Too Much of a Good Thing: Thyroid Cancer Suppressive Therapy and Atrial Fibrillation

The Case

A 63-year-old man with a distant history of thyroid cancer presented to the emergency department with complaints of chest pain, palpitations and shortness of breath. He had been losing weight over the last year, which he attributed to chemotherapy for prostate cancer, diet and exercise. He was admitted to the coronary care unit on a rule-out myocardial infarction protocol. It was noted at that time his TSH level was suppressed (<0.005 mU/L) and he was currently on a dose of 200 micrograms of levothyroxine daily. There had been no dosage adjustments for over five years. His levothyroxine dose was placed on hold and he was discharged four days later with the diagnosis of atrial fibrillation likely due to thyrotoxicosis and underlying coronary artery disease. He was instructed to follow-up with an endocrinologist and a cardiologist.

At his appointment with his new endocrinologist, he reviewed his long history of papillary thyroid cancer, which was diagnosed about 20 years ago. He had a total thyroidectomy, which was followed by radioactive iodine ablation therapy. The original pathology report indicated that the nodule was 1.5 cm in its greatest dimension, confined to the right lobe of the thyroid. His post-treatment nuclear medicine scan was reported as normal. After his initial diagnosis was made, his endocrinologist explained the importance of keeping his TSH level suppressed on levothyroxine and having his blood work checked at least once or twice a year. For several years he followed up with his endocrinologist, who ordered several nuclear medicine body scans which were reported as normal. His thyroglobulin level, off suppressive therapy, was undetectable. An ultrasound of his neck was also reported as normal. Ten years ago his endocrinologist died, and he has been followed by his primary care provider since then. On one occasion his doctor was going to reduce his levothyroxine dose but decided not to do so because of concerns expressed to him by the patient.

The Commentary

The levothyroxine dosage placed the patient at a significantly higher risk for complications associated with sub-clinical or overt thyrotoxicosis. The risk of atrial fibrillation has been shown to be inversely related to the TSH level. This is especially true in the older population (3). The benefit to risk ratio was reduced or inverted, as his thyroid cancer became less of an issue as time passed without evidence of recurrence or metastasis.

Current guidelines for thyroid cancer emphasize the importance of categorizing the cancer into one of three groups based on the likelihood of a recurrence or metastasis (4). Consideration should be made based on the patient’s age and co-morbid conditions such as risks for coronary artery disease. Patients at a high risk for recurrences as demonstrated in retrospective studies have improved outcomes when their TSH levels are suppressed below 0.1 mU/L (4). This has not been shown to be the case for low risk patients (4-6). A summary of these groups and treatment recommendations follows:

If the patient has persistent disease, the serum TSH should be maintained below 0.1 mU/L as long as it can be safely administered.
If the patient is free of disease, but at high risk for recurrence or metastasis, the TSH should be kept between 0.1 and 0.5 mU/L for five to 10 years.
Those at low risk and free of disease may be titrated to TSH levels in the low normal range between 0.3 to 2 mU/L.

The patient’s tumor was a stage 1, T1N0M0. Over the last 20 years there has been no evidence of recurrence or metastasis. This information would place him in the low risk and free of disease category. Keeping his TSH level in the normal range would be appropriate. A suppressed TSH would place him at a high risk for complications associated with hyperthyroidism.

There are several issues in this case which should be addressed. The initial assessment and documentation of any cancer is extremely important. The staging of the tumor allows for appropriate treatment and continuity of care. As in all areas of medicine, treatment protocols change as more research is completed and published. Keeping up with this information is extremely important so the risks and benefits can be assessed and acted on by appropriate changes in the treatment plan. After the initial staging is completed and documented it is also important to change course if there is a significant change in the patient’s prognosis or general health status. In this case several factors likely contributed to his acute presentation in the emergency department. His loss in weight, which started with his chemotherapy, caused his thyroxine level to rise, resulting in overt thyrotoxicosis which further contributed to his weight loss. This vicious cycle, accelerated by over-treatment of levothyroxine, is often overlooked and attributed only to the precipitating event. Even if his tumor classification was considered high risk and followed for only a short period of time, TSH suppression-therapy should be closely monitored to ensure a sub-clinical hyperthyroid state does not progress into overt hyperthyroidism. Follow-up evaluations should not only include a TSH level but also a Free T4 in conjunction with a complete history and physical exam. Hyperthyroidism also causes osteoporosis and should be monitored by DEXA scans and preventive measures including education, calcium and vitamin D supplementation.

The patient was given information at the time of his diagnosis, that his TSH levels should be kept suppressed in order to minimize the chance of recurrence. This statement alone was considered appropriate at the time, 25 years ago. On the other hand, it is not unusual for a primary care provider to question the suppressed level and reduce the thyroid hormone dosage if it is not clear that the patient is on suppression therapy for persistent thyroid cancer. Although patient education is always important, the initial information they are given often becomes outdated. In this case, the risk of recurrent thyroid cancer was less than the risk from atrial fibrillation due to excessive levels of thyroid hormone.

Although physicians should respect their patient’s point of view, the patient may be following out-dated advice. A re-consult with a specialist could have prevented this problem.

Take-Home Points

Treatment of differentiated thyroid cancer has changed significantly over time.
It is often prudent to consult experts in their respective clinical specialties to re-evaluate clinical problems which appear to be long-standing or even stable.
Patients should be given up-to-date information regarding their disease state, treatment options and follow-up plan, reinforcing the importance of timely re-evaluations.
Not all differentiated thyroid cancers are alike and treatment, based on staging and risks for recurrences or metastasis, varies significantly.
Co-morbid conditions and disease-free intervals must be considered when determining the aggressiveness of the treatment plan.

References

Bates D, Clark NG, Cook RI, Hellman R, et al. American College of Endocrinology and American Association of Clinical Endocrinologists position statement on patient safety and medical system errors in diabetes and endocrinology. EndocrPract. 2005;11:197-202. [go to PubMed]
Bates DW, Gawande AA. Improving safety with information technology. N Engl J Med. 2003;348:2526-2534. [go to PubMed]
Consequences of mild thyrotoxicosis and atrial fibrillation.Sawin CT, et al. N Engl J Med. 1994;331:1249-1252
Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer The American Thyroid Association Guidelines Taskforce* Members: David S. Cooper,(Chair), Gerard M. Doherty,Bryan R. Haugen,Richard T. Kloos, Stephanie L. Lee,Susan J. Mandel,Ernest L. Mazzaferri,BryanMcIver,Steven I. Sherman, and R. Michael Tuttle.
Cooper DS, Specker B, Ho M, Sperling M, Ladenson PW, Ross DS, Ain KB, Bigos ST, Brierly JD, Hangen BR, Klein I, Robbins J, Sherman SI, Taylor T, Maxon HR 3rd 1998 Thy- rotropin suppression and disease progression in patients with differentiated thyroid cancer: Results from the National Thyroid Cancer Treatment Cooperative Registry.
Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol C1996 Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 81:4318–4323.