In September 1995, the Thyroid Foundation of Canada and the Thyroid Foundation of America jointly sponsored a symposium offering an up- to-date review of common thyroid problems by experts from around the world. Here we feature summaries of these talks by Drs. Basil S. Hetzel, Robert Volpé, Anthony D. Toft, Paul Walfish, W. Michael G. Tunbridge, David Becker, and David S. Cooper.
The First International Goitre Congress was held in 1929 in Berne following the introduction of iodized salt in Switzerland and the United States. Iodine deficiency and goitre have since disappearedin many industrialized countries.
Until 1985, however, only limited progress had been made in developing countries. Thyroidologists then took the initiative to establish the International Council for Control of Iodine Deficiency Disorders (ICCIDD), a global multidisciplinary group of 400 members from 70 different countries. Their aim was to bridge the gap between available knowledge (particularly on the effects of iodine deficiency on brain development) and its application in developing countries. Iodine deficiency is now recognized as the most common cause of preventable mental defect.
Iodine deficiency in the mother seriously affects her child in infancy and first two years of rapid development. It's at that time that the thyroid gland needs iodine to produce enough thyroid hormone for the development of the body, and particularly of the brain.
The over one billion people who live in areas of iodine deficient soil (mountains and flooded valleys) are estimated to be at risk of iodine deficiency disorders(IDD). Of these 200 million have goitre and 20 million are suffering from brain damage due to the effects of iodine deficiency in pregnancy and infancy. These can be prevented by the use of iodized salt or iodized oil.
One example of both tragedy and great opportunity is the case of amother in China and her four sons. The first three are cretins, the youngest, however, who was born after iodized salt was introduced, is quite bright.
In Canada, about one in 4,000 newborns have low levels of thyroid hormone; in iodine-deficient areas, about 10% of newborns have this deficiency, a great threat to the brain function of a population. Upto 70% of people in iodine-deficient areas suffer from severe hypothyroidism.
Important steps have been taken since 1983, when the IDD concept was put forward with emphasis on effects on the brain. The ICCIDD was founded in 1985 and has worked with the World Health Organization (WHO) and UNICEF in the development of national programs in Africa, Asia, Latin America and Europe, with excellent progress in the last decade. In 1990, the virtual elimination of IDD by the year 2000 was accepted as a goal by WHO, UNICEF and the World Summit for Children and endorsed in 1992 by the International Conference on Nutrition. In 1993 Kiwanis International adopted the virtual elimination of IDD as ther World Service Project. Most recently, the salt industry has joined the global partnership between people, governments, agencies and the ICCIDD through a link established with the Council.
The thyroid gland is normally controlled by the pituitary gland. One of the several hormones produced by this gland is TSH, thyroid stimulating hormone. TSH Attaches to every cell in the thyroid bymeans of a receptor on the surface of the thyroid cells, and causes the thyroid cells to become activated and make thyroid hormone.
The thyroid hormone goes to all the tissues and determines the rate at which they work, i.e. the metabolism of the cells. The hormone also feeds back to the pituitary; if too little thyroid hormone is being produced, the pituitary will try to stimulate the thyroid by means of excess TSH. Like a jockey trying to beat a tired horse to try to win a race, excess TSH beats the thyroid to try to make it make thyroid hormone. If too much thyroid hormone is being produced, it inhibits the pituitary which makes less TSH, or even no TSH as with Graves' disease.
In the thyroid, each of the cells surrounds an open space. Hormone produced by these cells is stored in the open space, and when needed goes back into the bloodstream. Each of the cells has TSH receptor. These are important when we consider Graves' disease. In this case, the open spaces are quite small and are surrounded by many more cells - bigger cells producing a tremendous amount of hormone.
Why do they do this? Antibodies are substances we produce to combat bacteria, viruses and other antigens. A characteristic antibody has two "hooks", or antigen-binding sites, to neutralize the antigen, which is desirable in the case of external antigens such as bacteria or a virus. But we can also make antibodies to our own antigens - auto-antibodies. Lymphocytes, the immune cells thatmakeantibodies, contain genes to make auto-antibodies to almost any body tissue. This is prevented by a mechanism of immunoregulation.
In Graves' disease, the TSH receptors are on the surface of each thyroid follicle, the antibodies form against that receptor, and the receptor is then the antigen; the antibody stimulates the thyroid in a manner indistinguishable from TSH. It's stimulating the thyroid cell to make excess thyroid hormone, which then inhibits TSH, which is thus low in Graves' disease. This is a completely uncontrolled system causing excess thyroid hormone to be produced, which goes to all the tissues and causes the person to have symptoms of hyperthyroidism.
Graves' disease is a genetic abnormality of the immune system; the regulation of the immune system is not adequate to prevent the antibodies from being formed. Other genetic autoimmune diseases can occur with Graves' disease, such as diabetes. But genetics are not sufficient to cause the disease; some other impact on the immune system is needed. Factors important in the development of Graves' disease include stress, infection, trauma, aging, drugs, smoking.
Exophthalmos, the puffiness above and below the eyes of Graves' disease patients, is due to an increase in the size of the muscles that control the eyes. The connection with thyroid disease is unclear; current theory suggests that it's due to a cross-reactive antigen within the eye tissue, maybe due to the same TSH receptor that is on thyroid cells. Treating the thyroid does not treat the eyes.
The three basic means of treatment of Graves' disease have not changed over the years: antithyroid drugs, surgery, radioactive iodine. Most endocrinologists in North America use radioactive iodine. Dr. Volpe suggests anti-thyroid drugs first for at least a year in the hope that a remission may occur (and it does occur in 30%-40% of people). If there is no remission, then radioactive iodine is the choice of treatment for all adults.
In the U.K. and the rest of Europe the commonest cause of hyperthyroidism is due to Graves' disease. This results from the presence in the bloodstream of an antibody which stimulates excessive thyroid hormone production by the thyroid gland, and in many cases goitre formation by increased growth of the gland.
In some 15-20% of patients, the hyperthyroidism is due to the presence of a multinodular goitre. This begins in youth and early adulthood as a small goitre which functions normally; if the stimulus to goitre formation in the first place remains, and in most cases it has not been identified, the gland becomes nodular and further increases in size over a period of 10-20 years. At that stage thyroid hormone concentrations are usually normal and concern is usually expressed for cosmetic reasons. In the following 10-20 years the nodules increase in size and number further and, functioning without any control of the pituitary gland, cause hyperthyroidism.
Nodular goitres are usually treated with radioactive iodine, but in the case of a large goitre causing significant compression of surrounding structures, surgery may be necessary. Attempts to prevent goitre growth in areas with adequate iodine in the diet have been largely unsuccessful and in the U.K. at least, there is little support for the use of treatment with thyroxine; indeed this may simply precipitate the onset of hyperthyroidism with serious consequences in elderly patients.
Radioactive iodine treatment of patients with multinodular goitres results in hypothyroidism much less frequently than similar treatment in patients with Graves' disease.
Occasionally the symptoms of hyperthyroidism are associated with pain in the thyroid radiating to the jaw and ears, and a fever. This is known as subacute (de Quervain's) thyroiditis, and is thought to be due to a viral infection. Characteristically the hyperthyroidism is mild and short-lived, lasting a few weeks only, followed by a similar short-lived period of mild hypothyroidism before recovery. Treatment is not usually necessary.
Hyperthyroidism may be caused by drugs. The major culprit is amiodarone used in the treatment of heart irregularities such as atrial fibrillation. Amiodarone contains a large amount of iodine and will induce hyperthyroidism in patients with underlying thyroid disease, such as nodular goitre. As the drug is stored in the body fat, its effects may persist for up to 12 months after it has been stopped.
From time to time patients, usually nurses, will take excessive quantities of thyroid hormones in an attempt to lose weight by inducing a state of hyperthyroidism. This is difficult to achieve taking simply thyroxine (Synthroid or Eltroxin), but not so with preparations of thyroid extract which contain both thyroxine and triiodothyronine - a rare but well recognized cause of hyperthyroidism.
Currently, however, the major controversy is about whether a little too much thyroxine replacement therapy for patients with hypothyroidism is harmful. Doses which suppress the concentration of the pituitary hormone, thyroid stimulating hormone, in the blood have been shown to cause minor changes in the function of most organs, similar to but much less marked than those recorded in hyperthyroidism. Most anxiety relates to the effect on bone and whether excessive thyroxine therapy may be a factor in the development of osteoporosis. The case is not proven, and indeed if thyroxine is a factor in the induction of osteoporosis, it is a very very minor factor, and nothing as significant as other factors such as premature menopause, lack of exercise and smoking.
At times patients, when they are admitted to hospital with a variety of non-thyroid illnesses such as heart failure or major trauma, have changes in the metabolism of the thyroid hormones which may lead the inexperienced resident to assume that the patient might have hyperthyroidism, and that might lead to unnecessary further investigations and treatment.
In all cases, it is sensible to try to adhere to the recommendations of the American Thyroid Association in the management of primary hypothyroidism, namely that "the goal of therapy is to restore most patients to the euthyroid state and to normalize serum T4 and TSH concentrations."
In the community at large, there is a whole pool of people, male and female, who have autoimmune thyroid failure, that may eventually, but not inevitably, destroy the thyroid. Some will have biochemical abnormalities which the first mark of is a rise in TSH. Only a small proportion of these people will have gross thyroid failure.
A study 20 years ago defined the frequency of hyperthyroidism by testing every 4th or 5th person in Whickham, U.K. The prevalence of hypothyroidism among women was 3/1000 of new cases, and 10/1000 of those treated with radioiodine or surgery. Similar figures were found by others from countries around the world with Caucasian populations (Finland: New, 2/1000; New Zealand: New and treated, 6/1000).
If we could pick hypothyroidism earlier, perhaps we would save a lot of morbidity. The condition most often afflicts middle-aged women who perhaps attribute their symptoms, wrongly, to aging and menopause. The symptoms are all fairly nonspecific, which is why doctors sometimes forget about it too: lethargy, constipation, weight gain, cold intolerance, facial puffiness, dry skin, hair loss, hoarseness, tingling and numbness due to compression of nerves in the hand.
The signs of hypothyroidism are nonspecific as well: change in appearance; swelling around the eyes; dry, flaking skin; hair loss; slow pulse rate; signs of median nerve compression.
Hypothyroidism could be diagnosed in early stages by the thyroid test measuring TSH, which is a very sensitive marker which can be picked up in very early stages.
The people with thyroid antibodies are those who are at risk. In the Whickham study, only 2-3% of the men have acquired thyroid disease. In women the percentage rises to about 12% of women of allages and tends to increase with age. The peak is around 50, about the same time women reach menopause.
We postulate that people who are vulnerable, who have these antibodies, will gradually have thyroid failure. The first marker will be the rise in TSH. A 20-year follow-up to the Whickham study added some figures regarding the incidence of hypothyroidism in women: at first about one dozen were diagnosed, in the 20 years since another 48 were diagnosed by their family doctors, and when we rescreened the original population (90% of those who participated originally were traced) we found another 21. The incidence of hypothyroidism is thus about 3 or 4 per 1000 women per year, with the frequency of thyroid failure correlating with the strength of the antibodies.
Fortunately this condition is treatable with regular doses of thyroxine; patients feel better within three months. Our present- day treatment started in 1891 when a doctor, Dr. George Redmayne Murray, despite being scoffed by his colleagues, cut the thyroid out of a sheep, strained it through a handkerchief, and injected the thyroid extract into a patient with hyperthyroidism. He was completely successful in his first such attempt at treatment.
Since many thyroid diseases frequently occur in females between the ages of 20 to 40, the recognition and treatment during and after pregnancy requires special consideration. Appropriate management of thyroid disease at that time is based on a familiarity with the known influences of pregnancy on thyroid physiology and autoimmunity in both the mother and the fetus. Our increasing knowledge of the effects of pregnancy on thyroid function and autoimmunity over the past 20-30 years has led to the detection of a variety of syndromes of thyroid dysfunction and the development of new guidelines and principles of management.
Changes of Thyroid Physiology in Pregnancy
Thyroid Dysfunction in Pregnancy
Hyperthyroidism in Pregnancy
Fetal Thyroid Function in Utero Fetal thyroid develops its own autonomous thyroid pituitary access by the 12th-14th week of gestation, or as early as the 10th week. Thyroid hormone administered to mothers cannot be transferred to the fetus. Iodides and antithyroid medication can be transferred, however, which risks the induction of fetal goitre and hypothyroidism. Blocking or stimulating TSH receptor antibodies can be transferred across the placenta, inducing either neonatal hypothyroidism or hyperthyroidism. Once the antibody passes, however, the baby recovers.
Autoimmune Thyroid Disease in Pregnancy
1995 is an interesting anniversary year - it is the 100th anniversary of Röntgen's discovery of the X- ray, and thus of the introduction of X-ray treatment; the 50th anniversary of the first major introduction of radioactive iodine into clinical medicine for the treatment of hyperthyroidism; and the 9th year after Chernobyl.
Radioactive iodine is an isotope of iodine, a most important element in thyroid physiology. The gland needs to make hormone, and needs iodine to make it; the more hormone it makes, the more iodine it needs. Since the body cannot tell the difference between non radioactive iodine and radioactive iodine, the latter can be used to trace the pathways of iodine metabolism in the body and to measure iodine uptake. This reflects a degree of thyroid function. The test is performed by giving a small measured amount of radioactive iodine and passing a detector over the patient's neck which accurately measures how much of the radioactive iodine is taken up by the gland.
Another procedure is thyroid scanning, which maps the distribution of the radioactive iodine in the gland. Pictures are made of the thyroid which show a map of dots; the higher the density of the dots, the more radioactive iodine and thus more activity. You can determine the size of the gland and how it functions.
The goal of general hyperthyroid management is to decrease thyroid hormone secretion. This can be done chemically, with antithyroid drugs, mechanically, with surgery, by taking out part of the thyroid gland; or physically by using radioactive iodine to affect the cells of the thyroid. This works because the radioactive iodine is accumulated by the thyroid follicular cells, and the more active theses cells are, the more iodine is taken into the gland.
But the iodine isotope used clinically has a half-life of eight days. As it decays, it gives off beta and gamma rays, which affect all cells, including thyroid tissue. When radioactive iodine is given in large amounts, these rays interfere with thyroid cell viability and its ability to reproduce. The end result is a decrease in the number of functioning thyroid cells. This is one of the reasons radioactive iodine does not work immediately in hyperthyroidism. It takes at least four to six weeks, and usually up to two to three months to decrease thyroid size as well as thyroid hormone secretion.
There are two sides to the question of radiation and the thyroid. In the 50s and 60s high doses of external X-ray treatments were applied to the necks of infants and children for a number of important medical problems. These treatments, however, have caused thyroid nodules and thyroid cancer, some appearing as late as 35 years after exposure. There are no such problems with radioactive iodine, which delivers radiation in a different way, over a longer period of time, and its distribution is different in the gland. Radioactive iodine has been used since 1950 for diagnosis and treatment, in small and large amounts, in literally millions of patients and there is no evidence of any significant deleterious effects. In the U.S., radioactive iodine is now the routine preferred treatment for hyperthyroidism.
Problems do arise with other isotopes of iodine. Nuclear reactors contain large amounts of many iodine isotopes. Many of these have relatively short half-lives, which means their effects are more like those of external X-rays and may be more likely to cause thyroid nodules. A major reactor accident, like the Chernobyl accident in 1986, can release varying amounts of isotopes from the reactor core, and iodine is only on of perhaps 60 or 70 radioactive materials that can be released.
After Chernobyl, radioactive particles were deposited in water supplies and vegetation, reaching the milk pathway, a particular concern for children. The resulting accumulations of radioactive iodine into the thyroid could have been prevented. A thyroid blocking agent, most effectively potassium iodide, can saturate the gland and prevent the accumulation of radioactive iodine, but it must be given before exposure, or immediately afterwards, and continued for the duration of exposure. However, knowledge of the reactor accident was only made public almost two weeks after the accident. In areas of highest concentration of fall out, there appears to be a 20-fold increase in the incidence of thyroid childhood cancer, a normally rare childhood disease.
There is a positive side: We now know a great deal about thyroid cancer and its management. Properly treated, most of these children will survive and do very well. Ironically, the major modality of treatment actually involves the use of radioactive iodine.
Very often people who have thyroid nodules are not aware of them; it is usually they physician who discovers the nodules during a routine physical examination.
Thyroid nodules are extremely common. Surveys have found that up to one out of every 10-20 people have thyroid nodules in North America. Frequency increases with age, and they are much more common in women than men. Fortunately, they are almost always benign, 90-95% of thyroid nodules are not cancerous, but they always require evaluation.
Physicians examining a thyroid nodule consider "three big questions": 1. Is it cancer? 2. Is it associated with hyperthyroidism or hypothyroidism? 3. Is it causing symptoms such as choking, hoarseness, or trouble swallowing? The diagnostic steps taken to answer those questions are a fine needle aspiration biopsy to detect cancer; test the level of TSH for 2.; and for symptoms ofcompression, follow a medical history with tests such as barium swallow, pulmonary function test, or CAT scan.
Thyroid cancers are much more likely in a thyroid nodule if it occurs in a younger person, especially a child. People who have radiation treatment to their head and neck can develop thyroid cancer decades later. On the other hand, if older people have nodules, they are less likely to be cancerous. Women also tend to have a lower frequency of cancer. Men don't get nodules as frequently but they have a higher frequency of cancer. If a nodule is painful, it's less likely to be cancer.
Thyroid Scans and Sonograms: What is their role?
The role of these procedures is diminishing rapidly. Thyroid scans can tell if the thyroid nodule is functioning and taking up radioactive iodine correctly (always benign) or non-functioning, where there is a chance it is cancerous. However, 90-95% of all nodules are non-functioning, therefore, from an economic point of view it's not reasonable to do scans since everyone with non- functioning nodules needs a biopsy anyway.
Similarly, thyroid ultrasounds, even though they are useful for certain purposes, cannot distinguish a benign nodule from a cancerous one. They can distinguish if a nodule is a lump that is solid, or contains a liquid, which means it's a cyst or if a nodule is solitary or one of many and can measure the size of nodules.
Because of considerations of cost and convenience, most endocrinologists in the U.S. have recommended that if a person has a thyroid nodule, the first test, after a TSH test, to determine ifthere is hypo- or hyperthyroidism, is a biopsy. If the result shows cancer, surgery is the response; if benign, nothing needs to be done. If there is insufficient material, another biopsy should be done; if results are indeterminate, i.e. can't tell if benign or malignant, then a scan is recommended.
Benign Thyroid Nodules: Treatment
Thyroid hormone can be used to try to suppress TSH in the hope that the thyroid might shrink. This is controversial, however, and there are studies that do not show this is particulary beneficial in some patients. Also there may be risks to giving women, especially post menopausal women, high doses of thyroid hormone to suppress their TSH levels; this treatment could have possible effects on the skeleton and the heart.
If a nodule is functioning excessively and causing hyperthyroidism, the patient is given radioactive iodine. If the nodule is causing compression in the neck, trouble swallowing or breathing, then surgery is usually the main answer.
Treatment of Thyroid Cancer
Thyroid cancer is a fairly rare form of cancer. The major form of thyroid cancer is capillary cancer, which is good because this form has the best prognosis over any other kind of cancer. It affects all age groups; it is a very slow-growing tumour, it commonly can spread to the lymph glands, and rarely spreads to other parts of the body. Other types of thyroid cancer are follicular, medular, and anaplastic.
Surgery is the primary treatment for all forms of thyroid cancer; in some cases, radioactive iodine and thyroid hormone are used. How do you choose a good surgeon? The main qualification is that thesurgeon must have a lot of experience in thyroid surgery, performing at least one surgery per week.
Reviewed 2000