Pituitary DOI 10.1007/s11102-014-0559-8
Central hypothyroidism in adults: better understanding for better care Solange Grunenwald • Philippe Caron
Springer Science+Business Media New York 2014
Abstract Central hypothyroidism (CH) is a rare cause of hypothyroidism generally related to a hypothalamic–pituitary disorder or arising as an iatrogenic complication. In adults, CH may be secondary to quantitative and/or qualitative alterations in thyroid-stimulating hormone (TSH) secretion. The disease is difficult to diagnose clinically because it lacks specific clinical signs and these may be masked by other anterior pituitary hormone secretion deficiencies. In patients with long-standing and marked CH, a diagnosis may be made based on low free T4 levels and normal, low or moderately increased TSH levels. In patients with early-stage or moderate CH, exploration of the circadian TSH cycle, determination of TSH response after a TRH test or recombinant TSH injection, estimation of TSH index, or evaluation of peripheral indexes of thyroid hormone metabolism may be required to establish a diagnosis. Regarding treatment, patients should receive levothyroxine replacement therapy, but hormone objectives during follow-up need to be precisely determined in order to reduce cardiovascular risks and to improve the quality of life of patients.
or qualitative alterations in thyroid-stimulating hormone (TSH) secretion, most often by a normal thyroid gland. Central hypothyroidism is a complex disorder due to the large spectrum of underlying pathophysiological mechanisms, e.g. congenital CH, isolated or CH combined with other pituitary hormone deficiencies, CH acquired in the case of lesions affecting the pituitary gland (secondary hypothyroidism) or the pituitary stalk and the hypothalamus (tertiary hypothyroidism). In patients with hypothalamic–pituitary lesions, the diagnosis is often difficult because the clinical signs are non-specific and insidious, and established laboratory criteria are lacking except in severe cases. Patients should be given replacement therapy with levothyroxine but the thyroid function parameters to be monitored during treatment need to be defined in order to improve quality of life of these patients.
Keywords Central hypothyroidism Pathophysiology Causes Diagnosis Treatment Levothyroxine Free T4
Central hypothyroidism can occur at any age and contrary to peripheral hypothyroidism, it affects both sexes equally. It is a rare disease in children with a prevalence estimated at 1/20,000–1/120,000 based on neonatal hypothyroidism screening data whereas acquired CH is more frequent in adults with pituitary diseases [1, 2]. On the other hand CH appears to be more common in certain populations such as patients with dyslipidemia, a consequence of hypothyroidism (5.6/1,000) [3]. In adults, its prevalence is probably underestimated because its clinical signs are insidious and there is no consensus regarding laboratory diagnostic criteria. Furthermore, hormone assessments do not allow diagnosis of CH if only TSH is assayed: CH was detected in 2.8/10,000 subjects having undergone a TSH assay [4].
Introduction Central hypothyroidism (CH) is characterized by insufficient thyroid hormone production secondary to quantitative
S. Grunenwald P. Caron (&) Cardiovascular and Metabolic Unit, Department of Endocrinology and Metabolic Diseases, CHU Larrey, 24 chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex, France e-mail: [email protected]
Epidemiology
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Finally, the incidence of CH according to age has not been specifically studied, but thyroid hormone and TSH concentrations and response to the thyrotropin-releasing hormone (TRH) test decrease with age [5].
Table 1 Principal causes of CH in adults (1) Tumours Secreting and non-secreting pituitary macroadenomas Craniopharyngiomas, dysgerminomas, gliomas, meningiomas Metastases, lymphomas, Rathke cleft cysts
Pathophysiology TSH is a heterodimeric glycoprotein hormone consisting of two sub-units, the a subunit common to follicle stimulating hormone (FSH), luteinizing hormone (LH) and chorionic gonadotropin (hCG), and the b subunit specific to TSH. TSH secretion normally occurs in a circadian pattern with lower concentrations in the afternoon and higher concentrations during the night [6, 7]. Therefore, a normal TSH cycle can be defined by a more than 50 % increase in TSH levels between 12 p.m. and 4 a.m. relative to TSH levels between 3 p.m. and 7 p.m. [6]. TSH secretion is mainly regulated by a negative feedback effect of thyroid hormones and by a stimulatory effect of TRH. Somatostatin, dopamine, cortisol and glucocorticosteroids also inhibit TSH release. Finally, TSH secretion can also be affected by sex steroid hormones and leptin [2]. In adults, CH can be secondary to alterations in TSH secretion which may be quantitative (absence of TSH secretion, disappearance of the nocturnal surge of TSH [6, 7]) or qualitative [8] or both. In qualitative defects due to altered glycosylation of the TSH molecule, the ability to stimulate the TSH receptors of follicular cells is decreased [9–11], although the TSH molecule remains immunereactive which leads to the secretion of a TSH molecule with a decreased biological to immunological ratio. Furthermore, glycosylation alterations lead to decreased hepatic clearance and an increase in the half-life of TSH and therefore, to normal or slightly increased TSH concentrations. Qualitative-defective TSH secretion, mainly described for CH related to hypothalamic disorders, can be normalized by chronic TRH administration [12].
(2) Infiltrative lesions Auto-immune hypophysitis, sarcoidosis, histiocytosis X, eosinophilic granuloma, hemochromatosis (3) Injuries Post-radiotherapy, post-surgical, head traumas (4) Iatrogenic causes Bexarotene, mitotane, growth hormone, metformin Thyroid hormone analogues (5) Other causes Recovery phase of any episode of thyrotoxicosis Tuberculosis, syphilis, viral or fungal infections Vascular causes: pituitary apoplexy, post-partum necrosis, Carotid aneurysm (6) Congenital causes Mutations of TRH receptor gene Mutations of TSH beta subunit gene IGSF1 mutations Mutations in genes regulating pituitary transcription factors
2.
Etiology The main causes of CH are listed in Table 1: 1.
Secreting and non-secreting pituitary macroadenomas are responsible for more than 50 % of CH cases [2] and they are often associated with more general anterior pituitary insufficiency, caused either by compression or destruction of pituitary cells, or compression of the pituitary stalk or the hypothalamus. Other tumors of the sellar region can also cause CH, and surgical removal of a pituitary gland lesion may also result in more or less complete hypopituitarism.
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3.
Autoimmune hypophysitis generally causes disturbances in several functions of the pituitary gland. The thyrotroph axis is the second most affected axis after the corticotroph axis [13]. Lymphocytic hypophysitis may be isolated or part of an autoimmune polyendocrine syndrome type 1 [14]. Recently, three cases of adultonset combined GH, PRL, and TSH deficiencies without corticotropin and gonadotropin deficiency were reported: the endocrine phenotype was linked to autoimmunity directed against the PIT-1 protein [15]. Finally, hypophysitis may be observed in almost 20 % of patients treated with anti-CTLA-4 antibody therapy, a promising immunotherapy for renal carcinoma and metastatic melanoma. While corticotropin deficiency appears irreversible, 37–50 % of patients are able to stop levothyroxine replacement therapy a few months after withdrawal of ipilimumab [16]. Anterior pituitary insufficiency is a common complication after external radiotherapy for tumors of the head and neck. Anterior pituitary insufficiency is observed in patients given doses of 20 Gy and higher [17]. Damage caused to the thyrotropic axis is dose-dependent, at 5 years 9 % of patients treated with 20 Gy and 52 % of patients treated with 45 Gy are affected [18]. Surveys in patients who survived childhood cancer therapy show that 7.7 % of patients present with hypothyroidism without making a distinction between the peripheral and
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4.
5.
central forms [19]. Hypothalamic–pituitary axis deficiency is more commonly observed following radiation therapy for sellar or cerebral tumors than for head and neck tumors. Finally, the thyroid gland may be irradiated concomitantly, resulting in mixed hypothyroidism with more severe clinical signs. The incidence of hypopituitarism following traumatic brain injury is difficult to determine due to disparities between different studies: severity of the injury, time of assessment, hormone test used. The incidence of CH ranges from 0 to 19 % [20]. If a vascular mechanism is recognized as the initial cause of the thyrotroph insufficiency, the appearance of pituitary dysfunction after repeated head traumas might be associated with the presence of anti-pituitary and/or anti-hypothalamus antibodies [21]. Drugs that affect synthesis and/or secretion of TSH:
Op’DDD (mitotane) is indicated in the treatment of adrenocortical carcinoma and certain forms of Cushing syndrome. Concentrations of free T4 decrease rapidly (3 months) and are below normal range in 92 % of patients after 1 year of treatment with no significant change in TSH and free T3 concentrations. The decrease in free T4 is inversely correlated to mitotane blood concentrations [22]. In addition to increasing thyroxine-binding globulin (TBG) levels (oestrogen-like effect) and interfering with total T4 levels due to competition with T4 for TBG binding sites, mitotane induces apoptosis of thyrotroph cells, which leads to decreased TSH production [23]. CH requires treatment with high doses of levothyroxine, and the thyrotroph cell insufficiency may persist after mitotane treatment is discontinued. Retinoids, including bexarotene indicated in the treatment of cutaneous lymphomas, have numerous effects on the hypothalamic–pituitary–thyroid axis. They lead to a decrease in b-TSH mRNA levels and b-TSH promoter activity, resulting in decreased TSH production and CH. An increase in type 1 deiodinase activity in the liver and the pituitary gland is also observed [24]. Therefore, bexarotene treatment results in rapid-onset CH (2 weeks) with marked clinical, metabolic and hormonal effects, but that are reversible following treatment withdrawal [25]. Growth hormone (GH) administration both in adults and children stimulates peripheral T4 to T3 conversion in a dose-dependent manner due to stimulation of type 2 deiodinase and decreases pituitary secretion of TSH [26]. Therefore, GH treatment to patients with hypothalamic– pituitary lesions may lead to a decrease in free T4 levels and to unmask underlying TSH deficiency [27], which requires institution of levothyroxine treatment or an increase in the levothyroxine dose in patients already treated for CH.
Recent studies suggest that metformin influences TSH levels by lowering the circulating concentrations of the pituitary hormone to a subnormal level [28] without causing clinically significant CH, according to some authors only in patients with type 2 diabetes mellitus and treated for primary hypothyroidism [29] or with normal thyroid function and TSH [ 4.5 mU/L, independently of the presence of anti-TPO antibodies [30]. A recent metaanalysis confirms that metformin induces a reduction in TSH levels both in overt and in subclinical hypothyroidism whereas no change in TSH level is observed in euthyroid patients [31]. The mechanisms associated with the decrease in TSH have not been elucidated, but an emerging hypothesis to explain the effect of metformin on TSH involves its action on 50 AMP-activated protein kinase (AMPK) or a central effect related to a decrease in circulating fatty acids [32]. Thyroid hormone analogues may give rise to different clinical and hormonal features [33], not associated with CH and that are reversible after drug discontinuation. Cortisol, even at low doses, may decrease TSH levels, but long term treatment with glucocorticoids or endogenous Cushing’s syndrome do not appear to cause clinically evident CH requiring thyroid hormone replacement. The decrease in TSH concentrations is due to a hypothalamic effect of the cortisol or the glucocorticosteroids which decrease TRH mRNA levels [34]. Acute administration of dopamine leads to a reduced TSH pulse amplitude [25]. However, the decrease in pituitary secretion of TSH does not appear to cause CH in patients treated with dopamine agonists for functional hyperprolactinemia or prolactinomas. Somatostatin and somatostatin analogues decrease TSH concentrations through direct effects on specific receptors (SST) of thyrotroph cells. The effect is temporary and treatment with somatostatin analogues (octreotide, somatuline) does not appear to cause a significant decrease in free thyroid hormone concentrations in patients with GHsecreting pituitary adenomas [25]. Thus, metformine, glucocorticosteroids, dopamine and dopamine agonists and somatostatin analogues may decrease TSH concentrations. However, the decreases are moderate, do not result in clinically significant CH and do not require treatment [25]. 6.
7.
Other causes: during the recovery phase of any episode of thyrotoxicosis (medical treatment of Graves’ disease, sudden discontinuation of levothyroxine therapy), the inactivity of the thyrotropic axis, which depends on the intensity and duration of the episode of thyrotoxicosis, may cause transient CH. Congenital causes of CH including mutation of the TRH receptor gene [35, 36], mutation of the TSH
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b-subunit with a recessive transmission [37, 38], mutations of pituitary transcription factor genes with several phenotypic manifestations and dominant and/ or recessive inherence can also be observed in adults [2, 39]. Recently, a novel X-linked syndrome caused by loss-of-function mutations or deletions in Immunoglobulin Superfamily member 1 (IGSF1) gene has been described with CH secondary to reduced pituitary TRH receptor expression, macroorchidism, prolactin deficiency and increased body mass index [40, 41].
Diagnosis Central hypothyroidism can be difficult to diagnose because its signs are mild and non-specific (asthenia, attention disorders, sexual dysfunction) [42], and hypothyroidism is less intense than in the peripheral forms due to possible persistence of thyroid hormone secretion related to the constitutive activity of TSH receptors on the thyroid cells or to other mechanisms of TSH-independent thyroid hormone synthesis [43]. Moreover, patients often present other pituitary hormone deficiencies (corticotropin, gonadotropin, somatotropin), the clinical signs of which may mask or overlap those of CH. Nonetheless, CH is associated with deterioration in the quality of life of patients. In clinical practice, CH should be suspected in all patients with an acute or chronic hypothalamic–pituitary disorder. On the other hand, in adults isolated CH is rare except in cases of drug complications. Hormonal diagnosis of CH is based on a low free T4 concentration without a ‘‘mirrored’’ increase in TSH levels. Generally, free T4 levels are decreased or in the lower quartile of the normal range while TSH levels are most often normal, although they may be found to be low or slightly elevated, particularly in hypothalamic forms [42, 44]. Thus, thyroid function parameters may be normal or subnormal, which makes the disease very difficult to diagnose, particularly in patients with acute pituitary damage (pituitary surgery, apoplexy, Sheehan syndrome) or presenting with early CH or CH with atypical signs. Additionally, free T3 levels are usually normal (stimulation of the activity of type 2 deiodinase) and are not helpful in making the diagnosis [42]. When the clinical context is not evocative, and the hormonal assessment is compatible with CH, it is important to eliminate all potential sources of interference in TSH and free T4 measurements. Potential interference with TSH levels most likely arises from heterophilic antibodies (which usually increase TSH levels). Classically dilution studies and/or immuno-substraction or gel electrophoresis can be performed, but treating the samples with heterophilic blocking tubes (HBT) allows for simple, rapid elimination of
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false positive heterophilic interference and validation of the assay. Regarding estimations of free T4, the techniques the least sensitive to interferences are those in two steps using immunoextraction and mass spectrometry. Equilibrium dialysis is no longer used in routine clinical practice because it is time consuming. Labelled analogue methods [2] that give low free T4 estimations (comparable to those observed in patients with CH) in patients presenting with severe nonthyroidal illness syndrome should be avoided. Therefore, patients should systematically be screened for severe diseases at the time of the hormone assessment, before a formal diagnosis of CH is made. However, in the presence of a possible underlying cause (large pituitary tumor, after pituitary surgery or brain irradiation) other hormonal and biochemical parameters may also be useful to evoke the diagnosis of CH at an early stage and/or when the disease does not manifest classical signs: Hormonal parameters A significant time-related decrease in free T4 levels ([20 % using the same assay kit) observed in a patient with a hypothalamic–pituitary disorder, followed-up for several years, would be an argument in favour of CH [42]. The TRH stimulation test may be used to diagnose CH (decrease or absence in the response of the free fractions of thyroid hormones) and to suggest its origin, i.e. pituitary in the absence of response of TSH to TRH or hypothalamic in the event of a delayed, exaggerated and prolonged response of TSH [45, 46]. However, the negative predictive value of the TRH test is poor 42). Absence or deficiency of the circadian pattern of TSH secretion (no nocturnal surge in mean TSH concentration) is observed in most patients with CH [6, 7, 46], but investigation of the nyctohemeral secretion of TSH requires hospitalisation of the patient. Secretion of TSH molecule with a decreased biological to immunological ratio may be evidenced in vitro or in vivo by variations in the concentrations of the free fractions of thyroid hormones (with respect to TSH concentrations) using the long TRH test, particularly when the CH is of hypothalamic origin. TSH index, derived from thyroid function tests, can provide an estimate of the severity of pituitary dysfunction in patients with chronic pituitary diseases [47]. After injection of 0.9 mg of recombinant TSH, the free T4 response is decreased in patients presenting with untreated CH compared to subjects with pituitary lesion and normal thyrotropic function [48]. In clinical practice, a time-related decrease in free T4 concentrations, the absence of a nocturnal TSH surge, or deficiency of a response of TSH and of the free fractions of
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thyroid hormones to the TRH test during monitoring of a patient with hypothalamic–pituitary damage could allow the diagnosis of early-stage or mild CH. Other parameters Indexes of peripheral thyroid hormone action such as creatine phosphokinases (CPK), total cholesterol or sex hormone-binding globulin (SHBG) may be used to assess thyroid status in patients with primary hypothyroidism, but they have insufficient sensitivity and specificity for diagnosis of CH, particularly in patients who present other pituitary hormone deficiencies. Hypercholesterolemia has been reported in patients with CH, but most abnormalities persisted after treatment of CH reflecting the multifactorial nature of the dyslipidemia [42, 44]. Sex hormone-binding globulin, a marker of the hepatic activity of thyroid hormones, is of limited value for detecting CH because its plasma concentrations depend on gonadal and/or somatotropic status [44]. Markers of bone metabolism and bone densitometry depend on numerous pituitary hormones (somatotroph, gonadal or adrenal functions), which make them poor indicators of thyroid hormone action in cases of hypothalamic–pituitary diseases. Recently, increases in the isovolumic contraction time, the isovolumic contraction time to total ejection time ratio and the myocardial performance index were demonstrated in patients with CH, although their free T4 levels were within normal limits. These echocardiographic abnormalities improved after institution of treatment with levothyroxine and restoration of normal thyroid function [49].
Therefore, treatment of CH is based on levothyroxine therapy [52, 53], as for primary thyroid deficiency. In longstanding CH, the dosage of levothyroxine should be progressively increased to 1.1–1.6 lg/kg/day [42, 44]. Replacement therapy should commence with low doses of levothyroxine (25–50 lg/day) and increase in gradual increments (25 lg/day every 2–3 weeks) as a function of the patient’s symptoms (increments of 12.5 lg/day every 3–4 weeks in patients with ischemic heart failure that has not been stabilised). After an acute episode (pituitary surgery, pituitary apoplexy, Sheehan syndrome), the total replacement dose may be prescribed right away. The dose of levothyroxine prescribed depends on the age of the patient, with patients under 60 years requiring higher doses (1.6 lg/kg/day) than older patients (1.3–1.6 lg/kg/day) [42, 44]. Despite the secretion of thyroid hormones related to mechanisms of TSHindependent thyroid hormone synthesis, in practice the doses of levothyroxine administered are similar to those recommended for the treatment of primary hypothyroidism. Recently, Koulouri et al. [52] confirmed the results of older studies [44, 54, 55] according to which most patients with CH are inadequately treated. Unlike primary hypothyroidism, there is no consensus regarding objectives during levothyroxine therapy of CH. Thyroid function parameters may help to determine whether the levothyroxine dose is adequate for the patient: •
• Treatment In patients with CH, the aim of treatment is to restore clinically normal thyroid function with normal serum levels of the free fractions of thyroid hormones in order to reduce cardiovascular risks [50] and to improve quality of life. In adults, CH is often associated with other pituitary hormone deficiencies. Therefore, patients must be tested for corticotropin deficiency and treated before receiving levothyroxine replacement therapy, since restoration of normal thyroid function could aggravate the corticotropin deficiency, which until that time might have only given few or no symptoms. Treatment with TRH or TSH is not justified because it is more costly, less easily available or practicable, and its superiority in terms of efficacy has not been demonstrated. A combination of T3 and levothyroxine has not demonstrated superior efficacy in patients with CH [51].
•
The concentration of free T4 is an essential parameter to monitor patients receiving levothyroxine replacement therapy for CH. Free T4 levels should be assessed prior to administration of the daily dose of levothyroxine, and the aim is to maintain free T4 concentrations in the upper half of the normal range [42, 44, 52]. The negative feedback of thyroid hormones on TSH secretion persists in CH, but the decrease in numbers of thyrotroph cells results in the lowering of the set-point values of the negative feedback of T4 on TSH secretion. Thus, low TSH values (\0.5 mU/L) are associated with substitutive free T4 concentrations in most patients ([80 %) [54], while TSH values within normal limits and/or above 1 mU/L indicate undertreatment [33, 43]. Finally, the concentration of free T3 must remain within normal limits, and an increased level of free T3 is a sign of over-treatment [54].
In clinical practice, for normal thyroid function to be restored in patients with CH, the aim of levothyroxine treatment should be to maintain free T4 levels in the upper half of the normal range, to maintain normal free T3 levels and to lower TSH levels to less than 0.5 mU/L or even 0.1 mU/L. Indexes of the peripheral activity of thyroid hormones are affected by combined pituitary hormone deficiencies
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and therefore are not very useful for monitoring the treatment of CH. In practice, levothyroxine over-treatment (increased concentration of serum-soluble interleukin-2 receptor, increased Sex Hormone-Binding Globulin, hypocholesterolemia) rather than under-treatment [44] may be diagnosed by the longitudinal evaluation of such indexes of the peripheral activity of thyroid hormones. Finally, in patients with CH, introduction of GH therapy (stimulation of type 2 deiodinase) or oestrogen therapy (increase in the concentration of TBG) requires levothyroxine doses to be increased and the thyroid function test to be re-evaluated after 1–2 months [42, 56, 57]. Similarly, other drugs (calcium salts, ferrous salts, cholestyramine, proton-pump inhibitors) interfere with the absorption of levothyroxine and should be taken at a distance from levothyroxine.
Conclusion Although much progress has been made during the last few years, many questions still need to be answered regarding the diagnosis and treatment of CH in adults. Identification of the pathophysiological mechanisms responsible for the congenital idiopathic and acquired forms of CH should allow a better understanding of the pathological mechanisms involved in CH and the development of new tools for its diagnosis, particularly the mild and early forms of the disease. New studies should make it possible to optimize levothyroxine replacement therapy in order to restore normal thyroid function in adults presenting with CH. Prospective studies need to be developed to assess the value of clinical or biochemical parameters for determining the peripheral activity of thyroid hormones to optimize CH replacement therapy in order to reduce cardiovascular risks and to improve the quality of life of adult patients with CH. Conflict of interest of interest.
The authors declare that they have no conflict
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42. Alexopoulou O, Beguin C, De Nayer P et al (2004) Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol 150:1–8 43. Barbesino G, Sluss PM, Caturegli P (2012) Central hypothyroidism in a patient with pituitary autoimmunity: evidence for TSH-independent thyroid hormone synthesis. J Clin Endocrinol Metab 97:345–350 44. Ferretti E, Persani L, Jaffrain-Rea ML et al (1999) Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 84:924–929 45. Faglia G, Beck-Peccoz P, Ferrari C, Ambrosi B, Spada A, Travaglini P, Paracchi S (1973) Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders. J Clin Endocrinol Metab 37:595–601 46. Yamakita N, Komaki T, Takao T et al (2001) Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion. J Clin Endocrinol Metab 86:1054–1060 47. Jostel A, Rydert WD, Shalet SM (2009) The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH index. Clin Endocrinol 71:529–534 48. Filipsson H, Nystrom E, Johannsson G (2008) Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism. Eur J Endocrinol 159:153–160 49. Doin FC, Rosa-Borges M, Martins MR et al (2012) Diagnosis of subclinical central hypothyroidism in patients with hypothalamic–pituitary disease by Doppler echocardiography. Eur J Endocrinol 166:631–640 50. Klose M, Marina D, Hartoft-Nielsen ML et al (2013) Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients. J Clin Endocrinol Metab 98:3802–3810 51. Slawik M, Klawitter B, Meiser E et al (2007) Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J Clin Endocrinol Metab 92:4115–4122 52. Koulouri O, Auldin MA, Agarwal R et al (2011) 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) 74:744–749 53. Beck-Peccoz P (2011) Treatment of central hypothyroidism. Clin Endocrinol 74:671–672 54. Shimon I, Cohen O, Lubetsky A et al (2002) Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid 12:823–827 55. Carrozza V, Csako G, Yanovski JA et al (1999) Levothyroxine replacement therapy in central hypothyroidism: a practice report. Pharmacotherapy 19:349–355 56. Porretti S, Giavoli C, Ronchi C et al (2002) Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T4 therapy become mandatory? J Clin Endocrinol Metab 87:2042–2045 57. Arafah BM (2001) Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 344: 1743–1749
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Central hypothyroidism in adults: better understanding for better care Solange Grunenwald • Philippe Caron
Springer Science+Business Media New York 2014
Abstract Central hypothyroidism (CH) is a rare cause of hypothyroidism generally related to a hypothalamic–pituitary disorder or arising as an iatrogenic complication. In adults, CH may be secondary to quantitative and/or qualitative alterations in thyroid-stimulating hormone (TSH) secretion. The disease is difficult to diagnose clinically because it lacks specific clinical signs and these may be masked by other anterior pituitary hormone secretion deficiencies. In patients with long-standing and marked CH, a diagnosis may be made based on low free T4 levels and normal, low or moderately increased TSH levels. In patients with early-stage or moderate CH, exploration of the circadian TSH cycle, determination of TSH response after a TRH test or recombinant TSH injection, estimation of TSH index, or evaluation of peripheral indexes of thyroid hormone metabolism may be required to establish a diagnosis. Regarding treatment, patients should receive levothyroxine replacement therapy, but hormone objectives during follow-up need to be precisely determined in order to reduce cardiovascular risks and to improve the quality of life of patients.
or qualitative alterations in thyroid-stimulating hormone (TSH) secretion, most often by a normal thyroid gland. Central hypothyroidism is a complex disorder due to the large spectrum of underlying pathophysiological mechanisms, e.g. congenital CH, isolated or CH combined with other pituitary hormone deficiencies, CH acquired in the case of lesions affecting the pituitary gland (secondary hypothyroidism) or the pituitary stalk and the hypothalamus (tertiary hypothyroidism). In patients with hypothalamic–pituitary lesions, the diagnosis is often difficult because the clinical signs are non-specific and insidious, and established laboratory criteria are lacking except in severe cases. Patients should be given replacement therapy with levothyroxine but the thyroid function parameters to be monitored during treatment need to be defined in order to improve quality of life of these patients.
Keywords Central hypothyroidism Pathophysiology Causes Diagnosis Treatment Levothyroxine Free T4
Central hypothyroidism can occur at any age and contrary to peripheral hypothyroidism, it affects both sexes equally. It is a rare disease in children with a prevalence estimated at 1/20,000–1/120,000 based on neonatal hypothyroidism screening data whereas acquired CH is more frequent in adults with pituitary diseases [1, 2]. On the other hand CH appears to be more common in certain populations such as patients with dyslipidemia, a consequence of hypothyroidism (5.6/1,000) [3]. In adults, its prevalence is probably underestimated because its clinical signs are insidious and there is no consensus regarding laboratory diagnostic criteria. Furthermore, hormone assessments do not allow diagnosis of CH if only TSH is assayed: CH was detected in 2.8/10,000 subjects having undergone a TSH assay [4].
Introduction Central hypothyroidism (CH) is characterized by insufficient thyroid hormone production secondary to quantitative
S. Grunenwald P. Caron (&) Cardiovascular and Metabolic Unit, Department of Endocrinology and Metabolic Diseases, CHU Larrey, 24 chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex, France e-mail: [email protected]
Epidemiology
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Finally, the incidence of CH according to age has not been specifically studied, but thyroid hormone and TSH concentrations and response to the thyrotropin-releasing hormone (TRH) test decrease with age [5].
Table 1 Principal causes of CH in adults (1) Tumours Secreting and non-secreting pituitary macroadenomas Craniopharyngiomas, dysgerminomas, gliomas, meningiomas Metastases, lymphomas, Rathke cleft cysts
Pathophysiology TSH is a heterodimeric glycoprotein hormone consisting of two sub-units, the a subunit common to follicle stimulating hormone (FSH), luteinizing hormone (LH) and chorionic gonadotropin (hCG), and the b subunit specific to TSH. TSH secretion normally occurs in a circadian pattern with lower concentrations in the afternoon and higher concentrations during the night [6, 7]. Therefore, a normal TSH cycle can be defined by a more than 50 % increase in TSH levels between 12 p.m. and 4 a.m. relative to TSH levels between 3 p.m. and 7 p.m. [6]. TSH secretion is mainly regulated by a negative feedback effect of thyroid hormones and by a stimulatory effect of TRH. Somatostatin, dopamine, cortisol and glucocorticosteroids also inhibit TSH release. Finally, TSH secretion can also be affected by sex steroid hormones and leptin [2]. In adults, CH can be secondary to alterations in TSH secretion which may be quantitative (absence of TSH secretion, disappearance of the nocturnal surge of TSH [6, 7]) or qualitative [8] or both. In qualitative defects due to altered glycosylation of the TSH molecule, the ability to stimulate the TSH receptors of follicular cells is decreased [9–11], although the TSH molecule remains immunereactive which leads to the secretion of a TSH molecule with a decreased biological to immunological ratio. Furthermore, glycosylation alterations lead to decreased hepatic clearance and an increase in the half-life of TSH and therefore, to normal or slightly increased TSH concentrations. Qualitative-defective TSH secretion, mainly described for CH related to hypothalamic disorders, can be normalized by chronic TRH administration [12].
(2) Infiltrative lesions Auto-immune hypophysitis, sarcoidosis, histiocytosis X, eosinophilic granuloma, hemochromatosis (3) Injuries Post-radiotherapy, post-surgical, head traumas (4) Iatrogenic causes Bexarotene, mitotane, growth hormone, metformin Thyroid hormone analogues (5) Other causes Recovery phase of any episode of thyrotoxicosis Tuberculosis, syphilis, viral or fungal infections Vascular causes: pituitary apoplexy, post-partum necrosis, Carotid aneurysm (6) Congenital causes Mutations of TRH receptor gene Mutations of TSH beta subunit gene IGSF1 mutations Mutations in genes regulating pituitary transcription factors
2.
Etiology The main causes of CH are listed in Table 1: 1.
Secreting and non-secreting pituitary macroadenomas are responsible for more than 50 % of CH cases [2] and they are often associated with more general anterior pituitary insufficiency, caused either by compression or destruction of pituitary cells, or compression of the pituitary stalk or the hypothalamus. Other tumors of the sellar region can also cause CH, and surgical removal of a pituitary gland lesion may also result in more or less complete hypopituitarism.
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3.
Autoimmune hypophysitis generally causes disturbances in several functions of the pituitary gland. The thyrotroph axis is the second most affected axis after the corticotroph axis [13]. Lymphocytic hypophysitis may be isolated or part of an autoimmune polyendocrine syndrome type 1 [14]. Recently, three cases of adultonset combined GH, PRL, and TSH deficiencies without corticotropin and gonadotropin deficiency were reported: the endocrine phenotype was linked to autoimmunity directed against the PIT-1 protein [15]. Finally, hypophysitis may be observed in almost 20 % of patients treated with anti-CTLA-4 antibody therapy, a promising immunotherapy for renal carcinoma and metastatic melanoma. While corticotropin deficiency appears irreversible, 37–50 % of patients are able to stop levothyroxine replacement therapy a few months after withdrawal of ipilimumab [16]. Anterior pituitary insufficiency is a common complication after external radiotherapy for tumors of the head and neck. Anterior pituitary insufficiency is observed in patients given doses of 20 Gy and higher [17]. Damage caused to the thyrotropic axis is dose-dependent, at 5 years 9 % of patients treated with 20 Gy and 52 % of patients treated with 45 Gy are affected [18]. Surveys in patients who survived childhood cancer therapy show that 7.7 % of patients present with hypothyroidism without making a distinction between the peripheral and
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4.
5.
central forms [19]. Hypothalamic–pituitary axis deficiency is more commonly observed following radiation therapy for sellar or cerebral tumors than for head and neck tumors. Finally, the thyroid gland may be irradiated concomitantly, resulting in mixed hypothyroidism with more severe clinical signs. The incidence of hypopituitarism following traumatic brain injury is difficult to determine due to disparities between different studies: severity of the injury, time of assessment, hormone test used. The incidence of CH ranges from 0 to 19 % [20]. If a vascular mechanism is recognized as the initial cause of the thyrotroph insufficiency, the appearance of pituitary dysfunction after repeated head traumas might be associated with the presence of anti-pituitary and/or anti-hypothalamus antibodies [21]. Drugs that affect synthesis and/or secretion of TSH:
Op’DDD (mitotane) is indicated in the treatment of adrenocortical carcinoma and certain forms of Cushing syndrome. Concentrations of free T4 decrease rapidly (3 months) and are below normal range in 92 % of patients after 1 year of treatment with no significant change in TSH and free T3 concentrations. The decrease in free T4 is inversely correlated to mitotane blood concentrations [22]. In addition to increasing thyroxine-binding globulin (TBG) levels (oestrogen-like effect) and interfering with total T4 levels due to competition with T4 for TBG binding sites, mitotane induces apoptosis of thyrotroph cells, which leads to decreased TSH production [23]. CH requires treatment with high doses of levothyroxine, and the thyrotroph cell insufficiency may persist after mitotane treatment is discontinued. Retinoids, including bexarotene indicated in the treatment of cutaneous lymphomas, have numerous effects on the hypothalamic–pituitary–thyroid axis. They lead to a decrease in b-TSH mRNA levels and b-TSH promoter activity, resulting in decreased TSH production and CH. An increase in type 1 deiodinase activity in the liver and the pituitary gland is also observed [24]. Therefore, bexarotene treatment results in rapid-onset CH (2 weeks) with marked clinical, metabolic and hormonal effects, but that are reversible following treatment withdrawal [25]. Growth hormone (GH) administration both in adults and children stimulates peripheral T4 to T3 conversion in a dose-dependent manner due to stimulation of type 2 deiodinase and decreases pituitary secretion of TSH [26]. Therefore, GH treatment to patients with hypothalamic– pituitary lesions may lead to a decrease in free T4 levels and to unmask underlying TSH deficiency [27], which requires institution of levothyroxine treatment or an increase in the levothyroxine dose in patients already treated for CH.
Recent studies suggest that metformin influences TSH levels by lowering the circulating concentrations of the pituitary hormone to a subnormal level [28] without causing clinically significant CH, according to some authors only in patients with type 2 diabetes mellitus and treated for primary hypothyroidism [29] or with normal thyroid function and TSH [ 4.5 mU/L, independently of the presence of anti-TPO antibodies [30]. A recent metaanalysis confirms that metformin induces a reduction in TSH levels both in overt and in subclinical hypothyroidism whereas no change in TSH level is observed in euthyroid patients [31]. The mechanisms associated with the decrease in TSH have not been elucidated, but an emerging hypothesis to explain the effect of metformin on TSH involves its action on 50 AMP-activated protein kinase (AMPK) or a central effect related to a decrease in circulating fatty acids [32]. Thyroid hormone analogues may give rise to different clinical and hormonal features [33], not associated with CH and that are reversible after drug discontinuation. Cortisol, even at low doses, may decrease TSH levels, but long term treatment with glucocorticoids or endogenous Cushing’s syndrome do not appear to cause clinically evident CH requiring thyroid hormone replacement. The decrease in TSH concentrations is due to a hypothalamic effect of the cortisol or the glucocorticosteroids which decrease TRH mRNA levels [34]. Acute administration of dopamine leads to a reduced TSH pulse amplitude [25]. However, the decrease in pituitary secretion of TSH does not appear to cause CH in patients treated with dopamine agonists for functional hyperprolactinemia or prolactinomas. Somatostatin and somatostatin analogues decrease TSH concentrations through direct effects on specific receptors (SST) of thyrotroph cells. The effect is temporary and treatment with somatostatin analogues (octreotide, somatuline) does not appear to cause a significant decrease in free thyroid hormone concentrations in patients with GHsecreting pituitary adenomas [25]. Thus, metformine, glucocorticosteroids, dopamine and dopamine agonists and somatostatin analogues may decrease TSH concentrations. However, the decreases are moderate, do not result in clinically significant CH and do not require treatment [25]. 6.
7.
Other causes: during the recovery phase of any episode of thyrotoxicosis (medical treatment of Graves’ disease, sudden discontinuation of levothyroxine therapy), the inactivity of the thyrotropic axis, which depends on the intensity and duration of the episode of thyrotoxicosis, may cause transient CH. Congenital causes of CH including mutation of the TRH receptor gene [35, 36], mutation of the TSH
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b-subunit with a recessive transmission [37, 38], mutations of pituitary transcription factor genes with several phenotypic manifestations and dominant and/ or recessive inherence can also be observed in adults [2, 39]. Recently, a novel X-linked syndrome caused by loss-of-function mutations or deletions in Immunoglobulin Superfamily member 1 (IGSF1) gene has been described with CH secondary to reduced pituitary TRH receptor expression, macroorchidism, prolactin deficiency and increased body mass index [40, 41].
Diagnosis Central hypothyroidism can be difficult to diagnose because its signs are mild and non-specific (asthenia, attention disorders, sexual dysfunction) [42], and hypothyroidism is less intense than in the peripheral forms due to possible persistence of thyroid hormone secretion related to the constitutive activity of TSH receptors on the thyroid cells or to other mechanisms of TSH-independent thyroid hormone synthesis [43]. Moreover, patients often present other pituitary hormone deficiencies (corticotropin, gonadotropin, somatotropin), the clinical signs of which may mask or overlap those of CH. Nonetheless, CH is associated with deterioration in the quality of life of patients. In clinical practice, CH should be suspected in all patients with an acute or chronic hypothalamic–pituitary disorder. On the other hand, in adults isolated CH is rare except in cases of drug complications. Hormonal diagnosis of CH is based on a low free T4 concentration without a ‘‘mirrored’’ increase in TSH levels. Generally, free T4 levels are decreased or in the lower quartile of the normal range while TSH levels are most often normal, although they may be found to be low or slightly elevated, particularly in hypothalamic forms [42, 44]. Thus, thyroid function parameters may be normal or subnormal, which makes the disease very difficult to diagnose, particularly in patients with acute pituitary damage (pituitary surgery, apoplexy, Sheehan syndrome) or presenting with early CH or CH with atypical signs. Additionally, free T3 levels are usually normal (stimulation of the activity of type 2 deiodinase) and are not helpful in making the diagnosis [42]. When the clinical context is not evocative, and the hormonal assessment is compatible with CH, it is important to eliminate all potential sources of interference in TSH and free T4 measurements. Potential interference with TSH levels most likely arises from heterophilic antibodies (which usually increase TSH levels). Classically dilution studies and/or immuno-substraction or gel electrophoresis can be performed, but treating the samples with heterophilic blocking tubes (HBT) allows for simple, rapid elimination of
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false positive heterophilic interference and validation of the assay. Regarding estimations of free T4, the techniques the least sensitive to interferences are those in two steps using immunoextraction and mass spectrometry. Equilibrium dialysis is no longer used in routine clinical practice because it is time consuming. Labelled analogue methods [2] that give low free T4 estimations (comparable to those observed in patients with CH) in patients presenting with severe nonthyroidal illness syndrome should be avoided. Therefore, patients should systematically be screened for severe diseases at the time of the hormone assessment, before a formal diagnosis of CH is made. However, in the presence of a possible underlying cause (large pituitary tumor, after pituitary surgery or brain irradiation) other hormonal and biochemical parameters may also be useful to evoke the diagnosis of CH at an early stage and/or when the disease does not manifest classical signs: Hormonal parameters A significant time-related decrease in free T4 levels ([20 % using the same assay kit) observed in a patient with a hypothalamic–pituitary disorder, followed-up for several years, would be an argument in favour of CH [42]. The TRH stimulation test may be used to diagnose CH (decrease or absence in the response of the free fractions of thyroid hormones) and to suggest its origin, i.e. pituitary in the absence of response of TSH to TRH or hypothalamic in the event of a delayed, exaggerated and prolonged response of TSH [45, 46]. However, the negative predictive value of the TRH test is poor 42). Absence or deficiency of the circadian pattern of TSH secretion (no nocturnal surge in mean TSH concentration) is observed in most patients with CH [6, 7, 46], but investigation of the nyctohemeral secretion of TSH requires hospitalisation of the patient. Secretion of TSH molecule with a decreased biological to immunological ratio may be evidenced in vitro or in vivo by variations in the concentrations of the free fractions of thyroid hormones (with respect to TSH concentrations) using the long TRH test, particularly when the CH is of hypothalamic origin. TSH index, derived from thyroid function tests, can provide an estimate of the severity of pituitary dysfunction in patients with chronic pituitary diseases [47]. After injection of 0.9 mg of recombinant TSH, the free T4 response is decreased in patients presenting with untreated CH compared to subjects with pituitary lesion and normal thyrotropic function [48]. In clinical practice, a time-related decrease in free T4 concentrations, the absence of a nocturnal TSH surge, or deficiency of a response of TSH and of the free fractions of
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thyroid hormones to the TRH test during monitoring of a patient with hypothalamic–pituitary damage could allow the diagnosis of early-stage or mild CH. Other parameters Indexes of peripheral thyroid hormone action such as creatine phosphokinases (CPK), total cholesterol or sex hormone-binding globulin (SHBG) may be used to assess thyroid status in patients with primary hypothyroidism, but they have insufficient sensitivity and specificity for diagnosis of CH, particularly in patients who present other pituitary hormone deficiencies. Hypercholesterolemia has been reported in patients with CH, but most abnormalities persisted after treatment of CH reflecting the multifactorial nature of the dyslipidemia [42, 44]. Sex hormone-binding globulin, a marker of the hepatic activity of thyroid hormones, is of limited value for detecting CH because its plasma concentrations depend on gonadal and/or somatotropic status [44]. Markers of bone metabolism and bone densitometry depend on numerous pituitary hormones (somatotroph, gonadal or adrenal functions), which make them poor indicators of thyroid hormone action in cases of hypothalamic–pituitary diseases. Recently, increases in the isovolumic contraction time, the isovolumic contraction time to total ejection time ratio and the myocardial performance index were demonstrated in patients with CH, although their free T4 levels were within normal limits. These echocardiographic abnormalities improved after institution of treatment with levothyroxine and restoration of normal thyroid function [49].
Therefore, treatment of CH is based on levothyroxine therapy [52, 53], as for primary thyroid deficiency. In longstanding CH, the dosage of levothyroxine should be progressively increased to 1.1–1.6 lg/kg/day [42, 44]. Replacement therapy should commence with low doses of levothyroxine (25–50 lg/day) and increase in gradual increments (25 lg/day every 2–3 weeks) as a function of the patient’s symptoms (increments of 12.5 lg/day every 3–4 weeks in patients with ischemic heart failure that has not been stabilised). After an acute episode (pituitary surgery, pituitary apoplexy, Sheehan syndrome), the total replacement dose may be prescribed right away. The dose of levothyroxine prescribed depends on the age of the patient, with patients under 60 years requiring higher doses (1.6 lg/kg/day) than older patients (1.3–1.6 lg/kg/day) [42, 44]. Despite the secretion of thyroid hormones related to mechanisms of TSHindependent thyroid hormone synthesis, in practice the doses of levothyroxine administered are similar to those recommended for the treatment of primary hypothyroidism. Recently, Koulouri et al. [52] confirmed the results of older studies [44, 54, 55] according to which most patients with CH are inadequately treated. Unlike primary hypothyroidism, there is no consensus regarding objectives during levothyroxine therapy of CH. Thyroid function parameters may help to determine whether the levothyroxine dose is adequate for the patient: •
• Treatment In patients with CH, the aim of treatment is to restore clinically normal thyroid function with normal serum levels of the free fractions of thyroid hormones in order to reduce cardiovascular risks [50] and to improve quality of life. In adults, CH is often associated with other pituitary hormone deficiencies. Therefore, patients must be tested for corticotropin deficiency and treated before receiving levothyroxine replacement therapy, since restoration of normal thyroid function could aggravate the corticotropin deficiency, which until that time might have only given few or no symptoms. Treatment with TRH or TSH is not justified because it is more costly, less easily available or practicable, and its superiority in terms of efficacy has not been demonstrated. A combination of T3 and levothyroxine has not demonstrated superior efficacy in patients with CH [51].
•
The concentration of free T4 is an essential parameter to monitor patients receiving levothyroxine replacement therapy for CH. Free T4 levels should be assessed prior to administration of the daily dose of levothyroxine, and the aim is to maintain free T4 concentrations in the upper half of the normal range [42, 44, 52]. The negative feedback of thyroid hormones on TSH secretion persists in CH, but the decrease in numbers of thyrotroph cells results in the lowering of the set-point values of the negative feedback of T4 on TSH secretion. Thus, low TSH values (\0.5 mU/L) are associated with substitutive free T4 concentrations in most patients ([80 %) [54], while TSH values within normal limits and/or above 1 mU/L indicate undertreatment [33, 43]. Finally, the concentration of free T3 must remain within normal limits, and an increased level of free T3 is a sign of over-treatment [54].
In clinical practice, for normal thyroid function to be restored in patients with CH, the aim of levothyroxine treatment should be to maintain free T4 levels in the upper half of the normal range, to maintain normal free T3 levels and to lower TSH levels to less than 0.5 mU/L or even 0.1 mU/L. Indexes of the peripheral activity of thyroid hormones are affected by combined pituitary hormone deficiencies
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and therefore are not very useful for monitoring the treatment of CH. In practice, levothyroxine over-treatment (increased concentration of serum-soluble interleukin-2 receptor, increased Sex Hormone-Binding Globulin, hypocholesterolemia) rather than under-treatment [44] may be diagnosed by the longitudinal evaluation of such indexes of the peripheral activity of thyroid hormones. Finally, in patients with CH, introduction of GH therapy (stimulation of type 2 deiodinase) or oestrogen therapy (increase in the concentration of TBG) requires levothyroxine doses to be increased and the thyroid function test to be re-evaluated after 1–2 months [42, 56, 57]. Similarly, other drugs (calcium salts, ferrous salts, cholestyramine, proton-pump inhibitors) interfere with the absorption of levothyroxine and should be taken at a distance from levothyroxine.
Conclusion Although much progress has been made during the last few years, many questions still need to be answered regarding the diagnosis and treatment of CH in adults. Identification of the pathophysiological mechanisms responsible for the congenital idiopathic and acquired forms of CH should allow a better understanding of the pathological mechanisms involved in CH and the development of new tools for its diagnosis, particularly the mild and early forms of the disease. New studies should make it possible to optimize levothyroxine replacement therapy in order to restore normal thyroid function in adults presenting with CH. Prospective studies need to be developed to assess the value of clinical or biochemical parameters for determining the peripheral activity of thyroid hormones to optimize CH replacement therapy in order to reduce cardiovascular risks and to improve the quality of life of adult patients with CH. Conflict of interest of interest.
The authors declare that they have no conflict
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