Elevated TSH in adults treated for hypothyroidism is associated with increased mortality

Akirov, Amit; Gimbel, Hannah; Grossman, Alon; Shochat, Tzipora; Shimon, Ilan

doi:10.1530/eje-16-0708

Cited by 22 publications

(10 citation statements)

References 28 publications

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“…Here, based on the observations of the direct effect of TSH on the K + currents, a mechanistic explanation is proposed for the TSH-dependent electrocardiographic alterations and its possible contribution to enhanced susceptibility to cardiac arrhythmias. These results, together with the recently published association between high normal TSH levels and increased risk of mortality, further contribute to answering the question of whether serum TSH reference ranges should be reexamined (1,2,39,40).…”

Section: Discussionmentioning

confidence: 65%

“…Recent studies highlight the importance of thyrotropin (TSH) levels in the mortality of both hypothyroid and euthyroid individuals. Patients with treated overt hypothyroidism with serum TSH levels between 0.5 and 5 mIU/L have significantly lower mortality rates than patients with TSH levels between 5 and 10 mIU/L (1). Moreover, a recent study demonstrated that high-normal TSH levels are associated with higher mortality than mid-normal levels in non-hypothyroid individuals (2), but the mechanisms responsible for this elevated mortality are unknown.…”

Section: Introductionmentioning

confidence: 99%

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High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism

Fernandez-Ruocco

Gallego

Rodríguez-de-Yurre

et al. 2019

Thyroid

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Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim of the present work was to investigate the direct effects of TSH on the heart and its possible causative role in the increased incidence of arrhythmia in hypothyroidism. Methods: A new rat model of central hypothyroidism (low TSH levels) was created and characterized together with the classical propylthiouracil-induced primary hypothyroidism model (high TSH levels). Electrocardiograms were recorded in vivo , and ionic currents were recorded from isolated ventricular myocytes in vitro by the patch-clamp technique. Protein and mRNA were measured by Western blot and quantitative reverse transcription polymerase chain reaction in rat and human cardiac myocytes. Adult human action potentials were simulated in silico to incorporate the experimentally observed changes. Results: Both primary and central hypothyroidism models increased the L-type Ca 2+ current (I Ca-L ) and decreased the ultra-rapid delayed rectifier K + current (I Kur ) densities. However, only primary but not central hypothyroidism showed electrocardiographic repolarization abnormalities and increased ventricular arrhythmia incidence during caffeine/dobutamine challenge. These changes were paralleled by a decrease in the density of the transient outward K + current (I to ) in cardiomyocytes from animals with primary but not central hypothyroidism. In vitro treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished I to density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1 , I to , and the delayed rectifier K + current (I Ks ) encoding proteins in a protein kinase A–dependent way. Transposing the changes produced by hypothyroidism and TSH to a computer model of human ventricular action potential resulted in enhanced occurrence of early afterdepolarizations and arrhythmia mostly in primary hypothyroidism, especially under β-adrenergic stimulation. Conclusions: The results suggest that suppression of repolarizing K + currents by TSH underlies most of the electrical remodeling observed in hypothyroidism. This work demonstrates that the activation of the TSH-receptor/protein kinase A pathway in the heart is...

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism

Fernandez-Ruocco

Gallego

Rodríguez-de-Yurre

et al. 2019

Thyroid

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“…For example, other hormonal deficiencies as a result of hypopituitarism or excessive steroid replacement in the past may contribute to adverse health outcomes (30). Similarly, poorly controlled hypothyroidism, to the level that causes secondary hyperprolactinaemia, has been shown to cause increased death rates (31), whilst the increased death risk for people with drug-induced hyperprolactinaemia may be due to the higher risk of diabetes and cardiovascular disease associated with antipsychotic drugs. Increased risk of suicide could also be expected for people on anti-psychotropic drugs.…”

Section: Discussionmentioning

confidence: 99%

Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study

Soto-Pedre

Newey

Bevan

et al. 2017

Endocrine Connections

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PurposeHigh serum prolactin concentrations have been associated with adverse health outcomes in some but not all studies. This study aimed to examine the morbidity and all-cause mortality associated with hyperprolactinaemia.MethodsA population-based matched cohort study in Tayside (Scotland, UK) from 1988 to 2014 was performed. Record-linkage technology was used to identify patients with hyperprolactinaemia that were compared to an age–sex-matched cohort of patients free of hyperprolactinaemia. The number of deaths and incident admissions with diabetes mellitus, cardiovascular disease, cancer, breast cancer, bone fractures and infectious conditions were compared by the survival analysis.ResultsPatients with hyperprolactinaemia related to pituitary tumours had no increased risk of diabetes, cardiovascular disease, bone fractures, all-cause cancer or breast cancer. Whilst no increased mortality was observed in patients with pituitary microadenomas (HR = 1.65, 95% CI: 0.79–3.44), other subgroups including those with pituitary macroadenomas and drug-induced and idiopathic hyperprolactinaemia demonstrated an increased risk of death. Individuals with drug-induced hyperprolactinaemia also demonstrated increased risks of diabetes, cardiovascular disease, infectious disease and bone fracture. However, these increased risks were not associated with the degree of serum prolactin elevation (Ptrend > 0.3). No increased risk of cancer was observed in any subgroup.ConclusionsNo excess morbidity was observed in patients with raised prolactin due to pituitary tumours. Although the increased morbidity and mortality associated with defined patient subgroups are unlikely to be directly related to the elevation in serum prolactin, hyperprolactinaemia might act as a biomarker for the presence of some increased disease risk in these patients.

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“…In 9,020 adults, SCH (TSH >5.60 mIU/L) and high-normal TSH (1.96-5.60 mIU/L) were associated with increased all-cause mortality (HR = 1.90 and 1.36) vs. the middle-normal TSH group (1.20-1.95 mIU/L) (104), with CVD mediating 14.3 and 5.9% of the association, respectively (104). A study on 611 hospitalized elderly patients evaluated all-cause mortality up to 66 months after discharge (105) and concluded that (i) in treated hypothyroid patients, median TSH levels of 5-10 IU/L associated with increased mortality, (ii) treatment should aim at achieving euthyroidism to improve survival (105).…”

Section: Current Research Gapsmentioning

confidence: 99%

L-T4 Therapy in the Presence of Pharmacological Interferents

Benvenga

2020

Front. Endocrinol.

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Pharmacological interference on L-thyroxine (L-T4) therapy can be exerted at several levels, namely from the hypothalamus/pituitary through the intestine, where the absorption of exogenous L-T4 takes place. A number of medications interfere with L-T4 therapy, some of them also being the cause of hypothyroidism. The clinician should be aware that some medications simply affect thyroid function tests with no need of modifying the dose of L-T4 that the patient was taking prior to their prescription. Usually, the topic of pharmacological interference on L-T4 therapy addresses the patient with primary hypothyroidism, in whom periodic measurement of serum thyrotropin (TSH) is the biochemical target. However, this minireview also addresses the patient with central hypothyroidism, in whom the biochemical target is serum free thyroxine (FT4). This minireview also addresses two additional topics. One is the costs associated with frequent monitoring of the biochemical target when L-T4 is taken simultaneously with the interfering drug. The second topic is the issue of metabolic/cardiovascular complications associated with undertreated hypothyroidism.

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Elevated TSH in adults treated for hypothyroidism is associated with increased mortality

Abstract: In treated hypothyroid adult patients and serial measurements of thyroid function tests, median TSH levels of 5-10 IU/L are associated with increased mortality with no effect of fT4 levels. Treatment should aim at achieving euthyroidism to improve survival.

Cited by 22 publications

References 28 publications

High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism

High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism

Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study

L-T4 Therapy in the Presence of Pharmacological Interferents

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