Management of Subclinical Hyperthyroidism

We compared serum TSH results determined in second and third generation assays in patients with thyroid disease and nonthyroidal illnesses (NTIs) to evaluate the usefulness of the more sensitive assay. We studied 19 subjects with untreated hyperthyroidism, 12 hyperthyroid subjects sampled at 4-week intervals after beginning carbimazole, 153 subjects receiving T4 replacement, and 300 hospital in-patients with a variety of NTIs. Serum TSH was measured, using a second generation immunometric method, together with free T4 and free T3. Samples with subnormal TSH (< 0.5 mU/L) were reassayed, using a more sensitive chemiluminescent immunometric method. Both assays revealed undetectable serum TSH levels in 18 of 19 overtly hyperthyroid patients. Undetectable TSH values (in both assays) were found in 30 of 33 patients with low serum TSH levels who were receiving treatment for hyperthyroidism, in association with normal thyroid hormone levels in 11. Undetectable TSH was evident in both patients receiving T4 and those with NTI, but use of the more sensitive assay led to a reduction in the number of subjects with undetectable TSH compared with the second generation results (T4-treated, 55 vs. 77 cases; NTI, 13 vs. 19 cases). There was a significant correlation between serum TSH and free T4 in the whole group on T4 (P < 0.001) and in those receiving T4 with low TSH (r = -0.33; P < 0.05); no significant correlation was evident in subjects with low serum TSH levels associated with NTI. An improvement in assay sensitivity led to a reduction in the number of patients being treated with T4 or with NTI in whom serum TSH was undetectable and, hence, an increase in those in whom overt hyperthyroidism could be excluded. Undetectable TSH results, even in a third generation assay, are not diagnostic of overt hyperthyroidism, but are also found in subjects with treated thyroid disease and NTI.

Background Coronovirus disease 2019 (COVID-19) infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus was officially declared a pandemic by the World Health Organization in March 2020. According to a search of PubMed for the term COVID-19 on May 5, 2021, thus far, there have been more than 130,000 papers on COVID-19 published in the medical literature. Since the previous comments on thyroid function in COVID-19 in Clinical Thyroidology (1,2) the number of papers on this topic has increased from a handful to 120 (PubMed search for the term COVID-19, thyroid disease on May 5, 2021), including a systematic review (3). One of these articles, the article by Campi et al. reviewed here (4), is a prospective study of thyroid function in patients hospitalized with COVID-19 infection at a single center in Milan, Italy. Methods The study included 144 consecutive patients with COVID-19 infection and associated pneumonia (97 men and 47 women; mean [±SD] age, 68.1±14.67 years [range, 26–96]) admitted to a single center in intensive or subintensive care units between March and May 2020 because of respiratory insufficiency of variable severity. SARS-Cov-2 infection was confirmed in all patients by RT-PCR testing on a nasopharyngeal swab. Those with previous thyroid dysfunction or who were taking interfering drugs were excluded. There was no control group. Different from previous reports, serum concentrations of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin (Tg), and anti-Tg autoantibodies (TgAbs) were measured at baseline and every 3 to 7 days thereafter. Serum C-reactive protein (CRP), cortisol, and interleukin-6 (IL-6) were also assayed. The overall mortality rate was 25% (36 of 144). The mean length of hospital stay was 21 days (range, 2–108). Serum Tg and TgAb concentrations were retrospectively measured in the subset of serum with reduced/suppressed TSH levels in order to diagnose or exclude destructive thyroiditis. Results Most patients had a normal TSH concentration at admission; most of these patients also had normal FT4 and FT3 levels. Low TSH concentrations were found either at admission or during hospitalization in 39% of patients, which was associated with low FT3 levels in half of these cases. Serum FT4 and Tg levels were normal, and TgAb was negative. Serum TSH and FT3 levels were invariably restored to normal at the time of discharge in survivors, whereas they were permanently low in most deceased cases. Only serum FT3 concentrations predicted mortality. Serum cortisol, CRP, and IL-6 concentrations were higher in patients with low TSH and FT3 concentrations. Almost half of the COVID-19 patients who were not taking interfering drugs had normal thyroid function tests both at admission and during follow-up. In this series, the transient finding of low TSH with normal FT4 and low FT3 levels inversely correlated with CRP, cortisol, and IL-6 levels and were associated with normal Tg concentrations and without clinical signs of a destructive thyroiditis. Longitudinal evaluations during the hospital stay showed that TSH suppression was transient in all the survivors, with 5 days (range, 2–9) as the median time to normalization. Serum Tg concentrations were invariably normal in the absence of TgAb interference in all 39 patients with low TSH, either at admission or during follow-up (median Tg, 7.6 µg/L, range: 3–70.3 µg/L). Conclusions The study suggests that cytokine release associated with COVID-19 infection causes slight transient central and peripheral thyroid function alterations, as characterized by reduced TSH with normal FT4 and low-normal FT3 levels. Serum thyroid function assessment during acute COVID-19 infection is not recommended. Clinical and biochemical monitoring after discharge/improvement are appropriate, as subacute thyroiditis may complicate the recovery.

Subclinical hyperthyroidism is a relatively common condition for which prospectively derived evidenced-based management guidelines do not exist. We have conducted a case-based mail survey to solicit opinions from members of the American Thyroid Association (ATA) about various issues that arise in the management of patients with this disorder. The survey was completed and returned by 185 of 300 (62%) of the original survey recipients. Four hypothetical cases varying in age, thyrotropin (TSH) level and underlying etiology were presented. The majority of respondents recommended further evaluation of all cases, most commonly choosing a radioactive iodine uptake (42%-71%), thyroid scan (39%-68%) and antithyroid (TPO/Tg) antibodies (49%-55%) as the additional tests to be ordered. The large majority (84%) recommended observation rather than active treatment for a young patient with a low but detectable serum TSH level. A small majority also recommended observation alone for a young woman with an undetectable serum TSH level (58%) and for an older woman with a low but detectable serum TSH value (63%). However, the majority (66%) favored treating an older woman with an undetectable serum TSH. When treatment was advised in the patients with subclinical hyperthyroidism, the respondents strongly favored anti-thyroid drugs when the etiology was Graves' disease and radioactive iodine when the etiology was toxic nodular thyroid disease. In the absence of adequate evidence-based guidelines, it is hoped that this survey of expert opinions may provide useful guidance for physicians providing care for patients with subclinical hyperthyroidism.

Introduction: Thyroid disorders have been associated with depression over many years, but the mechanisms involved in this association are difficult to define and previous published data are still conflicting. The majority of studies were performed in Europe and the United States, with a recent increase in Asia, and it is unknown if their results would replicate in the Brazilian population. Therefore, ELSA-Brasil presents the opportunity to study the association between thyroid dysfunction and depression in the Brazilian population and prospectively. Methods: TSH, free-thyroxine (FT4) and anti-TPO antibodies levels were evaluated at baseline. Depression diagnoses were performed using the Clinical Interview Schedule -Revised (CIS-R) at baseline and after the 4-year-followup. The following analysis were performed using Poisson regression models (95% confidence interval, CI95%): (1) association between thyroid dysfunction (overt and subclinical) and incident depression; (2) association between anti-TPO antibodies and incident depression; (3) association between anti-TPO antibodies together with only overt/subclinical hypothyroidism and incident depression; (4) TSH levels (3 quintile as reference) and incident depression among those with subclinical thyroid dysfunction and euthyroid individuals; (5) TSH levels (3 quintile as reference) and incident depression among euthyroid individuals; (6) TSH levels (1 quintile as reference) and incident depression among those with subclinical thyroid dysfunction and euthyroid individuals; (7) TSH levels (1 quintile as reference) and incident depression among euthyroid individuals; (8) TSH levels were stratified by sex when appropriate, and the multivariable model was adjusted for age, sex, race, education, body mass index (BMI), smoking, alcohol consumption, use of antidepressants/benzodiazepines and comorbidities. Results: This study showed an inverse association between overt hypothyroidism and incident depression (RR=0,54; 95% CI 0,35-0,84), but no association was found for subclinical hypothyroidism, overt and subclinical hyperthyroidism. Also, there was no association between presence of anti-TPO antibodies and incident depression (even when analyzing it together with overt and/or subclinical hypothyroidism only). Regarding TSH levels, among those with subclinical thyroid dysfunction and euthyroid individuals, low TSH levels were associated with an increased risk of depression, for all participants (RR=1,36; 95% CI 1,02-1,81) and for women (RR=1,64; 95% CI 1,15-2,33). Even within the normal range, for all (RR=1,46; 95% CI 1,08-1,99) and for women (RR=1,63; 95% CI 1,12-2,38). High TSH levels were associated with a lower risk of depression, also for all participants (RR=0,71; 95% CI 0,53-0,96) and for women (RR=0,67; 95% CI 0,47-0,95). The sensibility analysis with TSH Conclusion: Overt hypothyroidism was associated with a lower risk of depression after 4 years of follow-up. The higher risk seems to be associated with low TSH levels among those with subclinical thyroid dysfunction and euthyorid individuals, even within the normal range. Specially among women. High TSH levels were associated with lower risk of depression, also for women. No association between TSH levels and incident depression was found among men.

Disclosure: A. Skoczylas: None. W. Mularczyk: None. M. Zyla: None. E.C. Lubocka: None. A. Kluza: None. A. Partyka: None. A. Golebiowska: None. I. Linkert: None. J. Raniszewska: None. M. Skoczylas: None. P. Piwkowski: None. P. Wozniak: None. D. Jedrzejuk: None. Introduction An autonomous nodule with autonomous function on scintigraphy, usually (but not always) leading to hyperthyroidism are representing by around 5-10% of solitary thyroid nodules. Progressive development is observed from a compensated autonomous nodule (in which TSH is not yet completely suppressed, but accompanied by symptoms suggesting an excess of thyroid hormones - most often of cardiac origin) to overt hyperthyroidism in about 60% in 5 years. The method of choice used in the treatment of a solitary nodule with associated hyperthyroidism is radioactive iodine therapy (I-131). Due to the low TSH concentration, the iodine uptake of the remaining thyroid parenchyma is inhibited, which results in the low risk of an after-treatment hypothyroidism. Objective In patients with autonomous nodules without low TSH level but clinical symptoms, will radioactive iodine therapy be equally effective and the risk of hypothyroidism minimalized if suppression of TSH secretion has been achieved pharmacologically before treatment? Methods There were 20 patients (female, mean age of 61,1) with ultrasound-confirmed goiter and autonomous nodule with partial suppression of surrounding thyroid tissue on scintigraphy (mean iodine uptake 14.1%) and mean TSH concentration was 0.48 (0.1-0.83), who had related to the circulatory and nervous system symptoms. These patients were treated with radioiodine the mean activity 364 MBq (242-600MBq). Radioactive iodine therapy was preceded by a 4-week treatment period with 100 µg/d thyroxine and 20 µg triiodothyroxine for suppression of thyrotropin secretion and subsequent reduction of iodine uptake by the thyroid tissue outside the autonomous area and with 5mg/d bisoprolol to minimize thyrotoxicosis. As a result, suppression of thyrotropin secretion mean TSH 0.049 concentration on the day of treatment was achieved, accompanied with iodine uptake inhibition in the part of the thyroid gland outside the autonomous nodule. Radioactive iodine therapy was conducted under these conditions after one day discontinuation of thyroid hormones. Seven days after I-131treatmet each patient was issued to take thiamazole 5 mg/d for 4 weeks with bisoprolol. Results Clinical symptoms disappeared completely. One year after radioactive iodine therapy the mean TSH concentration was 1.46 (0.8-2.65) in all subjects. In 4 years of observation 85% of patients remained euthyreotic with main TSH of 3,0. The mean volume reduction of the autonomous nodules was 45,6% with a reduction of 21.5% of the remaining thyroid parenchyma. Conclusion Radioactive iodine therapy preceded by pharmacological TSH suppression can be used for radical treatment of patients with autonomous nodules with partial TSH reduction to remain the majority (85%) of these patients euthyreotic for 4 years of observation and to reduce radioiodine activity used for treatment. Presentation: Saturday, June 17, 2023

Metformin treatment may induce a decrease/suppression in serum TSH levels, mimicking sub-clinical hyperthyroidism (SHT). The aim of the present study was to retrospectively evaluate changes in several electrocardiographic indices in euthyroid subjects with diabetes who, after starting metformin treatment, developed a low serum TSH as compared to patients with SHT resulting from an underlying thyroid disease or TSH suppressive treatment with L-thyroxine. Heart rate, P wave duration, P wave dispersion, QTmax, QTmin and QT-dispersion were assessed in 23 patients with diabetes treated with metformin before and after 6 months of TSH-suppression and in 31 control patients with SHT. No significant changes in electrocardiographic parameters were observed from baseline to the TSH-suppression measurement. A significant difference in P wave duration (102.9 ± 7.4 vs. 92.1 ± 5.8 ms, p<0.001), P wave dispersion (13.1 ± 3.4 vs. 7.1 ± 3.5 ms, p<0.001), QTmax (399 ± 18 vs. 388 ± 16 ms, p=0.024), QTmin (341 ± 14 vs. 350 ± 17 ms, p=0.038) and QT dispersion (49.9 ± 9.6 vs. 30.9 ± 9.2 ms, p<0.001) were observed between the control group with SHT and the group of diabetic patients with low serum levels of TSH. Our results show that the TSH-suppressive effect observed in patients taking metformin is not associated with peripheral markers of thyroid hormone excess, at least at the cardiac level.

Should we treat mild subclinical/mild hyperthyroidism? No

A recent study on TSH receptor (TSHR) null mice suggested that skeletal loss occurring in hyperthyroidism is caused by the low TSH rather than high thyroid hormone levels. The aim of this study was to examine whether low TSH results in osteoporosis in the human. We determined bone mineral density (BMD) and markers of bone metabolism in two male siblings aged 9.8 and 6.8 years with isolated TSH deficiency, due to a mutation of the TSH beta-subunit gene. BMD was measured in the lumbar spine (L1-L4) by dual-energy X-ray absorptiometry. Laboratory investigation included the determination of serum calcium, phosphate, 25-hydroxy-vitamin D, parathyroid hormone concentrations, and urine calcium (Ca)/creatinine (Cr) ratio. Osteoblast activity was measured by serum bone alkaline phosphatase and osteocalcin levels, and osteoclast activity by urine cross-linked amino-terminal, carboxy-terminal telopeptides of type I collagen and deoxypyridinoline concentrations. BMD of both patients was within the normal range for age and sex; z-scores were -0.55 and -0.23 for patients 1 and 2 respectively. Serum calcium, phosphate, urine Ca/Cr ratio, and specific markers of bone metabolism were also within normal range. In childhood, chronic extremely low TSH levels, in the face of normal thyroid hormone levels, are not related to bone loss.

Recent studies have shown associations of hypothyroidism with arterial blood pressure, atherosclerosis, and inflammation. Based on these pathways, there might also be an association between hypothyroidism and retinal arteriolar narrowing (RAN), a marker of microvascular damage from hypertension, atherosclerosis, and inflammation. Against this background, the aim of this study was to investigate the putative association between serum thyrotropin (TSH) levels and RAN defined by arterio-venous ratio (AVR) from static vessel analysis. We used data from 3189 individuals from the second population-based cohort of the Study of Health in Pomerania (SHIP-TREND-0). Thyroid function was defined according to serum TSH and serum diiodothyronine (3,5-T2) levels. Low and high serum TSH levels were defined by the cutoffs 0.3 mIU/L and 3.0 mIU/L. Fundus photography of the central retina was recorded with a nonmydriatic camera, and images were evaluated by one experienced reader. An AVR <0.8 was defined as decreased. Serum TSH levels, low and high TSH, and serum 3,5-T2 levels were associated with AVR by linear regression and with AVR <0.8 by Poisson regression, both adjusted for age, sex, cigarette smoking, alcohol consumption, and intake of beta-blockers. Serum TSH levels were significantly associated with AVR (β=-0.028 [CI -0.049 to -0.007]; p=0.009) and with a decreased AVR <0.8 (relative risk=2.05 [CI 1.13-3.73]; p=0.019). Individuals with high TSH had a 1.43 higher risk for a decreased AVR ([CI 1.04-1.96]; p=0.027) than individuals with serum TSH levels within the reference range. Serum 3,5-T2 levels were also associated with a decreased AVR (relative risk for an increase of 1 nM=0.45 [CI 0.23-0.87]; p=0.017). Our results substantiate evidence for an association between hypothyroidism and RAN. Potential mechanisms explaining this association are long-term hypertension, atherosclerotic processes, and inflammation.

Babies born to mothers with thyroid disease

Just how benign is renal dopamine?

The primary aim was to study the risk of cardiovascular mortality in patients with differentiated thyroid carcinoma (DTC). Secondary aims were to evaluate all-cause mortality and explore the relation between thyroid-stimulating hormone (TSH; also known as thyrotropin) level and these outcome parameters. Subjects from two cohorts were retrospectively compared by Cox regression analyses; 524 patients with DTC and 1,572 sex- and age-matched controls from a large population-based study in the same geographic region. Mean age plus or minus standard deviation was 49 ± 14 years. Median follow-up was 8.5 years (interquartile range [IQR], 4.1 to 15.9 years) for patients with DTC and 10.5 years (IQR, 9.9 to 10.9 years) for controls. One hundred patients with DTC (19.1%) died, 22 (4.2%) as a result of cardiovascular disease, 39 (7.4%) as a result of DTC, and 39 (7.4%) as a result of other/unknown causes. Eighty-five controls (5.4%) died, 24 (1.5%) as a result of cardiovascular disease and 61 (3.9%) as a result of other/unknown causes. Patients with DTC had an increased risk of cardiovascular and all-cause mortality (hazard ratios [HRs], 3.35 [95% CI, 1.66 to 6.74] and 4.40 [95% CI, 3.15 to 6.14], respectively, adjusted for age, sex, and cardiovascular risk factors). Within the DTC group, TSH level was predictive for cardiovascular mortality; the adjusted HR was 3.08 (95% CI, 1.32 to 7.21) for each 10-fold decrease in geometric mean TSH level. The risk of cardiovascular and all-cause mortality is increased in patients with DTC, independent of age, sex, and cardiovascular risk factors. A lower TSH level is associated with increased cardiovascular mortality, supporting the current European Thyroid Association and the American Thyroid Association guidelines of tempering TSH suppression in patients with low risk of cancer recurrence. Furthermore, patients with DTC may benefit from assessment and treatment of cardiovascular risk factors.

Background: The prevalence of hypothyroidism (HT) has increased over time. To assess the effectiveness of treatment, we (1) studied thyrotropin (TSH) levels among patients receiving levothyroxine (LT4) and (2) determined the percentages of patients switching among LT4 formulations. Methods: Data on patients with HT receiving LT4 from the Optum™ Clinical and Claims Database were analyzed from March 2013 through February 2020. Eligible adult patients had ≥1 medical claim with an HT diagnosis and all patients were observed for ≥12 months. Patients included in Objective 1 were indexed on a randomly selected TSH result and had ≥2 results for TSH 1-15 months apart. Patients included in Objective 2 were indexed on a randomly selected LT4 pharmacy claim and had ≥2 LT4 claims ≥1 month apart and ≥1 claim during follow-up. Outcomes were the proportion of patients with low, normal, or high (<0.45, 0.45-4.5, or >4.5 mIU/L, respectively) TSH levels and the proportion of patients switching LT4 formulations, respectively. Data were stratified by age group, sex, and insurance type. All data reported were analyzed using descriptive statistics. Results: Of patients who were in the indexed TSH group, 81.1% [confidence intervals: 80.4-81.8; n/N = 9130/11,259] achieved normal TSH values. When stratified by age group, sex, and insurance type, ≥70% of patients in each of these subgroups exhibited normal mean TSH values at follow-up. For Objective 2 (N = 25,076), 24.9% (N = 6238) of the LT4-indexed group had ≥1 formulation switch in 12 months, of which 67.3% only switched once, and 41.4% (N = 10,370) had ≥1 formulation switch in up to 24 months. A significantly higher proportion of Medicare vs. commercially insured patients had switched formulations (26.2% vs. 23.1%, p < 0.001). Conclusions: Most LT4-treated patients maintain normal TSH levels, which is an improvement vs. previous reports. Continued physician engagement and patient education are advised to further reduce the number of patients who maintain off-target TSH levels. Contrary to clinical recommendations, about 25% of patients receiving LT4 switched formulations within 1 year, with >40% switching within 2 years; among patients who switched, most only switched once.

Congenital hypothyroidism is inadequate production of thyroid hormone in infants from birth. Treatment of hypothyroidism often involves an iodine-rich diet since iodine is a vital precursor for thyroid hormone synthesis. Red snapper fish is a saltwater fish that contain a high amount of iodine and other beneficial macro/micronutrients, yet no report was found on the effect of this fish consumption on hypothyroidism. The objective of this study was to determine the effectiveness of red snapper (Lutjanus sp.) fish on thyroid gland activity, manifested by low FT4 level and high TSH level, two diagnostic indicators of hypothyroidism. This study used a post-test and controlled group design. Pregnant female rats were given propylthiouracil orally for four weeks to induce hypothyroidism in their offspring. All hypothyroid offspring were divided into five treatment groups, i.e., negative control, positive control (thyroxin therapy), red snapper enriched diet at 25% and 50% dosage, also a combination of levothyroxine and red snapper. The thyroid gland activity was detected by measuring blood serum FT4 and TSH and histological examination of the thyroid gland using HE staining. The level of FT4 and TSH in each treatment group were analyzed with the one-way ANOVA test. The results showed that the group that received a 50% red snapper diet has a normal level of FT4 and TSH, whereas the FT4 level increased two-fold; the TSH level decreased significantly. The organization of the thyroid gland showed a remarkable change of the lumen diameter, indicating a higher amount of hormone production by the gland.

Evidence from epidemiological and clinical studies strongly suggest that young women in the preconception period are a group at risk for thyroid disorders which may lead to further aggravation of pre-existing chronic thyroid disease and complications during pregnancy. This paper is a literature review focusing on articles published in English between 2014-2017 searched in Medline database using terms 'young women', 'subclinical hyperthyroidism', 'subclinical hypothyroidism', 'nonthyroidal illness syndrome', 'obesity', 'depression'. Clinical assessment of young female patient including that of obtaining full medical history with a focus on the perceived changes in appearance, psychological symptoms and menstrual irregularities supported by laboratory tests indicative of metabolic status and characteristic changes in thyroid functions, may be the key to well-reasoned and justified individual therapeutic decisions.