world-wide tally of iatrogenic Creutzfeldt-Jakob disease (CJD) is shown in Table 1; except for the unexpected burst of Japanese cases due to contaminated Lyodura grafts in recent years, iatrogenic disease continues to be rare and random in occurrence. Cases due to the pre-1986 use of native growth hormone are accumulating at the rate of 3-4 cases per year, after longer and longer incubation periods; the current tally is shown in Table 2 for the three countries of major incidence. In the US, no case has yet occurred in which hormone therapy was begun after 1977 (the latest case started therapy in 1975), the date that hormone processing was changed to include chromatography purification; thus, it is still possible that this processing change will be found to coincide with the end of hormone-induced CJD in the US. The same cannot be said of France, where a different chromatography purification was being used to produce hormone taken by the majority of cases. Also in France, the comparatively large number of cases has allowed a preliminary idea of the influence of the codon 129 genotype on incubation periods: heterozygous cases have a mean incubation period of 11 years, homozygous methionine cases (the great majority), 9 years, and homozygous valine cases, 8 years.
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Table 1. Iatrogenic Creutzfeldt-Jakob disease (as of September, 1998)
Mode of Number of Agent entry Mean incubation Clinical
infection patients into brain period (range) presentation
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Corneal 3 Optic nerve 16, 18, 320 mos Dem/Cereb
transplant
Stereotactic 2 Intra-cerebral 18 mos (16, 20) Dem/Cereb
EEG
Neurosurgery 4 Intra-cerebral 20 mos (15, 28) Vis/Dem/Cereb
Dura mater 80 Cerebral 6 yrs (1.5-16) Cereb(Vis/Dem)
graft surface
Growth 106 Hematogenous 15 yrs (5-30) Cerebellar
hormone
Gonadotropin 4 Hematogenous 13 yrs (12-16) Cerebellar
------- Dem = dementia; cereb = cerebellar; vis=visual ---------
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Putting the growth hormone story into perspective recalls some observations that are sometimes lost sight of today, and some lessons that merit re-emphasis.
1) The first indication that an identifiable human genetic factor could play a role in non-familial transmissible spongiform encephalopathy (TSE) came from the analysis of the codon 129 genotype in 7 growth hormone patients in the UK, which suggested that valine homozygosity was a risk factor (we now know that it is not valine homozygosity but homozygosity per se that is the more important risk factor, and that it appears to operate in all forms of TSE, not just iatrogenic disease).
2) Analysis of growth hormone cases supported the idea that TSE incubation periods after low dose peripheral route infections can be extraordinarily long: this fact had been first advanced from the study of kuru in Papua New Guinea, and now was fully confirmed by incubation intervals of up to 30 years between termination of hormone therapy and onset of CJD.
3) In the search for ways to make hormone therapy safe for human use, native growth hormone was the first substance shown to retain biological activity after exposure to a decontamination procedure (6 M urea) that could reduce TSE infectivity to an insignificant level. Subsequently, brain ganglioside preparations and dura mater grafts have proven resistant to 1N NaOH, which also reduce TSE infectivity to nearly undetectable levels.
4) Undetectable levels of infectivity may not be the same thing as no infectivity. Studies to determine the effect of processing protocols on TSE "spiked" growth hormone taught us that the usual virological methods of sampling specimens to determine the presence of absence of infectivity could give misleading results, and that it is necessary to test the entire volume of any given product to detect the very small amount of infectivity remaining after a decontamination procedure. Results of one experiment yielded only 7 transmissions (1.8%) among a total of 381 animals inoculated with "decontaminated" growth hormone, a figure in keeping with the human experience of 100-odd cases of CJD (0.9%) in a total of about 12,000 treated hypopituitary patients, and with the experimental primate experience of a single transmission after inoculation of 228 animals (0.4%) with archived ampules of 76 different lots of US-manufactured growth hormone.
5) Individual intuitive genious can either put to march an army of bureaucrats, or become mired for years in "committee business". In 1985, the US pediatrician Raymond Hintz brought his insight about a possible connection between growth hormone and CJD to the attention of Dr. Mortimer Lipsett at the NIH, who immediately issued an alert that led to the discovery of two new cases, and the rapid demise of native growth hormone therapy by the combined agencies of the NIH and FDA. In contrast, the earlier intuition of Dr. Alan Dickinson (in 1976) about the possibility that pituitary growth hormone therapy might pose a risk of transmitting TSE underwent a prolonged game of ping-pong among various government committees in the UK, and even after the risk had been acknowledged, did not lead to effective donor screening criteria until many years had passed. (It should be noted that no effective donor screening criteria were ever promulgated in the US!).
6) Knowledge of the realities of tissue collection and processing of biological material used by humans is indispensable for a correct assessment of risk inherent in its use. Had scientists involved in laboratory work on CJD thought about the actual way in which pituitaries were collected and processed - the fact that glands were collected by deaners who were paid for their trouble and usually not supervised, the great likelihood that some brain tissue would be collected with pituitary glands, the lack of adequate inter-batch sterilization methods used in pituitary processing - there might have been a greater sense of urgency to address the potential problem of disease transmission. The same observation may be made about the bovine spongiform encephalopathy (BSE) epidemic and its extension to humans in the form of "new variant" CJD (Will-Ironside syndrome). Had we known about changes in animal carcass rendering procedures, thought about re-cycling of infectious bovine material into bovines, gone to slaughter houses to see how steers were actually cut up before distribution to the human food chain, we would have gained a more accurate appreciation of potential consequences, and with luck might have had the foresight to prevent them. This lesson is being put to good use in present-day discussions about the safety of blood products and other biologicals.
7) Scientists and clinicians would be well advised to pay attention to each others' concerns, because the public (and its lawyers) will punish oversight, or lack of foresight, just as easily as it does malpractice. The bringing of successful legal actions by families of iatrogenic CJD patients, and even by healthy recipients of pituitary hormone replacement therapy, bear witness to this unpleasant fact.
Last modified Monday, October 26, 1998 17:09:50
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AD Paul Brown (pwb@codon.nih.gov), Laboratory of CNS Studies, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD 20892, USA
SP englisch