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Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimers disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-β. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-β, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

OBJECTIVE: To examine the relationship between thyroid status and incident kidney dysfunction/chronic kidney disease (CKD) progression. PATIENTS AND METHODS: We examined incident thyroid status, ascertained by serum thyrotropin (TSH) levels measured from January 1, 2007, through December 31, 2018, among 4,152,830 patients from the Optum Labs Data Warehouse, containing deidentified retrospective administrative claims data from a large national health insurance plan and electronic health record data from a nationwide network of provider groups. Associations of thyroid status, categorized as hypothyroidism, euthyroidism, or hyperthyroidism (TSH levels >5.0, 0.5-5.0, and 5.0-10.0, >10.0-20.0, and >20.0 mIU/L, respectively) were associated with increasingly higher risk of the composite end point (reference: TSH level, 0.5 to

Immune checkpoint inhibitors (ICIs) can trigger immune-related adverse events (irAEs). The appearance pattern of irAEs, who is prone to them, and their mechanisms are still uncertain. In this study, we aimed to monitor patients initiated on ICIs for endocrinological aspects and to investigate the potential predictive markers in the development of endocrine-irAEs. The study prospectively included 43 patients with metastatic disease scheduled for anti-PD-1/ L1 therapy. Endocrinological follow-up was conducted at specified intervals as well as in response to any additional reported complaints. Serum concentrations of CXCL10, IL-1beta, and IL-17A were measured prior to ICI and during the endocrine-irAEs. A total of 39.5% of the patients experienced endocrine-irAEs, with a median onset time of 3 months. Among patients, 34.9% developed thyroid-related adverse events, and 4.6% experienced hypophysitis. Thyroid autoantibodies were associated with a higher incidence of thyroid-related irAEs (P = 0.004). In the irAE group, median pre-ICI CXCL10 and baseline thyroid stimulating hormone (TSH) levels were significantly higher, baseline total testosterone level in men was lower than in the non-irAE group (P < 0.05), whereas IL-1beta and IL-17A levels did not differ (P > 0.05). Serum CXCL10, IL-1beta, and IL-17A concentrations did not differ significantly pre-ICI and during adverse events (P > 0.05). Pre-ICI CXCL10 concentration was correlated positively with anti-TPO levels in patients with at least one thyroid autoantibody positivity (r = 0.706, P = 0.01) and negatively with baseline total testosterone level of men (r = 0.509, P = 0.002). Our results suggest that higher pre-ICI serum CXCL10 and TSH levels might have a predictive role in the development of endocrinopathies. Besides, baseline thyroid antibody measurements could be beneficial in predicting thyroid dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Acute or chronic exposure to excess iodine has detrimental effects on thyroid physiology; therefore, this study aimed to determine the prevalence of overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) in an elderly population residing in geographical areas with chronic exposure to excess iodine intake and to analyse contributing risk factors. Design: This cross‐sectional study was conducted from 2016 to 2017 in areas of Jiangsu Province that have documented chronic exposure to high iodine intake. Patients: We enroled 2559 adult participants using a multistage, stratified sampling method. Measurements: Urinary iodine concentration (UIC), serum thyroid‐stimulating hormone (TSH) level and other relevant parameters were measured. Demographic information was recorded using a standardized questionnaire. The age‐specific TSH references were determined by the National Academy of Clinical Biochemistry guidelines. Univariate and multivariate logistic regression analyses were performed to identify risk factors for hypothyroidism in the study population. Results: The median UIC of participants was 307.3 µg/L (interquartile range: 200.7, 469.8 μg/L). The prevalence of OH in subjects ≥70 years using laboratory reference ranges was 2.37%; however, it decreased to 1.78% with the use of an age‐specific reference range. Similarly, the prevalence of SCH also declined drastically from 29.59% to 2.96% with the application of an age‐specific reference range. In both univariate and multivariate models, advanced age, female gender and high UIC were identified as risk factors for hypothyroidism. Conclusions: Usage of age‐specific TSH reference ranges led to a significantly lower prevalence of OH and SCH in the study population, thus preventing unnecessary over‐diagnosis and over‐treatment. [ABSTRACT FROM AUTHOR]

Purpose: The association between thyroid dysfunction and exudative age‐related macular degeneration (AMD) is unknown. Methods: In this Danish longitudinal nationwide registry‐based cohort study we included all Danish residents aged 50–100 between 2008 and 2018. Using the Danish national registries, we studied the association between thyroid dysfunction and exudative AMD. Thyroid dysfunction was classified as two consecutive redeemed prescriptions of thyroid hormones (hypothyroidism) or anti‐thyroid medication (hyperthyroidism). Exudative AMD was classified as an ICD diagnosis of AMD and a code for anti‐VEGF treatment. All patients are treated for exudative AMD in a hospital in Denmark, and we therefore have complete registration of this patient group. Results: We included 2 087 305 individuals, of which 1 072 567 (51.4%) were women; 59 318 (2.8%) had hypothyroidism, and 33 922 (1.6%) had hyperthyroidism. During a median follow‐up of 11 years, 26 998 (1.3%) people developed exudative AMD. Hypothyroidism (adjusted hazard ratio [HR]: 1.17; 95% confidence interval [CI] 1.10–1.25; p < 0.001) and hyperthyroidism (HR: 1.23; 95% CI:1.13–1.34; p < 0.001) were both associated with the development of exudative AMD. The age‐stratified analyses yielded similar results to the main analyses, except that the risks were exaggerated in the older part of the population. Conclusion: This is the first longitudinal nationwide study showing that both hypo‐ and hyperthyroidism are associated with an increased risk of exudative AMD. AMD is a quantitative problem in the population and our findings could have a public health impact. Further studies are needed to study the underlying mechanisms of the association. [ABSTRACT FROM AUTHOR]

Persistent symptoms are common in the general population and even more so in people with hypothyroidism. When symptoms are unexplained and brought to medical attention, they can be referred to as medically not yet explained symptoms (MNYES), a term preferred to other descriptors by patients, care-givers and experts. MNYES might be neglected by endocrinologists or misattributed to hypothyroidism. Awareness of MNYES could open up more effective and less harmful interventions for patients who present to endocrinologists with unexplained symptoms than costly over-investigations and over-treatment with thyroid hormones (such as levothyroxine and liothyronine). The role of the endocrinologist is to recognize and acknowledge that MNYES could be underlying a patient's presentation, to communicate effectively with the patient and others involved in the patient's care, to apply a 'two-track approach' in management by paying equal attention to physical and psychosocial contributors, and to collaborate with other relevant health professionals. Categorization of patients into levels of risk for symptom deterioration helps in selecting suitable therapies. Effective management of MNYES demands time, training, expertise and resources. Medically not yet explained symptoms (MNYES) are an important consideration in patients treated for hypothyroidism who experience persistent symptoms. This Perspective brings attention to the issue of MNYES in hypothyroidism and considers effective management. [ABSTRACT FROM AUTHOR]

Background: The neuropathophysiological mechanisms of brain damage underlying hypothyroidism remain unclear. Fractional amplitude of low-frequency fluctuations (fALFF) has been established as a reliable indicator for investigation of abnormal spontaneous brain activity that occurs at specific frequencies in different types of mental disorder. However, the changes of fALFF in specific frequency bands in hypothyroidism have not yet been investigated. Methods: Fifty-three hypothyroid patients and 39 healthy controls (HCs) underwent thyroid-related hormone levels tests, neuropsychological assessment, and magnetic resonance imaging (MRI) scans. The fALFF in the standard band (0.01-0.1 Hz), slow-4 (0.027-0.073 Hz), and slow-5 bands (0.01-0.027 Hz) were analyzed. An analysis of Pearson correlation was conducted between fALFF, thyroid-related hormone levels, and neuropsychological scores in hypothyroid patients. Results: Compared to HCs, within the routine band, hypothyroidism group showed significantly decreased fALFF in left lingual gyrus, middle temporal gyrus (MTG), precentral gyrus, calcarine cortex, and right inferior occipital gyrus; within the slow-5 band, the hypothyroidism group exhibited decreased fALFF in left lingual gyrus, MTG, superior temporal gyrus, postcentral gyrus, and paracentral lobule, and increased fALFF in supplementary motor area (SMA) and right middle frontal gyrus; additionally, fALFF in the left lingual gyrus within the routine and slow-5 bands were negatively correlated with the level of thyroid stimulating hormone. Conclusions: In this study, the slow-5 frequency band exhibits better sensitivity than the standard band in detecting fALFF values. A decrease of fALFF values in the lingual gyrus and MTG was observed in both the standard and slow-5 bands and might present potential neuroimaging biomarkers for hypothyroidism. [ABSTRACT FROM AUTHOR]

Context For Muslim patients on levothyroxine (L-T4) therapy, the best approach for L-T4 intake during Ramadan fasting remains unclear. Objective We compared 2 practical approaches for L-T4 intake during Ramadan. Methods We randomly assigned 69 patients (21 males, 48 females, median age 44 years) with differentiated thyroid cancer (DTC) who underwent thyroidectomy in the past and are on stable LT4 doses to 2 arms. Arm A (33 patients) ingested their pre-Ramadan L-T4 dose at the evening meal and ate immediately. Arm B (36 patients) increased their pre-Ramadan dose by 25 µg if their regular L-T4 dose was ≤150 µg/day or by 50 µg if their pre-Ramadan dose was >150 µg/day and ate immediately. Results At the beginning of Ramadan (baseline), the median thyrotropin (TSH) level and the numbers of patients in euthyroidism, subclinical hyperthyroidism (Shyper), or subclinical hypothyroidism (Shypo) were comparable between the 2 arms (P =.69 and P =.65, respectively). At the end of Ramadan, in arm A there were 17 (51.5%), 3 (9.1%), and 13 (39.4%) patients in euthyroidism, Shyper, and Shypo compared with 17 (47.2%), 14 (38.9%), and 5 (13.9%) patients, respectively, in arm B (P =.005). The mean ± SD TSH levels in arms A and B at the end of Ramadan were 5.6 ± 6.0 mU/L and 1.67 ± 2.6 mU/L, respectively (P =.0001). Conclusion No overt thyroid dysfunction developed but there were more cases of Shypo in arm A and Shyper in arm B. Arm B achieved desirable levels of TSH (normal or slightly suppressed) in 86% of cases and might be a preferable approach, especially for patients who need TSH suppression (eg, DTC). [ABSTRACT FROM AUTHOR]

Background Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals. Methods We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per.1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals. Results The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were −5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity,.70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were −20% for the upper limit of TSH and −15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability. Conclusion We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits. [ABSTRACT FROM AUTHOR]

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Background: Long-term management of patients with hypothyroidism on thyroxine replacement requires thyroid function test (TFT) monitoring once every six–12 months as recommended by clinical practice guidelines. This study determined their thyroid function status during two-year follow-up visits in primary care, and the factors influencing their thyroid status, and assessed the optimal interval for TFTs. Methods: A retrospective cohort study was conducted on adults with a clinical diagnosis code for hypothyroidism in their electronic health records taken from a group of polyclinics in Singapore between July 2017 and June 2020. The follow-up thyroid status was categorized as under-replacement (TSH ≥ 3.70mIU/L), over-replacement (TSH ≤ 0.65mIU/L) or euthyroid (TSH 0.65–3.70mIU/L). The patients' demographic, clinical and TFT data were analyzed using appropriate statistical tests during the two-year follow-up. Stepwise logistic regression analysis identified the factors associated with suboptimal thyroid control. Kaplan–Meier analysis was used to compare their thyroid function status in association with the interval between TFT monitoring. Results: Data from 5,749 eligible subjects (mean age 62.1 ± 13.29 years; 79% female; 79.7% Chinese) were analyzed. After a two-year follow-up, 61.9% (n = 3558) of all subjects were euthyroid, with 29.5% (n = 1694) being under-replaced and 8.6% (n = 497) over-replaced. However, thyroid status did not differ significantly with the various dose regimen (daily, segmented, or alternate days) (p = 0.193). Stepwise logistic regression showed that thyroxine under-replacement was significantly associated with the male gender (AOR = 1.25,95%CI = 1.03–1.51,p = 0.02) and obesity (AOR = 1.34,95%CI = 1.08–1.66,p = 0.008). Every unit (μg/kg body weight) increase in the mean daily thyroxine dose was associated with 2.72 times greater odds of over-replacement. When comparing thyroid function monitoring at intervals of 13-24 months, monitoring at shorter intervals (≤ 12 months) was less likely to detect thyroxine under-replacement (AOR = 0.57,95%CI = 0.44–0.74,p < 0.001) and over-replacement (AOR = 0.62,95%CI = 0.41–0.97,p = 0.033). Among the 3,312 adults who were euthyroid at baseline, 22.2%, 41.7% and 59.6% had suboptimal thyroid control at 6, 12 and 24 months respectively (Kaplan–Meier analysis). Conclusion: Around six in ten patients were euthyroid with thyroxine replacement for hypothyroidism in primary care over two years. Thyroxine under-replacement was associated with male gender and obesity. The proportion of euthyroid patients developing abnormal thyroid function doubled with TFTs at six, 12 and 24-month intervals. [ABSTRACT FROM AUTHOR]

Myxedema coma is a rare life‐threatening form of hypothyroidism that manifests as neuropsychiatric, metabolic, respiratory, and cardiovascular dysfunction. From 2010 to 2022, our hospital managed three cases of myxedema coma. While the overall characteristics of these cases were similar to those in previous reports, we noticed that all cases were negative for thyroid autoantibodies and an autopsy in one of the cases exhibited end‐stage thyroiditis. During a systematic review of cases from 1999 to 2022, we also noticed that a significant proportion of myxedema coma was caused by seronegative primary hypothyroidism especially in Japan. [ABSTRACT FROM AUTHOR]

Background: Hypothyroidism and coronary heart disease are both common diseases in life and both are increasing in prevalence. Many studies have found a strong association between the two. However, they have not been able to prove a causal relationship. Furthermore, numerous studies have demonstrated that glycemic traits play a role in both. Consequently, the objective of this study was to ascertain the causal estimation of the association between hypothyroidism and coronary heart disease and to quantify the potential mediating role of glycemic traits in this relationship. Methods: We used two-sample Mendelian randomisation (UVMR) to explore causality between hypothyroidism and coronary heart disease. Additionally, multivariate Mendelian randomisation (MVMR) was applied to quantify the potential mediation of glycemic traits in this relationship. A variety of Mendelian randomization methods were employed in this study, including the inverse variance weighting (IVW) method, weighted median method, and MREgger test. Heterogeneity and horizontal pleiotropy were evaluated through MREgger intercept test, Cochran's Q test, and leave-one-out analysis to ensure the robustness of the study results. Results: The results of the MR analyses indicated that hypothyroidism was associated with an increased risk of coronary heart disease (IVW: OR=2.75, 95% CI: 1.53-4.94). In mediation analyses, the proportion of HbA1c-mediated effects of hypothyroidism on coronary heart disease was 7.3% (2.2%-12.5%). Conclusion: The results of our study indicate a causal relationship between hypothyroidism and coronary heart disease. Furthermore, HbA1c partially mediated the causal effect of hypothyroidism on coronary heart disease. Consequently, intervention in this factor may reduce the risk of coronary heart disease associated with hypothyroidism. [ABSTRACT FROM AUTHOR]

Hypercalcemia can result from either hyperparathyroidism or non-parathyroid conditions. When hypercalcemia is accompanied by undetectable parathyroid hormone (PTH) levels, hyperparathyroidism is rarely considered the diagnosis. Herein, we report the case of a 65-year-old Caucasian woman referred to our hospital for further evaluation of hypercalcemia. Her symptoms included fatigue and brain fog, with undetectable PTH levels. A comprehensive workup, including a series of laboratory and imaging tests, excluded common non-parathyroid causes such as malignancy and familial hypocalciuric hypercalcemia. Ultrasound identified a likely enlarged parathyroid gland, which was further confirmed by a sestamibi scan. After 2 weeks of cinacalcet treatment, the patient's calcium levels decreased, indicating the parathyroid gland as the likely source of hypercalcemia. Parathyroidectomy was subsequently performed, revealing a 1927 mg adenoma. Postoperatively, the patient's calcium levels normalized, PTH levels became detectable within the normal range, and her symptoms resolved, with a marked improvement in energy. This case demonstrates that primary hyperparathyroidism can present with hypercalcemia and undetectable PTH. A genetic mutation in the PTH gene within the adenoma may explain the undetectable PTH levels preoperatively. Plain Language Summary: This case report discusses a 65-year-old woman who was found to have high calcium levels in her blood, a condition known as hypercalcemia. Typically, hypercalcemia can result from either a condition where the parathyroid glands produce too much parathyroid hormone (PTH) or from other non-parathyroid-related issues like cancer. However, when hypercalcemia occurs with undetectable levels of PTH, it is unusual for hyperparathyroidism to be the cause. In this patient's case, she experienced symptoms like fatigue and brain fog, but her initial tests showed undetectable PTH levels. Further tests ruled out other common causes of high calcium, such as cancer or a genetic condition called familial hypocalciuric hypercalcemia. An ultrasound and a special scan called a sestamibi scan revealed an enlarged parathyroid gland, suggesting the presence of a parathyroid adenoma, a non-cancerous tumor. To confirm this, the doctors gave the patient a medication called cinacalcet, which is known to lower calcium levels if the parathyroid glands are involved. After two weeks of treatment, her calcium levels dropped, indicating that the parathyroid gland was indeed the source of the problem. The patient underwent surgery to remove the adenoma, which weighed nearly two grams. Following the surgery, her calcium levels returned to normal, and her PTH levels became detectable again within the normal range. Her symptoms, including fatigue, improved significantly, and she reported feeling more energetic. This case is unusual because it demonstrates that primary hyperparathyroidism can still be the cause of hypercalcemia even when PTH levels are initially undetectable. The doctors suspect that a genetic mutation in the adenoma might explain why PTH levels were undetectable before surgery. This case emphasizes the importance of thorough clinical evaluation, even when initial test results are not typical. [ABSTRACT FROM AUTHOR]

A 2‐year‐old cat was referred for suspected generalised seizure activity and reclusive behaviour, with a history of non‐resolving facial abscess. Magnetic resonance imaging (MRI) revealed a contrast enhancing lesion occupying the left calvarium and adjacent peripheral tissues. The intracranial lesion was causing significant mass effect, with oedema and transtentorial herniation. Nocardia nova was isolated from the lesion and identified by DNA sequencing. Treatment consisted of debridement via craniotomy and ventral bulla osteotomy, and combination antibiotic therapy with clarithromycin, amoxycillin and trimethoprim‐sulfonamide (sulfadoxine parenterally, then sulfadiazine orally). After several weeks of antibiotic therapy, the cat developed weakness, bicavitary effusion, myxoedema, non‐regenerative anaemia and azotaemia. Total thyroxine (TT4) was below the detectable limit and canine thyroid stimulating hormone (cTSH) assay was markedly elevated at 7.53 ng/mL (reference interval 0.15–0.3 ng/mL). Discontinuation of sulfonamides and administration of levothyroxine resulted in resolution of clinical signs. The cat was subsequently able to discontinue levothyroxine, with recovery of euthyroid state. To the authors' knowledge, this is the first report of clinical hypothyroidism in a cat treated with sulfonamide antibiotics and may influence antimicrobial selection and monitoring during therapy. This report also described the management of an atypical presentation of nocardiosis with intracranial extension. [ABSTRACT FROM AUTHOR]

Hypothyroidism, the deficiency of thyroid hormone, is a common condition worldwide. It affects almost all body systems and has a wide variety of clinical presentations from being asymptomatic to, in rare cases, life threatening. The classic symptoms of hypothyroidism include fatigue, lethargy, weight gain, and cold intolerance; however, these symptoms are non-specific and the diagnosis is typically made on biochemical grounds through serum thyroid function tests. The most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's thyroiditis), although other causes, including drugs (such as amiodarone, lithium, and immune checkpoint inhibitors), radioactive-iodine treatment, and thyroid surgery, are frequent. Historically, severe iodine deficiency was the most common cause. Reference ranges for thyroid function tests are based on fixed percentiles of the population distribution, but there is increasing awareness of the need for more individualised reference intervals based on key factors such as age, sex, and special circumstances such as pregnancy. Levothyroxine monotherapy is the standard treatment for hypothyroidism; it is safe and inexpensive, restores thyroid function tests to within the reference range, and improves symptoms in the majority of patients. However, 10% of patients have persistent symptoms of ill health despite normalisation of thyroid function tests biochemically and a substantial proportion of patients on levothyroxine have thyroid-stimulating hormone concentrations outside the reference range. Ongoing symptoms despite levothyroxine treatment has led to some patients using liothyronine or desiccated thyroid extract. Taken together, these factors have led to intense debate around the treatment thresholds and treatment strategies for hypothyroidism. In this Seminar, we review the epidemiology, genetic determinants, causes, and presentation of hypothyroidism; highlight key considerations and controversies in its diagnosis and management; and provide future directions for research. [ABSTRACT FROM AUTHOR]