Physiopathology, Diagnosis, and Treatment of Secondary Hypothyroidism
Secondary (or central) hypothyroidism (CH) is characterized by decreased thyroid hormone synthesis due to absent or insufficient thyroid stimulation by pituitary thyrotropin (TSH). The disease results from anatomical and/or functional disorder of the pituitary and/or the hypothalamus. The thyroid morphology and potential of hormone synthesis are usually normal, and the thyroid insufficiency is caused by dysfunction of the upper parts of the hypothalamus-pituitary-thyroid axis.
Rarely is CH an isolated insufficiency of thyrotropic cells and, in most cases, it is a part of combined (or multiple) pituitary hormone deficiency (CPHD).
The typical biochemical test results in CH include low free thyroxine (FT4) with decreased, low normal, or simply normal serum TSH concentration. Congenital CH (CoCH) is an important diagnostic challenge since routine screening for thyroid function, usually including TSH level only, can give misleading conclusion of normal thyroid function or even of hyperthyroidism. In most cases of CoCH, the genetic basis of hypothalamic and/or pituitary pathology is undefined. Among the already known molecular causes of CoCH, rarely occurring isolated TSH deficiency is a result of mutations in genes which control TSH synthesis (TSHβ, TRHR, TBL1X). Much more often CoCH is a part of CPHD resulting from mutations in one of several transcription factors important for the entire pituitary development, such as HESX1, LHX3, LHX4, SOX2, SOX3, OTX2, GATA2, ISL1, PITX1/2, PROP1, or POU1F1.
Acquired CH or CPHD of various extent and severity can be caused by intrasellar or extrasellar tumors, with pituitary adenomas and craniopharyngiomas being the most common ones. Surgical treatment of such tumors, as well as head irradiation, may lead to CH – either isolated or coexisting with additional pituitary deficiencies. Other important potential causes of CH include brain injuries, pituitary apoplexy, empty sella syndrome, parasellar aneurysm, subarachnoid hemorrhage, lymphocytic hypophysitis, and infiltrative or infectious diseases.
In every case of CH, detailed investigation of secretion of other pituitary hormones is obligatory, as additional anterior pituitary hormone deficiencies may be present in the majority of patients. Magnetic resonance imaging of the pituitary and the hypothalamus is mandatory in every case when CH is confirmed or suspected.
Treatment of CH is challenging as TSH cannot guide levothyroxine (L-T4) dose adjustment. Similarly to primary hypothyroidism, oral daily dose of L-T4 is a treatment of choice in CH. Before starting L-T4 administration, concomitant secondary adrenal insufficiency in the course of CPHD should always be excluded. If present, secondary adrenal insufficiency should be substituted before L-T4 treatment to avoid exacerbation of cortisol deficiency, which may even precipitate adrenal crisis.
The target level of FT4 during treatment should be maintained within the upper half of the normal range. Majority of CH patients require on average 1.5–1.6 μg L-T4/kg body weight daily. Older patients need lower doses of L-T4 than the young (approximately 1.1 μg L-T4/kg body weight daily). In infants and young children with CH, higher doses of L-T4 are required comparing to adults. It is recommended to start treatment in neonates with 10–15 μg/kg body weight daily and the dose should be decreased as the child gets older.
Concomitant treatment of CPHD significantly influences L-T4 requirement, and the dose should be re-established when estrogens, androgens, or recombinant human growth hormone (rhGH) are introduced or in the patients in whom hydrocortisone therapy is introduced or modified during L-T4 treatment.
KeywordsCentral hypothyroidism Central congenital hypothyroidism Pituitary Hypothalamus Thyroid L-T4 TSH FT4 TSHβ gene PROP1 POU1F1
- Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA. American association of clinical endocrinologists and American Thyroid Association taskforce on hypothyroidism in adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22:1200–35.CrossRefPubMedGoogle Scholar
- Heinen CA, Losekoot M, Sun Y, Watson PJ, Fairall L, Joustra SD, Zwaveling-Soonawala N, Oostdijk W, van den Akker EL, Alders M, Santen GW, van Rijn RR, Dreschler WA, Surovtseva OV, Biermasz NR, Hennekam RC, Wit JM, Schwabe JW, Boelen A, Fliers E, van Trotsenburg ASP. Mutations in TBL1X are associated with central hypothyroidism. J Clin Endocrinol Metab. 2016;101(12):4564–73.CrossRefPubMedPubMedCentralGoogle Scholar
- Hermanns P, Couch R, Leonard N, Klotz C, Pohlenz J. A novel deletion in the thyrotropin Beta-subunit gene identified by array comparative genomic hybridization analysis causes central congenital hypothyroidism in a boy originating from Turkey. Horm Res Paediatr. 2014;82: 201–5.CrossRefPubMedGoogle Scholar
- Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. American Thyroid Association task force on thyroid hormone replacement. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24: 1670–751.CrossRefPubMedPubMedCentralGoogle Scholar
- Koulouri O, Nicholas AK, Schoenmakers E, Mokrosinski J, Lane F, Cole T, Kirk J, Farooqi IS, Chatterjee VK, Gurnell M, Schoenmakers N. A novel thyrotropin-releasing hormone receptor missense mutation (P81R) in central congenital hypothyroidism. J Clin Endocrinol Metab. 2016;101:847–51.CrossRefPubMedPubMedCentralGoogle Scholar
- Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G. ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE; congenital hypothyroidism consensus conference group. European society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paediatr. 2014;81: 80–103.CrossRefPubMedGoogle Scholar