Ectopic lingual thyroid with subclinical hypothyroidism in children.

OBJECTIVES: Lingual thyroid is a rare condition that affects approximately 1 in 100,000 individuals. Although it is usually detected in the pediatric population through newborn screening tests or evaluation of congenital hypothyroidism, there are cases in which it remains undetected until adulthood or until symptoms arise because of glandular enlargement. The possible symptoms of lingual thyroid include foreign body sensation in the throat, dysphagia, dyspnea, and hemorrhage. Several cases of lingual thyroid are asymptomatic and accompanied by subclinical hypothyroidism. Herein, we present three cases of lingual thyroid treated with thyroid hormone suppressive therapy. CASE PRESENTATION: The three patients sought medical attention because of a sore throat or foreign body sensation in the throat. Their newborn screening tests and developmental histories were normal. These patients exhibited subclinical hypothyroidism and were treated with hormone suppression therapy. CONCLUSIONS: Patients with lingual thyroid frequently exhibit subclinical hypothyroidism. Hormone treatment may help to reduce the size of the ectopic thyroid and improve symptoms. If an increase in size is noted during follow-up or symptoms do not improve, surgical treatments may be considered.

Effects of maternal hypothyroidism on postnatal cardiomyocyte proliferation and cardiac disease responses of the progeny.

Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.

Melissa officinalis extract suppresses endoplasmic reticulum stress-induced apoptosis in the brain of hypothyroidism-induced rats exposed to γ-radiation.

The purpose of this study was to demonstrate the neuroprotective effect of Melissa officinalis extract (MEE) against brain damage associated with hypothyroidism induced by propylthiouracil (PTU) and/or γ-radiation (IR) in rats. Hypothyroidism induction and/or exposure to IR resulted in a significant decrease in the serum levels of T3 and T4 associated with increased levels of lipid peroxidation end product, malondialdehyde (MDA), and nitrites (NO) in the brain tissue homogenate. Also, hypothyroidism and /or exposure to IR markedly enhance the endoplasmic reticulum stress by upregulating the gene expressions of the protein kinase RNA-like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF6), endoplasmic reticulum-associated degradation (ERAD), and CCAAT/enhancer-binding protein homologous protein (CHOP) in the brain tissue homogenate associated with a proapoptotic state which indicated by the overexpression of Bax, BCl2, and caspase-12 that culminates in brain damage. Meanwhile, the PTU and /or IR-exposed rats treated with MEE reduced oxidative stress and ERAD through ATF6. Also, the MEE treatment prevented the Bax and caspase-12 gene expression from increasing. This treatment in hypothyroid animals was associated with neuronal protection as indicated by the downregulation in the gene expressions of the microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) in the brain tissue. Furthermore, the administration of MEE ameliorates the histological structure of brain tissue. In conclusion, MEE might prevent hypothyroidism-induced brain damage associated with oxidative stress and endoplasmic reticulum stress.

Permanent hypothyroidism following immune checkpoint inhibitors induced thyroiditis may be associated with improved survival: results of an exploratory study.

Background: Immune-related endocrinopathies are common after immune checkpoint inhibitor (ICI) therapy, among which destructive thyroiditis is the most prevalent. Improved survival outcomes have been associated with immune-related adverse events. We aimed to compare the clinical course and biochemical parameters of two subtypes of ICI-related destructive thyroiditis: a transient thyrotoxicosis that reverts to either euthyroidism (TT; transient thyroiditis) versus progression to permanent hypothyroidism (PH), and to identify prognostic markers in cancer patients receiving ICI therapy who developed DT. Methods: This retrospective observational study included 124 patients who developed a transient thyrotoxicosis due to a destructive thyroiditis after ICI therapy from January 1, 2016 to April 30, 2021 at the Montefiore Medical Center. Patients were categorized as either TT or PH based on spontaneous renormalization of the TSH or the permanent need for thyroid hormone replacement, respectively. Thyroid hormone and antibody levels, serum inflammatory markers, eosinophils, and metabolic uptake of the thyroid on PET imaging, each corresponding closest to a suppressed TSH, were characterized. Survival from TT and PH were also analyzed. Results: Of the 124 patients, 53 developed PH and 71 developed TT. The PH group developed thyrotoxicosis at a median of 42 days from the first ICI dose while the TT group took significantly longer at 56 days. Thyroidal PET uptake was increased in 18.9% of the PH group versus 6.0% of the TT group (P=0.04). Three different survival models consistently demonstrated a trend towards increased survival in the PH group, compared to the TT group. Conclusion: Our results suggest that PH developing after ICI-induced destructive thyroiditis may be associated with a more robust inflammatory and antitumor response to ICI therapy. The results suggests that PH may be a potential clinical predictor of improved survival.

Lumbar spine intervertebral disc desiccation is associated with medical comorbidities linked to systemic inflammation.

INTRODUCTION: Symptomatic disc degeneration is a common cause of low back pain. Recently, the prevalence of low back pain has swiftly risen leading to increased patient disability and loss of work. The increase in back pain also coincides with a rapid rise in patient medical comorbidities. However, a comprehensive study evaluating a link between patient's medical comorbidities and their influence on lumbar intervertebral disc morphology is lacking in the literature. METHODS: Electronic medical records (EMR) were retrospectively reviewed to determine patient-specific medical characteristics. Magnetic resonance imaging (MRI) was evaluated for lumbar spine intervertebral disc desiccation and height loss according to the Griffith-modified Pfirrmann grading system. Bivariate and multivariable linear regression analyses assessed strength of associations between patient characteristics and lumbar spine Pfirrmann grade severity (Pfirrmann grade of the most affected lumbar spine intervertebral disc) and cumulative grades (summed Pfirrmann grades for all lumbar spine intervertebral discs). RESULTS: In total, 605 patients (304 diabetics and 301 non-diabetics) met inclusion criteria. Bivariate analysis identified older age, diabetes, American Society of Anesthesiologists (ASA) class, hypertension, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, and hypothyroidism as being strongly associated with an increasing cumulative Pfirrmann grades. Multivariable models similarly found an association linking increased cumulative Pfirrmann grades with diabetes, hypothyroidism, and hypertension, while additionally identifying non-white race, heart disease, and previous lumbar surgery. Chronic pain, depression, and obstructive sleep apnea (OSA) were associated with increased Pfirrmann grades at the most affected level without an increase in cumulative Pfirrmann scores. Glucose control was not associated with increasing severity or cumulative Pfirrmann scores. CONCLUSION: These findings provide specific targets for future studies to elucidate key mechanisms by which patient-specific medical characteristics contribute to the development and progression of lumbar spine disc desiccation and height loss. LEVEL OF EVIDENCE: III (retrospective cohort).

Effects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism.

The increasing knowledge of the molecular mechanisms in the cell signaling pathways of malignant cells, has recently led to the discovery of several tyrosine kinases (TKs), mainly TK receptors (TKR), which play a major role in the pathogenesis of many types of cancer. These receptors, physiologically involved in cell growth and angiogenesis, may harbor mutations or be overexpressed in malignant cells, and represent a target for anticancer therapy. Indeed, several therapeutic agents targeting specific altered pathways such as RET, BRAF, RAS, EGFR and VEGFR, have been identified. Tyrosine kinase inhibitors (TKIs) affect TK dependent oncogenic pathways by competing with ATP binding sites of the TK domain, thus blocking the activity of the enzyme, and thereby inhibiting the growth and spread of several cancers. Although the therapeutic action may be very effective, these molecules, due to their mechanism of multitargeted inhibition, may produce adverse events involving several biological systems. Both hypothyroidism and thyrotoxicosis have been reported during treatment with TKI, as well as an effect on the activity of enzymes involved in thyroid hormone metabolism. The pathogenic mechanisms leading to thyroid dysfunction and changes in serum thyroid function tests occurring in patients on TKI are reviewed and discussed in this manuscript.

Antioxidant Potential of Parsley Leaf (Petroselinum crispum) Essential Oil on Hypothyroidism and Testicular Injury in Mice Intoxicated by Carbon Tetrachloride.

The aim of the present study was to investigate the ameliorative potential of parsley (Petroselinum crispum) leaf essential oil (PO) against the detrimental effects of carbon tetrachloride (CCl4) on the thyroid gland and testes of mice. Twenty-four adult male mice were divided into four groups and treated for 4 weeks. The 1st control group received 3 mL/kg olive oil intraperitoneally, twice a week followed by 0.5 mL/kg saline intragastrically daily. The 2nd CCl4 group received CCl4 (3 mL/kg intraperitoneally, twice a week). The 3rd PO group received PO (0.5 mL/kg intragastrically daily), while the 4th CCl4+PO group received CCl4 coadministrated with PO at the aforementioned doses. CCl4 group recorded significant (p < 0.05) reduction in the activities of antioxidant enzyme catalase (CAT) and superoxide dismutase (SOD) and significant (p < 0.05) increase in the lipid peroxidation end product's level malondialdehyde (MDA) in the testes and thyroid glands. Meanwhile, serum levels of testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid hormones (thyroid-stimulating hormone (TSH), total triiodothyronine (T3), free triiodothyronine (fT3), total thyroxine (T4), and free thyroxine (fT4)) significantly decreased. Also, histopathologically, the testicular tissue showed hypospermatogenesis within irregular-shaped seminiferous tubules with prominent edema in the interstitial spaces confirming the aforementioned biochemical alterations. Treatment with PO significantly reduced the testicular and thyroid oxidative stress (p < 0.05) and elevated the testosterone (73.47%), FSH (92.11%), LH (33.33%), T3 (23.47%), fT3 (39.13%), T4 (27.91%), and fT4 (75%) as compared to that of CCl4-treated group corresponding values. The PO GC/MS analysis indicated bioactive monoterpenes (major component is 1,3,8-mentha triene 34.48%) and phenylpropenes (major component is myristicin 21.04%). Results suggested the ameliorative effect of PO against CCl4-induced hypogonadism in mice by suppressing oxidative stress and maintaining thyroid gland function.

Functional and biochemical changes in the thyroid gland following exposure to therapeutic doses of external beam radiotherapy in the head-and-neck cancer patients.

CONTEXT: Majority of the head-and-neck cancers are locoregionally advanced at the time of diagnosis. Hence, radiotherapy (RT) portals will invariably cover the whole neck and thus, the thyroid gland which may lead to its dysfunction. AIMS: The purpose of this study is to identify the functional and biochemical changes in the thyroid gland following RT to the neck using single-photon emission computed tomography-computed tomography (SPECT-CT) and thyroid function tests (TFTs). SUBJECTS AND METHODS: In this prospective study, 45 patients of the head-and-neck cancer, receiving RT with or without chemotherapy were investigated. Baseline TFTs and thyroid scans (on SPECT-CT) were done, and the same were repeated at the completion of RT, at 3 and 6 months. RESULTS: All patients received a minimum of 30 Gy to the whole neck. Baseline TFTs and thyroid scans were normal. None of them developed hypothyroidism clinical or subclinical (C/S) at the completion of RT. Six patients developed hypothyroidism (four subclinical, two clinical) at 3 months of the completion of treatment. At 6 months of follow-up 14 patients (31.1%) developed hypothyroidism (ten subclinical, four clinical) with P≤ 0.01. All patients having clinical or subclinical hypothyroidism had decreased uptake on thyroid scan. Patients having decreased uptake on thyroid scan only, with normal TFTs and no symptoms of hypothyroidism were zero at the completion of RT, 1 at 3 months follow-up, and seven at 6 months follow-up. CONCLUSIONS: Hypothyroidism (C/S) is an under-recognized but significant complication of therapeutic doses of RT to the neck. In our study, we recognized hypothyroidism as early as 3 months following the completion of RT. Hence, tests to evaluate functional and biochemical changes in the thyroid gland should be instituted as early as 3 months following RT.

Long Term Rescue of the TSH Receptor Knock-Out Mouse - Thyroid Stem Cell Transplantation Restores Thyroid Function.

The synergistic activation of transcription factors can lead to thyroid progenitor cell speciation. We have previously shown in vitro that mouse or human stem cells, expressing the transcription factors NKx2-1 and Pax8, can differentiate into thyroid neo-follicular structures (TFS). We now show that syngeneic mouse TFS when implanted into hypothyroid TSH receptor knockout (TSHR-KO) mice can ameliorate the hypothyroid state for an extended period. ES cells derived from heterozygous TSHR-KO blastocysts were stably transfected with Nkx2-1-GFP and Pax8-mcherry constructs and purified into 91.8% double positive cells by flow cytometry. After 5 days of activin A treatment these double positive cells were then induced to differentiate into neo-follicles in Matrigel for 21 days in the presence of 500µU/mL of TSH. Differentiated TFS expressing thyroglobulin mRNA were implanted under the kidney capsule of 4-6 weeks old TSHR-KO mice (n=5) as well as hind limb muscle (n=2) and anterior chamber of one eye (n=2). Five of the mice tested after 4 weeks were all rendered euthyroid and all mice remained euthyroid at 20 weeks post implantation. The serum T4 fully recovered (pre-bleed 0.62 ± 0.03 to 8.40 ± 0.57 µg/dL) and the previously elevated TSH became normal or suppressed (pre-bleed 391 ± 7.6 to 4.34 ± 1.25 ng/dL) at the end of the 20 week observation period. The final histology obtained from the implanted kidney tissues showed only rudimentary thyroid follicular structures but which stained positive for thyroglobulin expression. The presence of only rudimentary structures at the site of implant on these extended animals suggested possible migration of cells from the site of implant or an inability of TFCs to maintain proper follicular morphology in these external sites for extended periods. However, there were no signs of tumor formation and no immune infiltration. These preliminary studies show that TSHR-KO mice are a useful model for orthotropic implantation of functional thyroid cells without the need for thyroidectomy, radioiodine ablation or anti thyroid drug control of thyroid function. This approach is also proof of principle that thyroid cells derived from mouse ES cells are capable of surviving as functional neo-follicles in vivo for an extended period of 20 weeks.

Generation and Differentiation of Adult Tissue-Derived Human Thyroid Organoids.

Total thyroidectomy as part of thyroid cancer treatment results in hypothyroidism requiring lifelong daily thyroid hormone replacement. Unbalanced hormone levels result in persistent complaints such as fatigue, constipation, and weight increase. Therefore, we aimed to investigate a patient-derived thyroid organoid model with the potential to regenerate the thyroid gland. Murine and human thyroid-derived cells were cultured as organoids capable of self-renewal and which expressed proliferation and putative stem cell and thyroid characteristics, without a change in the expression of thyroid tumor-related genes. These organoids formed thyroid-tissue-resembling structures in culture. (Xeno-)transplantation of 600,000 dispersed organoid cells underneath the kidney capsule of a hypothyroid mouse model resulted in the generation of hormone-producing thyroid-resembling follicles. This study provides evidence that thyroid-lineage-specific cells can form organoids that are able to self-renew and differentiate into functional thyroid tissue. Subsequent (xeno-)transplantation of these thyroid organoids demonstrates a proof of principle for functional miniature gland formation.

The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions.

The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems from the hypothalamus to the pituitary and ultimately to the peripheral target organs. The hypothalamus and the pituitary gland are in close anatomical proximity at the base of the brain and extended through the pituitary stalk to the sella turcica. The pituitary stalk allows passage of stimulatory and inhibitory hormones and other signal molecules. The target organs are placed in the periphery and function through stimulation/inhibition by the circulating pituitary hormones. The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways and for many of them the interactive and integrated mechanisms are still not quite clear. The diagnosis of central hypothyroidism is complicated by itself but challenged further by concomitant affection of other hypothalamus-pituitary-hormone axes, the dysfunction of which influences the diagnosis of central hypothyroidism. Treatment of both the central hypothyroidism and the other hypothalamus-pituitary axes also influence the function of the others by complex mechanisms involving both central and peripheral mechanisms. Clinicians managing patients with neuroendocrine disorders should become aware of the strong integrative influence from each hypothalamus-pituitary-hormone axis on the physiology and pathophysiology of central hypothyroidism. As an aid in this direction the present review summarizes and highlights the importance of the hypothalamus-pituitary-thyroid axis, pitfalls in diagnosing central hypothyroidism, diagnosing/testing central hypothyroidism in relation to panhypopituitarism, pointing at interactions of the thyroid function with other pituitary hormones, as well as local hypothalamic neurotransmitters and gut-brain hormones. Furthermore, the treatment effect of each axis on the regulation of the others is described. Finally, these complicating aspects require stringent diagnostic testing, particularly in clinical settings with lower or at least altered à priori likelihood of hypopituitarism than in former obvious clinical patient presentations.

Geographical influences on thyroid abnormalities in adult population from iodine-replete regions: a cross-sectional study.

The studies on the increasing incidence of thyroid abnormalities are scarce. The aim of this current study was to ascertain the effects of geographical region on thyroid abnormalities under the context of universal salt iodization (USI). We randomly selected 1255 participants residing in inland and 1248 in coast, with the determination of urinary iodine concentration (UIC) and functional and morphological abnormalities of thyroid gland. The median UIC was significantly higher for the inland participants (188.5 µg/L) than the coastal participants (128.5 µg/L; p < 0.001), indicating iodine sufficiency in both populations according to the recommended assessment criteria by the World Health Organization. However, the spectrum of thyroid abnormalities varied between regions, with hypothyroidism prevalent in inland and thyroid nodules in coast. The associations between region and thyroid abnormalities via binary logistic regression models showed that the coastal participants were at a higher risk of total thyroid abnormalities than those from the inland (OR 1.216, 95% CI 1.020-1.449), after the adjustment of ten confounders (demographical characteristics, smoking status, metabolism syndrome, and hyperuricemia). These results indicated that further investigations of the adverse effects of hypothyroidism and thyroid nodules on health burden is urgently needed to sustain USI program.

Thyroid hormones modulate irisin concentrations in patients with recently onset hypothyroidism following total thyroidectomy.

PURPOSE: Irisin is a newly discovered adipo-myokine known for having significant effects on body metabolism. Currently, there is a discussion regarding the relation between thyroid function and irisin concentration. This study was designed to evaluate the influential role of levothyroxine replacement therapy on circulating levels of irisin in patients with recently onset hypothyroidism following total thyroidectomy. METHODS: Circulating levels of thyroid hormones, irisin and other metabolic parameters, were assessed in 40 recently thyroidectomized patients (34 females, mean age 50.1 ± 15.2 years) at baseline (5-7 day after surgery) and after 2 months under replacement therapy with levothyroxine. RESULTS: At baseline, circulating levels of thyroid hormones were indicative of hypothyroidism (TSH 12.7 ± 5.0 µU/mL, FT3 1.9 ± 0.7 pg/mL, FT4 8.7 ± 3.6 pg/mL). Mean serum irisin concentrations significantly increased after 2 months under replacement therapy with levothyroxine (from 2.2 ± 0.6 to 2.9 ± 0.6 µg/mL, p < 0.0001). Variations of circulating levels of irisin under levothyroxine replacement therapy were directly correlated with those of FT3 (Rho = 0.454, p = 0.0033) and FT4 (Rho = 0.451, p = 0.0035). Multivariate regression analysis revealed that changes in thyroid hormones concentrations explained up to 10% of the variations of serum irisin levels under levothyroxine replacement therapy (FT3 R2 = 0.098, FT4 R2 = 0.103). CONCLUSION: Our study suggests that levothyroxine replacement therapy mildly influences irisin metabolism in patients with recently onset hypothyroidism following total thyroidectomy.

Microstructural white matter abnormalities in hypothyroidism evaluation with diffusion tensor imaging tract-based spatial statistical analysis.

PURPOSE: Hypothyroidism is presented in a wide range from neuropsychiatric problems including depression, memory and cognitive disorders to poor motor coordination. Against the background of morphologic, functional and molecular changes on the white and grey matter of the brain, we aimed to investigate the effects of hypothyroidism on white matter (WM) integrity using tract-based spatial statistics (TBSS). METHODS: Eighteen patients with hyperthyroidism and 14 age-sex-matched healthy control subjects were included in this study. TBSS was used in the diffusion tensor imaging study for whole-brain voxel wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) of WM. RESULTS: When compared to the control group, the whole brain TBSS revealed extensive reductions of FA in the supratentorial WM including corticospinal tract, posterior limb of the internal capsule (PLIC), uncinate fasciculus, inferior longitudinal fasciculus (p < 0.005). The ROI analyses showed RD increment of superior longitudinal fasciculus, AD decrement of cingulum (CIN), external capsule, PLIC and corpus callosum (CC) in patients with hypothyroidism (p < 0.005). Autoimmune and non-autoimmune hypothyroidism patient subgroups showed a significant difference in terms of hippocampus FA, CIN MD, CC MD, CC AD, CIN RD, SLF RD, CC RD (p < 0.005). CIN FA values showed a negative correlation with the Beck Depression Inventory (p = 0.007, r = - 852). CONCLUSIONS: These preliminary results of TBSS analyses represented FA and AD decrement, and RD increment in several WM tracts and indicates the demyelination process underlying pathophysiology of clinical aspects of hypothyroidism.

Proteinuria in Severe Hypothyroidism: A Prospective Study.

CONTEXT: Hypothyroidism is associated with reversible decline in kidney function as measured by estimated glomerular filtration rate (eGFR). eGFR and proteinuria are the most important markers for clinical assessment of kidney function. Though hypothyroidism is associated with proteinuria in cross-sectional data, the impact of treatment on proteinuria is unknown. OBJECTIVE: This study explores the effect of thyroid hormone replacement therapy on eGFR and 24-hour urine protein excretion in patients with severe primary hypothyroidism. DESIGN AND PARTICIPANTS: This study was a prospective, observational cohort study in adults with severe primary hypothyroidism (serum thyrotropin [TSH] > 50 µIU/mL). Individuals with preexisting or past kidney disease, kidney or urinary tract abnormalities, calculi or surgery, diabetes mellitus, or hypertension were excluded. The participants received thyroid hormone replacement therapy. Thyroid functions, eGFR, 24-hour urine protein excretion, and biochemical parameters were measured at baseline and 3 months. SETTING: This study took place at a single center, a tertiary care referral and teaching hospital. RESULTS: Of 44 enrolled participants, 43 completed 3 months of follow-up. At 3 months, serum TSH levels decreased and thyroxine levels increased (P < .001 for both). Significant increases in eGFR (mean difference, 18.25 ± 19.49 mL/min/1.73 m2; 95% CI, 12.25 to 24.25, P < .001) and declines in 24-hour urine protein excretion (mean difference, -68.39 ± 125.89 mg/day; 95% CI, -107.14 to -29.65, P = .001) were observed. Serum cholesterol and low-density lipoprotein levels also significantly decreased (P < .001). CONCLUSIONS: Thyroid hormone replacement therapy in patients with severe primary hypothyroidism improves eGFR and decreases 24-hour urine protein excretion, thereby suggesting reversible alterations.

Primary hypothyroidism with pituitary hyperplasia characterized by hypogonadotropic hypogonadism: a case report and review of the literature.

Primary hypothyroidism with pituitary hyperplasia is a rare entity. It is characterized by hypogonadotropic hypogonadism and growth hormone (GH) deficiency. Despite advances in imaging, it is still not possible to clearly distinguish pituitary hyperplasia from pituitary tumors. We describe a case of primary hypothyroidism associated with pituitary hyperplasia. We reviewed 18 case reports of children or adolescents with short stature or hypogonadotropic hypogonadism from 2001 to 2019. In the present report, we studied a 15-year-old adolescent male whose first diagnosis was low gonadotropin development and growth retardation. Imaging examination revealed nodular signals in the saddle area of the pituitary gland, and endocrine function tests showed primary hypothyroidism. Levothyroxine tablets were taken as replacement therapy. A literature search found that 17 studies reported delayed bone age and growth retardation, but only 6 studies measured GH; 5 studies showed a decrease in GH. To distinguish primary hypothyroidism with subsequent pituitary hyperplasia from pituitary tumors, the definitive diagnosis should be based on clinical symptoms, endocrine examination, and prognosis following medication. For patients with hypothyroidism, thyroid hormone replacement therapy can result in a satisfactory prognosis, as well as improvements in clinical symptoms and serologic values. The pituitary function of those with pituitary hyperplasia can be slowly restored after negative feedback inhibition is rebalanced. However, patients with pituitary tumors should undergo surgery.

Epidemiology of thyroid disorders in the Lifelines Cohort Study (the Netherlands).

BACKGROUND: Thyroid hormone plays a pivotal role in human metabolism. In epidemiologic studies, adequate registration of thyroid disorders is warranted. We examined the prevalence of thyroid disorders, reported thyroid medication use, thyroid hormone levels, and validity of thyroid data obtained from questionnaires in the Lifelines Cohort Study. METHODS: We evaluated baseline data of all 152180 subjects (aged 18-93 years) of the Lifelines Cohort Study. At baseline, participants were asked about previous thyroid surgery and current and previous thyroid hormone use. At follow-up (n = 136776, after median 43 months), incident thyroid disorders could be reported in an open, non-structured question. Data on baseline thyroid hormone measurements (TSH, FT4 and FT3) were available in a subset of 39935 participants. RESULTS: Of the 152180 participants, mean (±SD) age was 44.6±13.1 years and 58.5% were female. Thyroid medication was used by 4790 participants (3.1%); the majority (98.2%) used levothyroxine, and 88% were females. 59.3% of levothyroxine users had normal TSH levels. The prevalence of abnormal TSH levels in those not using thyroid medication was 10.8%; 9.4% had a mildly elevated (4.01-10.0 mIU/L), 0.7% had suppressed (<0.40 mIU/L), while 0.7% had elevated (>10.0 mIU/L) TSH levels. Over 98% of subjects with TSH between 4 and 10 mIU/L had normal FT4. Open text questions allowing to report previous thyroid surgery and incident thyroid disorders proved not to be reliable and severely underestimated the true incidence and prevalence of thyroid disorders. CONCLUSIONS: Undetected thyroid disorders were prevalent in the general population, whereas the prevalence of thyroid medication use was 3.1%. Less than 60% of individuals using levothyroxine had a normal TSH level. The large group of individuals with subclinical hypothyroidism (9.4%) offers an excellent possibility to prospectively follow the natural course of this disorder. Both structured questions as well as linking to G.P.'s and pharmacists' data are necessary to improve the completeness and reliability of Lifelines' data on thyroid disorders.

Incidence of hypothyroidism after treatment for breast cancer-a Danish matched cohort study.

BACKGROUND: Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment. METHODS: Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996-2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities. RESULTS: We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7-1.9) and 1.6% (95%CI = 1.5-1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25-4.67) and 3.81 (95%CI = 3.73-3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11-1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50-2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14-1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45-2.01 and HR = 1.36, 95%CI = 1.17-1.58, respectively]. CONCLUSIONS: BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol.

CONTEXT: Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. OBJECTIVE: To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. DESIGN: Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). SETTING: University hospital setting in The Netherlands. PATIENTS: Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. MAIN OUTCOME MEASURES: HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). RESULTS: During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P ≤ 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P < 0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P < 0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. CONCLUSION: During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism.