Bjørn Olav Åsvold

Thyrotropin Levels and Risk of Fatal Coronary Heart Disease: The HUNT Study

BACKGROUND Recent studies suggest that relatively low thyroid function within the clinical reference range is positively associated with risk factors for coronary heart disease (CHD), but the association with CHD mortality is not resolved. METHODS In a Norwegian population-based cohort study, we prospectively studied the association between thyrotropin levels and fatal CHD in 17,311 women and 8002 men without known thyroid or cardiovascular disease or diabetes mellitus at baseline. RESULTS During median follow-up of 8.3 years, 228 women and 182 men died of CHD. Of these, 192 women and 164 men had thyrotropin levels within the clinical reference range of 0.50 to 3.5 mIU/L. Overall, thyrotropin levels within the reference range were positively associated with CHD mortality (P for trend = .01); the trend was statistically significant in women (P for trend = .005) but not in men. Compared with women in the lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L), the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively. CONCLUSIONS Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD.

Thyroid Function and Cancer Risk: A Prospective Population Study

Background: It has been hypothesized that thyroid function may influence cancer risk, but few studies with adequate statistical power have investigated this question, and the results have not been consistent. Methods: In a prospective study of 29,691 people (19,710 women and 9,981 men) without previously known thyroid disease, thyrotropin was measured at baseline, and cancer incidence was recorded during 9 years of follow-up. Using Cox regression analysis, we studied the associations (hazard ratios) of thyrotropin categories with total cancer risk, and specifically, with risk of lung, colon, prostate, and breast cancer adjusted for age, sex, and smoking status. Results: Low thyrotropin levels (<0.50 mU/L) were associated with increased cancer risk [adjusted hazard ratio (HR), 1.34; 95% confidence interval (CI), 1.06-1.69] compared with the euthyroid reference group. The higher risk was driven by lung cancer (adjusted HR, 2.34; 95% CI, 1.24-4.40) and prostate cancer (adjusted HR, 1.97; 95% CI, 1.04-3.76). After excluding the first 2 years of follow-up, the associations were strengthened to 2.91 (1.49-5.70) for lung cancer and 2.60 (1.36-4.99) for prostate cancer. Conclusion: Thyrotropin levels suggestive of hyperthyroid function are associated with increased cancer risk, and specifically, with increased risk of lung and prostate cancer, whereas hypothyroid function does not seem to be associated with cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(2):570–4)

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Association of Serum TSH with High Body Mass Differs between Smokers and Never-Smokers

CONTEXT Recent studies have suggested that the association of low thyroid function with high body mass is restricted to nonsmokers. OBJECTIVE The aim was to study the association of thyroid function with body mass separately for smokers and never-smokers. DESIGN AND SETTING We conducted a cross-sectional, population-based study. SUBJECTS We studied 27,097 individuals older than 40 yr of age who were without previously known thyroid disease. MAIN OUTCOME MEASURES We measured mean body mass index (BMI) and odds ratio for obesity (BMI > or = 30.0 kg/m(2)) according to categories of thyroid function, in women and men, and separately for current smokers and never-smokers. We also studied the association with BMI within the reference range of TSH (0.50-3.5 mU/liter). RESULTS TSH within the reference range was positively associated with BMI (P for trend < or = 0.001 in all groups) and with the prevalence of obesity (P for trend < 0.005 in all groups). Among women, the association did not differ between current smokers and never-smokers, but in men the association was stronger for current smokers. Hypothyroid function was associated with higher BMI and higher prevalence of obesity in women (subclinical and overt hypothyroidism) and men (subclinical hypothyroidism), both in current smokers and in never-smokers. CONCLUSION The association of low thyroid function with high body mass was as least as strong in current smokers as in never-smokers, and our results clearly show that the association is not limited to nonsmokers, as previously suggested.

Cognitive Function in Type 1 Diabetic Adults With Early Exposure to Severe Hypoglycemia A 16-year follow-up study

OBJECTIVE We assessed adulthood cognition in relation to early exposure to severe hypoglycemia (SH). RESEARCH DESIGN AND METHODS Sixteen years subsequent to a study of cognitive function in 28 diabetic children and 28 matched control subjects, we reexamined the same subjects with a 96% participation rate. Diabetic subjects were classified as with (n = 9) or without (n = 18) early (≤10 years of age) SH, which was defined as convulsions or loss of consciousness. RESULTS Overall, cognitive scores were 0.9 SDs lower in subjects with early SH compared with subjects without early SH (P = 0.003). The two diabetic groups particularly differed with respect to problem solving, verbal function, and psychomotor efficiency. Earlier age at first incident of SH was associated with poorer cognition (P for trend = 0.001). CONCLUSIONS The findings suggest that early exposure to SH may have lasting and clinically relevant effects on cognition.

Association of thyroid function with estimated glomerular filtration rate in a population-based study: the HUNT study

OBJECTIVE Low thyroid function may be associated with reduced glomerular filtration rate (GFR). We therefore studied the association of thyroid function with estimated GFR (eGFR) in a population-based study. DESIGN A cross-sectional, population-based study of 29 480 individuals above 40 years of age, without previously known thyroid disease. METHODS We calculated geometric mean eGFR and odds ratio (OR) of chronic kidney disease (CKD; eGFR <60 ml/min per 1.73 m(2)) according to categories of thyroid function, using people with TSH in the lower third of the reference range (0.50-1.4 mU/l) as the comparison group. RESULTS TSH within the reference range (0.50-3.5 mU/l) was negatively associated with eGFR (P for trend <0.001). Compared with people with TSH in the lower third of the reference range (83.0 ml/min per 1.73 m(2)), eGFR was lower in people with TSH in the middle (81.6 ml/min per 1.73 m(2)) and highest third (80.3 ml/min per 1.73 m(2)) of the reference range, and in people with subclinical (79.3 ml/min per 1.73 m(2), P<0.001) or overt hypothyroidism (76.5 ml/min per 1.73 m(2), P<0.001). The prevalence of CKD was higher in people with TSH in the middle (OR 1.20, 95% confidence interval (CI) 1.07-1.35) or highest third (OR 1.31, 95% CI 1.13-1.52) of the reference range, compared with people in the reference group. Also, CKD was more common in people with subclinical (OR 1.63, 95% CI 1.38-1.93) or overt (OR 1.98, 95% CI 1.22-3.20) hypothyroidism. CONCLUSIONS These findings suggest that low thyroid function, also within the clinically normal range, is associated with reduced GFR.

Pre-eclampsia, Soluble fms-like Tyrosine Kinase 1, and the Risk of Reduced Thyroid Function: Nested Case-Control and Population Based Study

Objective To determine if pre-eclampsia is associated with reduced thyroid function during and after pregnancy. Design Nested case-control study during pregnancy and population based follow-up study after pregnancy. Setting Calcium for Pre-eclampsia Prevention trial of healthy pregnant nulliparous women in the United States during 1992-5, and a Norwegian population based study (Nord-Trondelag Health Study or HUNT-2) during 1995-7 with linkage to the medical birth registry of Norway. Participants All 141 women (cases) in the Calcium for Pre-eclampsia Prevention trial with serum measurements before 21 weeks’ gestation (baseline) and after onset of pre-eclampsia (before delivery), 141 normotensive controls with serum measurements at similar gestational ages, and 7121 women in the Nord-Trondelag Health Study whose first birth had occurred in 1967 or later and in whom serum levels of thyroid stimulating hormone had been subsequently measured. Main outcome measures Thyroid function tests and human chorionic gonadotrophin and soluble fms-like tyrosine kinase 1 concentrations in the Calcium for Pre-eclampsia Prevention cohort and odds ratios for levels of thyroid stimulating hormone above the reference range, according to pre-eclampsia status in singleton pregnancies before the Nord-Trondelag Health Study. Results In predelivery specimens of the Calcium for Pre-eclampsia Prevention cohort after the onset of pre-eclampsia, thyroid stimulating hormone levels increased 2.42 times above baseline compared with a 1.48 times increase in controls. The ratio of the predelivery to baseline ratio of cases to that of the controls was 1.64 (95% confidence interval 1.29 to 2.08). Free triiodothyronine decreased more in the women with pre-eclampsia than in the controls (case ratio to control ratio 0.96, 95% confidence interval 0.92 to 0.99). The predelivery specimens but not baseline samples from women with pre-eclampsia were significantly more likely than those from controls to have concentrations of thyroid stimulating hormone above the reference range (adjusted odds ratio 2.2, 95% confidence interval 1.1 to 4.4). Both in women who developed pre-eclampsia and in normotensive controls the increase in thyroid stimulating hormone concentration between baseline and predelivery specimens was strongly associated with increasing quarters of predelivery soluble fms-like tyrosine kinase 1 (P for trend 0.002 and <0.001, respectively). In the Nord-Trondelag Health Study, women with a history of pre-eclampsia in their first pregnancy were more likely than other women (adjusted odds ratio 1.7, 95% confidence interval 1.1 to 2.5) to have concentrations of thyroid stimulating hormone above the reference range (>3.5 mIU/l). In particular, they were more likely to have high concentrations of thyroid stimulating hormone without thyroid peroxidase antibodies (adjusted odds ratio 2.6, 95% confidence interval 1.3 to 5.0), suggesting hypothyroid function in the absence of an autoimmune process. This association was especially strong (5.8, 1.3 to 25.5) if pre-eclampsia had occurred in both the first and the second pregnancies. Conclusion Increased serum concentration of soluble fms-like tyrosine kinase 1 during pre-eclampsia is associated with subclinical hypothyroidism during pregnancy. Pre-eclampsia may also predispose to reduced thyroid function in later years.

Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway

Objective  Thyroid function and body mass are related, but the causal relationship remains unclear. Our objective was to investigate the longitudinal relationship between thyroid stimulating hormone (TSH) and body mass measures [body weight, body mass index (BMI), waist circumference (WC) and waist‐hip‐ratio (WHR)].

Angiogenic Factors in Maternal Circulation and the Risk of Severe Fetal Growth Restriction

Maternal angiogenic factors (placental growth factor, soluble fms-like tyrosine kinase 1 (Flt-1), and soluble endoglin) may be associated with fetal growth restriction, and the associations may differ according to stage of pregnancy. Among children born to pregnant women without preeclampsia in Norway between 1992 and 1994, 217 singletons with severe growth restriction (small for gestational age (SGA), <2.5th percentile) were compared with 378 singleton controls. For each angiogenic factor, SGA risk was related to concentrations in maternal serum collected in the first 2 trimesters, by using women with a serum concentration in the middle third at both samplings as reference. A low placental growth factor (lowest third) at both samplings was associated with high risk of SGA (odds ratio=3.8, 95% confidence interval: 1.6, 8.8). An increase from the lowest to the highest third of soluble Flt-1 was associated with high SGA risk (odds ratio=6.2, 95% confidence interval: 2.4, 16.1). Women with high soluble endoglin (highest third) at the second sampling had approximately a 3.5-fold increased risk of SGA. Low maternal soluble Flt-1 in early pregnancy followed by a strong subsequent increase in soluble Flt-1 and soluble endoglin was associated with a particularly high risk of severe fetal growth restriction.

Thyroid function and the risk of coronary heart disease: 12‐year follow‐up of the HUNT Study in Norway

In a mortality follow‐up of the HUNT Study, serum TSH within the reference range was positively associated with the risk of coronary death in women. We now aimed to confirm the association of high serum TSH with the risk of coronary heart disease, using hospital‐based diagnoses of myocardial infarction.