Alexandra P. Bremner

Context: Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce. Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia. Design: Individual participant data meta-analysis. Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162). Main Outcome Measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women). Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)]. Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups. Conclusion: Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction. Cross-sectional analysis of the population-based Busselton Health Study. We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method. Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing. The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.

Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) −4.07 (−6.37 to −1.78) and −2.40 (−3.78 to −1.02) mL/min/1.73 m² lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50–4.52) mL/min/1.73 m² higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

Background: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. Methods: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. Results: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26–1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. Conclusions: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.

Female sterilisation is usually performed on an elective basis at perceived family completion, however, around 1–3% of women who have undergone sterilisation elect to undergo sterilisation reversal (SR) at a later stage. The trends in SR rates in Western Australia (WA), proportions of SR procedures between hospital types (public and private), and the effects of Federal Government policies on these trends are unknown. Using records from statutory state-wide data collections of hospital separations and births, we conducted a retrospective descriptive study of all women aged 15–49 years who underwent a SR procedure during the period 1st January 1990 to 31st December 2008 (n = 1868 procedures). From 1991 to 2007 the annual incidence rate of SR procedures per 10,000 women declined from 47.0 to 3.6. Logistic regression modelling showed that from 1997 to 2001 the odds of women undergoing SR in a private hospital as opposed to all other hospitals were 1.39 times higher (95% CI 1.07–1.81) and 7.51 times higher (95% CI 5.46–10.31) from 2002 to 2008. There were significant decreases in SR rates overall and among different age groups after the Federal Government interventions. Rates of SR procedures in WA have declined from 1990 to 2008, particularly following policy changes such as the introduction of private health insurance (PHI) policies. This suggests decisions to undergo SR may be influenced by Federal Government interventions.

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower TSH and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45-4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, non-vertebral, and vertebral fractures. Results were presented as hazard ratios (HR) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45-0.99mIU/L; 1.00-1.49mIU/L; 1.50-2.49mIU/L; 2.50-3.49mIU/L; 3.50-4.49mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565/56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05-1.49) for TSH 0.45-0.99mIU/L, 1.19 (1.01-1.41) for TSH 1.00-1.49mIU/L, 1.09 (0.93-1.28) for TSH 1.50-2.49mIU/L, and 1.12 (0.94-1.33) for TSH 2.50-3.49mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 (HR [95%CI] 1.22 [1.11-1.35] per one standard deviation increase in FT4). FT4 only was associated with any and non-vertebral fracture. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

Background: The aim of this research was to investigate the association of various structural measurements of the forefoot with Morton’s neuroma (MN). Methods: Weightbearing anteroposterior and lateral foot radiographs of subjects attending the University of Western Australia (UWA) Podiatry Clinic and the first author’s private practice were included in this study. A single assessor measured the following angles: lateral intermetatarsal angle (LIMA), intermetatarsal angle (IMA), hallux valgus angle (HVA), digital divergence between the second and third digits (DD23), digital divergence between the third and fourth digits (DD34) and relative metatarsal lengths of the first to fifth metatarsals (Met1-5), and the effect of MN size as measured by ultrasonograph on digital divergence. Intratester reliability of all radiographic measurements was assessed on all radiographic measurements. The study included 101 subjects, of whom 69 were diagnosed with MN and 32 were control subjects without MN. The mean (± standard deviation) age of MN subjects was 52 (±15) years and for control subjects, 48 (±12) years. Results: When comparing all feet, there were no significant differences in the LIMA, HVA, IMA, digital divergence angles and the relative metatarsal distances between subjects with MN and control subjects. No relationship between MN size and digital divergence was found in either foot, or in either neuroma location. Conclusion: We were unable to demonstrate any relationship in this study between radiographic metatarsal length and angular measurements in a symptomatic MN group compared to a control group. In addition, we did not find any correlation between the size of MN as measured from ultrasonographic images and radiographic evidence of digital divergence. Level of Evidence: Level III, case control study.

Context: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. Design and Setting: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T₄, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. Results: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1–13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65–0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62–1.09) for fatal stroke. For the free T₄ analyses, the hazard ratio was 1.08 (95% CI 0.99–1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04–1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes. Conclusion: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

Objective: To examine the ability of paramedics to identify patients who could be managed in the community and to identify predictors that could be used to accurately identify patients who should be transported to EDs.Methods: Lower acuity patients who were assessed by paramedics in the Perth metropolitan area in 2013 were studied. Paramedics prospectively indicated on the patient care record if they considered that the patient could be treated in the community. The paramedic decisions were compared with actual disposition from the ED (discharge and admission), and the occurrence of subsequent events (ambulance request, ED visit, admission and death) for discharged patients at the scene was investigated. Decision tree analysis was used to identify predictors that were associated with hospital admission.Results: In total, 57 183 patients were transported to the ED, and 10 204 patients were discharged at the scene by paramedics. Paramedics identified 2717 patients who could potentially be treated in the community among those who were transported to the ED. Of these, 1455 patients (53.6%) were admitted to hospital. For patients discharged at the scene, those who were indicated as suitable for community care were more likely to experience subsequent events than those who were not. The decision tree found that two predictors (age and aetiology) were associated with hospital admission. Overall discriminative power of the decision tree was poor; the area under the receiver operating characteristic curve was 0.686.Conclusion: Lower acuity patients who could be treated in the community were not accurately identified by paramedics. This process requires further evaluation.