Low Free Thyroxine Levels Research Articles

Lower Free Thyroxine Levels Are Associated with Diabetic Kidney Disease in Males with Type 2 Diabetes Mellitus: An Observational Cross-Sectional Study.

Objectives: We aimed to explore the correlation between thyroid function and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 7516 T2DM patients were enrolled and grouped according to DKD status. Clinical parameters, including blood glucose parameters, thyroid function, and indicators of renal impairment, were collected and compared between the DKD and Non-DKD groups. Correlation analysis and univariate/multivariate logistic regression analyses were performed. Results: Age, T2DM duration, the use of insulin and lipid-lowering drugs, systolic and diastolic blood pressure, body mass index, and fasting blood glucose levels were greater in the DKD group than in the Non-DKD group (p < 0.001). Notably, compared with those in the Non-DKD group, patients in the DKD group had lower triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) levels and higher thyrotropin levels (p < 0.001). Univariate logistic regression analysis revealed that T3, T4, FT3, and FT4 levels were negatively correlated with the risk of DKD. Spearman correlation analysis confirmed that T3, T4, FT3, and FT4 levels were negatively correlated with blood urea nitrogen levels, blood creatinine levels, and the urinary albumin-to-creatinine ratio (p < 0.05). Multivariate logistic regression analysis revealed that a greater FT4 level was a protective factor against DKD in T2DM patients, especially in males, with a cut-off value of 13.35 pmol/L (area under the curve = 0.604). Conclusions: Thyroid hormone levels, especially FT4 levels, were significantly negatively correlated with DKD in T2DM patients.

8412 Resolution of Central Hypothyroidism shortly after Transsphenoidal Surgery For Cushing’s Disease

Abstract Disclosure: L. Esper: None. A. Ibrahim: None. N. El Asmar: None. Background: Cushing's disease is a rare endocrine disorder characterized by excessive cortisol production, resulting in various metabolic disturbances. Hypercortisolism is known to cause central hypothyroidism. The mechanism is complex and involves hypercortisolism mediated decreased TRH and TSH secretion in addition to inhibition of peripheral deiodination. This case details the successful management and recovery of a patient with Cushing's disease and reversal of central hypothyroidism after pituitary surgery.Case:A 43-year-old man was evaluated for central hypogonadism, 20 pound weight gain with central weight distribution, and the development of purple abdominal striae for the past year. He had a normal thyroid exam and appeared euthyroid. He was alsodiagnosed with hypertension and prediabetes in the past yearrequiring medical therapy.A low dose dexamethasone suppression test (DST) resulted in AM cortisol of 12.9 mcg/dl. Two adequate 24hr Urinary cortisol measurements showed elevated cortisol excretion at 458 and 378mcg/24. Lab evaluation revealed elevated cortisol levels along with elevated adrenocorticotropic hormone (ACTH) levels(ACTH of 172 pg/ml with a cortisol level of 23.9 mcg/dl). A high dose DST demonstrated suppression of cortisol to 3.4 mcg/dl. MRI pituitary was performed which showed a clearright sided 7mm pituitary adenoma.Thyroid function tests performed were consistent with central hypothyroidism, with low levels of free thyroxine (FT4) at 0.67ng/dl along with an inappropriately low normal thyroidstimulating hormone (TSH) at 0.596 uIU/ml. Total T4 was low at 4 ug/dl in addition to a low total T3 of 66 ng/dl. Remaining labs revealed central hypogonadism along with slightly elevated prolactin of 16 ng/ml. He was not started on thyroid hormone.He then underwent transsphenoidal surgery for tumor removal. He developed post-operative adrenal insufficiency (cortisol 2.12 mcg/dl) 16 hours post-op after which he was started on hydrocortisone replacement, indicating remission. 12 hours post-op, his TSH was 0.656 uIU/ml with a free t4 of 0.79 ng/dl, both in the normal range. 36 hours post-op, TSH was 0.524 uIU/ml and free t4 was 1.15 ng/dl. Histopathological examination confirmed the diagnosis of an ACTH-secreting pituitary adenoma.At 4 weeks post-op, thyroid labs showed normal FT4 (1.07ng/dl) and TSH (2.06uIU/ml). Conclusion: Hypercortisolism causes a global inhibition of the thyroid axis, with decreased levels of TSH, T4, and T3 (1). Previous studies suggest the monitoring of thyroid function at 6 and 12 months after surgical cure of hypercortisolism. Our case suggests that the resolution of hypothyroidism occurs shortly after surgery for Cushing’s disease and the need for earlier monitoring. Presentation: 6/3/2024

A confusing situation in the clinic: isolated maternal hypothyroxinemia

Isolated maternal hypothyroxinemia (IMH) is a common problem in the clinic. There is a normal maternal thyroid stimulating hormone (TSH) level with a low maternal free thyroxine (FT4) level. The aim of this review is to explain IMD in the light of current literature and to contribute to clinicians in the management of IMH. Iodine deficiency is the most important factor in etiology. The effects of IMH on the pregnant woman and the fetus are not clear. However, it is a serious concern among serious clinicians, especially considering the importance of the effect of thyroid hormones on fetal brain development. As for the treatment of IMH, the number of studies conducted is not sufficient and there is no consensus and evidence on levothyroxine treatment. However, there is a consensus on iodine supplementation and it is recommended to take 250 mg of iodine daily. As a result, IMH is a problem that should be taken seriously during pregnancy and care should be taken regarding its diagnosis and treatment. Additionally, more research is needed on the effects and treatment of IMH on pregnant and fetal health

Clinical efficacy of multigene panels in the management of congenital hypothyroidism with gland in situ.

Congenital hypothyroidism (CHT) is a diverse condition with various genetic etiologies. This study aimed to investigate the utility of next-generation sequencing (NGS) analysis in guiding treatment decisions and predicting prognosis for CHT patients with gland in situ (GIS). A retrospective analysis was conducted on 33 CHT patients with GIS who underwent NGS analysis at a single institution between 2018 and 2023. Patients were classified as having permanent (PCH), transient congenital hypothyroidism, or ambiguous congenital hypothyroidism (ACH) CHT based on their response to levothyroxine discontinuation at 3 years of age. Among the 33 patients, genetic variants were identified in 26, with the most prevalent variants found in DUOX2 (26.92%), TSHR (30.77%), TG (19.35%), and DUOXA2 (19.23%). Patients with high initial thyroid-stimulating hormone levels (>50 mIU/L) and low free thyroxine levels (<0.89 ng/dL) at diagnosis tended to have compound heterozygous or homozygous variants in DUOX2, DUOXA2, and TG, and were more likely to develop PCH. In contrast, patients with heterozygous variants in these genes often exhibited ACH. TSHR variants were associated with diverse clinical manifestations, ranging from PCH to ACH, and were more common in patients with initial thyroid-stimulating hormone levels <50 mIU/L. The study highlights the potential utility of NGS analysis in predicting the clinical course and guiding treatment decisions for CHT patients with GIS. Genetic analysis may aid in determining the appropriate duration of levothyroxine therapy and monitoring strategies, particularly in cases where traditional clinical indicators are inconclusive.

Massive fetal goiter treated by intra-amniotic injection of levothyroxine: a case report

Abstract Objectives Fetal dyshormonogenetic goiter is a rare condition associated with perinatal complications and sequelae in infants. Although prenatal management remains controversial, further evidence is required for optimal management. Case presentation A 30-year-old pregnant woman with no history of thyroid disease was referred to our hospital with polyhydramnios. Fetal ultrasonography revealed fetal goiter. Cordocentesis revealed increased thyroid-stimulating hormone (TSH) and low levels of free thyroxine 4 (fT4), which was the basis of diagnosis of fetal hypothyroidism. Intra-amniotic injections of levothyroxine were administered, resulting in a reduction in the goiter size, amount of amniotic fluid, and level of maternal TSH. The mother was euthyroid during pregnancy. The infant was delivered vaginally at full term with a normal thyroid size and no respiratory disorders except hypothyroidism. At 2 years of age, her neurodevelopment is normal. Conclusions Intra-amniotic injections of levothyroxine for fetal hypothyroidism with massive goiter and polyhydramnios may improve perinatal outcomes.

A Japanese Boy with Dysmorphic Syndrome with Multiple Pituitary Hormone Deficiency and Gingival Fibromatosis Due to a Pathogenic KCNQ1 Variant.

A six-year-old boy presented with short stature and gingival fibromatosis (GF). Dysmorphic features included slant optic fissures, a high-arched palate, thick earlobes, and an edematous face. Laboratory tests showed low levels of serum insulin-like growth factor-1 and serum free thyroxine but normal serum thyrotropin levels. Provocative tests suggested growth hormone deficiency, central hypocortisolemia, and hypothalamic hypothyroidism. At 12 years old, hypogonadotropic hypogonadism was observed. Next-generation sequencing revealed a heterozygous missense variant, KCNQ1 p. (P369L), in the proband and mother. The coexistence of multiple pituitary hormone deficiencies and GF helps diagnose KCNQ1-variant dysmorphic syndrome through genetic testing.

Clinical and molecular analyses of isolated central congenital hypothyroidism based on a survey conducted in Japan.

Central congenital hypothyroidism (CH) can occur as an isolated deficiency or as part of combined pituitary hormone deficiency. Unlike primary CH, central CH cannot be detected by newborn screening (NBS) using dry filter paper blood TSH levels, and early diagnosis remains challenging. In this study, the clinical and genetic backgrounds of patients with isolated central CH were determined through a questionnaire-based survey among members of the Japanese Society for Pediatric Endocrinology. The known causes of isolated central CH were studied in 14 patients, including six with previously reported patient data. The results revealed IGSF1 and TBL1X pathogenic variants in nine and one patient, respectively. All six patients with low free thyroxine (FT4) levels detected in NBS carried IGSF1 pathogenic variants. Five patients with isolated central CH diagnosed after 3 months of age were variant-negative, except for one female patient with a heterozygous IGSF1 variant. Two of the four variant-negative patients and a variant-positive patient were diagnosed with pituitary hypoplasia. One and two patients with IGSF1 variant had obesity and intellectual disability, respectively. Left amblyopia was identified in the patient with a TBL1X variant. The study revalidated that IGSF1 variants comprise the most frequent pathogenic variant in patients with isolated central CH in Japan. The neonatal period is the optimal time for the diagnosis of central CH, particularly IGSF1 abnormalities, and the introduction of T4 screening should be considered in the future, taking cost-effectiveness into consideration.

Prognostic role of euthyroid sick syndrome in MIS-C: results from a single-center observational study.

Euthyroid sick syndrome (ESS) is characterized by low serum levels of free triiodothyronine (fT3) with normal or low levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) and is reported in different acute clinical situations, such as sepsis, diabetic ketoacidosis and after cardiac surgery. Our aim was to evaluate the predicting role of ESS for disease severity in patients with Multisystem Inflammatory Syndrome in children (MIS-C). A single-centre observational study on consecutive patients with MIS-C. Before treatment clinical, and laboratory data were collected and, in a subset of patients, thyroid function tests were repeated 4 weeks later. Variables distribution was analyzed by Mann-Whitney U-test and correlations between different parameters were calculated by Spearman's Rho coefficient. Forty-two patients were included and 36 (85.7%) presented ESS. fT3 values were significantly lower in patients requiring intensive care, a strong direct correlation was shown between fT3 and Hb, platelet count and ejection fraction values. A significant inverse correlation was retrieved between fT3 levels and C-reactive protein, brain natriuretic peptide, IL-2 soluble receptor and S-100 protein. Subjects with severe myocardial depression (EF < 45%) had lower fT3 values than subjects with higher EF. The thyroid function tests spontaneously normalized in all subjects who repeated measurement 4 weeks after admission. ESS is a frequent and transient condition in acute phase of MIS-C. A severe reduction of fT3 must be considered as important prognostic factor for severe disease course, with subsequent relevant clinical impact in the management of these patients.

Increased prevalence of nodular thyroid disease in patients with Klinefelter syndrome

PurposeThyroid dysfunction in patients with Klinefelter syndrome (KS) remains an unresolved issue. Although low free thyroxine (FT4) levels within the normal range and normal thyroid stimulating hormone (TSH) levels have been reported, there is currently no data on nodular thyroid disease in this population. This study aims to evaluate the results of thyroid ultrasound (US) examinations in KS patients compared with healthy controls.MethodsA cohort of 122 KS and 85 age-matched healthy male controls underwent thyroid US screening and thyroid hormone analysis. According to US risk-stratification systems, nodules ≥1 cm were examined by fine needle aspiration (FNA).ResultsThyroid US detected nodular thyroid disease in 31% of KS compared to 13% of controls. No statistical differences in the maximum diameter of the largest nodules and in moderate and highly suspicious nodules were found between patients and the control group. Six KS patients and two controls with nodules underwent FNA and were confirmed as cytologically benign. In line with published data, FT4 levels were found significantly near the lower limit of the normal range compared to controls, with no differences in TSH values between the two groups. Hashimoto’s thyroiditis was diagnosed in 9% of patients with KS.ConclusionsWe observed a significantly higher prevalence of nodular thyroid disease in KS compared to the control group. The increase in nodular thyroid disease is likely linked to low levels of FT4, inappropriate TSH secretion, and/or genetic instability.

MAFLD in Patients with Cushing's Disease Is Negatively Associated with Low Free Thyroxine Levels Rather than with Cortisol or TSH Levels.

This study aims to analyze the clinical characteristic of metabolic associated fatty liver disease (MAFLD) in patients with active Cushing's disease (CD) and determine associations of thyroid hormones with MAFLD. Patients with active CD were included in this cross-sectional study. All subjects were assessed for hepatic steatosis by abdominal ultrasonography and thyroid functions. Demographic and clinical characteristic parameters were collected for correlation analysis and logistic analysis. 290 individuals with active CD were included in Huashan hospital from January 2014 to February 2022. We found that the prevalence of CD with MAFLD was 33.79%. The MAFLD group had a lower level of FT4 and a higher level of FT3/FT4 but no difference in levels of cortisol, 24 h UFC, TSH, TT4, TT3, and FT3. Correlation analysis showed positive associations of TSH, TT4, TT3, FT3, and FT3/FT4 with BMI. In age-, BMI-, sex-, cortisol-, and 24 h UFC-adjusted analysis, FT4 was independently associated with MAFLD in patients with CD. This association remained similar even after adjusting for the presence of metabolic syndrome components. Lower FT4 levels were associated with higher risk of MAFLD in patients with CD. FT4 may be used as a helpful indicator to predict MAFLD and provide novel ideas for the treatment of MAFLD in patients with CD in the future.

Association between third trimester maternal isolated hypothyroxinemia and adverse pregnancy outcomes.

To study the effects of third trimester maternal isolated hypothyroxinemia (serum low free thyroxine and normal thyroid stimulating hormone level) on pregnancy outcomes, we performed a retrospective cohort study in women with singleton pregnancy between February 2009 and June 2012. Pregnant women were assigned to two groups, a hypothyroxinemia group (with maternal isolated hypothyroxinemia in the third trimester and normal thyroid function in the first and second trimesters) and a control group (with normal serum thyroid functions). The pregnancy outcomes, including preterm birth, fetal distress, birth weight, premature rupture of membranes, and Apgar score at one minute after the birth, were recorded and compared between the two groups. A total of 3,945 pregnant women (median age 26 year old) were included in the study, with 195 women in the hypothyroxinemia group and 3,750 women in the control group. Compared with the women in the control group, women in the hypothyroxinemia group had higher incidences of premature rupture of membranes and low Apgar score at one minute after the birth. The multivariate logistic regression analysis showed that the low third trimester serum thyroxine level was the independent risk factor for the premature rupture of membranes and low Apgar score. There were no statistically significant differences in preterm birth, macrosomia, and intrauterine fetal distress between two groups. Third trimester maternal isolated hypothyroxinemia was associated with adverse pregnancy outcomes. The maternal serum thyroxine level should be monitored during late pregnancy and necessary management should be applied to improve the pregnancy outcomes.

Serum lipid profile in relation to free thyroxine and the effect of levothyroxine treatment on lipids in patients with isolated hypothyroxinemia during pregnancy: a single-center retrospective study

BackgroundThyroid function is widely considered a lipid metabolism regulator. However, studies on lipid metabolism in pregnant women with low free thyroxine (FT4) levels are limited and inconclusive. Furthermore, the association between maternal FT4 deficiency and adverse lipid metabolic parameters is unknown. Therefore, we aimed to investigate this association and the effects of levothyroxine (L-T4) treatment on these metabolic indicators.MethodsThis retrospective study included 164 patients with isolated hypothyroidism (IH) (FT4 levels below the 5th percentile with normal thyroid stimulating hormone levels according to the gestational-specific reference range) and 407 euthyroidism patients (control group who had regular antenatal examinations at Zhejiang Provincial People's Hospital, Hangzhou, China) between January 1, 2019, and December 31, 2020. Patients with IH were divided into levothyroxine (L-treatment group, n = 77) and dietary iodine supplement treatment groups (dietary treatment group, n=87) according to the hospital’s treatment policy and clinical experience. The intervention lasted for at least 8 weeks. Metabolic indicators, including thyroid function and lipid parameters, were collected at least twice before and after the intervention. Other data collected included maternal age, history of abortion, prepregnancy BMI, and gestational weight gain (Fig. 1).ResultsCompared with the control group, Patients with IH had a higher degree of dyslipidemia, reflected in elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) levels. In IH patients, an inverse correlation was found between FT4 and TG levels, which remained after adjusting for prepregnancy BMI. The L-treatment group demonstrated a significantly slower rate of hypercholesterolemia progression during pregnancy than the dietary treatment group. In addition, there was a relationship between the therapeutic effect and the degree of disease, with the main factors being FT4, TSH and TG levels prior to starting treatment.ConclusionsLow FT4 levels were associated with elevated blood lipid levels. Serum FT4 and lipid levels in patients could be improved by medical intervention.

Association of maternal triglyceride responses to thyroid function in early pregnancy with gestational diabetes mellitus.

The prevalence of Gestational Diabetes Mellitus (GDM) is increasing globally, and high levels of triglyceride (TG) and low levels of free thyroxine (FT4) in early pregnancy are associated with an increased risk of GDM; however, the interaction and mediation effects remain unknown. The aim of the present study is to examine the impact of FT4 and TG combined effects on the prevalence of GDM and the corresponding casual paths among women in early pregnancy. This study comprised 40,156 pregnant women for whom early pregnancy thyroid hormones, fasting blood glucose as well as triglyceride were available. GDM was diagnosed using a 2-hour 75-g oral glucose tolerance test (OGTT) according to the American Diabetes Association guidelines, and the pregnant women were grouped and compared according to the results. An L-shaped association between FT4 and GDM was observed. The prevalence of GDM increased with increasing TG levels. After accounting for multiple covariables, the highest risk for GDM was found among pregnant women of lower FT4 with the highest TG concentrations (odds ratio, 2.44, 95% CI, 2.14 to 2.80; P<0.001) compared with mothers of higher FT4 with the TG levels in the lowest quartile (Q1). There was a significant interaction effect of maternal FT4 and TG levels on the risk for GDM (P for interaction = 0.036). The estimated proportion of the mediating effect of maternal TG levels was 21.3% (95% CI, 15.6% to 36.0%; P < 0.001). In the sensitivity analysis, the mediating effect of TG levels was stable across subgroups. This study demonstrated an L-shaped association between maternal FT4 levels and GDM and the benefit of low TG levels, in which maternal TG levels act as an important mediator in this association. Our findings suggested that pregnant women who treat hypothyroidism should also reduce triglycerides levels in early pregnancy to prevent GDM development.

PSAT350 Autoimmune Polyglandular Syndrome Type II Presenting with Hashimoto's Thyroiditis, Diabetes Mellitus Type I and Addison's Disease: A Case Report

Abstract A. BACKGROUND/SIGNIFICANCE Autoimmune polyglandular syndrome Type II (APS-II) is a rare polyendocrinopathy with a prevalence of 1 to 2 in 100,000, instigated by immune-mediated destruction of several organs. Knowledge of APS-II is crucial, especially in the early detection of polyglandular disorder among patients with endocrine autoimmunity. B. CASE This case is of a 40-year-old male who initially presented with Grave's disease after showing signs and symptoms of hyperthyroidism, as supported by low thyrotropin (&amp;lt;0.05 uIU/mL; nv: 0.35-4.94) and high free thyroxine levels (2.05 ng/dL, nv: 0.71-1.85). He was maintained on methimazole. Five months following diagnosis, he developed symptoms of Diabetes Mellitus Type 1 (T1DM) as confirmed by high capillary blood glucose, undetectable C-peptide, and positive anti-Glutamic acid decarboxylase. Insulin and rosuvastatin were added on his maintenance medications. Ten months later, he discontinued methimazole and became lost to follow-up. One month after discontinuation, he sought consult again after experiencing symptoms of fatigue, muscle cramps, cold intolerance, forgetfulness, abdominal pain, diarrhea, and episodes of hypoglycemia at home. On examination, he was noted to have hypotension of 80/60 mmHg and skin hyperpigmentation. His random blood sugar was 408 mg/dL. High thyrotropin (57.8777 uIU/Ml, nv: 0.35-4.94), low free thyroxine (0.57 ng/dL, nv: 0.71-1.85), and positive antithyroid peroxidase antibody levels revealed Hashimoto's thyroiditis. Low fasting 8 am serum cortisol (81 nmol/L, nv: 138-635) and low serum cortisol 30 mins (403.85 nmol/L) and 1 hour (542.31 nmol/L, normal response: &amp;gt;550 nmol/L) after adrenocorticotropic hormone stimulation test in addition to the clinical manifestations, supported the diagnosis of Addison's disease. With the combination of Addison's disease, Autoimmune thyroid disease, and T1DM, a diagnosis of APS Type II was made. Management included insulin, prednisone, and levothyroxine. These resulted in significant improvement in the patient's symptoms. He is now clinically well and compliant to regular follow-up. C. LEARNING POINTS/CONCLUSION It is crucial in APS-II management to identify and manage the associated autoimmune disorders to prevent significant morbidity and mortality. Therefore, in the presence of any autoimmune disorder, a high index of suspicion for APS-II is essential. There should be regular follow-up and observation of patients with autoimmune endocrine disorders to ensure early detection of APS-II. Patient health education must include identifying symptoms of the disorders for which they are at high risk. Keywords: APS Type 2, Addison's Disease, DM Type 1, Hashimoto's Thyroiditis Sources of Support: None Conflicts of Interest: None Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The application of new concepts of the assessment of the thyroid state to pregnant women.

Recently proposed concepts regarding the nature and assessment of the thyroid state have provided a model more consistent with empiric evidence. It now appears likely that there are no such entities as thyroid set points and individual euthyroidism. Rather than there being discrete thyroid states, peripheral organ parameters are associated with thyroid function in a continuous manner. Thyroid hormone levels and, in particular, levels of free thyroxine now appear to be superior to thyrotropin levels as indicators of the thyroid state. Complicating the assessment of the correlations of the thyroid state with pregnancy outcomes are the contribution of the placenta to maternal thyroid function, fetal thyroid development, the multiple potential pathways to any particular outcome, the likely presence of small critical periods of time, the differing genetics of fetal and maternal tissues, and the unreliability of thyroid hormone assays. Nevertheless, there is no apparent reason for there to be a change in pregnancy to the basic principles of thyroid hormone action. The relationships between mild abnormalities of the thyroid state and pregnancy outcomes and the value of treating such mild abnormalities remain uncertain and controversial. The evidence suggests that further investigation of these clinical questions might better be based on thyroid hormone, particularly free thyroxine, levels. In the investigation of borderline low thyroid states, the categories of subclinical hypothyroidism and isolated hypothyroxinemia might both be abandoned with attention being directed to low free thyroxine levels regardless of the thyroid-stimulating hormone (TSH) levels. For these changes to occur, there would ideally be improvements in the assays for free thyroxine in pregnancy. The evidence suggests that, just as in the non-pregnant situation, pregnancy guidelines based on thyrotropin levels may need revision.

Novel TSHB variant (c.217A>C) causing severe central hypothyroidism and pituitary hyperplasia.

SummaryBiallelic pathological variants in the thyroid stimulating hormone (TSH) subunit β gene (TSHB) result in isolated TSH deficiency and secondary hypothyroidism, a rare form of central congenital hypothyroidism (CCH), with an estimated incidence of 1 in 65 000 births. It is characterised by low levels of free thyroxine and inappropriately low serum TSH and may therefore be missed on routine neonatal screening for hypothyroidism, which relies on elevated TSH. We describe a patient with CCH who developed recurrence of pituitary hyperplasia and symptomatic hypothyroidism due to poor compliance with thyroxine replacement. She was diagnosed with CCH as a neonate and had previously required trans-sphenoidal hypophysectomy surgery for pituitary hyperplasia associated with threatened chiasmal compression at 17 years of age due to variable adherence to thyroxine replacement. Genetic testing of TSHB identified compound heterozygosity with novel variant c.217A>C, p.(Thr73Pro), and a previously reported variant c.373delT, p.(Cys125Valfs*10). Continued variable adherence to treatment as an adult resulted in recurrence of significant pituitary hyperplasia, which subsequently resolved with improved compliance without the need for additional medications or repeat surgery. This case describes a novel TSHB variant associated with CCH and demonstrates the importance of consistent compliance with thyroxine replacement to treat hypothyroidism and prevent pituitary hyperplasia in central hypothyroidism.Learning pointsPathogenic variants in the TSH subunit β gene (TSHB) are rare causes of central congenital hypothyroidism (CCH).c.217A>C, p.(Thr73Pro), is a novel TSHB variant, presented in association with CCH in this case report.Thyroxine replacement is critical to prevent clinical hypothyroidism and pituitary hyperplasia.Pituitary hyperplasia can recur post-surgery if adherence to thyroxine replacement is not maintained.Pituitary hyperplasia can dramatically reverse if compliance with thyroxine replacement is improved to maintain free thyroxine (FT4) levels in the middle-to-upper normal range, without the need for additional medications or surgeries.

Could maternal thyroid function during pregnancy affect daughters’ age at menarche through child growth? A mediation analysis

Early menarche is associated with adverse health outcomes during adolescence as well as breast and other reproductive cancers later in adulthood. However, the causes of early menarche and the pathways through which they operate are not fully understood. Though maternal thyroid function during pregnancy affects child growth, and rapid childhood growth is associated with a decreased age at menarche, the relationship between prenatal maternal thyroid function and daughters’ age at menarche has not been examined. We conducted a mediation analysis in a historical cohort of 260 mother-child pairs to estimate the total and indirect effects of maternal prenatal thyroid function on daughters’ age at menarche. No association was observed between thyroid stimulating hormone (TSH) or anti-thyroid peroxidase antibodies (ATPO) and daughters’ age at menarche. Using a sample-specific, a-priori cutoff at the 10th percentile, low levels of maternal free thyroxine (FT4) were associated with earlier daughter age at menarche, with a hazard ratio (95 % CI) of 1.70 (1.02, 2.84) comparing the bottom 10th percentile with the top 90th percentile of exposure levels. Higher maternal FT4 was associated with rapid child weight gain from ages 5–9, and rapid child weight gain from ages 5–9 was associated with earlier age at menarche; the estimated indirect effect of this pathway was null. While maternal FT4 is associated with earlier age at menarche in daughters, this is not mediated by rapid weight gain in our study population, suggesting that maternal FT4 is operating through a different pathway.

An Unexpected Thoracic Finding in a Patient With COVID-19

Question: A 75-year old woman presented to the emergency department with a history of epigastric discomfort and rapidly worsening thoracic pain. She had no fever or cough. On physical examination, she appeared overweight (102 kg, height 162 cm). Laboratory examination revealed normal cardiac troponin levels and slight increase in inflammatory markers (C-reactive protein and neutrophil-lymphocyte ratio). As a nasal screening swab was positive for coronavirus 2019 (COVID-19) infection, she was transferred to the COVID isolation ward. A subsequent computed tomography scan of the chest showed no interstitial lung disease. However, the presence of a monstrous esophageal dilatation with sigmoid shape and dislodgment of the surrounding structures was seen. The esophagus appeared full of solid content compatible with accumulated undigested food residues (Figure A–C). The patient was then referred to our gastroenterology unit. Upper endoscopy was performed under general anesthesia with endotracheal intubation. Endoscopic esophageal findings are shown in Figure D. What is the most likely diagnosis and how should it be managed? Look on page 1112 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The patient was suffering from type II achalasia, which was refractory to previous endoscopic and surgical treatment. In detail, she had undergone three endoscopic pneumatic dilation sessions in 2005 and ultimately laparoscopic Heller-Dor myotomy in 2015. In 2018, an esophageal high-resolution manometry was unsuccessful, probably because the catheter did not reach the stomach in the sigmoid dilated esophagus. We treated our patient with prolonged fasting and nasoesophageal tube placement at 35 cm from the incisors teeth. Multiple daily irrigations with saline solution were performed without apparent benefit. Three endoscopic sessions were then performed to clean the entire esophagus from the huge amount of feces-like food residues. We believe that 2 reasons were behind this ominous presentation. First, the patient suffered from poorly controlled hypothyroidism for which she was taking levothyroxine per os. Laboratory examination revealed high levels of thyrotropin (103 μU/mL) and low levels of free thyroxine (<2.5 pg/mL) and free tri-iodothyronine (1.5 pg/mL). Her severe hypothyroidism was probably due to the inability of oral levothyroxine to reach the stomach, thus decreasing the subjective awareness of her own clinical condition. Second, she was edentulous and this affected the chewing phase, favoring episodes of food impaction and accumulation of food in the esophagus. Surprisingly, she did not experience weight loss and her general nutritional status was good. Achalasia is an uncommon esophageal motility disorder, usually characterized by dysphagia to solids and liquids, chest pain, regurgitation, and weight loss. High-resolution esophageal manometry is the gold standard test for the diagnosis. Diagnostic findings include distal esophageal aperistalsis and integrated relaxation pressure of >15 mm Hg. Achalasia is classified as type 1 classic, type 2 compartmentalized high pressure in esophageal body, and type 3 spastic.1Weusten B.L.A.M. Barret M. Bredenoord A.J. et al.Endoscopic management of gastrointestinal motility disorders - part 1: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.Endoscopy. 2020; 52: 498-515Crossref PubMed Scopus (41) Google Scholar In the last few years, peroral endoscopic myotomy is the most frequent endoscopic intervention for achalasia leading to outcomes that are comparable with those of laparoscopic Heller myotomy. Additional interventions are represented by pneumatic dilation and botulinum toxin injection. Esophagectomy is the last option to manage end-stage achalasia.2Familiari P. Greco S. Volkanovska A. et al.Achalasia: current treatment options.Expert Rev Gastroenterol Hepatol. 2015; 9: 1101-1114Crossref PubMed Scopus (11) Google Scholar,3Hammad A. Lu V.F. Dahiya D.S. et al.Treatment challenges of sigmoid-shaped esophagus and severe achalasia.Ann Med Surg (Lond). 2020; 61: 30-34Crossref PubMed Scopus (5) Google Scholar Peroral endoscopic myotomy was not considered for our patient because of the patent cardia (Figure E), the lack of manometric data, and the poor expected outcome in sigmoid esophagus. She was referred to the endocrinologist for further therapeutic workup. Moreover, dental prosthesis implantation was recommended.

Risk factors for hypothyroidism and thyroid hormone replacement after hemithyroidectomy in papillary thyroid carcinoma.

Thyroid lobectomy is now preferred over total thyroidectomy to preserve thyroid function and reduce complications in patients with low-risk papillary thyroid carcinoma (PTC). One inevitable consequence of thyroidectomy includes hypothyroidism. This study aimed to evaluate the risk factors for hypothyroidism and thyroid hormone replacement after hemithyroidectomy in patients with PTC. We retrospectively studied 353 patients with PTC who underwent hemithyroidectomy with or without central neck dissection from January 2012 to January 2019. We excluded patients who had hypo- or hyperthyroidism preoperatively and those who underwent total or subtotal thyroidectomy. We analyzed various risk factors related to postoperative hypothyroidism and thyroid hormone supplementation. Of the patients, 54.7% showed hypothyroidism after hemithyroidectomy (n=193 with n=157, subclinical hypothyroidism; n=36, overt hypothyroidism). Ninety-one percent of postoperative hypothyroidism cases developed within 7 months postoperatively. Eventually, 43.1% (n=152) of patients received levothyroxine after hemithyroidectomy. Preoperative high thyroid-stimulating hormone (TSH) level and low free thyroxine (fT4) level were significantly associated with postoperative hypothyroidism and the need for thyroid hormone supplementation postoperatively. Preoperative TSH and fT4 levels are predictive risk factors of hypothyroidism and need for supplementation of levothyroxine after hemithyroidectomy in patients with PTC. Finally, approximately 43% of patients need levothyroxine supplementation after hemithyroidectomy, and individual preoperative counseling is necessary for these patients.

Prevalence of Subclinical Hypothyroidism in Chronic Kidney Disease in a Population-based Study: Tehran Thyroid Study.

BackgroundChronic kidney disease (CKD) is a rising public health concern that has detrimental effects on cardiovascular health and overall survival. Subclinical hypothyroidism (SCH) has been associated with poor outcomes in the general population. It is thought to be more prevalent in CKD subjects, and their coexistence may contribute to poor outcomes in these patients. We aimed to determine the prevalence of SCH in CKD.MethodsUsing data from the Tehran thyroid study, which is a prospective population-based cohort study, adult subjects with an estimated Glomerular Filtration Rate (eGFR) of 60 mL/min/1.73 m2 or less were selected for studying the prevalence of thyroid abnormalities, as well as other known cardiovascular risk factors.ResultsOf 5,626 subjects recruited, 823 (14.6%) individuals had CKD. Individuals with CKD were older, heavier, had a higher prevalence of diabetes, higher serum thyrotropin, and thyroid peroxidase anti-body levels, but lower free thyroxine levels. The prevalence of SCH was 7.3% and 5.2% (P < 0.001) in kidney disease and non-kidney disease subjects, respectively. However, there was no difference in the risk of SCH between CKD and non-CKD subjects after adjustment for age, sex, BMI, smoking, and TPOAb (OR: 1.28; 95%CI, 0.89 - 1.83). None of the metabolic markers compared between the CKD subgroups of those with and without SCH remained statistically significantly different after adjusting for age and gender.ConclusionsThe prevalence of SCH was not higher in CKD after controlling for confounding factors. Besides, CKD subjects with and without SCH had no different metabolic parameters.