ThyrotropinomA: Diagnosing a Rare Cause of Hyperthyroidism

Case: The patient is a 40-year-old male who presented for evaluation of hyperthyroidism with symptoms including palpitations, increased bowel movements, anxiety, and worsening tremor. With a family history of Graves’ disease and an ultrasound showing a hyperemic thyroid, there was initial suspicion for Graves’ disease. Although a radioactive iodine thyroid scan showed diffuse uptake that was elevated, 21.4% at 4 hours and 33.1% at 24 hours, lab evaluation appeared inconsistent with Graves’ disease revealing: TSH 1.65 µU/mL (upper limit of normal [ULN] 4.5), free thyroxine (FT4) 1.99 ng/dL (ULN 1.17), free triiodothyronine 6.16 ng/dL (ULN 3.98), thyroid stimulating immunoglobulin 92% (ULN 122), and thyroid receptor antibodies less than 1.0 IU/L (ULN 1.75). Lab results were reproducible with elevated FT4 even by equilibrium dialysis at 3.9 ng/dL (ULN 2.4) and high-normal TSH with serial dilution that ruled out assay interreference. Given these findings, our focus turned to rare causes of hyperthyroidism including thyrotropinoma and thyroid hormone resistance (RTH). Unique to the diagnosis of thyrotropinoma is an elevated serum α subunit in 50-85% of cases (1). Therefore, we obtained an α subunit level which was 0.35 ng/mL (ULN 0.55) with a molar ratio of 2.2 (ULN 2.4). Since the α subunit level was normal, the patient obtained genetic testing for mutations in the thyroid hormone receptor β gene seen in 85% of RTH cases (1). However, no sequence variants were identified. Since initial lab and genetic analyses were undifferentiating, additional tests were obtained including an insulin-like growth-factor 1 level of 209 ng/mL (ULN 237) and prolactin level of 10.1 ng/mL (ULN 20) which can be elevated in 30% of mixed thyrotropinoma cases (1). The first evidence to suggest a thyrotropinoma was a mildly elevated sex-hormone binding globulin at 102 nmol/L (ULN 80). Further evaluation with pituitary magnetic resonance imaging showed a 6-milimeter lesion. Although the pituitary lesion is suggestive of a thyrotropinoma, it is not definitive, as they are present in 20% of RTH cases (1). Therefore, with increased suspicion of a thyrotropinoma, we pursued the more robust T3 suppression test which showed 56% suppression of TSH consistent with a thyrotropinoma. The patient had pituitary surgery with pathology confirming weak immunoreactivity for TSH. Post-operatively, his symptoms improved and free thyroid hormones normalized. Discussion: It is important to distinguish between thyrotropinoma and RTH as the treatment is different with 80% of thyrotropinoma cases achieving euthyroidism after surgery (1). In our case, the diagnosis was initially unclear thus it was important to broaden the lab and genetic evaluation considering the limitations of the studies. One such limitation is the α subunit may not be elevated in microadenomas as occurred in our case. 1. Beck-Peccoz et al. J Endocrinol Invest. 2019; 42:1401-6

Associations between maternal thyroid function in pregnancy and child neurodevelopmental outcomes at 20 months in the Seychelles Child Development Study, Nutrition Cohort 2 (SCDS NC2)

Maternal thyroid hormones facilitate optimal foetal neurodevelopment; however, the exact role of the thyroid hormones on specific cognitive outcomes is unknown. The present study aimed to investigate associations between maternal thyroid function and neurodevelopmental outcomes in the Seychelles Child Development Study (SCDS) Nutrition 2 cohort (n 1328). Maternal free thyroid hormones (fT3, fT4 and fTSH) were assessed at 28 weeks’ gestation with a range of child cognitive outcomes analysed at 20 months. Dietary iodine intake was analysed for a subset of women through a Food Frequency Questionnaire. Linear regression analysis was used to test associations between serum concentrations of maternal thyroid hormones and child neurodevelopment outcomes. Thyroid hormones were analysed as continuous data and categorised as quintiles. 95% of mothers had optimal thyroid function based on fTSH concentrations. Overall, the present study shows that maternal thyroid function is not associated with neurodevelopmental outcomes in this high fish-eating population. However, a positive association, using quintiles for fT3, was reported for the Mental Developmental Index, between Q3 v. Q4 (β 0⋅073; P 0⋅043) and for Q3 v. Q5 (β value 0⋅086; P 0⋅018). To conclude, mothers in our cohort, who largely have optimal thyroid function and iodine intakes, appear able to regulate thyroid function throughout pregnancy to meet neurodevelopmental needs. However, it is possible that minor imbalances of fT3, as indicated from our secondary analysis, may impact offspring neurodevelopment. Further investigation of the relationship between maternal thyroid function and infant neurodevelopment is warranted, particularly in populations with different dietary patterns and thereby iodine intakes.

The effect of specific binding proteins on immunoassay measurements of total and free thyroid hormones and cortisol

Background: Immunoassay (IA) measurements of thyroid hormones have previously given inaccurate results of triiodothyronine (T3), free triiodothyronine (FT3), and free thyroxine (FT4) when concentrations of TBG are low. We evaluate the hypothesis that abnormal concentrations of specific binding proteins (BPs) affect IA measurements and provide results which might misguide the diagnosis and treatment of patients. This study assesses IAs for the measurement of T3, FT3, and cortisol when levels of TBG and CBG are high or low. Comparisons are made between IA and LC-MS/MS. Methods: Serum or plasma samples with high (>95th percentile, n = 25) or low (<5th percentile, n = 27) concentrations of BP were collected. The concentrations of T3, FT3, and cortisol were measured by validated IA and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Spearman correlation and Wilcoxon matched-pairs signed rank analyses were used to compare the two methods. Results: When TBG levels are <5th percentile, the differences between the IA and LC-MS/MS results for T3 and FT3 are statistically significant (T3, p = 0.0011; FT3, p = 0.0003). When CBG levels are >95th percentile, the difference between the IA and LC-MS/MS measurements of cortisol is statistically significant ( p = <0.0001). Conclusion: Abnormal BP concentrations appear to affect the accuracy of IA measurements of T3, FT3, and cortisol. The population of patients with either high or low levels of BPs is significant. Our samples reflect that 65% of women aged between 15 and 49 years are taking oral contraceptives in the US, and thus have elevated levels of BPs. In this group, IA results for cortisol are falsely low. Our samples reflect that patients with protein losing diseases have low BP concentrations. Among a group with renal complications, IA measurements of T3 are overestimated, while those of FT3 are underestimated. Are the Food and Drug Administration and diagnostic companies adequately assessing the accuracy of IA tests?

The Diurnal Variation of Thyroid Hormones in Individuals Attending Tertiary Care Hospital, Kanchipuram District

Free thyroxin hormones FT4 and FT3 are unbounded thyroid hormone are biologically active and involves in regulation of metabolism. Measuring the concentrations of free thyroid hormones is of great diagnostic value. A cross sectional study was carried out during the March 2019 to September 2019 in patients between 18 years to 60 years. A total of 60 samples were collected from 30 patients attending Karpaga Vinayaga Institute of Medical Sciences at morning (6am-8am) and 2nd sampling at night (8pm-9pm). FT4, FT3 and TSH were measured by Enzyme linked immunosorbent assay, using Avantor kit.In our study 36.67% participants were males, 63.3% participants were females. The mean FT3, FT4 and TSH in day are 2.43±0.56, 1.14±0.44 and 2.74±3.16 respectively. The mean night FT3, FT4 and TSH are 2.66±0.55, 1.3±0.61 and 3.21±3.18 respectively. The one sample t test shows difference of FT3, t 4.489 and p value 0.000, FT4, t value 3.092 and p value 0.004 and TSH t value 3.394 and p value 0.002. The time of blood sampling has an important role in the interpretation of TSH levels. However fluctuations in diurnal variations in thyroid hormone levels are less. In our study although statistically significant, all the values are within the normal biological reference interval Further studies in larger cohorts is essential to desire important conclusions.

Associations of Thyroid Hormones and Resting Heart Rate in Patients Referred to Coronary Angiography

Resting heart rate (RHR) is associated with increased risk of cardiovascular morbidity and mortality. Thyroid hormones exert several effects on the cardiovascular system, but the relation between thyroid function and RHR remains to be further established. We evaluated whether measures of thyroid hormone status are associated with RHR in patients referred to coronary angiography. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxin (FT4), and RHR were determined in 2795 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Median (25th to 75th percentile) serum concentrations were 1.25 (0.76–1.92) mU/l for TSH, 4.8 (4.2–5.3) pmol/l for FT3 and 17.1 (15.4-19.0) pmol/l for FT4, and mean (±standard deviation) RHR was 68.8 (±11.7) beats/min. Comparing the highest versus the lowest quartile, RHR (beats/min) was significantly higher in the fourth FT4 quartile [3.48, 95% confidence interval (CI): 2.23–4.73; p <0.001] and in the fourth FT3 quartile (2.30, 95% CI: 1.06–3.55; p <0.001), but there was no significant difference for TSH quartiles. In multiple linear regression analyses adjusting for various potential confounders, FT3 and FT4 were significant predictors of RHR (p <0.001 for both). In subgroups restricted to TSH, FT3, and FT4 values within the reference range, both FT3 and FT4 remained significant predictors of RHR (p <0.001 for all). In conclusion, in patients referred to coronary angiography, FT3 and FT4 but not TSH were positively associated with RHR. The relationship between free thyroid hormones and RHR warrants further investigations regarding its diagnostic and therapeutic implications.

Determinants of deranged thyroid function parameters in children admitted for management of diabetic ketoacidosis/diabetic ketosis

Background: Euthyroid sick syndrome (ESS) frequently arises in children admitted with diabetic ketoacidosis/diabetic ketosis (DKA/DK). This study evaluates the interplay of various metabolic factors with occurrence of deranged thyroid function tests in children suffering from DKA/DK.Methods: 98 DKA and 96 DK pediatric patients were selected from hospital records. Those on thyroxine replacement, with overt hypothyroidism, or with positive anti-thyroperoxidase (TPO) antibody were excluded. Tests for liver function, renal function, lipid profile, serum osmolarity, thyroid function, c-peptide levels, and glycosylated hemoglobin were done on all patients. Children were divided into euthyroid (n=88) and ESS groups (n=106).Results: The ESS group had a higher level of white blood cell count (WBC), plasma glucose (PG), beta-hydroxybutyric acid (β-HB), triglyceride (TG), anion gap (AG), glycosylated hemoglobin (HbA1c) and a lower level of HCO3-, prealbumin (PA), and albumin (ALB) compared with the euthyroid group (P<0.05). Free T3 (FT3) levels were significantly correlated to β-HB, HCO3-, AG, PA, and HbA1c (r=-0.642, 0.681, -0.377, 0.581, -0.309, respectively; P<0.01). Free T4 (FT4) levels were significantly correlated to β-HB, HCO3-, and ALB levels (r=-0.489, 0.338, 0.529, respectively; P<0.01). TSH levels were significantly affected by HCO3– only (r=-0.28; P<0.01). HCO3– level was the most important factor deciding euthyroid or ESS on logistic regression analysis (OR=0.844, P=0.004, 95%CI=0.751-0.948).Conclusions: Lower levels of free thyroid hormones and occurrence of ESS were associated with a higher degree of acidosis in children with DKA/DK.

Determinants of deranged thyroid function parameters in children admitted for management of diabetic ketoacidosis/diabetic ketosis

Background: Sick euthyroid syndrome is frequent in children admitted with diabetic ketoacidosis/diabetic ketosis (DKA/DK). This study evaluates the interplay of various metabolic factors with occurrence of deranged thyroid function tests in children admitted for management of DKA/DK.Methods: 98 DKA and 96 DK children patients were selected from hospital records, among which individuals on thyroxine replacement, with overt hypothyroidism or positive anti-thyroperoxidase (TPO) antibody were excluded. Tests for liver function, renal function, lipid profile, serum osmolarity, thyroid function, c-peptide levels, and glycosylated hemoglobin were done for all. Children were divided into euthyroid (n=88) and euthyroid sick syndrome（ESS）groups (n=106).Results: The ESS group had a higher level of white blood cell count (WBC), plasma glucose (PG), beta-hydroxybutyric acid (β-HB), triglyceride (TG), anion gap (AG), glycosylated hemoglobin (HbA1c) and a lower level of HCO3-, prealbumin (PA), and albumin (ALB) compared with the euthyroid group (P<0.05). Free T3 (FT3) levels were significantly correlated to β-HB, HCO3-, AG, PA, and HbA1c (r=-0.642, 0.681, -0.377, 0.581, -0.309, respectively; P<0.01). Free T4 （FT4） levels were significantly correlated to β-HB, HCO3-, and ALB levels (r=-0.489, 0.338, 0.529, respectively; P<0.01). TSH levels were significantly affected by HCO3– only (r=-0.28; P<0.01). HCO3– level was the most important factor deciding euthyroid or ESS on logistic regression analysis (OR=0.844, P=0.004, 95%CI=0.751­-0.948).Conclusions: Lower levels of free thyroid hormones and occurrence of ESS were associated with a higher degree of acidosis in children with DKA/DK.

Neonates Born to Mothers with Graves’ Disease: 15 Year Experience of a Pediatric Endocrinology Department

Introduction: Graves disease is characterized by the existence of autoantibodies directed to the thyrotropin receptor, which can have a stimulatory/inhibitory action, in women with the condition, their fetus or neonate. Our aim was to review the case series of these neonates in order to establish neonatal thyroid function predictors.Material and Methods: Retrospective cohort study of the database of the Department of Pediatric Endocrinology, including patients born to mothers with Graves’ disease, between 2002 and 2017. Clinical and biochemical data were collected from mothers and offspring.Results: Fifty newborns, from 46 women with a median of 3.5 years after diagnosis, were included. During all trimesters of pregnancy, more than half of women had positive autoantibodies directed to the thyrotropin receptor. Not every woman had a complete thyroid function evaluation every trimester. In 32 newborns, cord blood screening was done. During the neonatal period, there were three cases of hypothyroidism and two of hyperthyroidism. The mothers of these five newborns had higher levels of free thyroid hormones during the second trimester (p = 0.03). The level of antibodies directed to the thyrotropin receptor was significantly higher in the cord blood (p = 0.03) and in the first neonatal test (p = 0.03) of these dysthyroid newborns.Discussion: Our results reinforce the need for every pregnant woman with Graves’ disease to be subject to thyroid function and autoantibodies evaluation during every trimester, as well as the importance of evaluating these antibodies in cord blood.Conclusion: High levels of free thyroid hormones during the second trimester of pregnancy and antibodies directed to the thyrotropin receptor value in cord blood are predictors of dysthyroidism in neonates born from women with Grave’s disease.

Effective Preoperative Plasmapheresis Treatment of Severe Hyperthyroidism in a Patient with Giant Toxic Nodular Goiter and Methimazole-Induced Agranulocytosis

Agranulocytosis is a rare but very serious complication of thyrostatic therapy. In severe hyperthyroidism, the removal of circulating thyroid hormones by plasmapheresis may be an effective therapeutic option. This report describes the therapeutic difficulties and successful preoperative treatment with plasmapheresis in a 63-year-old patient admitted to the Endocrinology Clinic with severe hyperthyroidism, during the course of giant toxic nodular goiter and agranulocytosis, which occurred after 2 weeks of taking methimazole. During hospitalization, methimazole treatment was discontinued and therapy with steroids, a beta blocker, propylthiouracil, Lugol’s solution, lithium carbonate, and antibiotics were initiated. Granulocyte colony growth stimulating factor was also used to resolve agranulocytosis. Due to the failure to achieve euthyreosis using this approach, we decided to conduct thyroid surgery, as a life-saving action, after preparation of the patient by plasmapheresis. Two plasmapheresis procedures were performed, resulting in a decrease in the concentration of free thyroid hormones. Total thyroidectomy was performed and there were no complications during surgery. We conclude that plasmapheresis may be considered as an effective alternative treatment option for the preparation of patients with hyperthyroidism for surgery, when the clinical situations prevent the use of conventional treatments for hyperthyroidism and when immediate life-saving surgery is necessary.

Screening for New Markers to Assess Thyroid Hormone Action by OMICs Analysis of Human Samples

ABSTRACTDetermination of the levels of thyroid-stimulating hormone (TSH) and free thyroid hormones (fTHs) is crucial for assessing thyroid function. However, as a result of inter-individual genetic variability and different environmental factors individual set points exist for TSH and fTHs and display considerable variation. Furthermore, under specific pathophysiological conditions like central hypothyroidism, TSH secreting pituitary tumors, or thyroid hormone resistance the established markers TSH and fTH fail to reliably predict thyroid function and adequate supply of TH to peripheral organs. Even in case of overt hyper- and hypothyroidism circulating fTH concentrations do not correlate with clinical symptoms. Therefore, there is a clear need for novel, more specific biomarkers to diagnose and monitor thyroid function. OMICs screening approaches allow parallel profiling of hundreds to thousands of molecules and thus comprehensive monitoring of molecular alterations in tissues and body fluids that might be associated with changes in thyroid function. These techniques thus constitute promising tools for the identification of urgently needed novel biomarkers. This mini review summarizes the findings of OMICs studies in thyroid research with a particular focus on population-based and patient studies as well as interventional approaches investigating the effects of thyroid hormone administration.