James V. Hennessey

Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association

OBJECTIVE Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. METHODS The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. RESULTS Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. CONCLUSIONS Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

Growth hormone administration and exercise effects on muscle fiber type and diameter in moderately frail older people.

OBJECTIVE: Reduced muscle mass and strength are characteristic findings of growth hormone deficiency (GHD) and aging. We evaluated measures of muscle strength, muscle fiber type, and cross sectional area in response to treatment with recombinant human growth hormone (rhGH) with or without a structured resistance exercise program in frail older subjects.

Tissue-Engineered Human Bioartificial Muscles Expressing a Foreign Recombinant Protein for Gene Therapy

Murine skeletal muscle cells transduced with foreign genes and tissue engineered in vitro into bioartificial muscles (BAMs) are capable of long-term delivery of soluble growth factors when implanted into syngeneic mice (Vandenburgh et al., 1996b). With the goal of developing a therapeutic cell-based protein delivery system for humans, similar genetic tissue-engineering techniques were designed for human skeletal muscle stem cells. Stem cell myoblasts were isolated, cloned, and expanded in vitro from biopsied healthy adult (mean age, 42 +/- 2 years), and elderly congestive heart failure patient (mean age, 76 +/- 1 years) skeletal muscle. Total cell yield varied widely between biopsies (50 to 672 per 100 mg of tissue, N = 10), but was not significantly different between the two patient groups. Percent myoblasts per biopsy (73 +/- 6%), number of myoblast doublings prior to senescence in vitro (37 +/- 2), and myoblast doubling time (27 +/- 1 hr) were also not significantly different between the two patient groups. Fusion kinetics of the myoblasts were similar for the two groups after 20-22 doublings (74 +/- 2% myoblast fusion) when the biopsy samples had been expanded to 1 to 2 billion muscle cells, a number acceptable for human gene therapy use. The myoblasts from the two groups could be equally transduced ex vivo with replication-deficient retroviral expression vectors to secrete 0.5 to 2 microg of a foreign protein (recombinant human growth hormone, rhGH)/10(6) cells/day, and tissue engineered into human BAMs containing parallel arrays of differentiated, postmitotic myofibers. This work suggests that autologous human skeletal myoblasts from a potential patient population can be isolated, genetically modified to secrete foreign proteins, and tissue engineered into implantable living protein secretory devices for therapeutic use.

Regulatory T cells in Graves’ disease

Context  Graves’ disease (GD) involves auto‐immunity against thyroid cell antigens, but the reasons for induction of auto‐immunity are uncertain. We wished to determine whether there was a deficiency of regulatory T cells in patients with active GD.

Two-week low iodine diet is necessary for adequate outpatient preparation for radioiodine rhTSH scanning in patients taking levothyroxine.

We evaluated a self-managed, outpatient, low iodine diet (LID) (<50 microg/day) designed to decrease total body iodine (TBI) in preparation for radioiodine (131I) scans. However, levothyroxine (LT4) ingestion is a significant source of dietary iodine in recombinant human TSH (rhTSH)-stimulated studies. Measuring urine iodine to creatinine ratios (I/Cr), a reflection of TBI, we evaluated the LID for 7-day and 14-day periods to determine the efficacy of our LID to deplete TBI, with and without LT4. Patients following the LID for 14 days (n = 28) without LT4 attained the goal of an iodine deficient state (I/Cr <50 microg/g) in 78% of cases, establishing the diets efficacy in significantly reducing TBI. In patients taking LT4, 7 days of the LID was insufficient to attain this goal of true iodine deficiency. However, a 14 day LID while taking LT4 resulted in 21% of patients being iodine deficient. For diagnostic purposes, a 7 day LID period (n = 21) suboptimally but adequately (I/Cr <100 microg/g) prepared 41% of the patients, whereas 14 days on the diet (n = 24) adequately prepared 71% of the patients taking LT4. Our simple, self-managed, outpatient, LID effectively makes patients iodine deficient. Though less efficacious when taking LT4, this LID adequately reduces TBI for rhTSH-stimulated 131I uptake scans when followed for 14 days.

Performance of the Afirma Gene Expression Classifier in Hürthle Cell Thyroid Nodules Differs from Other Indeterminate Thyroid Nodules

BACKGROUND The recently introduced Afirma gene expression classifier (AGEC) provides binary results (benign or suspicious) to guide management of cytologically indeterminate thyroid nodules. The AGEC is intended to reduce unnecessary surgeries for benign nodules, and management algorithms favor surgery for suspicious results. Limited data are available on the performance of this test for Hürthle cell nodules (HCNs). This study hypothesized that a predominance of Hürthle cells leads to an increased rate of suspicious AGEC results with a potential for overtreatment, despite a relatively low risk of malignancy. METHODS The pathology databases from three tertiary care facilities were queried from 2010 to 2014 for fine-needle aspirates (FNAs) diagnosed as suspicious for Hürthle cell neoplasm (SHCN) or atypia of undetermined significance/follicular lesion of undetermined significance concerning for Hürthle cell neoplasm (AFHCN). Cytology diagnoses were rendered internally prior to AGEC testing. The patient demographics, FNA diagnosis, AGEC result, surgical procedure, and pathologic outcomes were recorded. RESULTS The cohort consisted of 134 patients with HCNs. Prior to AGEC availability, 62 patients underwent surgery: 81% (50/62) of patients had surgery, and 34% (17/50) of the resected index nodules were malignant. After introduction of the AGEC, 72 patients underwent AGEC testing: 65% (47/72) of patients had surgery, and 13% (6/46) of the resected nodules were malignant. Thirty-two percent (23/72) of patients had a benign AGEC result and did not undergo surgery, and 4% (3/72) had surgery despite a benign AGEC result with benign final pathology, whereas 63% (45/72) of patients had suspicious AGEC results, with 96% of these patients (43/45) undergoing surgery, and 14% (6/43) of these index nodules were malignant. CONCLUSIONS While 32% of tested patients declined surgery based on a benign AGEC, 86% of patients with suspicious AGEC findings had unnecessary surgery, reflecting a substantially lower rate of malignancy from what was previously reported for all indeterminate nodules. Given the approximate pretest malignancy risk of 25-35% for an FNA diagnosis of SHCN or AFHCN, a suspicious AGEC diagnosis does not increase the probability of malignancy in an HCN, and patients should be counseled accordingly.

Effective half-life of 131I in thyroid cancer patients.

The oral administration of radioactive 131I is a standard treatment for thyroid carcinoma. One consideration for this therapy is assuring that other people do not receive significant radiation exposure. In particular, federal and state regulatory authorities stipulate that no individual should receive more than 5 mSv (500 mrem) effective dose-equivalent from the released patient. Patients receiving more than 1.11 GBq (30 mCi) of 131I were traditionally confined as in-patients by regulation until their burdens of radioactivity fell below that level or until the external dose rates were less than 50 microSv (5 mrem) per hour at 1 m. Recent regulatory guidance recommends the use of biological elimination as well as physical decay in calculating the confinement time to keep the effective dose-equivalent to members of the public less than 5 mSv. Analysis of a database of more than 250 administrations of 131I for thyroid cancer shows a median effective half-life of at least 14 h, with substantial variation. Thus, discharge criteria for radiation safety purposes should be calculated on the basis of individual measurements. The release of these patients should not always be as prompt as the guidance indicates. The results also challenge some long-used assumptions regarding iodine excretion in this patient population.

Subclinical hypothyroidism, mood, and cognition in older adults: a review.

To perform a critical review of the literature on the mood and cognitive changes associated with subclinical hypothyroidism (SCH), with an emphasis on older adults. To evaluate these data against the Consensus Statement on the management of SCH from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society.

Adverse event reporting in patients treated with levothyroxine: results of the pharmacovigilance task force survey of the american thyroid association, american association of clinical endocrinologists, and the endocrine society.

OBJECTIVE To survey physicians to determine whether potency and consistency issues with levothyroxine sodium (LT4) have been resolved and to assess current experience regarding safety of substituting LT4 products. METHODS Members of the American Association of Clinical Endocrinologists, American Thyroid Association, and The Endocrine Society collaborated to create a survey instrument that would effectively sample the clinical experience of their society members and frequent prescribers of LT4. More than 18,000 e-mailed requests for information were generated, and the Web sites of each society provided links to the data collection form. The survey provided an opportunity to collect clinical observations of adverse events or product availability problems from physicians caring for patients with thyroid disease who required use of contemporary LT4 preparations. RESULTS After adjustment for known reasons for unstable results from thyroid function tests, 199 reports of adverse events associated with changes in thyrotropin values were further analyzed. One hundred seventy-seven reports (88.9%) were associated with a change in the source of LT4; no change was noted in 21 (10.6%). Details regarding the circumstances of the change were provided in 167 of the 177 reports (94.4%), The reporting physicians themselves or their office staff had changed the LT4 preparation in only 1 of the 167 cases (0.6%). The remainder of changes had been made by the patients pharmacy, either with the physicians knowledge (in 13 of 167 cases [7.8%]) or without his/her knowledge (in 153 of 167 cases [91.6%]). Fifty-four of 199 cases (27.1%) described serious adverse events; 52 of these (96.3%) were associated with a substitution of one LT4 preparation for another. CONCLUSIONS The clinical use of contemporary LT4 products continues to be associated with some adverse outcomes. A small number of reports were associated with continued use of the same LT4 products. The most frequently reported adverse outcomes were associated with the approved generic substitution of LT4 products, frequently without the prescribing physicians knowledge.

Muscle carnitine in hypo- and hyperthyroidism

Weakness is common in both hyper‐ and hypothyroidism, and skeletal muscle L‐carnitine may play a role in this regard, as suggested by studies indicating abnormal levels of carnitine in serum and urine of patients with thyroid dysfunction. Skeletal muscle samples were obtained for carnitine analysis from control subjects, and from hyperthyroid and hypothyroid patients before and after treatment. There was a significant reduction in carnitine, especially the esterified portion, in hyperthyroid individuals, with a return to normal as euthyroid status was regained. In hypothyroid patients, there was a trend for carnitine to be lower than normal and for improvement once euthyroid status was attained. Our data indicate that muscle carnitine levels are affected by both hypo‐ and hyperthyroidism. A decrease in muscle carnitine in both conditions may contribute to thyroid myopathy. Muscle Nerve, 2005