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New thyroid therapies raise management questions

From the May 1995 ACP Observer, copyright 1995 by the American College of Physicians.

By Sylvia Wrobel, PhD

New advances have greatly improved the diagnosis and management of thyroid disorders--and raised questions about existing therapies and when to treat some thyroid diseases.

During a special presentation, Ian R. Hart, MACP, professor of medicine at the University of Ottawa, discussed research that might change physicians' treatment choices for hyperthyroidism:

  • Is subclinical hyperthyroidism dangerous? The answer may depend on age and sex, Dr. Hart said. The first possible consequence of subclinical hyperthyroidism, decreased bone mineral density, has been found in postmenopausal women but not in men or younger women with the same thyroid level. Cardiac dysfunction, the second possible consequence, may be age-related. A recent Framingham study found that a significant number of subjects with thyroid stimulating hormone (TSH) less than 0.1 had developed atrial fibrillation on 10-year follow-up, suggesting low TSH is a risk factor in older patients, as a surrogate measure of subtle hyperthyroidism.
  • Is iodine 131 (131I) radiation treatment bad for bad eyes? Earlier retrospective studies suggested eye changes following treatment were more related to the development of hyperthyroidism than to the primary mode of therapy, whether the antithyroid drugs favored by Europeans or the 131I more often used by North Americans. However, a more recent two-year prospective study concluded that 131I treatment produced a threefold increase in worsening of eye problems. Dr. Hart agrees with published data suggesting that if the goiter is small and hyperthyroidism mild to moderate, you may want to use antithyroid drugs more often. If you use 131I in a patient who already has ophthalmopathy, you may consider steroid coverage. Always explain to patients the advantages and risks of treatment options.
  • Does adding thyroxine (T4) to the thyroid inhibitor methimazole decrease relapse following withdrawal of antithyroid drugs? Relapse rates following withdrawal of antithyroid drugs range from 10% to 75%, with no good predictors of which patients are likely to relapse. Unfortunately, new research does not provide a definitive answer, Dr. Hart said. A 1991 New England Journal of Medicine article found a 3% relapse after three years in patients with T4 added to methimazole, compared to a 33% relapse rate in patients on methimazole alone. A Scottish paper found no difference. We need to keep watching, Dr. Hart concluded.
  • Is pretreatment to euthyroidism before 131I treatment dangerous? Despite extremely limited data, many physicians pretreat for several weeks for fear radiation thyroiditis will release thyroid hormones into the circulation, leading to an immediate increase in the severity of hyperthyroidism. This could have disastrous effects on patients already at high risk.

But Dr. Hart cited a new study by panel co-member Leonard Wartofsky, MACP, chairman of the department of medicine at Washington (D.C.) Hospital Center, that raises the concern of rebound. In patients at risk, Dr. Hart has begun to consider stopping pretreatment only two days before giving 131I in hope of preventing such problems. Again, he concluded, more work is needed.

On the issue of thyroid nodules and their management, panel member Paul W. Ladenson, FACP, director of the division of endocrinology and metabolism at Johns Hopkins University School of Medicine, said fine needle aspiration biopsy has reduced the number of patients referred to surgery by 40%; among patients referred to surgery, twice as many were found to have cancer. The cost of care was reduced by 25%.

While sensitive imaging techniques such as ultrasound have allowed physicians to find even more nodules in older adults, only 5%-10% of these nodules prove to be cancerous. As a result, Dr. Ladenson said, it is increasingly important to refine the population referred to surgery, because surgery has risks and costs. This is where fine need aspiration biopsy comes in; after clinical assessment and measurement of serum TSH, the vast majority of patients can proceed directly to fine needle aspiration biopsy. Only those with undetectable or extremely low TSH require a scan.

How good is fine needle aspiration biopsy? It is sensitive, finding cancer in 95%-98% of cases with a 75% specificity. Although most of the 20% of patients whose nodules fall in an indeterminate category will have to go to surgery, only 20% of those patients are likely to have cancer. (Dr. Ladenson did caution physicians to carefully differentiate between indeterminate biopsy and a biopsy with inadequate sample. Referring to the skill needed, he also stressed that physicians who did not do at least 10 fine needle aspiration biopsies per year should probably not do any.)

Another improvement of magnitude appears on the horizon, according to Dr. Ladenson. Currently, patients with previously treated thyroid cancer are periodically taken off thyroxine therapy about four weeks before radioactive iodine scans or treatment with 131I. This lets the pituitary TSH-secreting cells awaken and begin to produce TSH in order to elevate serum TSH to stimulate radioiodine uptake by any residual thyroid tissue.

But if these same levels of serum TSH could be achieved with injection of human TSH, patients could continue to take thyroxine without undergoing the unpleasant state of hypothyroidism. Already, researchers have cloned and sequenced genes for TSH, transfected those genes into Chinese hamster ovary cells, and, in collaboration with industry, generated large amounts of these recombinant cells in a bioreactor. In an early human clinical trial comparing scans after injection of human recombinant TSH and scans done after conventional withdrawal, human recombinant TSH scans were equal or better in 86% of cases. And the patients taking human recombinant TSH felt immensely better.

Repetition of this trial will begin this spring, and Dr. Ladenson expressed hope that physicians could look forward to FDA approval of the method and a new way to manage patients with thyroid cancer within two years.

Sylvia Wrobel is director of health sciences news and information at Emory University. She writes frequently on medical issues.

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