The management of subclinical hyperthyroidism by thyroid specialists.

Should we treat mild subclinical/mild hyperthyroidism? No

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.

In otherwise euthyroid patients presenting with thyroid enlargement, reduction in serum thyrotrophin (TSH) concentrations measured in a sensitive assay may be a marker of thyroid autonomy and may therefore indicate a benign underlying pathology. We investigated prospectively a cohort of 467 subjects presenting consecutively to our thyroid clinic with nodular or diffuse enlargement of the thyroid. Subjects were divided into those with normal (0.4-5.5 mU/l), low but detectable (0.1-0.39 mU/l) or undetectable (< 0.1 mU/l) serum TSH concentrations. The final pathological diagnosis was defined by fine-needle aspiration cytology and clinical follow-up of at least 2 years or by fine-needle aspiration cytology and histology following surgical treatment. Serum TSH concentrations below normal were found in 75 patients (16.1%), those with low serum TSH results having higher mean free T4 concentrations, were older and were more likely to be female. In those with undetectable serum TSH, no patient had a diagnosis of thyroid neoplasia and in those with low but detectable TSH, thyroid neoplasms were diagnosed in two patients (3.4%). In those with normal serum TSH, 12.0% had a final diagnosis of thyroid neoplasm (p = 0.013). Overall, thyroid malignancy was found in one patient (1.3%) of those with a serum TSH measurement below the normal range and 6.9% of those with normal serum TSH (p < 0.06). Reduction in serum TSH at presentation may identify a group which requires less intensive investigation and follow-up than those without biochemical evidence of thyroid autonomy.

Although much controversy continues to rage in regard to what constitutes the normal upper limit for TSH in the context of subclinical hypothyroidism, it is generally accepted thata stateofmildhyperthyroidismexistswhen the TSH level is less than 0.3 mIU/liter. The term “subclinical” hyperthyroidism has been applied when such low TSH levels are accompanied by normal to high normal reference range values for T4 and T3. The laboratory results indicating this diagnosis may have been obtained during routine physical examination or because some signs or symptoms suggested the possibility of hyperthyroidism to the physician. Because TSH may be suppressed transiently for various reasons, confirmationof theresult is important.Onceresultsareobtained with a subsequent repeat test, the clinician should deal next with a determination of the cause of the low TSH and whether or not a remedy may need to be applied (1). Other causes of a low TSH level are excluded as we look for a cause of subclinical hyperthyroidism with a focus on disease of the thyroid gland. Thus, in the differential diagnosis for a low serum TSH level, we can exclude pituitary or hypothalamic disease, the euthyroid sick syndrome, or drugs that suppress TSH such as dobutamine, dopamine, and steroids because these entities do not reflect thyroid disease per se and would be associated with low or low normal serum T4 and T3. The low TSH usually seen in the first trimester of pregnancy is a physiological change, although a degree of subclinical hyperthyroidism may exist with human chorionic gonadotropin stimulation of the thyroid causing augmented hormone secretion, and total T3 and T4 levels rising to or above the reference range enhanced by estrogen-mediated increases in thyroid hormone binding proteins. Factitial or unintentional iatrogenic TSH suppression due to excessive thyroid hormone ingestion as a cause of low TSH can also be excluded by history, and of course its management is not rocket science, merely being dosage adjustment as required. Having excluded these various nonthyroidal causes of a low TSH value, we are left with the likelihood of subclinical hyperthyroidism due to either transient or longterm endogenous thyroid hormone excess usually on the basis of Graves’ disease or nodular goiter. The compelling imperative to make the diagnosis is based upon the consequences of long-term untreated subclinical hyperthyroidism, which may include atrial fibrillation (2–4), diastolic dysfunction (5), a suggestion of higher rates of death due to cardiovascular disease (6), and osteopenia, osteoporosis, and increased fracture rate, especially in postmenopausal women (7, 8). Given these potential consequences of untreated subclinical hyperthyroidism, it would seem logical to implement treatment. However, the necessity for treatment may be arguable depending upon factors such as the degree of TSH suppression ( 0.1 vs. between 0.1–0.4 mIU/liter) (9), the patient’s age, and the presence of comorbid conditions. Moreover, it is possible that the TSH suppression may not be “permanent,” that the subclinical state will not progress to overt hyperthyroidism, and therefore that intervention would not be required. In this issue of the JCEM, Vadiveloo et al. (10) report epidemiological data on the prevalence, incidence, and natural history of 2024 subjects with subclinical hyperthyroidism with data up to 7 yr after diagnosis. In brief, most of the subjects continued to maintain a low TSH level over the course of follow-up, about a third had reverted to normal values by 5–7 yr, and very few ( 1%) actually progressed to overt hyperthyroidism. This experience is very similar to that reported by Rosario (11), but it differs from that reported by Diez and Iglesias (12), who observed that 45% of patients progressed to overt disease during the course of follow-up.

Serum TSH assessment is the most sensitive screening test for the diagnosis of thyroid dysfunction in the absence of pituitary or hypothalamic disease. This test has been used increasingly in the last decade to detect subclinical thyroid dysfunction (STD). Recent data suggest that STD is a common disorder that may be associated with important adverse events (1–5). The American Association of Clinical Endocrinologists (AACE) and American Thyroid Association (ATA) 2012 guidelines recommend treatment of subjects with persistent increased serum TSH levels 10 mIU/L and undetectable serum TSH ( 0.1 mIU/L) (6, 7). The treatment of mild thyroid hormone excess (TSH 0.1–0.4 mIU/L) ordeficiency (serumTSH 10mIU/L) is controversial (1,2). However, what is the normal TSH reference range? Obviously, this issue is critical in deciding whether or not to treat patients with mild STD and in identifying individuals with high-normal or low-normal serum TSH. It is also important in defining the TSH target level in patients receiving thyroid hormone replacement therapy. In 2002, the National Health and Nutrition Examination Survey (NHANES) III, a US population-based study, evaluated the normal TSH range in the “thyroid disease-free adult population” (8).Theauthors excludedsubjectswith risk factorsandafamilyhistoryofthyroiddysfunction,self-reported thyroid disease or goiter, and thyroid autoimmunity. The study suggested that 95% of the US disease-free population had a serum TSH concentration between 0.45 and 4.12 mIU/L (8). However, TSH values did not have a Gaussian distribution because the curve was skewed by individuals with occult autoimmune thyroid dysfunction despite negative thyroid peroxidase antibodies (9). In 2005, the National Academy of Clinical Biochemistry (NACB) recommended that thyroidultrasonographybeperformedineuthyroidsubjects to exclude the presence of occult thyroid autoimmunity in order to define the serum TSH reference interval more accurately (10). They suggested that the upper limit of the TSH reference range be lowered to 2.5 mIU/L (10). The upper and lower limits of the normal serum TSH concentration continue to be debated by expert clinical thyroidologists. In 2005, two back-to-back articles appeared in the JCEM: one article, by Wartofsky and Dickey (11), favored a narrower TSH reference range, but according to the other, by Surks et al (12), the TSH range should remain unchanged. It should be mentioned that the sensitivity and specificity of TSH assays can affect the evaluation of serum TSH because some assays may detect biologically inactive circulating TSH isoforms (1). The upper TSH reference limit has progressively declined over the last decade thanks to more sensitive TSH assays, more accurate thyroid antibody tests, and a more accurate selection of the reference population. Different TSH cut-off limits have been reported in population-based studies conducted in various countries (1). Subsequent findings confirmed that ethnicity, iodine intake, gender, age, and body mass index can influence the reference range of serum TSH. In fact, the normal TSH upper limit was lower in African Americans (3.6 mIU/L) than in Mexican Americans or Caucasians (4.2 mIU/L) (8). Reanalysis of these data 5 years later showed that the upper limit of normal serum TSH at the 97.5th percentile was 3.5 mIU/L in individuals 20–29 years old, 4.5 mIU/L in those 50–59 years old, and 7.5 mIU/L in those older than 80 years (13). Variations in thyroid function within the reference range have been associated with body weight in several cross-sectional and longitudinal studies (14). Moreover, serum TSH levels at the upper limit of the normal range have been found in obese adults and have been positively correlated with body mass index (14).

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.

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.

Several patients with nontoxic goiter have reduced serum TSH levels, as measured with new sensitive assays. Whether this is a sign of subclinical hyperthyroidism, thus having the potential of adverse effects on different organs with time, is not known. We have measured serum levels of 2 markers of thyrometabolic status at the tissue level, bone gamma-carboxyglutamic acid-containing protein (BGP), reflecting the function of osteoblasts, and sex hormone-binding globulin (SHBG), reflecting the function of hepatocytes, in 44 patients (41 women and 3 men) with nontoxic goiter (11 diffuse and 33 nodular goiters; serum T4, T3, free T4, and free T3 levels had been normal and stable for at least 0.5 yr). Serum TSH levels ranged from normal to unmeasurably low values (less than 0.05 mU/L). Serum TSH levels correlated negatively to serum BGP levels (r = -0.60; P less than 0.001). Due to the postmenopausal surge in serum BGP levels, premenopausal women (n = 21) were tested separately without changing the significance (r = -0.53; P less than 0.02). Expressing serum BGP values as a percentage of the mean value in control subjects of the same age and sex did not change the correlation (r = -0.63; P less than 0.001). Six patients had serum BGP levels above the normal range, and patients with reduced serum TSH levels (less than 0.45 mU/L; n = 12) had significantly enhanced serum BGP levels [median, 1.53 nmol/L (range, 1.02-4.24) vs. 1.23 nmol/L (0.62-3.71); P less than 0.05]. Serum TSH also correlated negatively to serum SHBG levels (r = -0.56; P less than 0.001; women alone: r = -0.58; P less than 0.001). Eight patients had serum SHBG levels above the normal range, and patients with reduced serum TSH levels had significantly enhanced serum SHBG levels, expressed as a percentage of the mean control value for the relevant sex [203% (range, 75-288) vs. 120% (42-317); P less than 0.01]. It is concluded that the lower serum TSH levels in patients with nontoxic goiter, the higher are serum BGP and SHBG levels. This suggests a progressively generalized (not only pituitary) tissue overexposure to thyroid hormones, the lower the serum TSH levels. Therefore, the finding of a reduced serum TSH level in patients with nontoxic goiter might reflect supraphysiological levels of T4 and/or T3, which could possibly be harmful.

Levothyroxine (L-T4) treatment aims to minimize the risk of differentiated thyroid cancer (DTC) recurrence and should be tailored to patient risk stratification and potential morbidity from adverse effects. To evaluate the effectiveness of current recommendations on L-T4 treatment of DTC patients in clinical practice. We submitted to in-person interviews and revised the charts of 139 low-risk (LR) and 57 not-low-risk (NLR) DTC patients. A second evaluation made 24-60 months after surgery reclassified 131 patients who maintained (thyroglobulin) Tg≤2 ng/dl with no evidence of relapse/recurrence as LR, whereas the remaining 65 cases were considered NLR. Only 27% LR patients were appropriately controlled; 18% were kept suppressed; 49% maintained serum TSH levels between 0.11-0.4 mU/l; 21% had TSH=2.5- 4.5 mU/l; and 12% TSH>4.5 mU/l. Among the NLR patients, 24 (37%) of the patients presented serum TSH levels above goal, including 13 (20%) patients with TSH>4.5 mU/l. There were 4 NLR elders whose TSH levels were kept between 0.41 and 4.5 for medical reasons; likewise, 28 NLR patients maintained with low but not undetectable serum TSH levels had cardiovascular and/or bone risk factors, but all the remaining 24 NLR patients were not adequately controlled because of poor treatment compliance. On the other hand, 45% of 152 inappropriately controlled patients presented risks for bone fractures, including 33 patients kept with low serum TSH levels without medical indication. We concluded that guidelines are not adequately applied and alternative strategies aiming to increase adherence are urgently needed for DTC patients.

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.

The risk of papillary thyroid cancer (PTC) is related to serum TSH, and the development of thyroid autonomy by reducing TSH levels decreases the frequency of PTC in patients with nodular goiter. Our aim was to investigate the effect of L-thyroxine (LT(4)) on the frequency of PTC diagnosed by cytology in a large series of patients with nodular goiter untreated (n=20 055) or treated with L-T(4) (n=7859). L-T(4)-treated patients with respect to untreated patients presented significantly lower serum TSH (median, interquartile range: 0.30 muU/ml, 0.08-0.62 microU/ml versus 0.70 muU/ml, 0.38-1.14 muU/ml; P<0.0001) and prevalence of PTC (3.2 vs 5.1%; P<0.0001). The frequency of PTC was closely related to serum TSH, with it being lowest in patients with TSH below the normal range (<0.4 muU/ml; 189/10 059, 1.9%) and highest in patients with TSH above the normal range (>3.4 muU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of L-T(4)-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 muU/ml) with respect to untreated patients (12,599/20,055, 62.8%; chi(2) P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with L-T(4) is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC.

An Analysis of the Natural Course of Subclinical Hyperthyroidism

A new TSH immunoenzymometric assay was found to be capable of discriminating between the serum TSH values of normal subjects [2.28 +/- 1.02 (+/-SD); range, 0.6-6.5 microU/ml] and those of clinically euthyroid, antithyroid drug-treated (n = 22) or clinically thyrotoxic (n = 34) patients. While a wide spectrum of basal TSH values was found in the antithyroid drug group [ranging from undetectable (less than 0.05 microU/ml: 57%) to 17.9 microU/ml], all clinically thyrotoxic patients had undetectable values. In 33 patients receiving chronic oral T4 therapy for treatment of goiter (n = 15) or thyroid cancer (n = 18), 48% (6 of 33) had undetectable basal TSH levels and no TSH response to TRH stimulation. Detectable TSH levels were found in 42% (14 of 33), and TRH responsiveness was found in 52% (17 of 33). The TSH response to TRH stimulation was less than 2.0 microU/ml in 7 patients. Serum free T4 index, free T3 index, and free T4 levels and oral T4 dosage were inferior predictors of TRH responsiveness compared to the basal TSH value. No patient receiving more than 0.2 mg T4 daily or having a free T4 index above 18, a free T3 index above 205 or a free T4 level above 3.0 ng/dl had a TSH response to TRH. Seventy-six percent (16 of 21) of the patients, when reevaluated 1-6 weeks after increased oral T4 dosage, had a significant reduction in their serum thyroglobulin level. This was true of both patients with initially detectable (11 of 14) as well as undetectable (5 of 7) basal serum TSH levels. These findings support the concept that subnormal and, for that matter, as yet undetectable levels of circulating TSH may exert stimulatory effects on thyroid tissue.

Patients with subclinical hyperthyroidism (reduced serum TSH and normal free T4 and T3 concentrations) have slightly increased bone turnover and might have reduced bone mass, especially among postmenopausal women (due to concomitantly reduced oestrogen production), as also seen during suppressive L-T4 treatment. We have evaluated whether normalization of serum TSH using radioiodine treatment (RAI) in postmenopausal women with a nodular goitre and subclinical hyperthyroidism, protects against bone loss? Prospective, non-randomized study, outpatients 2 years follow-up. Postmenopausal women with a nodular goitre, biochemically subclinical hyperthyroidism (TSH < 0.2 mU/I, and signs of a growing goitre or compression symptoms. Sixteen were treated with RAI (median dose 555 MBq) (+RAI), whereas 12 were followed without treatment (-RAI). Serum TSH (third generation technology), free T4 and T3 indices, and bone mass (BMD) as measured by Dual Photon Absorptiometry (4 in each group) (only spine) or Dual X-ray Absorptiometry (DEXA) (both spine and hip), were measured yearly for up to 2 years. The two groups did not differ regarding age, thyroid hormone parameters, and absolute levels of BMD at spine and hip. RAI resulted in normalization of TSH in all 16 women, and FT4I as well as FT3I decreased to 78% after one year (P < 0.01). These parameters did not change in the untreated group, thus serum TSH remained reduced. BMD at the spine tended to increase (n.s.) after RAI to (median) 101.9% after one year, and 101.5% after 2 years. In contrast the -RAI group experienced a continued fall in BMD to 97.3% after one year, and 95.5% after 2 years, both reduced as compared to the +RAI group (P < 0.02). BMD of the hip also increased after RAI, to 102.3% after one year, and 101.7% after 2 years. In contrast BMD in the -RAI group decreased to 94.8% after one year, and 98.0% after 2 years, both lower than in the +RAI group (P < 0.01). Subclinical hyperthyroidism due to a nodular goitre in postmenopausal women resulted in a continued loss of bone mass of about 2% per year. Radioiodine treatment resulting in normalization of serum TSH prevented this continued bone loss for at least 2 years. Our study supports earlier intervention in such patients.

There is current controversy on the association between subclinical hyperthyroidism and hypertension. Data from cohort studies have not been available yet. The present study was designed to longitudinally investigate possible associations of subclinical hyperthyroidism with blood pressure, pulse pressure and the risk of hypertension. We used data from the population-based, prospective cohort Study of Health in Pomerania and included 2910 subjects (1469 women) aged 20-79 years with completed 5-year examination follow-up. Subjects with increased serum TSH levels or overt hyperthyroidism were excluded. Serum TSH levels below 0.25 mIU/l with free triiodothyronine and free thyroxine levels within the reference range were defined as subclinical hyperthyroidism. Blood pressure was measured according to standard methods. Multivariable analyses adjusted for age, sex, overweight, obesity, smoking status and time between the examinations did not reveal any statistically significant association between subclinical hyperthyroidism and any of the blood pressure-related variables in the whole study population. Although the 5-year hypertension incidence was higher in subjects with subclinical hyperthyroidism compared with those without (31.4 vs 19.2%; risk ratio 1.64; 95% confidence interval (CI) 1.17-2.28, P=0.006), both groups did not differ with respect to the risk of hypertension, after analyses were adjusted for confounders (relative risk 1.23, 95% CI 0.91-1.68, P=0.182). Analyses yielded similar results in subjects without thyroid disease and in those who took no antihypertensive medication. Subclinical hyperthyroidism is not associated with changes in blood pressure, pulse pressure or incident hypertension.