Are you sure the patient has Central Hypothyroidism?

Disorders affecting either the pituitary or the hypothalamus may cause hypothyroidism due to insufficient thyrotropin (TSH) stimulation of an otherwise normal thyroid gland. Central hypothyroidism (CH) may be congenital or familial due to genetic defects (mutations of genes encoding hypothalamic and pituitary transcription factors, TSH beta subunit, or the TRH receptor), but in the majority of cases, it is sporadic as a consequence of hypothalamic lesions, pituitary tumors, breech delivery, external brain irradiation, Sheehan’s syndrome, and other causes. CH may present as an isolated finding or may be associated with other pituitary hormone deficiencies.

Transient or reversible forms of CH may be observed during nonthyroidal illnesses (NTI), in which hypothalamic TRH synthesis and feedback setpoints may be downregulated to result in central hypothyroidism. In addition, recovery from thyrotoxicosis may be followed by a transient form of CH. Finally, many drugs (including cocaine, somatostatin analogs, glucocorticoids, dopaminergic compounds, and bexarotene), may affect the neuroendocrine mechanisms of TSH regulation to produce a form of CH.

Patients with central hypothyroidism usually display mild to moderate symptoms and signs similar to those of primary hypothyroidism, which include fatigue, constipation, dry skin and weight gain. Moreover, the presence of signs and symptoms of other pituitary hormone deficiencies may mask underlying CH. Inheritable forms of CH are generally associated with severe neonatal onset and characterized by typical manifestations of congenital primary hypothyroidism (jaundice, macroglossia, coarse cry, failure to thrive, retarded growth, umbilical hernia, and hypotonia). In patients with transcription factor defects, the presence of combined pituitary hormone defects is suggested by the association of CH with hypoglycemia, adrenal insufficiency, typical craniofacial abnormalities, or severe growth retardation.

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However, in most forms of CH, the signs and symptoms are nonspecific. The diagnosis is usually obtained on a biochemical basis either incidentally or in patients under evaluation for hypothalamic or pituitary disorders.

What else could the patient have?

The etiology of sporadic CH is quite heterogeneous, and the following differential diagnoses should be considered:

  • invasive lesions of hypothalamus or pituitary (craniopharyngiomas, gliomas, meningiomas, pituitary macroadenomas and metastases and empty sella)
  • iatrogenic causes (cranial surgery or irradiation, drugs)
  • injuries (head traumas, breech delivery)
  • infarctions [post-partum necrosis (Sheehan’s syndrome), pituitary apoplexy, vascular accidents affecting pituitary or hypothalamus]
  • immunologic diseases (lymphocytic hypophysitis)
  • infiltrative lesions (sarcoidosis, hemochromatosis, histiocytosis X)
  • infective diseases (tuberculosis, syphilis, mycoses)
  • idiopathic forms of unknown causes

Key laboratory and imaging tests

The hallmark of CH are low serum levels of circulating free thyroxine (FT4) into the hypothyroid range associated with low/normal serum TSH concentrations. Some patients with CH with a predominantly hypothalamic defect may have high serum TSH levels, a potentially misleading diagnosis which may be confused with subclinical primary hypothyroidism. Although serum TSH levels may be normal or high, the TSH is biologically inactive and cannot stimulate the thyroidal TSH receptor. The measurement of serum free triiodothyronine (FT3) levels is highly unreliable, as more than 30% of patients with CH have normal levels of this hormone.

Measurement of anti-thyroid autoantibodies may help in differentiating CH from primary hypothyroidism, as they will be undetectable in patients with CH.

The measurement of different parameters of peripheral thyroid hormone action, such as sex hormone-binding globulin, ferritin, bone markers, serum lipids and others, does not appear diagnostically useful, as they lack sufficient sensitivity and specificity for the diagnosis of hypothyroidism.

In every patient with CH, Computerized Tomography (CT) scan or Magnetic Resonance Imaging (MRI) study of the hypothalamic-pituitary region should be carried out.

Dynamic testing should be considered. The TRH test (not available in the U.S.) may be useful in confirming the suspicion of CH, although distinguishing between tertiary (hypothalamic) and secondary (pituitary) hypothyroidism may be difficult.

Management and treatment of the disease

The aim of treatment in patients with CH is to restore normal serum concentrations of circulating thyroid hormones by administering replacement levo-thyroxine (LT4). LT4 replacement is easily titrated in patients with primary hypothyroidism by measurement of serum TSH levels. However, this method is not useful in patients with CH, although unsuppressed serum TSH levels during LT4 treatment strongly suggest undertreatment.

Measurement of the serum free thyroid hormones is the major determinant of adequate L-T4 treatment in patients with CH. However, several recent papers regarding replacement LT4 therapy in patients with CH have outlined some of the problems in achieving optimal replacement. In one recent study, Koulouri et al identified patients in their hospital with hypothalamic-pituitary lesions and stratified them into high risk and low risk groups for having CH. Serum FT4 values in these groups of patients were generally lower than in patients with primary hypothyroidism adequately treated with LT4 (normal TSH).

Moreover, they suggest that levels of FT4 around 16 pmol/L (their laboratory reference range being 9–25 pmol/L) might represent an appropriate target in patients treated for CH. Finally, it has been suggested to measure both serum FT3 and FT4 levels. However, most current methods of measuring FT3 are inaccurate and are rarely used in the follow-up of patients with CH. The evaluation of clinical and other biochemical indices of peripheral thyroid hormone action also have a limited role in monitoring LT4 treatment in CH patients.

In patients at risk for combined pituitary hormone deficiencies (CPHD), potential concomitant central adrenal insufficiency must be excluded before starting LT4 therapy due to the risk of precipitating an adrenal crisis. If adrenal function cannot be assessed prior to the start of LT4, prophylactic treatment with steroids is advised. Treatment with LT4 should be started at low daily dosage (e.g. 25 mcg/day), particularly in those with longstanding hypothyroidism, and gently titrated upward to the full replacement dose. The dose of replacement LT4 may be different in patients with CPHDs compared to those with CH.

For example, recombinant human growth hormone treatment interferes with the activity of the hypothalamic-pituitary-thyroid axis and may either unmask a state of central hypothyroidism or render LT4 replacement therapy insufficient. In addition, treatment strategies are different between patients with CH that is diagnosed during the neonatal period than during early childhood. Treatment should be started at full-replacement doses (10-15 mg/kg of LT4) in neonates to minimize the risk of hypothyroidism at a critical period of neurological development.

In conclusion, LT4 replacement therapy should be carried out in patients with CH with the following considerations:

  • Start therapy only after the exclusion of adrenal insufficiency
  • Establish the final dose based on age and sex (about 1.4-1.7 mg/kg bw) of the patient
  • Maintain the levels of serum FT4 in the middle of the normal laboratory reference range
  • Reassess the dose of LT4 in a patient with combined pituitary hormone deficiency
  • Monitor serum FT4 levels drawn before daily ingestion of LT4 tablets
  • Suspect undertreatment when TSH levels are >0.2 mU/L
  • In iodine-deficient countries, consider the possible presence of a nodular goiter with autonomous thyroid hormone secretion in order to prevent possible LT4 overtreatment

What’s the Evidence?/References

Agha, A, Walker, D, Perry, L, Drake, WM, Chew, SL, Jenkins, PJ, Grossman, AB, Monson, JP. “2007 Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients”. Clin Endocrinol (Oxf). vol. 66. 2007. pp. 72-77. (In a series of 84 patients with severe GH deficiency, the authors demonstrate that 30 of them became hypothyroid during the treatment with recombinant hGH, thus confirming previous studies on the subject. They conclude that GH deficiency may mask central hypothyroidism and that patients with FT4 values in the lower limit of the normal range should be treated with LT4 prior to commencement of GH replacement.)

Alexopoulou, O, Beguin, C, De Nayer, P, Maiter, D. “Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients”. Eur J Endocrinol. vol. 150. 2004. pp. 1-8. (In this paper, the authors underline the fact that undoubtedly FT4 measurement is the best indicator of central hypothyroidism, but remains in the low normal range in a significant subset of patients. Moreover, they suggest that time-related decreases in circulating FT4 concentrations larger than 20% as compared with the basal FT4 values may indicate the presence of central hypothyroidism.)

Bonomi, M, Proverbio, MC, Weber, G, Chiumello, G, Beck-Peccoz, P, Persani, L. ” Hyperplastic pituitary gland, high serum glycoprotein hormone a-subunit, and variable circulating thyrotropin levels as hallmark of central hypothyroidism due to mutations of the TSHβ gene”. J Clin Endocrinol Metab. vol. 86. 2001. pp. 1600-1604. (Although mutations in the gene encoding TSH beta subunit are rare, this publication suggests a series of clinical and biochemical characteristics to reach a precise diagnosis.)

Ferretti, E, Persani, L, Jaffrain-Rea, ML, Giambona, S, Tamburrano, G, Beck-Peccoz, P. “1999 Evaluation of the adequacy of L-T4 replacement therapy in patients with central hypothyroidism”. J Clin Endocrinol Metab. vol. 84. 1999. pp. 924-929. (In the evaluation of the adequacy of L-T4 replacement therapy, both serum FT4 and TSH levels together with some biochemical indexes of thyroid hormone action appear necessary to a more accurate disclosure of over- or under- treated patients. The authors suggest to maintain the levels of circulating FT4 in the middle of the laboratory reference values.)

Giavoli, C, Porretti, S, Ferrante, E, Cappiello, V, Ronchi, CL, Travaglini, P, Epaminonda, P, Arosio, M, Beck-Peccoz, P. “Recombinant hGH replacement therapy and the hypothalamus-pituitary-thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?”. Clin Endocrinol (Oxf). vol. 59. 2003. pp. 806-810. (In this paper, the authors show that contrary to that observed in patients with multiple pituitary hormone deficiencies (MPHD), rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD.)

Haugen, BR. “2009 Drugs that suppress TSH or cause central hypothyroidism”. Best Pract Res Clin Endocrinol Metab. vol. 23. 2009. pp. 793-800. (A useful review of all the drugs that can interfere with the central regulation of thyroid function.)

Koulouri, O, Auldin, MA, Agarwal, R, Kieffer, V, Robertson, C, Falconer Smith, J, Levy, MJ, Howlett, TA. “Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of underreplacement with levothyroxine”. Clin Endocrinol (Oxf). vol. 74. 2011. pp. 744-749. (Using their department’s clinical information system, the authors identified all patients with a diagnosis of any type of pituitary tumour who had been seen in clinic over a 2-year period. They divided the patients into those at high risk and low risk of TSH deficiency based on the presence of macroadenoma and/or intervention by surgery or radiotherapy. We compared fT4 values in these patients with values in patients with primary thyroid disease in their hypothyroid register within the same timescale, assessing only those samples considered euthyroid in which TSH was in the normal range. Levothyroxine doses were generally under-replaced in pituitary patients compared to primary thyroid disease and the data imply that some untreated patients were actually TSH deficient.)

LaFranchi, SH. “Newborn screening strategies for congenital hypothyroidism: an update”. J Inherit Metab Dis. vol. 33. 2010. pp. S225-S233. (This is an updated review on LT4 replacement therapy in patients with congenital primary or central hypothyroidism.)

Persani, L, Ferretti, E, Borgato, S, Faglia, G, Beck-Peccoz, P. “Circulating TSH bioactivity in sporadic central hypothyroidism”. J Clin Endocrinol Metab. vol. 85. 2000. pp. 3631-3635. (The secretion of TSH with low bioactivity in patients with central hypothyroidism accounts for the lack of correlation between immunoreactive TSH and free thyroid hormone concentrations, and the absent/impaired increments in free thyroid hormone after acute stimulation of endogenous TSH by TRH. The secretion of TSH molecules with reduced bioactivity is a common alteration in the patients with hypothalamic-pituitary lesions, contributing along with the impairment of pituitary TSH reserve to the pathogenesis of CH.)

Pfäffle, R, Klammt, J. “Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency”. Best Pract Res Clin Endocrinol Metab. vol. 25. 2011. pp. 43-60. (In this review, the authors summarize the recent knowledge on the genetic causes of congenital central hypothyroidism when combined with multiple pituitary hormone deficiencies.)

Yamada, M, Mori, M. “Mechanisms related to the pathophysiology and management of central hypothyroidism”. Nat Clin Pract Endocrinol Metab. vol. 4. 2008. pp. 683-694. (In this review, the authors focus on the prevalence of CH and thyroid hormone status, particularly serum TSH level in each disorder, and discuss appropriate management.)