Approach to adult patients with primary hypothyroidism in some special situations: a position statement from the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM).

Primary hypothyroidism is a common disorder in clinical practice. The management of most cases of hypothyroidism is usually straightforward, but the best approach in some special situations may raise questions among physicians. This position statement was prepared by experts from the Brazilian Society of Endocrinology and Metabolism to guide the management of three special situations, namely, hypothyroidism in the elderly, subclinical hypothyroidism in patients with heart disease, and difficult-to-control hypothyroidism. The authors prepared the present statement after conducting a search on the databases MEDLINE/PubMed, LILACS, and SciELO and selecting articles with the best evidence quality addressing the selected situations. The statement presents information about the current approach to patients in these special situations.

Thyroid function before and after Roux-en-Y gastric bypass: an observational study.

BACKGROUND: Population studies have shown a positive association between thyroid-stimulating hormone (TSH) and body mass index. Recent studies have shown a significant increase in the prevalence of subclinical hypothyroidism (SCH) in obesity. Weight reduction after Roux-en-Y gastric bypass (RYGB) seems to significantly decrease TSH levels. OBJECTIVES: The purpose of this study was to evaluate the prevalence of SCH in obese patients (class II and III) and to observe the behavior of thyroid hormones (TSH, hormone triiodothyronine, thyroxine, free thyroxine) with significant weight loss after RYGB. SETTING: Hospital Nossa Senhora das Graças, Curitiba, Paraná, Brazil. METHODS: We retrospectively reviewed the medical records of 215 obese patients who underwent RYGB between 2005 and 2012 with a follow-up of at least 2 years. The study was observational and descriptive. The selected times for clinical and laboratory evaluations were preoperative, 3, 6, 12, and 24 months after the procedure. Association, correlation, and variance analyses were performed. RESULTS: The prevalence of SCH preoperatively was 9.3%. SCH was corrected in 89.5% of patients 12 months after RYGB. We did not find an association between TSH and BMI (r = .002, P = .971). There was a positive impact of bariatric surgery on all metabolic variables. We showed that serum TSH level had no positive correlation with the presence or absence of metabolic syndrome. CONCLUSIONS: Weight loss after bariatric surgery leads to normalization of TSH levels in most patients and none developed overt hypothyroidism. Obese patients with SCH should not be treated with thyroid hormone replacement. Serial monitoring of thyroid function after obesity therapy seems to be a reasonable approach.

ACR TI-RADS and ATA US scores are helpful for the management of thyroid nodules with indeterminate cytology.

BACKGROUND: Cytologically indeterminate thyroid nodules currently present a challenge for clinical decision-making. The main aim of our study was to determine whether the classifications, American College of Radiology (ACR) TI-RADS and 2015 American Thyroid Association (ATA) guidelines, in association with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), could be used to stratify the malignancy risk of indeterminate thyroid nodules and guide their clinical management. METHODS: The institutional review board approved this retrospective study of a cohort of 140 thyroid nodules in 139 patients who were referred to ultrasound-guided fine-needle aspiration cytology (FNAC) from January 2012 to June 2016 with indeterminate cytological results (44 Bethesda III, 52 Bethesda IV and 44 Bethesda V) and in whom pre-FNAC thyroid US images and histological results after surgery were available. Each included nodule was classified by one radiologist blinded to the cytological and histological diagnoses according to the ACR TIRADS scores and the US patterns as recommended in the 2015 ATA guidelines. The risk of malignancy was estimated for Bethesda, TI-RADS scores, ATA US patterns and their combination. RESULTS: Of the 140 indeterminate thyroid nodules examined, 74 (52.9%) were histologically benign. A different rate of malignancy (p < 0.001) among Bethesda III, IV and V was observed. The rate of malignancy increased according to the US suspicion categories (p < 0.001) in both US classifications (TI-RADS and ATA). Thyroid nodules classified as Bethesda III and the lowest risk US categories (very low, low and intermediate suspicion by ATA and 2, 3 and 4a by TI-RADS) displayed a sensitivity of 95.3% for both classifications and a negative predictive value of 94.3 and 94.1%, respectively. The highest risk US categories (high suspicion by ATA and 4b,4c and 5 by TI-RADS) were significantly associated with cancer (odds ratios [ORs] 14.7 and 9.8, respectively). CONCLUSIONS: Ultrasound classifications, ACR TI-RADS and ATA guidelines, may help guide the management of indeterminate thyroid nodules, suggesting a conservative approach to nodules with low-risk US suspicion and Bethesda III, while molecular testing and surgery should be considered for nodules with high-risk US suspicion and Bethesda IV or V.

MANAGEMENT OF ENDOCRINE DISEASE: Pitfalls on the replacement therapy for primary and central hypothyroidism in adults.

Hypothyroidism is one of the most common hormone deficiencies in adults. Most of the cases, particularly those of overt hypothyroidism, are easily diagnosed and managed, with excellent outcomes if treated adequately. However, minor alterations of thyroid function determine nonspecific manifestations. Primary hypothyroidism due to chronic autoimmune thyroiditis is largely the most common cause of thyroid hormone deficiency. Central hypothyroidism is a rare and heterogeneous disorder characterized by decreased thyroid hormone secretion by an otherwise normal thyroid gland, due to lack of TSH. The standard treatment of primary and central hypothyroidism is hormone replacement therapy with levothyroxine sodium (LT4). Treatment guidelines of hypothyroidism recommend monotherapy with LT4 due to its efficacy, long-term experience, favorable side effect profile, ease of administration, good intestinal absorption, long serum half-life and low cost. Despite being easily treatable with a daily dose of LT4, many patients remain hypothyroid due to malabsorption syndromes, autoimmune gastritis, pancreatic and liver disorders, drug interactions, polymorphisms in DIO2 (iodothyronine deiodinase 2), high fiber diet, and more frequently, non-compliance to LT4 therapy. Compliance to levothyroxine treatment in hypothyroidism is compromised by daily and fasting schedule. Many adult patients remain hypothyroid due to all the above mentioned and many attempts to improve levothyroxine therapy compliance and absorption have been made.

TSH levels are associated with increased risk of thyroid carcinoma in patients with nodular disease.

INTRODUCTION: Several studies have shown an increased risk of thyroid malignancies in patients with elevated TSH levels, even if these levels fell within the normal range. The aim of this study was to evaluate the relationship between TSH and risk of malignancy in patients with thyroid nodules. MATERIAL AND METHODS: We included 622 patients with thyroid nodules evaluated by fine needle aspiration and/or thyroidectomy and diagnosed by cytology or histology. Clinical and laboratory data, such as gender, weight, ultrasound findings, serum TSH, and free T4, were obtained from medical records or collected during each patient's first visit to our centre, prior to any intervention. RESULTS: Thyroid cancer was more prevalent in males (p = 0.012) and in patients with a solitary nodule (p < 0.01). Malignant tumours were predominantly solid, whereas benign tumours were solid or mixed (p = 0.053). The carcinoma risk in patients with thyroid nodules increased with increasing serum TSH concentration, with a significant elevation in patients with serum TSH levels above 1.64 mU/L (p < 0.001). This relationship persisted even when the subgroup of patients undergoing thyroidectomy was analysed separately. Patients with follicular lesions presented with significantly higher TSH levels compared to patients with benign cytology (p < 0.001). We also found correlation between elevated TSH and tumour size (p = 0.005). CONCLUSIONS: Our results suggest that in patients with nodular thyroid disease the carcinoma risk rose in parallel with serum TSH concentration, with significant increases evident in patients with serum TSH greater than 1.64 mU/L.

Serum thyrotropin levels following levothyroxine administration at breakfast.

BACKGROUND: Hypothyroidism is treated with oral levothyroxine. Some patients fail to attain adequate control because of poor compliance. Delaying breakfast to take levothyroxine on an empty stomach can decrease adherence to hypothyroidism treatment. The objective of this study was to evaluate whether administering levothyroxine with breakfast can maintain thyrotropin (TSH) levels in the therapeutic range, without major clinical changes. METHODS: A prospective, randomized, open-label, crossover study was conducted to compare usual levothyroxine administration while in a fasting state with administration during breakfast. From September 2008 to April 2009, 45 patients with primary hypothyroidism who received levothyroxine were recruited. The patients completed 180 days of the protocol and were randomized to 90 days of each levothyroxine administration regimen (while fasting or with breakfast). Clinical and biochemical analyses were performed at baseline and on days 45, 90, 135, and 180. The primary outcome was TSH level. RESULTS: Forty-two patients completed the protocol. The TSH level was higher for levothyroxine administration with breakfast than while fasting (2.89 vs. 1.9 mIU/L, p=0.028). Uncontrolled hypothyroidism (TSH ≥3.5 mIU/L) occurred regardless of the type of levothyroxine administration (p=0.26). No risk factors were identified for TSH elevation. CONCLUSIONS: Levothyroxine administration with breakfast could be an alternative regimen for patients who have adherence difficulties due to the need for delaying intake, and is more likely to cause variability in the TSH level, meaning the patient should be followed more closely. For patients in whom a specific serum TSH goal is important, taking levothyroxine while fasting is recommended.

Evidence for higher success rates and successful treatment earlier in Graves' disease with higher radioactive iodine doses.

BACKGROUND: Graves' disease is commonly treated with curative intent using radioactive iodine (RAI). While higher doses have been shown to increase success rates, more evidence is needed. Further, very few studies assess the time to treatment success without the need for antithyroid drugs after a single dose of RAI within the first year post-dose, despite earlier success being an important treatment objective. We aimed to evaluate the outcome of different RAI doses in terms of success rates and time to achieve this success (eu- or hypothyroidism). We hypothesized that higher doses would not only increase success rates, but bring about successful treatment earlier. METHODS: We retrospectively analyzed the medical records of all patients diagnosed with Graves' disease between 1994 and 2009. Details of RAI treatment and outcomes thereof were documented. In our analysis, we divided the patients who received RAI treatment into three groups according to the dose received: I (≤15 mCi); II (16-20 mCi); III (≥21 mCi). RESULTS: There were 498 patients diagnosed with Graves' disease. However, 105 were either lost to follow-up or still undergoing treatment. Of the remaining 393, there were 258 who received RAI treatment. The average initial dose was 21.42±6.5 mCi and overall success rate was 86%. Success rates were 74%, 85%, and 89% (p<0.05), while average time to successful treatment was 8.1, 4.6, and 2.9 months, respectively (p<0.001), for groups I, II, and III. When 20 mCi was given empirically, 85% obtained successful treatment; most of these within 3 months (mean 3.9; mode and median 3 months). CONCLUSIONS: This study provides additional evidence that success post-treatment correlates with administered dose and shows clearly, for the first time, that successful treatment is achieved earlier with higher doses. This knowledge is relevant to all clinicians managing Graves' disease as it can be taken into consideration when discussing treatment plans with patients.

Changes associated with percutaneous ethanol injection in the treatment of thyroid nodules.

Percutaneous ethanol injection (PEI) is an alternative therapy for thyroid nodules (TN). However, some concern is raised on its carcinogenic effects. To evaluate the cytological and clinical changes caused by PEI in patients with benign TN. Thirty-nine patients with TN (23.1% hyperfunctioning) were submitted to a median of three PEI sessions. After a median of 17 months, patients were reassessed. A new ultrasound-guided fine needle biopsy (US-FNB) was performed, and the smears were analyzed after May-Grünwald-Giemsa staining. The diagnostic findings and the cellular characteristics were compared before and after treatment. There was an increase in the proportion of nondiagnostic/unsatisfactory results (from 2.5% to 18.9%). No malignant cases were observed. The proportion of moderate/intense macrophage infiltration decreased from 60% to 15%. Before treatment, 23.1% patients had hyperthyroidism, which was completely or partially resolved in 66.7%. By ultrasound, the percentage of homogeneous nodules decreased from 64.0% to 38.4% (p=0.0235), and the mean nodule volume decreased from 13.4 ± 12.2 to 5.3 ± 5.1 cm(3). We demonstrate that PEI increases the proportion of nondiagnostic/unsatisfactory results from US-FNB. Therefore, cytological findings after PEI must be evaluated with caution. Our results also suggest that PEI is an efficacious and safe therapeutic option, with no carcinogenic effects observed on cytological evaluations. Safety and efficacy must be evaluated in larger studies with longer follow-up periods.

Adequacy and diagnostic accuracy of aspiration vs. capillary fine needle thyroid biopsies.

Thyroid nodules can be biopsied by fine needle aspiration (FNA) or fine needle capillary (FNC) biopsies. However, there is controversy on whether one technique is superior to another. In a randomized cytopathologist-blinded cross-sectional study, 260 patients (238 females, age 43.2 +/- 12.6) with nodular (82.7%) and diffuse goiter (17.3%) underwent 520 FNAs and 520 FNCs (not guided by ultrasound). Smears were scored for sample adequacy, and diagnosed as malignant, benign, suspicious, or nondiagnostic. Diagnostic accuracy was calculated based on the histological findings of 58 patients submitted to surgery. Intra-technique diagnostic accuracy and sample adequacy was seen in all samples. FNA and FNC provided similar cytological diagnosis, respectively (benign: 75.8% vs. 74.2%, p = 0.600; malignant: 3.8% vs. 3.8%, p = 0.871; suspicious: 10.4% vs. 10.8%, p = 0.913; and nondiagnostic: 10.0% vs. 11.2%, p = 0.598). Adequacy scores were similar by FNA (7.94 +/- 2.84) and FNC (7.96 +/- 2.81, p = 0.909). The same proportion of adequate or superior samples was seen in both techniques (91.6%). Sensitivity was equal to 85.7% for FNA and 100% for FNC. Similarly, specificity was 100% for both techniques. FNA and FNC provide the similar sample adequacy and diagnostic accuracy. The choice of technique should be based on the operator's personal preferences and experience.

Effects of selective serotonin reuptake inhibitors on thyroid function in depressed patients with primary hypothyroidism or normal thyroid function.

BACKGROUND: Several studies with ambiguous results have examined the effects of selective serotonin reuptake inhibitors (SSRIs) on thyroid function. This study aimed to establish the effects of fluoxetine and sertraline treatments on thyroid function and thyroid autoimmunity in patients with major depression and primary hypothyroidism and in patients with major depression and normal thyroid function. METHODS: This was a prospective, controlled, intervention study involving 67 subjects: 28 patients with major depression and hypothyroidism on adequate levothyroxine therapy randomized for treatment with fluoxetine (n = 13) or sertraline (n = 15); 29 patients with major depression and normal thyroid function treated with fluoxetine (n = 15) or sertraline (n = 14) and 10 control patients with hypothyroidism on adequate levothyroxine therapy without depression. Main outcome measures included thyrotropin, thyroxine (T(4)), free thyroxine, triiodothyronine (T(3)), anti-thyroid peroxidase antibodies, and Hamilton depression (HAM-D) rating scale. RESULTS: Patients with normal thyroid function who were treated with fluoxetine demonstrated a significant reduction of T(3) after 15 and 30 days of treatment (p = 0.034 and p = 0.011) and a significant reduction of T(4) throughout the intervention period (p = 0.04 after 15 days; p = 0.015 after 30 days; and p = 0.029 after 90 days). However, all thyroid parameters remained within the euthyroid range. No changes were observed among hypothyroid patients on levothyroxine replacement therapy who were treated with either SSRI. The degree of improvement in depression symptoms (HAM-D rating scale) after 90 days of SSRI treatment was correlated with T(3) levels reduction among patients with normal thyroid function randomized for sertraline and among patients with hypothyroidism randomized for fluoxetine. T(3) levels remained within the euthyroid range during the study period. CONCLUSIONS: Neither fluoxetine nor sertraline was associated with clinically significant changes in thyroid function or thyroid autoimmunity in either primary hypothyroid or normal thyroid function patients with depression. However, results suggest that patients with normal thyroid function who were treated with fluoxetine are more susceptible to minor changes within the serotoninergic system than patients with hypothyroidism on the same SSRI therapy. To the best of our knowledge, this is the first study to demonstrate the safety of administering SSRIs in hypothyroid patients.

[The relation between thyroid function and depression: a review]. / A relação entre a função tireoidiana e a depressão: uma revisão.

OBJECTIVE: The role of the thyroid gland in primary depressive disorder is unclear. Although there is evidence that patients with subtle underlying defects in thyroid function may be more prone to developing depressive disease, the specific abnormality in thyroid function associated with depressive disorders remains poorly understood. In this review, we outline the major findings concerning depression and thyroid function, with particular attention on the relationship between thyroid function and cerebral monoamines. METHODS: Literature searches were performed by Medline, with secondary-source follow-up. RESULTS: The documented hypothalamus-pituitary-thyroid (HPT) axis abnormalities in some depressed patients are: elevated T4 concentrations, abnormal TSH responses to TRH; presence of antithyroid antibodies and elevated CSF - TRH concentrations. The relation of these abnormalities of HPT function, the main monoamines and the diagnostic subtypes of patients with depression is complex and does not directly support a linear relationship. CONCLUSIONS: After many years of research, the precise relationship between the HPT axis and depressive disorders remains obscure, and the mechanism underlying the thyroid abnormalities in depressive patients remains indeterminate. Thus, considerable further investigation will be necessary to understand the role of the HPT axis in the pathogenesis and treatment of depressive disorders.