Update Follow-Up Study of NHPP Growth Hormone Recipients: NIDDK
Article title: Update Follow-Up Study of NHPP Growth Hormone Recipients: NIDDK
Conditions: CJD, adrenal insufficiency
- Symptoms of CJD
- CJD Risk and Timing of hGH Treatment
- Analysis of hGH Preparations
- Information About Your Treatment
- No Test Can Predict CJD Risk
- CJD in Overseas Recipients
- CJD and "Mad Cow" Disease
- Research Sheds Light on CJD
- Diagnosing CJD
- Other Health Problems in Recipients
- No Link Between hGH and HIV
- CJD Not Transmitted Through Sex or Casual Contact
- Blood/Organ Donation
- Discussing CJD Risk
- Helping with the Follow-up Study
- Support and Information
Before scientists learned how to make synthetic hormones, animals were the source of many hormones, such as insulin. However, growth hormone from animals did not work in humans, so the U.S. Public Health Service (PHS) supported a program to make human growth hormone (hGH) from human pituitary glands. From 1963 to 1985, the National Hormone and Pituitary Program (NHPP) sent hGH to hundreds of doctors across the country. Doctors used the hormone to treat nearly 8,000 children for failure to grow. In 1985, the PHS learned that three young men treated with hGH died of Creutzfeldt-Jakob Disease (CJD), a rare and incurable brain disease. The PHS immediately stopped distribution of the hormone and began a national study to answer important questions raised by these deaths. The PHS still monitors recipients to inform them and their doctors about health risks linked to hGH.
About 8,000 patients in the United States received NHPP growth hormone. Of these, we now believe that 22 may have developed CJD. Six overseas patients who received hGH from U.S. labs that produced the hormone for NHPP may also have developed CJD. The experts who help us with the follow-up study have concluded that a CJD diagnosis is confirmed or likely in 19 U.S. cases. We are still evaluating the medical records of three suspected U.S. cases.
Early in the follow-up study, we found over 6,200 patients who had received NHPP growth hormone. Hormone may have been provided for up to 2,000 more patients, but treatment centers did not have the information to help us identify and contact them. Thus, we had no good way of finding out about possible deaths in that group. We hoped we would learn of any CJD cases in these patients from the many doctors who were given information about this problem. This has proven true. Five of the 22 CJD cases occurred in the group of up to 2,000 additional recipients whose records were incomplete. We believe the effort to inform patients and doctors as soon as the CJD problem was recognized has helped us learn of all CJD cases so that we can report them accurately.
Symptoms of CJD
CJD does not cause the same symptoms in everyone. Often, the first signs of CJD in hGH recipients were unsteadiness in walking, dizziness, clumsiness, and problems with balance. Later, they began to slur their words, lost muscle control, or had problems with vision, memory, or thinking clearly. Once symptoms began, the disease advanced quickly. In 2 to 3 months, patients could not walk or do other simple tasks.
Headaches are not a symptom of CJD. Mild symptoms that come and go over a long period, such as being clumsy, irritable, or forgetful, are not signs of CJD.
Most CJD cases are not linked to growth hormone, and scientists do not fully understand what causes the disease. When CJD is not linked to hGH, the first symptoms are usually mental changes such as confusion, problems with thinking, memory loss, behavior changes, and dementia. In patients with CJD transmitted by hGH, the first symptoms tend to be problems with balance, walking, and coordination. Though symptoms may differ, there are similar changes in the brain tissue of all patients with CJD.
CJD Risk and Timing of hGH Treatment
CJD takes a long time to develop. Because most patients received growth hormone for many years, we do not know exactly when they were exposed to CJD. In U.S. patients, average CJD onset was 19 years after the midpoint of hGH treatment. CJD developed as soon as 4 years and as long as 25 years after stopping therapy, and from 14 years to 33 years after starting treatment.
There are still no CJD cases in Americans who began treatment after newer methods of purifying hormone were introduced in the United States in 1977. After 1977, all NHPP growth hormone was purified using a chromatography process that greatly reduced CJD infectious material. As each year goes by without CJD appearing in the patients who received only the purer hormone, we are more encouraged about its safety. Still, CJD can take 30 years to develop. More time must pass before we can be sure that the hormone made after 1977 was safer than hGH made before 1977.
Analysis of hGH Preparations
In 1985 the Public Health Service tested all available preparations of NHPP growth hormone to see if a specific preparation could transmit CJD to animals. If an animal became sick with CJD, it clearly had received a contaminated vial of hormone. But if an animal did not get CJD from a vial of hormone, it would not prove that other vials of the same preparation were safe.
The time it takes to get CJD depends on how much infectious material is given and how it is given. The disease takes longer to develop when very little infectious material is given. It takes less time to develop when the infectious material is injected into the brain. To shorten the time for animals to get CJD to less than 3 years, hGH was injected into the brains of test animals. The animals were watched for 10 years. The brains of all animals that died were examined for signs of CJD. Only one animal has developed the disease. This animal became sick 5 1/2 years after injection of hormone. Two other animals received the same hormone preparation but did not develop CJD.
We do not believe that the patients who received the hormone preparation that transmitted CJD to the animal have a greater risk of developing CJD than other growth hormone recipients. None of the people who developed CJD are known to have received this hormone preparation. At most, two patients (whose records are incomplete) may have received this hormone preparation.
We continue to analyze the hormone preparations received by patients who got CJD. We believe that multiple preparations of hormone had very low levels of CJD contamination. With such low levels of contamination, some vials of a preparation might carry CJD while many other vials would not.
Information About Your Treatment
The best person to give you information on your treatment is the doctor who gave you growth hormone or a doctor who has access to your treatment records. The PHS gathered dates of treatment from doctors and interviews with patients and their parents in 1988. We know which hGH preparations were sent to each treatment center and when they were sent. We don't know which preparation each patient received. We have tried to find this information in medical records of patients who developed CJD, but many doctors did not note the preparation in their records. When records were incomplete, we assumed that patients who got CJD might have been exposed to all preparations sent to their treatment center during the time they received hGH. Since we cannot confidently identify high-risk or risk-free hormone preparations, we do not think that information on the hormone preparations you received will be helpful to you. If you still wish to learn this, the doctor who treated you is the best person to tell you about your treatment.
No Test Can Predict CJD Risk
Genetic variations are seen in the structure of the brain protein that becomes abnormal in CJD. These differences may make some people more likely to get CJD than others. While a person's genetic makeup may affect the risk of CJD, there is no test that can identify who will or will not develop CJD.
Researchers cannot accurately predict the risk of developing CJD in individual recipients. We do know that risk is influenced by when a person was treated and for how long. In the United States, the average length of treatment with NHPP growth hormone was a little less than 3 years. In those who got CJD, the average length of treatment was much longer, nearly 10 years. All 22 people with confirmed or suspected CJD began treatment before 1977. At least 14 began treatment before 1970. The precise treatment dates for one patient are unclear, though we do know treatment was before 1977. The method of hormone production changed in 1977, but more time must pass before we can know if any patients who began treatment after 1977 will develop CJD.
CJD in Overseas Recipients
U.S. Public Health Service doctors share information about CJD in growth hormone recipients with their colleagues around the world. From these contacts and from published reports, we know that CJD has developed in patients who received pituitary growth hormone in many countries.
New Zealand has reported 5 CJD cases among 184 people who received pituitary growth hormone. All 5 cases appeared in 46 people who received growth hormone made by the U.S. lab that supplied most NHPP growth hormone before 1977. This very high rate--5 out of 46 (11 percent) in those who received American hormone--is unexplained.
New Zealand has little information on the hormone preparations these patients got. The five CJD cases have no period of treatment in common. One person who developed CJD was treated from 1965 to 1972, one from 1966 to 1972, one from 1964 to 1966, one from 1967 to 1969, and another from 1970 to 1973. Since there is no common period of treatment, a single preparation is unlikely to be the source of exposure for the five cases.
We have some information on the hormone preparations sent to New Zealand from the lab that also produced hormone for the NHPP. Preparations from this lab had many hormone-rich fragments from many batches of pituitaries. Sometimes the same hormone preparations were used in both countries. Generally, though, the preparations sent to the NHPP and to New Zealand were not identical but did have some common components.
The time between the start of treatment and CJD onset was similar in the United States (from 14 to 33 years) and New Zealand (from 17 to 32 years). The New Zealand patients who developed CJD were treated with growth hormone for an average of 4 years. In the United States, average treatment time was nearly 10 years in patients who developed CJD.
In France, there have been 62 CJD cases among 1,700 growth hormone recipients. The pattern of exposure to CJD is very different in France than in the United States. In France, people who received hormone preparations in 1984 and 1985 appear to be at highest risk for CJD. The greater number of cases and shorter time between treatment and CJD onset suggest that the level of contamination in French hormone preparations was higher than in the U.S. preparations. France did not make growth hormone the same way the United States did and by 1985 still had not added the purification step that was later shown to reduce CJD contamination.
England has had 32 cases of CJD among 1,900 hGH recipients. There have also been single confirmed cases of CJD after hGH treatment in Brazil, Holland, and Australia. Four Australian women developed CJD after receiving other pituitary hormones as fertility treatments. France, England, and Australia made their own hormone preparations, but the 5 New Zealand patients who got CJD received growth hormone made by one U.S. lab. The patient in Brazil received growth hormone from another U.S. lab that made NHPP hormone before 1977. All told, 28 CJD patients received U.S.-produced hormone.
CJD and "Mad Cow" Disease
CJD is one of a group of diseases called transmissible spongiform encephalopathies. CJD is closely related to certain animal diseases such as scrapie, a brain disease of sheep. Since at least 1985, cattle in England have developed a similar disease called bovine spongiform encephalopathy (BSE) or mad cow disease. Before this problem was recognized, ground-up carcasses from sheep and other livestock were fed to cattle as a nutritional supplement. In 1988, this practice was banned in England. Millions of cattle were slaughtered to protect the food supply. Largely as a result of this ban, the number of newly infected cattle has fallen sharply.
There has been concern that CJD could be transmitted to people who may have eaten beef products contaminated with the BSE agent. By May 2, 2000, England had officially reported 56 people who were confirmed to have developed a new form of CJD at an unusually young age. They had not received any therapy known to cause CJD such as growth hormone, corneal transplantation, or a dura mater graft. For the 54 of these patients on whom studies of brain tissue were available, the studies confirmed the presence of a new variant form of CJD.
The PHS has begun to look more closely for both the classic and new variant forms of CJD. No new variant CJD has been found in the United States. There is no evidence of BSE in cattle in the United States.
The clues that alerted us to the link between growth hormone and CJD also played a role in suggesting a link between BSE and new variant CJD in England. In both cases, the first symptoms of CJD were unusual, and the patients were much younger than most people who develop CJD. These clues may be useful to scientists trying to understand how CJD developed in both situations. However, the new variant CJD, which may have been transmitted through beef products contaminated with the BSE agent, and the CJD transmitted through hGH are separate and distinct.
Research Sheds Light on CJD
The usual type of CJD occurs worldwide and strikes about one in a million people per year. Most people with CJD are between 55 and 79 years old. About 10 percent of cases are inherited. Some cases have been spread by medical procedures such as growth hormone injections, dura mater grafts, or corneal transplants. Scientists don't fully understand what causes CJD. Evidence suggests that a unique infectious agent called a prion [pree'-on] may be responsible. Unlike viruses, bacteria, and other infectious agents that contain genetic material, prions consist of protein without any genetic material.
The prion that may cause CJD is a protein that takes on different forms. In its normal, harmless form, the protein is curled into a spiral. In its infectious form, the protein folds into a different shape. Somehow, the abnormal protein may interact with the normal copies of this protein in the brain, changing them to the abnormal shape. People with inherited CJD have a change in the gene for the prion protein. This gene makes the protein likely to assume the abnormal shape. Exposure to the abnormal form of the protein may occur through injection of contaminated growth hormone or some other source of exposure to infected brain tissue. The abnormal protein changes the normal protein into an abnormal shape, setting off a chain reaction.
If CJD results from a defect in protein folding, it might be possible to identify drugs that can help the prion protein assume its proper shape and slow or stop the change to an abnormal form. While there is now no effective treatment for CJD, researchers hope that understanding how the disease arises may yield clues for future treatment. Though CJD is a rare disorder, some of the world's leading researchers are focusing their efforts on this disease.
In 1996, researchers developed a test that helps doctors diagnose CJD in patients with symptoms. Before, when a patient had CJD symptoms, only a brain biopsy, which requires major surgery, could confirm the diagnosis. Now doctors can detect an abnormal protein in a sample of spinal fluid. It is much easier to take a sample of spinal fluid for diagnosis than to do a brain biopsy. However, this test cannot be used to identify patients without symptoms or to predict who may develop CJD in the future.
In 1996, researchers developed a test that helps doctors diagnose CJD in patients with symptoms. Before, when a patient had CJD symptoms, only a brain biopsy, which requires major surgery, could confirm the diagnosis. Now doctors can detect an abnormal protein in a sample of spinal fluid. It is much easier to take a sample of spinal fluid for diagnosis than to do a brain biopsy. However, this test cannot be used to identify CJD in patients without symptoms or to predict who may develop CJD in the future.
In a recent issue of Lancet, British researchers reported success using magnetic resonance imaging (MRI) to diagnose variant CJD in people with symptoms of the disease. (View the article.) Further studies will show whether MRI proves useful in diagnosing other forms of CJD.
Other Health Problems in Recipients
Many growth hormone recipients had brain tumors, other brain diseases, or birth defects that caused growth hormone deficiency. Many had pituitary problems that led to deficiencies of more than one hormone. It is important for people who have other hormone deficiencies to read the information below and discuss it with their doctor.
The pituitary makes several key hormones besides growth hormone. A pituitary hormone stimulates the adrenal glands to make cortisol, a hormone necessary for life. Cortisol helps the body respond to stress from infections, trauma, or surgery. The normal adrenal gland responds to serious illness by making more cortisol. If cortisol levels are low, a person must take medicine to replace the hormone. Hydrocortisone, prednisone, or dexamethasone are the usual replacement medicines. These drugs must be adjusted when a person is ill and needs more cortisol.
Symptoms of adrenal insufficiency are weakness, fatigue, nausea, lack of appetite, and weight loss. During stress, if cortisol levels are too low, an adrenal crisis can arise. Adrenal crisis is extremely serious and can cause death if not treated promptly. The PHS has identified some deaths in hGH recipients with pituitary hormone deficiencies that appear to have been caused, in part, by adrenal crisis. These deaths can be prevented if the condition is recognized and treated promptly.
If you take one of the drugs listed above, you must learn how to increase the dosage when you become ill. It is important to discuss this with your doctors. If you become very ill, especially if you are vomiting and cannot take pills, seek emergency medical care. Carry an ID card or bracelet to notify emergency personnel that you have adrenal insufficiency so treatment can be started promptly if you are injured.
Some people who received growth hormone as children may have decreased growth hormone as adults. The Human Growth Foundation is one source of information about growth-related disorders. It can be reached at 1-800-451-6434.
No Link Between hGH and HIV
Human growth hormone did not spread HIV, the virus that causes AIDS. The CJD infectious agent is highly resistant to destruction, but HIV would be destroyed by the methods used to make growth hormone.
CJD Not Transmitted Through Sex or Casual Contact
There is no evidence that CJD is transmitted through casual contact or sexual intercourse. Spouses of patients with CJD are not at increased risk. With the exception of genetic forms of CJD, children of patients with CJD are not at increased risk for getting the disease. A pregnant mother does not transmit CJD to her child. The type of CJD associated with growth hormone treatment does not cause genetic changes and would not be passed on to future generations.
Doctors and blood bank officials agree that the risk, if any, of CJD being transmitted by blood transfusions is extremely small. Because there is no test to detect CJD infection before symptoms occur, officials want to prevent even remote risks to the safety of the Nation's blood supply. For this reason, blood banks do not collect blood from anyone who was treated with pituitary growth hormone. This does not apply to people treated only with biosynthetic growth hormone, which has been used since 1985. Recently, blood banks stopped taking blood from relatives of patients with CJD. This policy sought to prevent donation by people from families with rare genetic forms of CJD, who might harbor CJD but have no symptoms. Family members of those at risk of CJD because they received growth hormone are not affected by this policy.
Discussing CJD Risk
Many recipients, who were children when the problem of CJD was recognized, are now adults. In our updates, we have stressed that parents should discuss the risk of CJD with their sons and daughters as they mature. This is a painful situation for all concerned, but it can be more upsetting for a person to learn of the risk from the media or other sources. If you are the parent of an adult recipient who is not receiving these mailings, please share his or her address with us so we can send this information.
Helping with the Follow-up Study
Recipients, their families, and their doctors can contribute a great deal to researchers' efforts to understand CJD and the health problems of growth hormone recipients. Your assistance helps us keep you informed of new developments. It is most important for PHS doctors to know if CJD is suspected or diagnosed in someone who received growth hormone. Also, we ask that family members or doctors notify us of deaths from any cause in hGH recipients. By giving PHS doctors permission to review the medical records of a deceased recipient, a family adds to a growing knowledge base that may benefit thousands of people.
In 1988, a Japanese report suggested a higher risk of leukemia in growth hormone recipients. PHS researchers analyzed leukemia cases in NHPP growth hormone recipients and published their findings in 1993. In recipients who did not have brain tumors or radiation treatments, the number of leukemia cases was the same as expected in the general population. A more recent study by the Japanese researchers did not find a higher rate of leukemia in hGH recipients without these risk factors. To help monitor the health of growth hormone recipients, we ask that leukemia in any hGH recipient be reported to the PHS. And, as before, we ask that you let us know your current address (and e-mail address, if you have one) so we can continue sending these updates. To report health information, please contact:
National Institutes of Health
NIDDK Office of Communications and Public Liaison
Building 31 Room 9A04
31 Center Dr MSC 2560
Bethesda, MD 20892-2560
1 (800) 472-0424
Support and Information
To contact us, please call the toll-free number 1-800-472-0424. A recording will ask you to leave your name, phone number, and a good time to reach you. A staff member will call you back promptly. You can call, write, or have your doctor contact us at the above address or by e-mailing NIDDK_Inquiries@nih.gov.
We have also created a web site. The site contains this update and a listing of articles about the health issues of former growth hormone recipients. The web site will be revised as we get new information. We will also mail updates like this one from time to time.
If you would like to contact others who received human growth hormone,
you may contact the MAGIC (Major
Aspects of Growth in Children) Foundation. The Foundation is a
national, nonprofit organization that provides support and education about
growth disorders in children and growth hormone deficiency in adults.
Staff will help connect you with others who have similar interests or
1327 N. Harlem Avenue
Oak Park, IL 60302
The Human Growth Foundation (HGF) is a nonprofit organization concerned with children's growth disorders and adult growth hormone deficiency. HGF has published a brochure on adult growth hormone deficiency. To obtain a copy, call 1-800-451-6434. HGF also supports an Internet mailing list to facilitate the exchange of information about adult growth hormone deficiency and adult growth hormone replacement therapy. To subscribe, follow the instructions on the HGF web page.
The Creutzfeldt-Jakob Disease Foundation Inc. was created in 1993 by two families who lost relatives to CJD and the neurologist who treated the patients. This nonprofit corporation seeks to promote research, education, and awareness of CJD and to reach out to people who have lost loved ones to this illness.
Finally, be assured that scientists at the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention continue to actively investigate this problem and stand ready to answer your questions.
This e-text is not copyrighted. NIDDK encourages users to duplicate and distribute as many copies as needed.
etext updated: May 2000
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