Editorial Preface: Growth hormone (GH) extracted from human pituitaries obtained at autopsy was first given to children in 1958. Twenty-seven years later (1985), the first cases of Creutzfeldt Jakob Disease (CJD) resulting from such injections were observed in individuals who had received GH injections 8 to 10 years prior to that time. The fact that no cases of CJD were reported reflects the long latent period between exposure and the onset of symptomatic disease.
The exact number of the pituitary injections that may have been contaminated with the CJD prion is unknown. GH from only one of three laboratories in the U.S. extracting pituitaries has been associated with CJD. All three of the laboratories extracting GH used different procedural techniques. In retrospect, the GH extraction procedure of two of the three laboratories eliminated the active prion from the final product. From 1985 until April 2003 only 26 cases of CJD were recorded among several thousand (7,700) recipients in the U.S. who had received native human growth hormone. All U.S. patients with CJD received GH prior to 1977; afterward a new purification step was added to the GH extraction procedure.
The early symptoms of CJD consist of degenerative neurological function. Death unfortunately follows within a period of 6 to 36 months. The number of catastrophes to date in the United States have been relatively small, particularly in light of the number anticipated in 1985 when the first two deaths were reported within a month of each other. Postulation, with reasonable justification, was that the incubation period and susceptibility to the disease were influenced by the dose of contaminated material, possibly the age of the recipient, and possibly by an individual’s genetic susceptibility. The latter was suspected on the basis of a few studies using scrapie disease in sheep as a prototype since CJD, occurring primarily in humans, is similar to scrapie disease in sheep. These diseases produce degenerative neurological alterations; although the histology of the pathological findings in the central nervous system are different. They are known as spongiform cerebral encephalopathies.
Abstract: In 1985 and 1986 a similar but different spongiform encephalopathy manifested itself in England when humans were first diagnosed with “mad cow disease” or bovine spongiform encephalopathy (BSE). Cows had been infected by the ingestion of commercially prepared food for cows to which had been added a food enforcement consisting of bovine CNS and other organ components that were unmarketable to humans. Cows ingesting these ground up organ components, when the organs were contaminated, developed BSE after a prolonged incubation period. Infected cattle in the presymptomatic stage were often sent to the slaughter house. This meat was sold in the markets and subsequently infected humans. Thus, the mad cow disease was perpetuated and humans developed a variant of CJD (vCJD). The brain pathology of CJD and vCJD are distinguishably different even though both are spongiform encephalopathies. Over one million cows in the UK were believed to be infected. Identification of infected asymptomatic cows is not easy even though the prion accumulates in the lymphoid tissue as well as in the central nervous system.
Spongiform encephalopathies result from a replicating abnormal protein called a prion. The prions proliferate, destroy cell membranes, and accumulate as they are not destroyed themselves. Clinical symptoms develop when the abnormal protein is diffusely spread through the CNS. Transmission from mother to fetus occurs during pregnancy in the cow. It is not known whether prions are transmitted in cow’s milk or colostrum. There are no data regarding transmission in humans by placenta, in human milk or colostrum.
At the end of 2001 in the UK there were 113 cases of vCJD, nine of whom were alive at that time. A few cases have occurred in other countries including France and Ireland and two cases in the United States. BSE crosses species barriers and consequently is found in squirrels and other mammals. The disease scrapie has been adapted to mice and genetic predisposition has been studied. Different strains of mice react differently to the exposure of the scrapie prion. Recently a genetic predisposition for susceptibility in humans has been demonstrated. At the time the referenced article was written, all of the human cases tested in the UK (87) shared a common genetic trait, being methionine homozygous (MM) at codon 29 of the prion protein (PrP) gene. Estimates in Caucasian populations are that 40% of the population share this trait. Of the other 60% of the population, 13% are valine homozygous (VV) and the remaining 47% heterozygous for methonine and valine (MV). The authors of the referenced article also refer to a report that there is a decreased risk of CJD in those with HLA-DQ7. This new finding, if correct, suggests complex multi gene determinations of patterns of susceptibility.
The authors discuss extensively the difficulty in predicting the potential magnitude of the UK epidemic. Of significant importance, the authors believe that even in the worst case scenario in which over 8,000 cases will appear by the year 2080, it is unlikely that a very large increase in case numbers would be expected in the short term (2-5 years).
The epidemiological determinants of the cause of the epidemic which make projections complex include; (a) incubation period distribution, (b) possible age dependent susceptibility to exposure to infection, (c) the effectiveness of the specified bovine ban in the UK, and (d) the genetic susceptibility to infection. For each of these determinants the data used for calculation are nebulous. However the best current estimate (guesstimate) of (a) for mean incubation period is stated with trepidation to be ca. 7 years, (b) the age dependent maximum susceptibility for individuals is 10-20 years of age, (c) for effectiveness of the specified bovine ban, the authors are unable to utilize current data in the calculation, and (d) in respect to utilizing genetic susceptibility, recent studies have indicated that there may be substantial genetic variation in susceptibility, which prevents more than speculation.
The authors conclude that the main priority, in view of all the above stated difficulties, is to develop a diagnostic test that is able to both detect infection early in the incubation period and which can be applied to large population samples in humans, bovine and other species.
Ghani AC, et al. Proc R Soc Lond B Biol Sci 2003;270:689-698.
Editor’s Comment: Disease curses continue to befall mankind. These are often of our own making such as in the instance of man promoting “mad cow disease”. Hopefully a test will be designed that permits identification early in the incubation period of the presence of the prions and thus make it possible to identify those animals affected. Much has yet to be learned about the prion and how it might be combated.
In respect to CJD in humans who received native pituitary growth hormone from autopsied bodies, we have suffered enough, even though only 26 of over 7,000 potentially infected subjects have died. A philosophical point, which hopefully we have learned, is that treatments which physicians prescribe today may not manifest their toxic effects for many years. As the Hippocratic Oath states, and as Lawson Wilkins practiced (Growth, Genetics & Hormones Vol. 19, No. 2) and taught, “do no harm to the patient”. Unfortunately we do not have a crystal ball to assist us with the decisions we must make.
Robert M. Blizzard, MD