Isolated central hypothyroidism: Underlying pathophysiology and relation to antidepressant and antipsychotic medications-A multi-centre South Wales study.

OBJECTIVE: Isolated biochemical central hypothyroidism is a presentation we are experiencing more frequently as endocrinologists, with variation in levels of investigation between physicians. We therefore conducted research to investigate the final diagnosis and clinical outcome of patients across multiple hospitals in South Wales with biochemical isolated central hypothyroidism; namely to establish whether this isolated biochemical picture was clinically significant. We also analysed whether there is an association between this biochemical picture and treatment with antidepressant and antipsychotic medications, and how common this is. DESIGN: We performed a retrospective observational study of patients across nine different hospitals in South Wales. We analysed patients referred to endocrinology at each site over a 6-year period with unexplained isolated biochemical central hypothyroidism. MATERIALS AND METHODOLOGY: 1022 individual patients' thyroid function test results were identified from our biochemical database using our inclusion criteria. After exclusion criteria were applied, 71 patients' results were analysed as to the final pathophysiology of their central hypothyroidism. RESULT: Of the 71 patients included in the study, none were found to have any clinically significant pathology on pituitary imaging. On reviewing their medications, 46/71 (65%) were found to be taking psychotropic medications. CONCLUSIONS: Our study strongly suggests isolated central hypothyroidism, in the absence of other pituitary hormone dysfunction or visual field defect, does not require further investigation, saving resources as well as sparing patients unnecessary anxiety. It also strongly supports a relationship between patients taking psychotropic medications and biochemical isolated central hypothyroidism, an association only described in a very limited amount of literature before this, and further supporting our previous single-centre study findings. The mechanism behind this is likely to be the suppression of thyrotropin secretion via antagonism of the dopamine-serotoninergic pathway. In our opinion, patients found to have isolated biochemical central hypothyroidism who are taking psychotropic medications can therefore be regarded to have a recognised cause for this biochemical finding and do not require further radiological investigation.

Age-related variation in thyroid function - a narrative review highlighting important implications for research and clinical practice.

BACKGROUND: Thyroid hormones are key determinants of health and well-being. Normal thyroid function is defined according to the standard 95% confidence interval of the disease-free population. Such standard laboratory reference intervals are widely applied in research and clinical practice, irrespective of age. However, thyroid hormones vary with age and current reference intervals may not be appropriate across all age groups. In this review, we summarize the recent literature on age-related variation in thyroid function and discuss important implications of such variation for research and clinical practice. MAIN TEXT: There is now substantial evidence that normal thyroid status changes with age throughout the course of life. Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations. Free triiodothyronine (FT3) levels fall with age and appear to play a role in pubertal development, during which it shows a strong relationship with fat mass. Furthermore, the aging process exerts differential effects on the health consequences of thyroid hormone variations. Older individuals with declining thyroid function appear to have survival advantages compared to individuals with normal or high-normal thyroid function. In contrast younger or middle-aged individuals with low-normal thyroid function suffer an increased risk of adverse cardiovascular and metabolic outcomes while those with high-normal function have adverse bone outcomes including osteoporosis and fractures. CONCLUSION: Thyroid hormone reference intervals have differential effects across age groups. Current reference ranges could potentially lead to inappropriate treatment in older individuals but on the other hand could result in missed opportunities for risk factor modification in the younger and middle-aged groups. Further studies are now needed to determine the validity of age-appropriate reference intervals and to understand the impact of thyroid hormone variations in younger individuals.

Myositis, rhabdomyolysis and severe hypercalcaemia in a body builder.

SUMMARY: A 53-year-old man who used growth hormone (GH), anabolic steroids and testosterone (T) for over 20 years presented with severe constipation and hypercalcaemia. He had benign prostatic hyperplasia and renal stones but no significant family history. Investigations showed - (1) corrected calcium (reference range) 3.66 mmol/L (2.2-2.6), phosphate 1.39 mmol/L (0.80-1.50), and PTH 2 pmol/L (1.6-7.2); (2) urea 21.9 mmol/L (2.5-7.8), creatinine 319 mmol/L (58-110), eGFR 18 mL/min (>90), and urine analysis (protein 4+, glucose 4+, red cells 2+); (3) creatine kinase 7952 U/L (40-320), positive anti Jo-1, and Ro-52 antibodies; (4) vitamin D 46 nmol/L (30-50), vitamin D3 29 pmol/L (55-139), vitamin A 4.65 mmol/L (1.10-2.60), and normal protein electrophoresis; (5) normal CT thorax, abdomen and pelvis and MRI of muscles showed 'inflammation', myositis and calcification; (6) biopsy of thigh muscles showed active myositis, chronic myopathic changes and mineral deposition and of the kidneys showed positive CD3 and CD45, focal segmental glomerulosclerosis and hypercalcaemic tubular changes; and (7) echocardiography showed left ventricular hypertrophy (likely medications and myositis contributing), aortic stenosis and an ejection fraction of 44%, and MRI confirmed these with possible right coronary artery disease. Hypercalcaemia was possibly multifactorial - (1) calcium release following myositis, rhabdomyolysis and acute kidney injury; (2) possible primary hyperparathyroidism (a low but detectable PTH); and (3) hypervitaminosis A. He was hydrated and given pamidronate, mycophenolate and prednisolone. Following initial biochemical and clinical improvement, he had multiple subsequent admissions for hypercalcaemia and renal deterioration. He continued taking GH and T despite counselling but died suddenly of a myocardial infarction. LEARNING POINTS: The differential diagnosis of hypercalcaemia is sometimes a challenge. Diagnosis may require multidisciplinary expertise and multiple and invasive investigations. There may be several disparate causes for hypercalcaemia, although one usually predominates. Maintaining 'body image' even with the use of harmful drugs may be an overpowering emotion despite counselling about their dangers.

Bariatric Surgery Is Accompanied by Changes in Extracellular Vesicle-Associated and Plasma Fatty Acid Binding Protein 4.

BACKGROUND: Bariatric surgery markedly reduces fat mass with beneficial effects on cardiometabolic health but the mechanisms involved are not fully understood. Extracellular vesicles (EVs) are secreted by a variety of cells, including adipocytes, and may mediate some of these benefits. However, the effects of bariatric surgery on circulating EVs are unclear. METHODS: Concentration of plasma EVs isolated by ultracentrifugation at baseline, 1 and 6 months post-bariatric surgery (n = 20) was established using Nanoparticle Tracking Analysis. EV origin (CD9: exosome; CD41: platelet; CD235a: erythrocyte; CD11b: leukocyte; CD144: endothelial), cytokine (interferon γ, interleukin-6, TNF-α) and adipocyte marker (adiponectin, FABP4, PPARγ) expression was measured by time-resolved fluorescence immunoassay. RESULTS: EV concentration and cell-of-origin markers (CD41, CD235a, CD11b, CD144) did not alter in response to surgery, neither did EV-expressed interferon γ, IL-6, TNF-α, adiponectin, PPARγ or CD9. EV-derived fatty acid binding protein 4 (FABP4) increased at 1 month (+ 49%) before returning to baseline by 6 months (- 51%, p < 0.05), corresponding to similar changes in circulating plasma FABP4 (+ 22 and - 24% at 1 and 6 months, respectively; p < 0.001). Patients who underwent biliopancreatic diversion had lower FABP4-expressing EVs at 6 months compared to those who underwent sleeve gastrectomy/gastric banding (p < 0.05), despite similar percentage weight reduction (- 19 vs - 20%, respectively). CD9 expression correlated with EV-expressed FABP4, adiponectin, TNF-α and interferon γ (r = 0.5, r = 0.59, r = 0.53, r = 0.41, respectively, p < 0.005), suggesting transport by an EV population of exosomal rather than microvesicular origin. CONCLUSIONS: Bariatric surgery leads to a transient change in circulating EV- and plasma-derived FABP4, reflecting alterations in adipose tissue homeostasis.

Predicting malignancy in thyroid nodules: feasibility of a predictive model integrating clinical, biochemical, and ultrasound characteristics.

BACKGROUND: Although the majority of thyroid nodules are benign the process of excluding malignancy is challenging and sometimes involves unnecessary surgical procedures. We explored the development of a predictive model for malignancy in thyroid nodules by integrating a combination of simple demographic, biochemical, and ultrasound characteristics. METHODS: Retrospective case-record review. We reviewed records of patients with thyroid nodules referred to our institution from 2004 to 2011 (n = 536; female 84 %, mean age 51 years). All malignancy was proven histologically while benign disease was either confirmed histologically, or on cytology with minimum 36-month observation period. We focused on the following predictors: age, sex, smoking status, thyroid hormones (FT4 and TSH) and nodule characteristics on ultrasound. Variables were included in a multivariate logistic regression and bootstrap analyses were used to confirm results. RESULTS: Independent predictors of malignancy in the fully adjusted model were TSH (OR 1.53, 95 % CI 1.10, 2.12, p = 0.01), male gender (OR 3.45, 95 % CI 1.33, 8.92, p = 0.01), microcalcifications (OR 6.32, 95 % CI 2.82, 14.1, p < 0.001), and irregular nodule margins (OR 5.45, 95 % CI 1.61, 18.6, p = 0.006) Bootstrap analyses strengthened these associations and a parsimonious analysis consisting of these variables and age-group demonstrated an area under the curve of 0.77. A predictive score was sensitive (86.9 %) at low scores and highly specific (94.87 %) at higher scores for distinguishing benign from malignant disease. CONCLUSIONS: A predictive model for malignancy using a combination of clinical, biochemical, and radiological characteristics may support clinicians in reducing unnecessary invasive procedures in patients with thyroid nodules.

Preconception thyroid-stimulating hormone and pregnancy outcomes in women with hypothyroidism.

OBJECTIVES: Maternal hypothyroidism may adversely affect pregnancy outcomes. International practice guidelines recommend that women with hypothyroidism should attain a preconception and early gestation serum thyroid-stimulating hormone (TSH) level of <2.5 mU/L. Our objective was to ascertain what proportion of women realize this target in practice and whether a TSH level above this threshold has adverse fetal and maternal consequences. METHODS: This was an observational study of women with hypothyroidism referred to an endocrine antenatal clinic between 2008 and 2010 (n = 78; mean age, 30.4 years; range, 19 to 43 years). Thyroid profiles (free thyroxine [FT4] and TSH) before conception and through pregnancy were documented. Obstetrics outcomes were examined, including low birth weight, preterm births, preeclampsia, caesarean sections, and admissions to special care neonatal units. RESULTS: Thyroid testing was undertaken in 80% of subjects before conception, and in 64, 94, and 96% of subjects in the first, second, and third trimesters of pregnancy, respectively. TSH >2.5 mU/L was seen in 49% of women before conception and in 68% of women in the first trimester. Six women were overtly hypothyroid before conception, attaining normal thyroid function at gestational ages ranging from 12 to 36 weeks. Neither the preconception nor the first postconception TSH level (>2.5 mU/L or ≤2.5 mU/L) was associated with gestational age at delivery, birth weight, or rates of caesarean section or preeclampsia. CONCLUSION: The majority of women with hypothyroidism do not achieve the recommended preconception and early gestation TSH targets. Preconception and early gestation TSH >2.5 mU/L was not associated with adverse fetal and maternal outcomes. Studies in larger cohorts will be required to confirm these findings, however.