4
Natural history, diagnosis and management of subclinical thyroid dysfunction

https://doi.org/10.1016/j.beem.2011.12.004Get rights and content

Subclinical thyroid dysfunction (STD) represents a condition of slight thyroid hormone excess or deficiency, which may be associated with important adverse effects.

This review will focus on the natural history, diagnosis and management of subclinical thyroid dysfunction.

Since STD is only detected as a thyroid stimulating hormone (TSH) abnormality, it is essential to exclude transient causes of abnormal serum TSH before treating this disorder.

Treatment of subclinical hyperthyroidism (SHyper) is recommended in elderly patients with undetectable serum TSH for the increased risk of atrial fibrillation, osteoporosis and bone fractures and for the higher risk of progression to overt disease.

Treatment of subclinical hypothyroidism should be considered in patients with serum TSH above 10 mU/L for the increased risk of progression to overt hypothyroidism and the increased risk of coronary heart disease and heart failure events, which have been documented in patients with TSH increase above 10 mU/L.

About 75% of patients with STD have mild dysfunction. The mild form of STD (low but detectable serum TSH in SHyper and mild increased serum TSH between 5 and 9 mU/L in SHypo is associated with a minor risk of disease progression to overt dysfunction. The best treatment for STD remains controversial. Treatment of the mild form of STD should be considered after evaluating the patients’ age, the adverse risk factors, the potential beneficial effects of treating this disorder and any underlying co-morbidities.

Mild SHypo should be treated in infertile and pregnant women.

Introduction

Subclinical thyroid dysfunction (STD) is an early condition of mild thyroid hormone excess (subclinical hyperthyroidism) or deficiency (subclinical hypothyroidism), characterized by abnormal serum thyroid stimulating hormone (TSH) and normal free thyroxine (FT4) and free tri-iodothyronine (FT3).1, 2

The upper limit of the normal range has progressively decreased in the last decades from 10–7.0 mU/L to 4.0–5 mU/L, with the use of thyroid antibody tests.

Subclinical hypothyroidism (SHypo) is characterized by elevated serum TSH and thyroid hormone levels at the lower limit but within their respective reference range.1, 2, 3, 4 It is necessary to distinguish between patients with mildly increased serum TSH levels (5–9 mU/L) and patients with more severely increased serum TSH levels (≥10 mU/L) (Table 1). About 75% of all SHypo patients have mild disease.

The enhanced sensitivity of the TSH assay with the second and the third generation immunometric evaluation has helped differentiate the lower limit of the normal range from complete and incomplete TSH suppression.1, 2, 3

Subclinical Hyperthyroidism (SHyper) is defined as low-undetectable serum TSH and thyroid hormone (FT4 and FT3) concentrations in the upper limit but within their respective reference range.1, 2, 3, 4 Clinicians usually distinguish mild SHyper when the serum TSH level is low, but still detectable (0.1–0.4 mU/L), from a more severe condition in which TSH is undetectable and fully suppressed (Table 1).

Mild SHyper is the prevalent form of this dysfunction because it is present in about 75% of patients.2

The high frequency and the various implications of STD require the need to establish a correct diagnosis, clinical assessment and treatment of this disorder.4, 5

Section snippets

Prevalence and etiology

The prevalence of SHypo has been reported to be between 4 and 20% of the adult population samples.1, 2, 6 This wide range reflects some important differences among the populations studied in terms of race and dietary iodine intake, the dissimilar characteristics among the patients evaluated (age, gender, body mass index) and the different methods of TSH evaluation (TSH cut-off values used to define SHypo).1, 2, 7

Hashimoto thyroiditis, an autoimmune disorder of the thyroid gland is the most

Prevalence and etiology

The most common cause of exogenous SHyper (Exo SHyper) is an excessive L-T4 replacement therapy in hypothyroid patients or an intentional TSH suppression in patients with differentiated thyroid cancer (DTC).1, 2, 72 Exogenous SHyper is present in about 20–40% of patients receiving L-thyroxine (L-T4) therapy.9

Long-term L-T4 suppression of TSH is the traditional treatment for patients with DTC at high-risk of recurrence and progression.75, 76 Experimental and clinical data have demonstrated that

Disclosure summary

The author has nothing to disclose.

Acknowledgment

Alfonso Gruosso for writing English assistance.

References (106)

  • B. Biondi et al.

    The clinical significance of subclinical thyroid dysfunction

    Endocrine Reviews

    (2008)
  • DS. Cooper et al.

    Subclinical thyroid disease

    Lancet

    (2012)
  • Z. Baloch et al.

    Guidelines Committee, National Academy of Clinical Biochemistry Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease

    Thyroid

    (2003)
  • M.I. Surks et al.

    Subclinical thyroid disease: scientific review and guidelines for diagnosis and management

    Journal of the American Medical Association

    (2004)
  • H. Gharib et al.

    The Endocrine Society consensus statement #1: subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society

    Journal of Clinical Endocrinology and Metabolism

    (2005)
  • G.J. Canaris et al.

    The Colorado thyroid disease prevalence study

    Archives of Internal Medicine

    (2000)
  • M.I. Surks et al.

    Age- and race-based serum thyrotropin reference limits

    Journal of Clinical Endocrinology and Metabolism

    (2010)
  • L.L. Somwaru et al.

    High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over

    Journal of Clinical Endocrinology and Metabolism

    (2009)
  • Biondi thyroid and obesity: an intriguing relationship

    Journal of Clinical Endocrinology and Metabolism

    (2010)
  • M. Imaizumi et al.

    Risk for progression to overt hypothyroidism in an elderly Japanese population with subclinical hypothyroidism

    Thyroid

    (2011)
  • Y. Li et al.

    Antithyroperoxidase and antithyroglobulin antibodies in a five-year follow-up survey of populations with different iodine intakes

    Journal of Clinical Endocrinology and Metabolism

    (2008)
  • J.P. Walsh et al.

    Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques

    Journal of Clinical Endocrinology and Metabolism

    (2010)
  • G. Huber et al.

    Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies

    Journal of Clinical Endocrinology and Metabolism

    (2002)
  • G.E. Krassas et al.

    Thyroid function and human reproductive health

    Endocrine Reviews

    (2010)
  • B. Biondi et al.

    Effects of subclinical thyroid dysfunction on the heart

    Annals of Internal Medicine

    (2002)
  • B. Biondi

    Cardiovascular effects of mild hypothyroidism

    Thyroid

    (2007)
  • A.R. Cappola et al.

    Hypothyroidism and atherosclerosis

    Journal of Clinical Endocrinology and Metabolism

    (2003)
  • B. Biondi et al.

    Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism

    Journal of Clinical Endocrinology and Metabolism

    (1999)
  • M. Akcakoyun et al.

    Abnormal left ventricular longitudinal function reserve assessed exercise pulsed wave tissue Doppler imaging in patients with subclinical hypothyrodism

    Journal of Clinical Endocrinology and Metabolism

    (2009)
  • P.J. Owen et al.

    Thyroid disease and vascular function

    Thyroid

    (2007)
  • S. Razvi et al.

    The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort

    Journal of Clinical Endocrinology and Metabolism

    (2010)
  • S.M. Boekholdt et al.

    Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study

    Clinical Endocrinology (Oxford)

    (2010)
  • B. Biondi et al.

    Hypothyroidism as a risk factor for cardiovascular disease

    Endocrine

    (2004)
  • N. Rodondi et al.

    Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death

    Archives of Internal Medicine

    (2005)
  • E.A. Palmieri et al.

    Subclinical hypothyroidism and cardiovascular risk: a reason to treat?

    Treatments in Endocrinology

    (2004)
  • L.H. Duntas et al.

    Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence?

    Thyroid

    (2007)
  • B. Biondi et al.

    Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency

    European Journal of Endocrinology

    (2009)
  • A.E. Hak et al.

    Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study

    Annals of Internal Medicine

    (2000)
  • B.O. Asvold et al.

    Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study

    Annals of Internal Medicine

    (2008)
  • M. Imaizumi et al.

    Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism

    Journal of Clinical Endocrinology and Metabolism

    (2004)
  • J.P. Walsh et al.

    Subclinical thyroid dysfunction as a risk factor for cardiovascular disease

    Archives of Internal Medicine

    (2005)
  • M.P. Vanderpump et al.

    The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community

    Thyroid

    (1996)
  • A.R. Cappola et al.

    Thyroid status, cardiovascular risk, and mortality in older adults

    Journal of the American Medical Association

    (2006)
  • S. Razvi et al.

    The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a meta-analysis

    Journal of Clinical Endocrinology and Metabolism

    (2008)
  • N. Ochs et al.

    Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

    Annals of Internal Medicine

    (2008)
  • N. Rodondi et al.

    Subclinical hypothyroidism and the risk of coronary heart disease and mortality

    Journal of the American Medical Association

    (2010)
  • J. Gussekloo et al.

    Thyroid status, disability and cognitive function, and survival in old age

    Journal of the American Medical Association

    (2004)
  • J. Sgarbi et al.

    Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5 year follow-up: the Japanese-Brazilian thyroid study

    European Journal of Endocrinology

    (2010)
  • G. Iervasi et al.

    Association between increased mortality and mild thyroid dysfunction in cardiac patients

    Archives of Internal Medicine

    (2007)
  • R. De Jongh et al.

    Endogenous subclinical thyroid disorders, physical and cognitive function, depression and mortality in older individuals

    European Journal of Endocrinology

    (2011)
  • Cited by (68)

    • Subclinical hypothyroidism in older individuals

      2022, The Lancet Diabetes and Endocrinology
      Citation Excerpt :

      One potential reason to treat subclinical hypothyroidism is to prevent progression to overt hypothyroidism. The annual rate of progression to overt hypothyroidism is 4·3% in patients of all ages with both high concentrations of serum TSH and positive thyroid peroxidase (TPO) antibodies,20,21 2·8% in patients of all ages with normal concentrations of serum TSH and positive TPO antibodies,20 and 2–6% in patients of all ages after partial thyroidectomy.20 Several cross-sectional and longitudinal studies in healthy people with no evidence of thyroid disease have shown that TSH concentration progressively increased with age without an accompanying fall in free T4 concentration.22–24

    • Thyroid Hormones

      2020, Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology
    • Thyroid Hormones

      2019, Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology
    • The Management of Thyroid Abnormalities in Chronic Heart Failure

      2019, Heart Failure Clinics
      Citation Excerpt :

      Moreover, SHypo can be a risk factor for cardiac death in patients with chronic HF.15 Treatment of overt hypothyroidism and SHypo with levothyroxine (LT4) is able to prevent the progressive left ventricle dysfunction and improve systolic and diastolic dysfunctions, SVR, and endothelial function, improve cardiac output thereby increasing (CO) and stroke volume.11,12,16 Therefore, LT4 in replacement doses is recommended by international guidelines and expert opinions in patients with serum TSH above 10 mU/L.2,3,17,18 This treatment also should be considered when serum TSH is persistently increased in mild disease (TSH 4.5–9.9 mU/L), especially in patients with a high CV background.2,3,17,18

    View all citing articles on Scopus
    View full text