A Review of the Clinical Consequences of Variation in Thyroid Function Within the Reference Range

Taylor, Peter N.; Razvi, Salman; Pearce, Simon H. S.; Dayan, Colin

doi:10.1210/jc.2013-1315

Cited by 249 publications

(207 citation statements)

References 79 publications

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“…Variation in thyrotropin (TSH) levels within the normal reference range generally shows an inverse relationship with fracture risk so that low-normal TSH values are associated with modest increases in the risk of fractures. (13)(14)(15) and with decreases in BMD. (13,16) Fracture risk may or may not be increased in patients with hypothyroidism and some studies have found discrepant outcomes for the two genders.…”

Section: Introductionmentioning

confidence: 90%

The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis

Abrahamsen

Jørgensen

Laulund

et al. 2014

Journal of Bone and Mineral Research

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The long-term relationship between hypothyroidism and fracture risk is challenging to dissect because of the modifying influence of subsequent thyroxine replacement with the potential for excessive replacement doses. We studied changes in serum thyrotropin concentration (TSH) over time and association with fracture risk in real-world patients presenting with elevated TSH. All TSH determinations were done in the same laboratory, which served all hospitals and general practices. The study population consisted of all adults with a first measurement of TSH >4.0 mIU/L (n ¼ 8414) or normal TSH (n ¼ 222,138; comparator). We used a Cox proportional hazards analysis incorporating additional time-dependent covariates to represent initiation of thyroxine replacement and cumulative number of periods with high versus low TSH after index date with a mean follow-up of 7.2 years. Elevated baseline TSH was not associated with an increased risk of hip fracture (HR 0.90; 95% CI, 0.80 to 1.02) or major osteoporotic fractures (HR 0.97; 95% CI, 0.90 to 1.05), nor was subsequent thyroxine prescription predictive of increased risk of fractures. The number of subsequent 6-month periods with low TSH-suggesting excessive thyroxine dosing-was significantly associated with increased risk of both hip fracture (HR 1.09; 95% CI, 1.04 to 1.15) and major osteoporotic fracture (HR 1.10; 95% CI, 1.06 to 1.14). When gender-and agestratified analyses for major osteoporotic fractures were undertaken, hyperthyroid time was identified as a predictor of fracture risk in postmenopausal women whereas hypothyroid time predicted increased fracture risk in men below age 75 years. In conclusion, among patients who present with an elevated TSH, the long-term risk of hip and other osteoporotic fractures is strongly related to the cumulative duration of periods with low TSH-likely from excessive replacement. An independent effect of elevated TSH could only be observed in young and middle-aged men, suggesting gender-discrepant consequences on risk.

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Section: Introductionmentioning

confidence: 90%

The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis

Abrahamsen

Jørgensen

Laulund

et al. 2014

Journal of Bone and Mineral Research

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“…Age, sex, smoking, iodine intake, and definition of the upper-limit of serum TSH are additional confounders, which might modify the relationship between BMI and serum TSH. A recent meta-analysis confirmed that a high-normal serum TSH is associated with a high BMI (68). However, the design of analyzed studies does not allow clarifying whether the high-normal serum TSH is the consequence or the cause of overweight.…”

Section: Thyroid Function and Structure In Obese Subjectsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

Santini

Marzullo

Rotondi

et al. 2014

European Journal of Endocrinology

204

185

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Obesity and thyroid diseases are common disorders in the general population and they frequently occur in single individuals. Alongside a chance association, a direct relationship between 'thyroid and obesity' has been hypothesized. Thyroid hormone is an important determinant of energy expenditure and contributes to appetite regulation, while hormones and cytokines from the adipose tissue act on the CNS to inform on the quantity of energy stores. A continuous interaction between the thyroid hormone and regulatory mechanisms localized in adipose tissue and brain is important for human body weight control and maintenance of optimal energy balance. Whether obesity has a pathogenic role in thyroid disease remains largely a matter of investigation. This review highlights the complexity in the identification of thyroid hormone deficiency in obese patients. Regardless of the importance of treating subclinical and overt hypothyroidism, at present there is no evidence to recommend pharmacological correction of the isolated hyperthyrotropinemia often encountered in obese patients. While thyroid hormones are not indicated as anti-obesity drugs, preclinical studies suggest that thyromimetic drugs, by targeting selected receptors, might be useful in the treatment of obesity and dyslipidemia.

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“…In fact, a number of studies have reported clinically relevant health consequences based on variations in thyroid function within the reference range. These outcomes have mainly been cardiovascular risk factors and events, metabolic parameters, bone density, and fracture risk [reviewed in Taylor et al (3)]. …”

Section: Introductionmentioning

confidence: 99%

Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects

Samuels

Kolobova

Smeraglio

et al. 2016

Thyroid

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Background: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function.Methods: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. Results: Subjects with low-normal (£2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels. Conclusions: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.

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A Review of the Clinical Consequences of Variation in Thyroid Function Within the Reference Range

Cited by 249 publications

References 79 publications

The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis

The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects

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