NR AOES
AU Yam,P.
TI The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases
QU Springer-Verlag 2003 Jun
IA http://www.thepathologicalprotein.com/
PT Book (category Popular Science)
VT CHAPTER 14 Laying Odds Are prion diseases more prevalent than we thought? Researchers and government officials badly underestimated the threat that mad cow disease posed when it first appeared in Britain. They didn't think bovine spongifbrm encephalopathy was a zoonosis_an animal disease that can sicken people. The 1996 news that BSE could infect humans with a new form of Creutzfeldt-Jakob disease stunned the world. It also got some biomedical researchers wondering whether sporadic CJD may really be a manifestation of a zoonotic sickness. Might it be caused by the ingestion of prions, as variant CJD is? Revisiting Sporadic CJD It's not hard to get Terry Singeltary going. "I have my conspiracy theo- ries," admitted the 49-year-old Texan.1 Singeltary is probably the nation's most relentless consumer advocate when it comes to issues in prion diseases. He has helped families learn about the sickness and coordinated efforts with support groups such as CJD Voice and the CJD Foundation. He has also connected with others who are critical of the American way of handling the threat of prion diseases. Such critics include Consumers Union's Michael Hansen, journalist John Stauber, and Thomas Pringle, who used to run the voluminous www.mad-cow.org Web site. These three lend their expertise to newspaper and magazine stories about prion diseases, and they usually argue that prions represent more of a threat than people realize, and that the government has responded poorly to the dangers because it is more concerned about protecting the beef industry than people's health. Singeltary has similar inclinations, but unlike these men, he doesn't have the professional credentials behind him. He is an 11-grade dropout, a machinist who retired because of a neck injury sustained at work. But you might not know that from the vast stores of information in his mind and on his hard drive. Over the years, he has provided unacknowledged help to reporters around the globe, passing on files to such big-time players as The New Tork Times, Newsweek, and USA Today. His networking with journalists, activists, and concerned citizens has helped medical authorities make contact with suspected CJD victims. He has kept scientists informed with his almost daily posting of news items and research abstracts on electronic newsgroups, including the bulletin board on www.vegsource.com and the BSE-listserv run out of the University of Karlsruhe, Germany. His combative, blunt, opinionated style sometimes borders on obsessive ranting that earns praise from some officials and researchers but infuriates others, especially when he repeats his conviction that "the government has lied to us, the feed industry has lied to us all over a buck." As evidence, Singeltary cites the USDA's testing approach, which targets downer cows and examined 19,900 of them in 2002. To him, the USDA should test 1 million cattle, because the incidence of BSE may be as low as one in a million, as it was in some European countries. That the U.S. does not, he thinks, is a sign that the government is really not interested in finding mad cows because of fears of an economic disaster. Singeltary got into the field of transmissible spongiform encephalopathy in 1997, just after his mother died of sporadic CJD. She had an especially aggressive version - the Heidenhain variant - that first causes the patient to go blind and then to deteriorate rapidly She died just ten weeks after her symptoms began. Singeltary, who said he had watched his grandparents die of cancer, considered her death by CJD to be much, much worse: "It's something you never forget." Her uncontrollable muscle twitching became so bad "that it took three of us to hold her one time," Singeltary recalled. "She did everything but levitate in bed and spin her head." Doctors originally diagnosed Alzheimer's disease, but a postmortem neuropathological exam demanded by Singeltary revealed the true nature other death. Laying Odds 225 Classifying a disease as "sporadic" is another way for doctors to say they don't know the cause. Normal prion proteins just turn rogue in the brain for no apparent reason. The term "sporadic" is often particularly hard for the victims' families to accept, especially when the patient was previously in robust health. Maybe it was something in the water, they wonder, or in the air, or something they ate - the same questions CJD researchers tried to answer decades ago. The names "sporadic CJD" and "variant CJD" also confuse the public and raise suspicions that U.S. authorities are hiding something when they say there have been no native variant CJD cases in the country. Singeltary suspected an environmental cause in his mother's demise - a feeling reinforced a year later when a neighbor died of sporadic CJD. For years, the neighbor had been taking nutritional supplements that contained cow brain extracts. Researchers from the National Institutes of Health collected samples of the supplement, Singeltary recounted, and inoculated suspensions into mice. The mice remained healthy_which only means that those supplement samples tested were prion-free. Scientists have made several attempts during the past few decades to find a connection between sporadic CJD and the environment. Often, these studies take the form of asking family members about CJD victims - their diet, occupation, medical history, hobbies, pets, and so forth - and comparing them with non-CJD subjects. Such case-control CJD studies have produced some intriguing - and sometimes contradictory - results. In 1985, Carleton Gajdusek and his NIH colleagues reported a correlation between CJD and eating a lot of roast pork, ham, hot dogs, and lamb, as well as rare meats and raw oysters.2 Yet they also recognized that the findings were preliminary and that more studies were needed. Following up, Robert Will of the U.K. National CJD Surveillance Unit and others pooled this data with those from two other case-control studies on CJD (one from Japan and one from the U.K.). In particular, they figured the so-called odds ratio-calculated by dividing the frequency of a possible factor in the patient group by the frequency of the factor in the control group. An odds ratio greater than 1 means that the factor may be significant. In their study, Will and his collaborators found an increase of CJD in people who have worked as health professionals (odds ratio of 1.5) and people who have had contact with cows (1.7) and sheep (1.6). Unfortunately, those connections were not statistically significant: The numbers of pooled patients (117) and control subjects (333) were so small that the researchers felt the odds ratios needed to reach 2.5 to 8 (depending on the assumptions) before they could be deemed statistically significant. The only statistically significant correlations they found were between CJD and a family history of either CJD (19.1) or other psychotic disease (9.9), although the latter might simply be correlated because psychotic disease may be an early symptom of undiagnosed CJD.3 In contrast with earlier findings, the team concluded that there was no association between sporadic CJD and the consumption of organ meats, including brains (0.6). Although these case-control studies shed a certain amount of light on potential risk factors for CJD, it's impossible to draw firm conclusions. Obtaining data that produces statistically meaningful results can be difficult because of the rarity of CJD and hence the shortage of subjects. Human memory is quite fragile, too, so patients' families may not accurately recall the lifestyle and dietary habits of their loved ones over the course of a decade or more. Consequently, researchers must cope with data that probably contain significant biases. In a review paper on CJD, Joe Gibbs of the NIH and Richard T.Johnson of Johns Hopkins University concluded that "the absence of geographic differences in incidence is more convincing evidence against major dietary factors, since large populations eschew pork and some consume no meat or meat products. A CJD study of lifelong vegetarians, they proposed, could produce some interesting data.4 The inconclusive results of case-control studies do not completely rule out the environment as a possible cause of CJD. "Dr. Prusiner's theory does fit much of the data of spontaneous generation of [mal-formed] PrP somewhere in the brain," Will remarked - that is, the idea that sporadic CJD just happens by itself falls within the realm of the prion theory. Still, "it's very odd, if you look at all the forms of human prion diseases there are, all of them are transmissible in the laboratory and could be due to some sort of infectious agent."5 One of the great difficulties, he explained, is that "given that this is a disease of an extraordinarily long incubation period, are we really confident that we can exclude childhood exposure that is transmitted from person to person, as people move around? It's difficult to be sure about that." There might a "carrier state" that leaves people healthy yet still able to infect others. If so, "you would never be able to identify what's causing the spread of the disease," concluded Will, who hasn't stopped looking for a possible environmental link. He has some preliminary data based on studies that trace CJD victims' lives well before the time symptoms began - up to 70 years; they suggest some degree of geographic clustering, but no obvious candidates for a source of infection. A Case for Undercounting The difficulty in establishing causal links in sporadic prion diseases - if there are any in the first place - underlines the importance of thorough surveillance. The U.K. has an active program, and when a victim of CJD is reported, one of Robert Will's colleagues visits and questions the victim's family. "No one has looked for CJD systematically in the U.S.," the NIH's Paul Brown noted. "Ever."6 The U.S., through the Centers for Disease Control and Prevention, has generally maintained a more passive system, collecting information from death certificates from the National Center for Health Statistics. Because CJD is invariably fatal, mortality data is considered to be an effective means of tabulating cases. The CDC assessed the accuracy of such data by comparing the numbers with figures garnered through an active search in 1996: Teams covering five regions of the U.S. contacted the specialists involved and reviewed medical records for CJD cases between 1991 and 1995. Comparing the actively garnered data with the death certificate infor- mation showed that "we miss about 14 percent," said CDC epidemiologist Lawrence Schonberger. "That's improving. Doctors are becoming more knowledgeable," thanks to increased scientific and media attention given to prion diseases.7 The active surveillance study of 1996, however, only looked at cases in which physicians attributed the deaths to CJD. Misdiagnosed patients or patients who never saw a neurologist were not tabulated - thus CJD may be grossly underreported. Many neurological ailments share symptoms, especially early on. According to various studies, autopsies have found that CJD is misdiagnosed as other ills, such as dementia or Alzheimer's disease, 5 to 13 percent of the time. The CDC finds that around 50,000 Americans die from Alzheimer's each year (about 4 million have the disease, according to the Alzheimer's Association). Therefore, one could argue that thousands of CJD cases are being missed. (On the flip side, CJD could be mistakenly diagnosed as Alzheimer's disease or dementia, but the number of CJD patients is so small that they wouldn't dramatically skew the statistics for other neurological ills.) In part to address the issue of misdiagnosis, CJD families have asked the CDC to place the disease on the national list of officially notifiable illnesses, which tends to include more contagious conditions such as AIDS, tuberculosis, hepatitis, and viral forms of encephalitis. Currently, only some states impose this requirement. CDC officials have discounted the utility of such an approach, arguing that it would duplicate the mortality data, which is more accurate than early diagnoses of CJD, anyway. Moreover, mandatory reporting of CJD cases does not necessarily guarantee the end to missed cases.8 One clue suggests that the passive system is undercounting CJD in the U.S.: racial difference. The number of black CJD victims is about 38 percent that of white victims. Rather than sporadic CJD being a one-in-a-million lottery, it's more like one-in-2.5-million for African-Americans. Access to medical care might be one reason. Schonberger recounted that the CDC had asked other countries with substantial black populations to submit CJD figures for comparison but found that the surveillance in those countries was inadequate. "We haven't been able to find any comparable literature on this issue, so it's still up in the air," Schonberger said. On the other hand, Alzheimer's disease is more common among black people than whites, with an estimated higher prevalence ranging from 14 percent to almost 100 percent, according to a February 2002 report by the Alzheimer's Association. Are some black CJD cases being misdiagnosed as Alzheimer's? Answering critics like Terry Singeltary, who feels that the U.S. undercounts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population. As Schonberger pointed out, no doctor would misdiagnose a 30-year-old CJD patient as having Alzheimer's. The average age of the first 100 variant CJD victims was 29; should the epidemiology of vCJD change - if older people start coming down with it - then there would be problems. "The adequacy of our overall CJD surveillance would be greatly reduced should the proportion of older individuals affected by variant CJD substantially increase," Schonberger explained.9 To date, only brain autopsies can confirm CJD. To encourage the necessary neuropathological studies, in 1997 the CDC helped establish the National Prion Disease Pathology Surveillance Center at Case Western Reserve University, under the directorship of Pierluigi Gambetti. But the number of brains examined has fallen far short of the number of CJD cases in the U.S.: Gambetti's lab, which receives brains based on referrals from local physicians and families, looked at only 99 sporadic CJD cases in 2000 and 138 in 2001, when about 300 each year are expected. "I'm very unhappy with the numbers," Gambetti lamented. "European countries see 100 or 90 percent of all the cases suspected. We see 30 to 40 percent."10 Most families don't think about having an autopsy done (which can cost upward of $1,500 if the hospitals don't pick up the tab), and members of the support group CJD Voice have said they were too distraught to think of shipping a loved one's brain by Federal Express to Gambetti's lab. (For accurate analyses of brain tissue, the autopsy must be performed within 72 hours of death, assuming the body has been kept refrigerated.) Moreover, physicians often do not suggest an autopsy, perhaps because of liability fears should the postmortem reveal that the original diagnosis was wrong. Gambetti has been working on establishing a network that would enable postmortems to be done near where the deceased person lived and without cost to the family. He is also working on advertising the existence of his surveillance center, via meetings and letters to neurologists, pathologists, and other specialists. Gambetti is also attempting to combat what he termed "hysteria" over the potential for infection that has pathologists irrationally shunning CJD cases while they willingly conduct arguably riskier AIDS autopsies. "In order to make people aware, you have to keep informing them over and over and over," he said. Money is the main reason why the U.S. lags behind Europe in terms of surveillance. To adequately survey the 290 U.S. million residents, "you need a lot of money," Robert Will explained. "There was a CJD meeting of families in America in which poor old Larry (Schonberger) got attacked fairly vigorously because there wasn't proper surveillance. You could only do proper surveillance if you have adequate resources. That's the bottom line. We're very fortunate in the U.K.; we have very generous resources for CJD surveillance." Moreover, the U.K. makes feline spongifbrm encephalopathy an officially notifiable disease. Domestic cats proved to be good sentinel animals because they dine on the meat not fit for human consumption - the parts more likely to harbor prion infectivity. In the U.S., FSE isn't federally notifiable. And while the USDA says it has sent educational material to private veterinarians and works with vet schools,21 it's not clear just how many vets can spot FSE, which has never been reported in the U.S. Certainly, not many cat postmortems are done. The only active portion of the U.S. CJD surveillance system are the follow-up investigations conducted for victims of CJD under 55 years of age. It began in 1996, when young people in the U.K. started succumbing to variant CJD. Victims under 30 years of age especially arouse interest, because such cases could indicate an infection from the environment. Except for the variant CJD case in Florida, the CDC has classified all of these more youthful cases of CJD as having either sporadic or familial origins. One such age cluster involved the three venison eaters that the CDC tried unsuccessfully to link to the deer-and-elk borne chronic wasting disease. A second grouping occurred in 2002 in a pair of Michigan men. The two - one 26 years old, the other 28 - did not know each other but lived in neighboring counties in Michigan and went to the same hospital for diagnosis.12 The CDC's investigation turned up nothing that suggested a new form of CJD had emerged. But the increased frequency of young CJD cases is disturbing. In the 18-year period between 1979 and 1996, the U.S. had 12 cases in patients under 30, and only one of them had the sporadic form of CJD. (The other cases resulted from heredity or from transmission via contami- nated growth hormone or dura mater grafts.13) Between 1997 and 2001, five people under 30 died of sporadic CJD: the three venison eaters and the two Michigan patients. That represents a substantial blip of five young cases in five years, as opposed to only one case in 18 years. Physicians at the University of Michigan Health System who examined the two Michigan men concluded: As a result of our findings, we feel that sporadic CJD may be more common than previously thought, that it may occur in younger individuals than currently perceived, and that some cases may go undiagnosed due to insufficient testing. . . . We recommend that physicians everywhere begin to consider CJD in rapidly progressive neurological decline of unknown causes in people under 30 years of age, and that brain biopsy and autopsy with genetic and prion analysis be performed in all such cases.14 Pathologically, the recent bout of young casualties in the U.S. appears to be no different from CJD already seen in America. Yet theoretically it may have come from a new source of infection, based on an unexpected result announced in late November 2002. John Collinge of the British Medical Research Council's Prion Unit found that not all transgenic mice infected with BSE prions developed the neuropathological and molecular characteristics of variant CJD; some of the mice instead generated the molecular features of sporadic CJD. Therefore, some CJD cases classified as sporadic may have actually been caused by BSE prions, Collinge hypothesized.15 So far, the epidemiology of CJD in the U.K. does not bear out that supposition - there has been no substantial uptick in sporadic CJD as would be expected if BSE could paint more than one pathological picture. But the preliminary study, taken at face value, could be seen as evidence that something infectious is happening in the cases of young, sporadic CJD victims in the U.S. Another mouse study, reported in March 2002, fueled concern that prion infections may be more common than previously thought.16 Stanley Prusiner's lab found that mice infected with mouse prions accumulated PrPsc in their skeletal muscles, mostly in those in the hind limbs. In some mice, each gram of muscle contained some 10 million infectious doses - on par with that in the brain in other experiments involving intracerebral inoculation. To some CJD researchers, this finding suggested that muscle meat from cows might not be safe, after all, and that the measures taken in Europe to protect the food supply - banning high-risk cow parts - may not be enough. Although this study may seem alarming, its implications are not as sweeping as they may appear. Only a minority of results in mouse studies end up having a direct analog in humans. The skeletal muscle discovery warrants further examination, but it would be premature to alter food policies. Prions are different for each species, and accumulation of prions varies from species to species and from disease to disease. Furthermore, BSE cattle muscle has failed to sicken mice in bioassay work, suggesting that little or no infectious prions lurk there. What such findings truly reveal is that prion diseases are complicated and still mysterious, and trying to quantify the risks for human health is fraught with uncertainties...
AD Philip Yam, New York, NY, USA
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englisch
PO Deutschland