Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report.

There is a frequently encountered subset of hypothyroid patients who are refractory to standard thyroid hormone replacement treatment and require unexpectedly high doses of levothyroxine. In addition to clinical situations where hypothyroid patients are non-compliant, or where there is the possibility of excipient-induced disease exacerbation (gluten/celiac disease), therapeutic failure may be due to impaired absorption of the administered drug. The common approach to managing patients with unusual thyroxine needs is to escalate the dose of levothyroxine until targeted TSH levels are achieved. This approach can increase the risk for prolonged exposure to supratherapeutic doses of levothyroxine, which increase the chances of adverse outcomes. Repeated adjustments of levothyroxine can also escalate the costs of treatment, as frequent office visits and laboratory tests are required to determine and maintain the desired dose. Clinicians should take a systematic approach to managing patients whom they suspect of having treatment-refractory hypothyroidism. This may include searching for, and adjusting, occult medical conditions and/or other factors that may affect the absorption of levothyroxine, before up-titrating the dose of traditional levothyroxine therapy. Depending on the underlying pathology, another approach that may be considered is to try alternative formulations of levothyroxine that are less susceptible to intolerance issues related to excipients, or, in some cases, to malabsorption. The early discovery of these factors via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for both patients and clinicians.

Leukemia after a small dose of radioiodine for metastatic thyroid cancer.

Radioiodine is widely used in the treatment of thyroid cancer. It is one of the most benign forms of therapy for malignancy. Leukemia is a rare complication of 131I therapy, usually occurring after cumulative dosages of more than 800 mCi and with intervals between doses of less than 12 months. We report the occurrence of acute myelogenous leukemia in a 28-yr-old woman 14 months after receiving a total dose of 300 mCi 131I for metastatic follicular thyroid cancer. We also review the published literature of the incidence of leukemia after low dose 131I.

An adult with 49,XYYYY karyotype: case report and endocrine studies.

Sex chromosome abnormalities, such as 47,XXX, 47,XXY, 47,XYY, and 45,X, are relatively common and occur in approximately 1 of 400 births. Sex chromosome tetrasomy and pentasomy are much rarer events. The somatic and developmental consequences of supernumerary sex chromosomes have not been studied adequately. This is especially true of individuals with only supernumerary Y chromosomes. Based on available case reports, the effects of extra Y chromosomes appear not as severe as those of supernumerary X chromosomes. Only two case reports of nonmosaic tetrasomy of the Y chromosome have been published. We evaluated a 30-year-old man with a 49,XYYYY karyotype and assessed his severe physical and mental handicaps (particularly the endocrine abnormalities) and attempted to clarify the effects of extra Y chromosomes on growth, development, and behavior.

Familial dysalbuminemic hyperthyroxinemia in pregnancy.

A 16-year-old pregnant Puerto Rican woman who had been treated for thyrotoxicosis previously was evaluated for goiter, increased total thyroxine (T4) and triiodothyronine (T3) and free T4 estimate, despite a normal thyroid-stimulating hormone (TSH) concentration. These findings are consistent with a TSH-producing pituitary adenoma or the syndrome of generalized thyroid hormone resistance. However, sera from the patient, her mother and subsequently her newborn daughter demonstrated the increased albumin binding of T4 but not T3 that is characteristic of familial dysalbuminemic hyperthyroxinemia (FDH). The free T4 estimate had been elevated artefactually by the increased affinity of FDH albumin for the analog in a one-step assay. The T3 and T4 concentrations were increased by pregnancy and T4 was increased further by FDH. This first report of FDH recognized during pregnancy emphasizes that the effects of pregnancy on thyroid hormone and TSH concentrations complicate the diagnosis of FDH. It is particularly important to distinguish this benign condition from thyrotoxicosis during pregnancy, because inappropriate treatment may affect fetal development.

Transient headache and impaired vision after intravenous thyrotropin-releasing hormone in a patient with pituitary macroadenoma.

We report a case of transient headache and impaired vision following administration of intravenous thyrotropin-releasing hormone (TRH) to a woman with a non-functioning pituitary macroadenoma, visual field defect, and elevated thyroid-stimulating hormone (TSH). The symptoms lasted for two hours and then resolved without known sequelae. There are a few other reported cases of similar adverse reactions to neuroendocrine manipulation in patients with pituitary macroadenomas. This is the second reported case of such adverse reactions to TRH alone and the first in which the patient had prior elevation of TSH.

Role of thyroid-stimulating immunoglobulin in aggressiveness of well-differentiated thyroid cancer.

OBJECTIVE: To assess whether a relationship exists between thyroid-stimulating antibodies and increased aggressiveness of thyroid cancer. METHODS: We analyzed clinical, histologic, and biochemical data, including thyroid-stimulating antibodies, from 26 patients (24 women and 2 men) who had had well-differentiated thyroid carcinoma for 1 to 5 years and had undergone total thyroidectomy and radioactive iodine ablative therapy. For analysis, the overall study cohort was divided into two groups: group 1 (N = 16), with stable disease and no evidence of metastatic activity, and group 2 (N = 10), with aggressive disease and substantiated metastatic involvement. RESULTS: The thyroid-stimulating antibodies ranged from 92 to 129% in group 1 and from 95 to 118% in group 2. Thus, both study groups had thyroid-stimulating antibody levels within the normal range (normal, <130%). CONCLUSIONS: Apparently, thyroid-stimulating antibodies had no contributory role in the growth of the metastatic lesions in the 10 patients with aggressive disease. Further studies should be undertaken to investigate other potential factors involved in stimulating the progression of thyroid cancer.

Misleading acute hypercalcemia due to hyperlipidemia: a method-dependent error.

OBJECTIVE: To report a case of artifactual hypercalcemia in a patient with hyperlipidemia. METHODS: We present clinical data and laboratory findings in a 33-year-old woman with generalized fatigue, a recent 5-kg weight loss, and a papular rash on the extremities as well as a history of diabetes and hypertension. RESULTS: Physical examination revealed an obese patient with eruptive xanthomas and lipemia retinalis. Laboratory tests showed hyperlipidemia, hypercalcemia (serum calcium measured by spectrophotometry), anemia, hyperproteinemia, hyperuricemia, and hyperbilirubinemia. After 4 days of a low-fat, low-cholesterol diet and gemfibrozil therapy, the serum triglyceride level decreased, and the serum calcium concentration returned to normal. CONCLUSION: In patients with hypercalcemia without an obvious cause, a spurious measurement should be considered.

Papillary carcinoma of the thyroid with manifestations resembling Graves' disease.

OBJECTIVE: To describe a case of papillary carcinoma of the thyroid that mimicked a diffuse toxic goiter. METHODS: We present a detailed case report, review related cases in the literature, and discuss the possible role of autoantibodies in promoting the growth of papillary thyroid tumor. RESULTS: A 28-year-old woman had a 6-month history of weight loss, palpitations, increased anxiety, and enlargement of her thyroid gland. Laboratory studies confirmed the presence of hyperthyroidism. A 1-cm nodule was identified at the left upper pole of the thyroid. Fine-needle aspiration biopsy of this nodule revealed papillary carcinoma of the thyroid. Total thyroidectomy and a modified radical neck dissection were performed. Microscopic examination showed that the entire gland was replaced by a papillary carcinoma with a predominantly follicular pattern of growth. Of 44 lymph nodes tested, 31 were positive for metastatic papillary thyroid carcinoma. The presence of thyroid antibodies may have had a role in the aggressiveness of the patient's disease. CONCLUSION: To our knowledge, this is the first published report of a papillary thyroid cancer with manifestations resembling Graves' disease.

Thyroid carcinoma in single cold nodules and in cold nodules of multinodular goiters.

OBJECTIVE: To examine the frequency of malignant growth in a nonfunctioning solitary thyroid nodule (SN) and in multinodular goiter (MNG). METHODS: We performed fine-needle aspiration biopsy (FNAB) of cold nodules in 154 patients. Eight patients with unsatisfactory FNAB specimens were excluded from the study. Of the remaining 146 patients, 95 (89 women and 6 men) had MNG. The other 51 patients (46 women and 5 men) had SN. The overall age range was 25 to 86 years (mean, 52). RESULTS: Of the 95 patients with MNG, 16 had abnormal cytologic findings and underwent surgical excision. Of these 16 patients, 12 had thyroid cancer (6 papillary, 3 follicular, and 3 Hürthle cell). Of the 51 patients with SN, 8 had suspicious cytologic findings, and 5 had surgical histologic evidence of thyroid cancer (3 papillary and 2 follicular). Four patients with papillary thyroid cancer (three from the MNG group and one from the SN group) had a history of exposure to neck irradiation. After exclusion of the patients with a history of neck irradiation, the rate of malignant involvement in cold nodules in the MNG group was 9.78%, in comparison with 8% in the group with SN (P = 0.89). Within the MNG group, 25% of the thyroid malignant lesions were of the Hürthle cell type. CONCLUSION: Multinodularity of a goiter should no longer be considered an indicator of probable benign disease. In the assessment of all thyroid nodules, both SN and those in MNG, a thyroid scan can be helpful, and it should be followed by FNAB and cytopathologic examination of any nonfunctioning lesions. The incidence of malignant involvement in cold nodules of MNG does not differ significantly from that found in SN.

Thyroid disease during pregnancy.

Physiologic changes in metabolism may make thyroid diseases difficult to diagnose during pregnancy. Such diagnoses depend principally on clinical acumen and an understanding of the alterations of laboratory values, particularly thyroid-stimulating hormone (TSH), induced by pregnancy. Untreated thyrotoxicosis may lead to abortion, stillbirth, neonatal death and low birth weight. The principal cause of thyrotoxicosis in pregnancy is Graves' disease, which may be treated with antithyroid drugs or surgery. The use of radioactive iodine is absolutely contraindicated during pregnancy. Hypothyroidism during pregnancy is associated with hypertension and premature labor. The goal of thyroxine replacement therapy is to maintain serum TSH levels in the normal range. Many thyroid conditions and treatments directly affect the fetus and the principal antithyroid drugs are secreted in breast milk. Both the mother and neonate require monitoring. In addition, autoimmune postpartum thyroiditis may recur following each pregnancy in susceptible patients.

Paraneoplastic hypercalcemia associated with uterine papillary serous carcinoma.

Hypercalcemia associated with endometrial carcinoma is rare. We report a patient with serous papillary endometrial carcinoma with paraneoplastic hypercalcemia due to parathyroid hormone-related peptide (PTHrP). To the best of our knowledge this is the first report of hypercalcemia due to PTHrP in this type of tumor.