Kenneth D. Burman

American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer

BACKGROUND Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Rapid evaluation and establishment of treatment goals are imperative for optimum patient management and require a multidisciplinary team approach. Here we present guidelines for the management of ATC. The development of these guidelines was supported by the American Thyroid Association (ATA), which requested the authors, members the ATA Taskforce for ATC, to independently develop guidelines for ATC. METHODS Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The quality and strength of recommendations were adapted from the Clinical Guidelines Committee of the American College of Physicians, which in turn was developed by the Grading of Recommendations Assessment, Development and Evaluation workshop. RESULTS The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues including end of life. The guidelines include 65 recommendations. CONCLUSIONS These are the first comprehensive guidelines for ATC and provide recommendations for management of this extremely aggressive malignancy. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach (surgery, radiation, systemic therapy) is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for a clinical trial or hospice/palliative care, depending upon their preference.

Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement

BACKGROUND A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. METHODS Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. RESULTS We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. CONCLUSIONS We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.

The effect of T3 and reverse T3 administration on muscle protein catabolism during fasting as measured by 3-methylhistidine excretion☆☆☆

Since recent studies have indicated that measurement in urine of the amino acid, 3-methylhistidine, accurately reflects the extent of muscle catabolism, and because it has been suggested that thyroid hormones may influence muscle breakdown, especially during fasting, the effect of T3 and reverse T3 (rT3) administration on the excretion of 3-methylhistidine was examined in obese subjects during fasting. The mean (+/- SE) 3-methylhistidine excretion in patients fed an egg protein diet (devoid of meat protein) was 256 +/- 35 mumoles/day and decreased to 190 +/- 14 mumoles/day during fasting. T3 administration (100 microgram/day x 5 days) increased 3-methylhistidine excretion to 304 +/- 37 mumoles/day during its ingestion and to 485 +/- 46 mumoles/day in the T3 posttreatment interval. T3 doses of 10 microgram every 4 hr (q4h) for the first 6 days of fasting also appeared capable of increasing 3-mehis excretion whereas 5 microgram T3 q4h administered during the first 6 days of fasting did not increase 3-mehis excretion. Reverse T3 administration (80 microgram q6h) during fasting was associated with a mean 3-methylhistidine of 130 +/- 13 mumoles/day, a value no higher than in patients fasted alone. These observations suggest that: (1) skeletal muscle catabolism decreases during fasting: and (2) pathophysiologic doses of T3 (60 microgram/day or more), but not reverse T3, enhance muscle catabolism during fasting.

Anaplastic Thyroid Cancer

Anaplastic thyroid cancer is an uncommon, typically lethal malignancy of older adults with no effective systemic therapy. The mean survival time is usually less than 6 months from the time of diagnosis and, unfortunately, this outcome is not fundamentally altered by available treatments. Histologic tissue confirmation is recommended if the diagnosis is not absolutely certain to exclude tumors with better prognosis or that require different treatment. Patency of the airway should be kept in mind throughout the patients course and individuals with impending airway obstruction, in the absence of imminent death from other sites of disease, should be considered for a tracheostomy to secure the airway. Enrollment in meaningful clinical trials should be given the highest priority at all decision points.

Ionized and Total Serum Calcium and Parathyroid Hormone in Hyperthyroidism

Total and ionized calcium concentrations as well as parathyroid hormone levels were measured in a group of hyperthyroid persons. Ionized and total calcium levels were elevated in 21 of 45 (47%) and in 12 of 45 (27%) thyrotoxic patients, respectively. Mean ionized and total calcium levels were higher in these 45 patients than in normal persons. Using two different radioimmunoassay systems for a total of 44 determinations, mean parathyroid hormone levels were lower in thyrotoxic patients than in subjects with proved hyperparathyroidism. These data suggest that [1] elevations of both ionized and total calcium concentrations occur frequently in thyrotoxic patients; [2] ionized calcium concentrations may be elevated in a higher percentage of hyperthyroid subjects than are total calcium concentrations; and [3] the hypercalcemia associated with thyrotoxicosis is not associated with elevated parathyroid hormone levels.

UNUSUAL TYPES OF THYROID NEOPLASMS

This article discusses several unusual forms of primary thyroid neoplasms. The TCV of PTC and insular thyroid carcinoma appears to have a more aggressive clinical behavior than DTC in most patient groups and may respond to thyroid hormone suppression and radioiodine. Anaplastic thyroid carcinoma, which may develop from differentiated thyroid tumors, has a poor prognosis which may be altered by surgery and radiation therapy but not typically by radioiodine and thyroid hormone suppression. Primary squamous cell carcinoma of the thyroid is an unusual entity that may be associated with a clinical syndrome that includes leukocytosis, fever, and hypercalcemia. Primary thyroid lymphoma is frequently associated with Hashimotos thyroiditis and should be considered especially in older patients with rapidly enlarging thyroid masses. Although there are no studies assessing this issue, it seems reasonable that patients who have undergone thyroidectomy for neoplasms of thyroid cells that are poorly differentiated and do not concentrate radioiodine (e.g., squamous cell, anaplastic) should receive sufficient thyroid hormone suppression, if tolerated, to reduce TSH (third-generation assay) to approximately 0.1 to 0.3 mu U/mL, because TSH may be a growth factor. If, however, the tumor concentrates or responds to radioiodine, suggesting more differentiated cells (e.g., TCV, insular carcinoma), the target TSH level (third-generation assay) should range from 0.01 to 0.1 mu U/mL, as tolerated. Patients with primary thyroid neoplasms arising from cells other than thyrocytes (e.g., lymphoma) can be maintained at a TSH level of 0.5 to 1.5 mu U/mL. Our conclusions and analyses are often based upon small, retrospective, poorly controlled reports, and further studies are required to allow a better understanding of the evaluation and treatment of these neoplasms.

Glucose modulation of alterations in serum iodothyronine concentrations induced by fasting.

In order to investigate the process by which dietary composition may regulate T4 conversion to T3 and reverse T3, iodothyronine levels were measured in the sera of seven obese subjects during consecutive study periods. These study periods included the ingestion of an approximate weight-maintaining diet (40% carbohydrate, 40% fat, 20% protein) during a control period of 4 days, a fast of 7 days thereafter, and then a 5-day period of glucose ingestion (50 g/day) only. The mean (±SE) serum T3 concentration was 117 ± 8 ng/dl on day 4 of the control period, and gradually decreased to 66 ± 11 ng/dl (p < 0.01) on the last day of fasting. The subsquent administration of glucose was associated with an increase in the mean serum T3 level to 94 ± 10 ng/dl (p < 0.01). Mean (±SE) serum levels of reverse T3 varied reciprocally and were 52 ± 9 ng/dl, 82 ± 12 ng/dl (p < 0.005), and 65 ± 9 ng/dl (compared to fasting, p < 0.05) during the fed and fasting states and during glucose administration, respectively. Furthermore, employing a similar protocol in a different group of subjects, serum sampled during the administration of 100 g of fructose orally during days 8–12 of fasting also was associated with an increase in mean serum T3 and a decrease in mean serum reverse T3, as compared to values obtained on day 6 or day 7 of fasting (T3: 83 ± 6 ng/dl, fasting vs. 111 ± 10, fructose (p < 0.05); rT3: 56 ± 9, fasting vs. 42 ± 6 ng/dl, fructose (p < 0.025)). Serum T4 concentrations were not significantly altered in any study period either during glucose or fructose ingestion. Despite the decrement in serum T3 levels observed during fasting, the mean peak TSH in response to TRH stimulation in a group of 15 obese subjects was decreased during fasting as compared to the fed state (8.1 ± 1.2 μU/ml, fast vs. 12.8 ± 2.0 μU/ml, fed). These observations suggest that both glucose and fructose are capable of modulating serum T3 and reverse T3 levels and that administration of these hexoses in doses of only 100–200 g/day for 5 days may be effective in altering T4 degradative pathways. Furthermore, despite the decreased serum T3 levels, the TSH response to TRH stimulation is decreased, paradoxically, during fasting.

Hanging from the Masthead: Reflections on Authorship

Authorship of a scientific article should imply expertise on its content and thorough knowledge of the investigation reported. Because the number of authors per article has dramatically increased, I question whether these criteria for authorship are applied. Another explanation for this increase is that authors add names to the byline without reference to any set of criteria, resulting in the designation of coauthorship when not warranted. The medical community needs to redefine the proper procedure and criteria for deciding on authorship and to strictly abide by these procedures. Specific recommendations center around the protocol as the initial instrument of communication. Who should be designated as author, and the order of names, should be negotiated before and during the study, and written communication with other involved laboratories should result in more appropriate authorship attribution.

Acute Bacterial Suppurative Thyroiditis: A Clinical Review and Expert Opinion

BACKGROUND Acute suppurative thyroiditis (AST) resulting from a bacterial infection is an infrequent but potentially life-threatening endocrine emergency. Traditional management of this disease has been surgery in conjunction with targeted antibiotic therapy. Recent nonrandomized reports of small series have demonstrated good outcomes using less invasive approaches. No randomized clinical trials have been performed. Here, we provide a review of the literature and an approach to this problem based on expert opinion. METHODS The literature was reviewed utilizing PubMed, and a representative case of AST was presented to a panel of experts. Endocrinology, surgery, and infectious disease experts responded to a series of questions regarding diagnosis, management, prognosis, and harm. RESULTS Combining a broad spectrum of clinical expertise and the published literature, the authors suggest a clinical algorithm as a guide to management, addressing both diagnosis and acute and long-term management. CONCLUSIONS Published studies indicate a trend toward less invasive management during active inflammation and infection and regarding definite therapy. Remaining questions are presented to foster an evidence-based approach to this disease. Ideally, future randomized, controlled trials will provide data to improve the therapy and outcome of AST.

Remission Rates with Antithyroid Drug Therapy: Continuing Influence of Iodine Intake?

We retrospectively reviewed the therapeutic efficacy of antithyroid drugs for Graves disease. Sixty-nine patients were divided into three categories according to their response: 28 (40.6%) were unable to achieve a remission; 6 (8.7%) achieved a remission and subsequently had a relapse; and 35 (50.7%) were able to sustain a remission. The mean duration for sustained remissions was 33 months. Our earlier review of outcome of antithyroid therapy showed markedly reduced remission rates, which appeared to be related to increases in dietary iodine intake. Although the greater percentage of patients entering remission today is in marked contrast to the 1973 report, average dietary iodine content has been decreasing. A continuing role for antithyroid drugs should be maintained as an option in the management of Graves disease. Daily dietary iodine intake may influence the anticipated remission rate after antithyroid drug therapy.