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  • Review Article
  • Published:

Central hypothyroidism — a neglected thyroid disorder

Nature Reviews Endocrinology volume 13, pages 588–598 (2017)Cite this article

Subjects

Key Points

  • Patients with signs and symptoms of hypothyroidism, recurrent headaches or visual field defects, as well as concomitant or pre-existing hypothalamic or pituitary disorders, should be investigated for central hypothyroidism

  • The presence of low levels of free T4 with an inappropriately normal to low TSH concentration is the hallmark of central hypothyroidism, along with reduced bioactivity of circulating TSH and variable TSH response to TSH-releasing hormone (TRH) tests

  • Patients who are younger than 14 years of age with central hypothyroidism accompanied by other pituitary hormone deficiencies might have a congenital form of the disease, and clinicians should screen patients for gene mutations of several pituitary transcription factors

  • The diagnosis of acquired central hypothyroidism needs the careful investigation of a patient's medical history, including drug treatment, recombinant human growth hormone replacement therapy, traumatic brain injury and concomitant autoimmune diseases

  • Levothyroxine therapy should only be initiated following the exclusion of adrenal insufficiency; levothyroxine replacement therapy should begin with low doses that are then slowly increased (every 3–6 weeks)

  • Levels of free T4 in the serum of patients should be maintained in the middle to upper part of the normal range, and blood should be drawn before levothyroxine administration. If serum levels of TSH are higher than 0.5 mU/l, then the patient is probably being undertreated

Abstract

Central hypothyroidism is a rare and heterogeneous disorder that is characterized by a defect in thyroid hormone secretion in an otherwise normal thyroid gland due to insufficient stimulation by TSH. The disease results from the abnormal function of the pituitary gland, the hypothalamus, or both. Moreover, central hypothyroidism can be isolated or combined with other pituitary hormone deficiencies, which are mostly acquired and are rarely congenital. The clinical manifestations of central hypothyroidism are usually milder than those observed in primary hypothyroidism. Obtaining a positive diagnosis for central hypothyroidism can be difficult from both a clinical and a biochemical perspective. The diagnosis of central hypothyroidism is based on low circulating levels of free T4 in the presence of low to normal TSH concentrations. The correct diagnosis of both acquired (also termed sporadic) and congenital (also termed genetic) central hypothyroidism can be hindered by methodological interference in free T4 or TSH measurements; routine utilization of total T4 or T3 measurements; concurrent systemic illness that is characterized by low levels of free T4 and normal TSH concentrations; the use of the sole TSH-reflex strategy, which is the measurement of the sole level of TSH, without free T4, if levels of TSH are in the normal range; and the diagnosis of congenital hypothyroidism based on TSH analysis without the concomitant measurement of serum levels of T4. In this Review, we discuss current knowledge of the causes of central hypothyroidism, emphasizing possible pitfalls in the diagnosis and treatment of this disorder.

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Figure 1: Measurement of the ratio between TSH bioactivity and TSH immunoreactivity (TSH B/I) in sera from patients with central hypothyroidism of hypothalamic origin.
Figure 2: Serum levels of TSH and free T4 in a large series of patients with central hypothyroidism investigated in our institution.
Figure 3: Proposed algorithm for the diagnosis of the different forms of central hypothyroidism.
Figure 4: TRH stimulation test in controls and in patients with hypothalamic hypothyroidism.

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Authors and Affiliations

  1. University of Milan, Via Petro Custodi 16, Milan, 20136, Italy

    Paolo Beck-Peccoz

  2. Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Endocrinology and Metabolic Diseases Unit, Via Francesco Sforza 35, Milan, 20122, Italy

    Giulia Rodari & Claudia Giavoli

  3. Department of Biomedical Sciences, Humanitas University and Endocrinology Unit, Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20086, Italy

    Andrea Lania

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P.B.-P., G.R. and C.G. researched data for the article. P.B.-P., C.G. and A.L. substantially contributed to discussions of the content. P.B.-P. wrote and edited the article before submission.

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Thyroid axis

Refers to the hypothalamic–pituitary–thyroid axis.

Immunometric assays

Methods involving antibody–antigen binding reactions, based on the law of mass action.

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Beck-Peccoz, P., Rodari, G., Giavoli, C. et al. Central hypothyroidism — a neglected thyroid disorder. Nat Rev Endocrinol 13, 588–598 (2017). https://doi.org/10.1038/nrendo.2017.47

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