Baseline serum TSH levels predict the absence of thyroid dysfunction in cancer patients treated with immunotherapy.

PURPOSE: Immunotherapy against immune checkpoints has significantly improved survival both in metastatic and adjuvant setting in several types of cancers. Thyroid dysfunction is the most common endocrine adverse event reported. Patients who are at risk of developing thyroid dysfunction remain to be defined. We aimed to identify predictive factors for the development of thyroid dysfunction during immunotherapy. METHODS: This is a retrospective study including a total of 68 patients who were treated with immune checkpoint inhibitors (ICIs) for metastatic or unresectable advanced cancers. The majority of patients were treated with anti-PD1 drugs in monotherapy or in combination with anti-CTLA4 inhibitors. Thyroid function and anti-thyroid antibodies, before starting immunotherapy and during treatment, were evaluated. Thyroid ultrasound was also performed in a subgroup of patients at the time of enrolment in the study. RESULTS: Eleven out of 68 patients (16.1%) developed immune-related overt thyroid dysfunction. By ROC curve analysis, we found that a serum TSH cut-off of 1.72 mUI/l, at baseline, had a good diagnostic accuracy in identifying patients without overt thyroid dysfunction (NPV = 100%, p = 0.0029). At multivariate analysis, both TSH and positive anti-thyroid antibodies (ATAbs) levels, before ICIs treatment, were independently associated with the development of overt thyroid dysfunction during immunotherapy (p = 0.0001 and p = 0.009, respectively). CONCLUSIONS: Pre-treatment serum TSH and ATAbs levels may help to identify patients at high risk for primary thyroid dysfunction. Our study suggests guidance for an appropriate timely screening and for a tailored management of thyroid dysfunctions in patients treated with ICIs.

Optimization and validation of patient-based real-time quality control procedure using moving average and average of normals with multi-rules for TT3, TT4, FT3, FT3, and TSH on three analyzers.

BACKGROUND: We have designed a patient-based real-time quality control (PBRTQC) procedure to detect analytical shifts and review analytical trends of measurement procedures. METHODS: All the nine months' patient results of total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin (TSH) measured by three identical analyzers were divided into three groups according to the source of inpatient patients, outpatient patients, and healthy people. The data in each group were truncated by optimized Box-Plot method and normalized by Box-Cox method if necessary. The z-score charts of internal quality control (IQC) samples' results and PBRTQC data were drawn by IQC levels and groups, respectively. The analytical shifts and analytical trends were detected by multi-rules of 2-2S rules and moving average rules. The performances of PBRTQC were compared with the BIQC in which IQC samples were measurand only once per day at the beginning of the analytical batch. Twelve quality control cases were listed to validate the performances. RESULTS: All the five analytes presented normal distributions when the parameter n of Box-Plot method was 1.2. The percentages of excluded data ranged from 2.9% to 11.6%. 31 and 14 rejections triggered in PBRTQC and BIQC, respectively. 96.8% of the shift rejections in PBRTQC were trend-related shifts and calibration-related shifts, while the proportion was 85.7% in BIQC but 78.6% of the shift rejections in TSH. 25.7% and 8.6% of 105 calibration events which caused analytical shifts were detected by PBRTQC and BIQC, respectively. However, the performance of PBRTQC was not well in TSH because of its large coefficient of variation. CONCLUSIONS: The optimized PBRTQC is high efficiency than BIQC in detecting analytical shifts, trends, and calibration events. The PBRTQC can be used as a low-cost supplementary procedure to IQC every day, especially at the end of the analytical batch on that day when the within-individual biological variation of analyte is not larger than its coefficient of variation in IQC. Further optimization and validation of PBRTQC are still needed.

Levothyroxine Therapy in Thyrodectomized Patients.

Administration of the optimal dose of levothyroxine (LT4) is crucial to restore euthyroidism after total thyroidectomy. An insufficient or excessive dosage may result in hypothyroidism or thyrotoxicosis, either one associated with a number of symptoms/complications. Most literature regarding the LT4 dosage deals with the treatment of primary hypothyroidism, whereas a limited number of studies handle the issue of thyroxin replacement after total thyroidectomy. A literature review was performed focusing on all papers dealing with this topic within the last 15 years. Papers that reported a scheme to calculate the proper LT4 dose were collected and compared to set up a review exploring limits and drawbacks of LT4 replacement therapy in the wide population of patients who had undergone thyroidectomy. Most of the methods for monitoring and adjusting thyroid hormone replacement after thyroidectomy for benign disease use LT4 at an empirical dose of approximately 1.6 µg/kg, with subsequent changes according to thyroid function test results and assessments of the patient's symptoms. Approximately 75% of patients require a dose adjustment, suggesting that factors other than body weight play a role in the determination of the proper LT4 dose. Hence, several schemes are reported in the literature for the proper initial dose of LT4. An inadequate level of thyroid hormone levels in these patients can be due to several factors. The most common ones that lead to the necessity of LT4 dose adjustments include lack of compliance, changes in LT4 formulation, dosage errors, increased serum levels of T4-binding globulin, body mass changes, and dietary habits. Moreover, concomitant ingestion of calcium supplements, ferrous sulfate, proton-pump inhibitors, bile acid sequestrants, and sucralfate might influence LT4 absorption and/or metabolism. Furthermore, some gastrointestinal conditions and their treatments can contribute to suboptimal LT4 performance by altering gastric acidity and thereby reducing its bioavailability, particularly in the solid form. Beyond the classic tablet form, new formulations of LT4, such as a soft gel capsule and an oral solution, recently became available. The liquid formulation is supposed to overcome the food and beverages interference with absorption of LT4 tablets.

Erroneous thyroid diagnosis due to over-the-counter biotin.

OBJECTIVES: Biotin is a component of the vitamin B complex used in standard immunoassays to detect serum levels of various hormones and non-hormones, including thyrotropin (TSH) and thyroxine. These assays involve a strong bond between streptavidin and biotin, which serves as an anchor for measured analytes. Large doses of exogenous biotin for the treatment of certain medical conditions have resulted in assay interference, causing TSH to be spuriously lowered. Smaller doses of biotin found in dietary supplements also have caused assay interference. METHODS: We describe four cases in which over-the-counter (OTC) biotin caused erroneous thyroid diagnosis and clinical confusion in patients with preexisting thyroid disease. Serum TSH and thyroxine were measured by the Vitros 5600 assay. CONCLUSIONS: Although the biotin-streptavidin interaction is sensitive for detecting serum levels of TSH, it is subject to interference by exogenous biotin at levels found in OTC products. The widespread use of OTC biotin for cosmetic purposes can adversely affect the diagnosis of the entire spectrum of functional thyroid disorders. Physicians must carefully and routinely question for the use of biotin before thyroid function testing.

Role of Strain Elastography and Shear-Wave Elastography in a Multiparametric Clinical Approach to Indeterminate Cytology Thyroid Nodules.

BACKGROUND In thyroid nodules with indeterminate cytology, further clinical assessment aimed at ruling out malignancy is often mandatory. Ancillary imaging techniques and genetic mutation analysis can improve the risk stratification of such lesions, thereby facilitating the clinician's decision to undertaken surgery or simple follow-up. The aim of this study was to evaluate the diagnostic performance of shear-wave elastography (SW), strain elastography (ELX 2/1), conventional ultrasound (US), contrast-enhanced ultrasound (CEUS), and BRAF V600E mutation analysis in the aforementioned lesions. MATERIAL AND METHODS We enrolled 81 patients, each with 1 indeterminate-cytology thyroid nodule. Thyroid function, thyroperoxidase antibodies and calcitonin were known in each case. SW, ELX 2/1, US, CEUS, and BRAF mutation analysis were subsequently performed, followed by a second FNAB. If the lesion was not downgraded to benign, surgery was recommended and histological reports collected. RESULTS There were 28 nodules (34%) that proved benign on the second FNAB; 38 nodules (47%) underwent surgery (17 benign, 21 malignant), and 15 nodules (19%) refused surgery. The only techniques related to histological outcome were US (AUC=0,766), ELX 2/1 (AUC=0.701), and BRAF analysis (AUC=0.762). ELX 2/1 and SW reports were not correlated with each other (P=0.45). A scoring system taking into account all the variables considered performed better than the single variables alone (AUC=0.831). CONCLUSIONS In indeterminate-cytology thyroid lesions, repeating FNAB can avoid unnecessary surgery. ELX 2/1 seems to perform better than SW in distinguishing malignancy; these techniques could, however, be complementary in describing such lesions. A multiparametric approach appears the most accurate in predicting nodule histology.

Hyperthyrotropinemia in newly diagnosed cystic fibrosis patients with pancreatic insufficiency reversed by enzyme therapy.

Patients with cystic fibrosis (CF) commonly present with an elevated TSH concentration, suggesting subclinical hypothyroidism. Its relation to concomitant pancreatic insufficiency and its natural course upon initiation of enzyme replacement have not been adequately studied. Herein, we investigated the thyroid function in newly diagnosed infants with CF and monitored the course of thyroid function response to pancreatic enzyme substitution treatment. Fourteen, newly diagnosed infants with CF and pancreatic insufficiency, were followed every 6-8 weeks for 6 months ensuing onset of pancreatic enzyme substitution therapy. All infants had normal TSH values on neonatal screening. Ten out of 14 (71%) had hyperthyrotropinemia and normal freeT4 values at presentation. No patient received thyroxine. Upon follow-up, after 6 months, TSH values normalized in 90% of infants with CF and hyperthyrotropinemia. Serum selenium levels were negatively correlated with TSH levels. CONCLUSION: Mild TSH elevation is a frequent finding in newly diagnosed cystic fibrosis patients with pancreatic insufficiency during infancy. TSH elevation resolves in most cases after initiation of enzyme substitution and improvement of nutritional status without any substitutive therapy with thyroxine. What is Known: • Newly diagnosed infants with cystic fibrosis often present with a state of hyperthyrotropinemia suggesting subclinical hypothyroidism. What is New: • Pancreatic enzyme substitution and improvement of nutrition restores normal TSH levels without the need of thyroxine therapy.

Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report.

BACKGROUND: Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroidism. The danger of health drinks should always be noted. CASE PRESENTATION: A 72-year-old Japanese woman was previously diagnosed with chronic lymphocytic thyroiditis caused by a goiter and had an elevated thyroid-stimulating hormone level (6.56 µIU/ml), a high anti-thyroid peroxidase antibody level (>600 IU/ml), and a high antithyroglobulin level (> 4000 IU/ml) but normal levels of free triiodothyronine (3.08 pg/ml) and thyroxine (1.18 ng/ml). She presented to our hospital with sudden-onset general malaise, edema, and hoarseness with an elevated thyroid-stimulating hormone (373.3 µIU/ml) level and very low triiodothyronine (< 0.26 pg/ml) and thyroxine (0.10 ng/ml) levels. It was determined that for 6 months she had been consuming a processed, solved health drink ("barley young leaf") in amounts of 9 g/day, which included soybean and kale powder extract. Hypothyroidism might be affected by ingredients of health drinks. She discontinued consumption of the health drink immediately and began taking 12.5 µg of levothyroxine. The amount of levothyroxine was gradually increased every 3 days up to 100 µg. At day 61, her thyroid-stimulating hormone level had decreased (6.12 µIU/ml), her free triiodothyronine (2.69 pg/ml) and thyroxine (1.56 ng/ml) levels had increased, and her general condition was improved. Among risky foods lowering thyroid function, some experimental studies have revealed that isoflavones reduce thyroid function. Therefore, we measured the presence of isoflavones in the patient's frozen serum with thin-layer chromatography. After she discontinued consumption of the health drink, two components quickly disappeared, and the other three components gradually decreased. On the basis of developing solvent composition and a positive ferric chloride reaction in thin-layer chromatography experiment, the five ingredients that disappeared or decreased were highly suspected to be soy isoflavones. CONCLUSIONS: This case emphasizes that consuming health drinks that include soy isoflavone powder extracts can lead to severe hypothyroidism.

Thyroid function in end stage renal disease and effects of frequent hemodialysis.

INTRODUCTION: End-stage renal disease (ESRD) is associated with perturbations in thyroid hormone concentrations and an increased prevalence of hypothyroidism. Few studies have examined the effects of hemodialysis dose or frequency on endogenous thyroid function. METHODS: Within the Frequent Hemodialysis Network (FHN) trials, we examined the prevalence of hypothyroidism in patients with ESRD. Among those with endogenous thyroid function (without overt hyper/hypothyroidism or thyroid hormone supplementation), we examined the association of thyroid hormone concentration with multiple parameters of self-reported health status, and physical and cognitive performance, and the effects of hemodialysis frequency on serum thyroid stimulating hormone (TSH), free thyroxine (FT4), and free tri-iodothyronine (FT3) levels. Conventional thrice-weekly hemodialysis was compared to in-center (6 d/wk) hemodialysis (Daily Trial) and Nocturnal (6 nights/wk) home hemodialysis (Nocturnal Trial) over 12 months. FINDINGS: Among 226 FHN Trial participants, the prevalence of hypothyroidism was 11% based on thyroid hormone treatment and/or serum TSH ≥8 mIU/mL. Among the remaining 195 participants (147 Daily, 48 Nocturnal) with endogenous thyroid function, TSH concentrations were modestly (directly) correlated with age (r = 0.16, P = 0.03) but not dialysis vintage. Circulating thyroid hormone levels were not associated with parameters of health status or physical and cognitive performance. Furthermore, frequent in-center and nocturnal hemodialysis did not significantly change (baseline to month 12) TSH, FT4, or FT3 concentrations in patients with endogenous thyroid function. DISCUSSION: Among patients receiving hemodialysis without overt hyper/hypothyroidism or thyroid hormone treatment, thyroid indices were not associated with multiple measures of health status and were not significantly altered with increased dialysis frequency.

Progress in standardizing and harmonizing thyroid function tests.

Iodine is an essential component of thyroid hormone. Because thyroid hormone synthesis is affected by iodine deficiency on the one hand and by excess iodine intake on the other, thyroid function biomarkers may be useful for assessing iodine status and studying the effects of iodine supplementation. However, reference intervals for some of the most useful thyroid function biomarkers, including serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and thyroglobulin, vary widely due to variability in the commercially available immunoassays for these tests. Recognizing the need for standardization of thyroid function testing, the International Federation of Clinical Chemistry and Laboratory Medicine established a working group, later restructured as the Committee for Standardization of Thyroid Function Tests, to examine its feasibility. The committee has established a conventional reference measurement procedure for FT4 and an approach to harmonization of results for TSH. Panels of single-donation human blood specimens that span the measuring interval of the immunoassays were used to assess the performance of commercially available immunoassays and form the basis for their recalibration. Recalibration of the manufacturers' methods for both FT4 and TSH has shown that the variability among immunoassays can be successfully eliminated for euthyroid individuals as well as for patients with thyroid disease. The committee is not investigating the standardization of thyroglobulin at the present time.

A Case of Capgras Syndrome Related to Hypothyroidism.

Hypothyroidism is commonly associated with a variety of psychiatric conditions, most commonly depression and cognitive impairment, but up to 5% to 15% of symptomatically hypothyroid patients may develop a nonaffective psychosis, classically referred to as "myxedema madness." We report the case of a woman who developed Capgras syndrome in the context of hypothyroidism, and whose psychosis rapidly resolved with levothyroxine supplementation. To date, very few cases of Capgras syndrome related to hypothyroidism have been reported. The pathophysiology of this condition remains unclear but it may be related to global cerebral hypometabolism or possibly to increased cerebral dopamine. Given the robust response of "myxedema madness" to thyroid replacement, psychiatrists should remain vigilant for covert hypothyroidism in patients with psychosis and atypical histories or presentations.

The epidemiology of thyroid disease.

INTRODUCTION: Thyroid disorders are prevalent and their manifestations are determined by the dietary iodine availability. SOURCES OF DATA: Data from screening large population samples from USA and Europe. AREAS OF AGREEMENT: The most common cause of thyroid disorders worldwide is iodine deficiency, leading to goitre formation and hypothyroidism. In iodine-replete areas, most persons with thyroid disorders have autoimmune disease. AREAS OF CONTROVERSY: Definition of thyroid disorders, selection criteria used, influence of age and sex, environmental factors and the different techniques used for assessment of thyroid function. GROWING POINTS: Increasing incidence of well-differentiated thyroid cancer. Environmental iodine influences the epidemiology of non-malignant thyroid disease. AREAS TIMELY FOR DEVELOPING RESEARCH: Iodine supplementation of populations with mild-to-moderate iodine deficiency. An evidence-based strategy for the risk stratification, treatment and follow-up of benign nodular thyroid disease. Is there any benefit in screening adults for thyroid dysfunction?

IFCC international conventional reference procedure for the measurement of free thyroxine in serum: International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group for Standardization of Thyroid Function Tests (WG-STFT)(1).

The IFCC Working Group for Standardization of Thyroid Function Tests proposes a candidate international conventional reference procedure (RMP) for measurement of the amount-of-substance concentration of free thyroxine in plasma/serum at physiological pH 7.40 and temperature (37.0°C). The unit for reporting measurement results is, by convention, pmol/L. The RMP is based on equilibrium dialysis isotope dilution-liquid chromatography/tandem mass spectrometry (ED-ID-LC/tandem MS). The rationale for proposing a conventional RMP is that, because of the physical separation step, it is unknown whether the measurement truly reflects the concentration of free thyroxine (FT4) in serum. Therefore, the ED part of the RMP has to strictly adhere to the following conditions: use of a dialysis buffer with a biochemical composition resembling the ionic environment of serum/plasma as closely as possible; buffering of the sample to a pH of 7.40 (at 37.0°C) before dialysis, however, without additional dilution; dialysis in a device with a dialysand/dialysate compartment of identical volume and separated by a membrane of regenerated cellulose and adequate cut-off; thermostatic control of the temperature during dialysis at 37.0°C±0.50°C. The convention does not apply to the ID-LC/tandem MS part, provided it is eligible to be nominated for review by the Joint Committee for Traceability in Laboratory Medicine. Here, we describe the ED procedure, inclusive its validation and transferability, in greater detail. We recommend a protocol for successful calibration, measurement and monitoring of the accuracy/trueness and precision of the candidate conventional RMP. For details on our ID-LC/tandem MS procedures, we refer to the Supplement.

Hypothyroxinemia and pregnancy.

OBJECTIVE: To evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy. METHODS: We review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T4) assays, impact of iodine deficiency on free T4 levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy. RESULTS: Hypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T4 on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T4 assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T4 during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist. CONCLUSIONS: Data published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy.

[Thyroid disorders and pregnancy]. / Schilddrüsenerkrankungen und Schwangerschaft.

Disorders of the thyroid in women are common during the reproductive years. Incorrect or delayed treatment during pregnancy can adversely affect the health of mother and child. Knowledge of the physiological changes during this time is essential. Thyroid disorders, in particular hypothyroidism, may compromise fertility. Autoimmune thyroiditis is associated with a higher risk of fetal loss. In women on thyroid hormone replacement therapy, the thyroxine dose has to be adjusted to meet the enhanced requirement during pregnancy. Thyroid hormone is vital to fetal brain development. During pregnancy and lactation, iodine supplementation is also recommended due to alterations in iodine metabolism. Hyperthyroidism during pregnancy can adversely affect pregnancy outcome and has to be treated accordingly. Propylthiouracil should be given using the least effective dose to keep free thyroxine levels at the upper limit of normal or slightly above. Hyperthyroidism in the fetus and the neonate can be induced by thyroid stimulating antibodies capable of passing the placenta.

Hipercalcemia como causa de lumbalgia, una entidad inusual / Hypercalcemia as a cause of low back pain, an unusual condition

Se presenta el caso de un paciente con síntomas de lumbalgia de características mecánicas. Inicialmente se trató con antiinflamatorios, sin mejoría. Se realizaron pruebas complementarias, que detectaron hipercalcemia secundaria a un adenoma de paratiroides. Tras la extirpación de la tumoración y normalización del calcio sérico, el paciente mejoró significativamente. El conocimiento y el diagnóstico diferencial de la lumbalgia son de interés en Atención Primaria, ya que supone un elevado número de consultas (AU)

A rare case of a male patient with low back pain symptoms with mechanical characteristics is presented. This was initially treated with anti-inflammatory treatment, with no improvement. Complementary tests shows hypercalcemia secondary to parathyroid adenoma. The patient significantly informed after extraction of the tumor and normalization of the serum calcium. Knowledge and differential diagnosis of low back pain is an important subject in Primary Care due to the elevated number of consultations (AU)

Best practice in primary care pathology: review 11.

This eleventh best practice review examines two series of common primary care questions in laboratory medicine: (i) thyroid testing, and (ii) hypercalcaemia and hypocalcaemia. The review is presented in the same question-answer format as in the previous reviews. These questions and answers deal with common situations in men and non-pregnant women. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. In the case of the thyroid series, the recommendations are drawn from the 2006 guidelines published by the Association for Clinical Biochemistry, the British Thyroid Association and the British Thyroid Foundation. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence based. They will be updated periodically to take account of new information.

Hypothyroidism and myxedema coma.

Hypothyroidism is a common endocrinopathy in dogs but is rare in cats. Lymphocytic thyroiditis and idiopathic thyroid atrophy are common causes of this condition. Specific thyroid function tests, in conjunction with clinical signs and physical examination findings, are used to help confirm a diagnosis of hypothyroidism. This disease can be managed with synthetic hormone supplementation and has an excellent prognosis. Myxedema coma is a rare and potentially fatal manifestation of severe hypothyroidism that can be successfully treated using intravenous levothyroxine.