J Pediatr Endocr Met 2014; 27(11-12): 1049–1057
Review article Gonul Catli, Ayhan Abaci*, Atilla Büyükgebiz and Ece Bober
Subclinical hypothyroidism in childhood and adolescense Abstract: Subclinical hypothyroidism (SH) is defined as a serum thyroid-stimulating hormone (TSH) level above the reference range with normal serum free thyroxin (sT4) and free triiodothyronine (sT3) levels. The prevalence of SH in children and adolescents is reported between 1.7% and 9.5%. Hashimoto’s thyroiditis is the most prevalent cause of SH in children. Although it has been suggested that SH is entirely an asymptomatic laboratory diagnosis, typical hypothyroid symptoms as well have been reported in some patients. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); neuromuscular system; and cognitive functions in the long term. The number of studies investigating the effect of childhood SH on growth, bone maturation, lipid parameters, carbohydrate metabolism, neuromuscular system, and cognitive and cardiac function is limited. Knowledge about the natural history of SH is unclear even though there are numerous studies upon this subject. In children and adults, treatment of SH with L-T4 is still a matter of debate, and there is no consensus on this issue yet. Keywords: treatment.
childhood;
subclinical
hypothyroidism;
DOI 10.1515/jpem-2014-0089 Received February 20, 2014; accepted July 22, 2014; previously published online August 25, 2014
*Corresponding author: Dr. Ayhan Abaci, Department of Pediatric Endocrinology, Dokuz Eylul University Faculty of Medicine, İzmir, Turkey, Phone: +90-232-412-6076, Fax: +90-232-412-6076, E-mail: [email protected] Gonul Catli and Ece Bober: Department of Pediatric Endocrinology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey Atilla Büyükgebiz: Department of Pediatric Endocrinology, Bilim University Faculty of Medicine, İstanbul, Turkey
Introduction Subclinical hypothyroidism (SH) is a serum thyroid-stimulating hormone (TSH) level above the reference range with serum free thyroxin (sT4) and free triiodothyronine (sT3) levels within the normal reference range (1, 2). The prevalence of SH ranges between 1% and 12.4% in the general population (1, 3–6). Nevertheless, the prevalence of SH increases with age reaching to 15%– 18% over the age of 60 years (4, 7). Due to the low prevalence rate and inadequacy of long-term studies, SH in childhood has not been well-defined (8). However, in recent years, thyroid function screening is more frequently performed because of presence of family history for thyroid disease, presence of goiter, and as a part of routine laboratory analyses; thus, the prevalence of childhood SH has been considered to be higher than expected (2). Despite insufficient data, the prevalence of SH in children and adolescents is reported between 1.7% and 9.5% (9, 10).
Etiology The etiology of SH is the same as the etiology of overt hypothyroidism. Hashimoto’s thyroiditis is the most prevalent cause of SH in children (9). It is essential to differentiate SH from other causes of physiological, artificial, or transiently increased serum TSH (10, 11). In particular, both healthy individuals and those with SH have a circadian fluctuation in serum TSH concentration, with a nadir in the early afternoon and approximately 30% higher concentrations being present during the evening and the night. Thus, it was suggested serum TSH concentrations should be measured at a 2–3 month interval to rule out a laboratory error or a transient increase caused, for example, by laboratory analytic problems, by drugs that interfere with thyroid function, by thyroiditis, and by possible toxic injury to the thyroid gland (10, 11). Causes of SH are summarized in Table 1 (1, 2, 4, 8, 10–12).
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1050 Catli et al.: Subclinical hypothyroidism
Table 1 Etiology of subclinical hypothyroidism. Persistent causes of SH – Chronic autoimmune thyroiditis (family history of autoimmune thyroid disease, personal or family history of associated autoimmune disorders, Down and Turner’s syndrome) – Subacute thyroiditis – Partial thyroidectomy or other neck surgery – Radioactive iodine therapy (head and neck) – Drugs (impairing thyroid function): iodine and iodine-containing medications (amiodarone, radiographic contrast agents); lithium carbonate; cytokines (interferon); aminoglutetimide; ethionamide; sulfonamides; and sulphonylureas – Increased T4 clearance (phenytoin, carbamazepine, phenobarbital, etc.) – Infiltrative disease of thyroid gland (amyloidosis, sarcoidosis, hemochromatosis, Riedel’s thyroiditis, cystinosis, AIDS, primary thyroid lymphoma) – Toxic substances, industrial and environmental agents – Germline loss of function mutations in the TSH receptor – İdiopatic Transient causes of SH – Obesity (especially, associated with insulin resistance and body mass index [leptin]), improved after weight loss – Laboratory analytic problems (assay variability, abnormal TSH isoform, heterophilic antibodies, etc.) – Elderly patients with small increases in serum TSH level – Pituitary problem (pituitary adenoma, isolated pituitary resistance to thyroid hormone, etc.) – After withdrawal of thyroid hormone therapy in euthyroid patients – Recovery phase of euthyroid sick syndrome – Renal dysfunction – Adrenal insufficiency – Irregular sleep patterns, following vigorous exercise, mood disorders/depression – Overt hypothyroidism receiving inadequate replacement therapy
Subclinical hypothyroidism and clinical symptoms Although it has been suggested that SH is entirely an asymptomatic biochemical diagnosis, typical hypothyroid symptoms as well have been reported in some patients (1). Clinical presentation of SH may vary from asymptomatic to mild nonspecific symptoms, which are probably related to age, individual sensitivity to thyroid hormone deficiency, and severity and duration of SH (4). A randomized study, which evaluated hypothyroid symptom scores in adults with SH demonstrated that the symptom scores significantly decreased after L-thyroxin therapy (13). Cerbone et al. conducted a study in adults with SH and reported no hypothyroidism-related clinical symptom in any of the patients (14). Previously, we have investigated 31 children and adolescents with SH and found higher symptom scores as compared to the control group, and a significant
decrease was observed in the hypothyroid symptom score after treatment. This result suggested that children with SH are, indeed, not asymptomatic, and it is necessary to question the symptoms in more detail (unpublished data). No comprehensive study exists about the effects of childhood SH on the metabolic and cardiovascular systems; the majority of studies are that comprising adult age group. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); and cognitive functions in the long term. In childhood, thyroid hormones have substantial effects on growth, puberty and metabolism. While short stature and retarded bone age are the other important findings in untreated overt hypothyroidism (14), the number of studies investigating the effect of childhood SH on growth and bone maturation is limited. In a study that followed 36 children with untreated SH, no impairment was observed in anthropometric parameters in the long term (2–9.3 years) (height standard deviation score [SDS] at the time of diagnosis: –0.8 ± 02 vs. –0.7 ± 0.2; bone age/chronological age: 0.92 ± 0.6 vs. 0.97 ± 0.03; body mass index [BMI] SDS: –0.1 ± 0.2 vs. 0.1 ± 0.2, respectively). In the same study, no hypothyroidism-related clinical symptom was reported in any of the patients (14). In a multicenter study from Italy, that included 92 children diagnosed with idiopathic SH, it was observed that the heights of patients were within the normal ranges, and no deviation occurred in the 2-year follow-up period (15). Çetinkaya et al. P1 evaluated growth and anthropometric parameters in children with SH and demonstrated that height velocity SDS was increased after L-T4 therapy (16). In a previous study (unpublished data), we determined no significant difference between SH and the control groups in terms of anthropometric parameters (p > 0.05).
Effects of subclinical hypothyroidism on other systems Subclinical hypothyroidism and dyslipidemia Thyroid hormones play an important role on lipid metabolism, regulating the activities of receptors and enzymes involved in lipoprotein metabolism (10, 17). There are several well-known mechanisms for the effect of thyroid status on lipid concentrations. Possible mechanisms are listed below (10). –– Thyroid hormones reduce cholesterol concentration mainly through the increased expression of low-density lipoprotein-cholesterol (LDL-C) receptors in the
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Catli et al.: Subclinical hypothyroidism 1051
liver and peripheral organs. LDL-C receptor level is mediated by “sterol regulatory element-binding protein-2,” which is regulated by triiodothyronine (T3). A decrease in LDL-C receptor leads to a decrease in the clearance of LDL-C and increases serum LDL-C concentration. –– Thyroid hormone also has an effect on plasma cholesterol ester transfer protein (CETP) activity and a strong correlation has been shown between thyroid hormone and plasma CETP activity (18). CETP enables high-density lipoprotein-cholesterol (HDL-C) to transfer into LDL-C and very low-density lipoproteincholesterol (VLDL-C) (19). CETP activity is increased in hyperthyroidism and decreased in hypothyroidism. This leads to a change in HDL-C levels in thyroid disorders (18). CETP deficiency, caused by mutations in the CETP gene, is associated with high plasma levels of HDL-C. HDL-C tends to be high in patients with hypothyroidism (18). –– Thyroid hormones increase hepatic lipase activity, which lowers triglyceride levels through hydrolysis of triglyceride-enriched lipoproteins and facilitation of cholesterol transfer from these lipoproteins to HDL-C (20). Increased levels of TSH are associated with a decrease in hepatic lipase activity, which leads to a change in the subfractions s of HDL-C (18, 19, 21). It is estimated that 1%–11% of all patients with dyslipidemia have SH; the effects of SH on serum lipid values are less clear (19). While hyperlipidemia has been reported in > 90% of the patients with overt hypothyroidism, elevated total cholesterol (TC) and LDL-C levels have been reported in 30% (22). Triglyceride (TG), HDL-C, and VLDL-C levels are mildly increased or normal in overt hypothyroidism. While it has been reported that lipid disorders due to overt hypothyroidism are reversible with L-T4 therapy, previous adult studies have indicated contradictory results regarding the impact of SH on lipid disorders and the response to L-T4 therapy (13, 23). A population-based adult study reported that TC level was closely associated with TSH. In this study, it was shown that when TSH level increased over 5.5 mIU/L a mean of 9 mg/dL elevation was observed in TC level. On the other hand, as the TSH was suppressed, the mean TC level decreased by 19 mg/dL (24). Posttreatment decrease in serum lipid levels was found to be more significant in those with a serum TSH level > 10 mIU/L (25). In a previous study, a significant decrease in HDL-C level was determined in the children with TSH level > 10 mIU/L, whereas a significant increase was determined in TC and LDL-C levels in the adults with
TSH level > 10 mIU/L. In contrast, no difference was observed in the lipid parameters of children and adults with TSH level 10 mIU/L, treatment is still questionable for a TSH level between 4.5 and 10 mIU/L (14). Effect of L-T4 therapy on lipid abnormalities in SH remains debatable (73). De Vries et al. (84) emphasized that children with a TSH level between 4.1 and 10 mIU/L and goiter need to be treated. The same study recommended treatment regardless of the presence of goiter for the patients with a TSH level > 10 mIU/L. Treatment is recommended in SH patients with the presence of goiter or clinical signs of hypothyroidism, in child or adolescent patients, a TSH level > 8 in at least two measurements, bipolar disorder and depression, infertility (ovulatory dysfunction), positive antithyroid antibodies, gradually increasing TSH levels, young patient age, and presence of hyperlipidemia (Table 2) (48). Wasniewska et al. (70) compared the SH children treated with L-T4 (n = 69) and those receiving no therapy (n = 92) after a treatment period of 24 months and found the number of patients with a TSH level returned to the normal range to be higher in the treated group. In contrast, while the TSH levels of 42 (60.9%) of 69 patients were within the normal ranges 3 months after the discontinuation of therapy, it increased over 5 mIU/L in 27 (39.1%) patients (TSH 5–10 mIU/L in 55.6%, TSH > 10 mIU/L in 44.4%). The authors (70) emphasized that treatment of SH patients has no effect on posttreatment high TSH levels and that Table 2 Indications for the treatment of subclinical hypothyroidism in childhood (TSH 5–10 mIU/L). – Goiter – Presence of hypothyroidism symptoms – Patient’s choice – Child and adolescent age group – TSH > 8 mIU/L in two measurements – Depression and bipolar disorder – Antithyroid antibody positivity – Progressive TSH elevation – Ovulatory dysfunction – Younger patient age – Hyperlipidemia
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TSH levels return to the baseline after discontinuation of therapy. The same study observed that, TSH increased over 10 mIU/L in the majority of these patients (83%) after discontinuation of therapy if the baseline TSH level of the treated group was > 9 mIU/L (70). According to the Cochrane database, results of the randomized studies on SH reveal that L-T4 therapy does not improve survival or reduce cardiovascular morbidity. However, it has been proven that L-T4 therapy provides an improvement in the left ventricle functions and lipid parameters (7).
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1056 Catli et al.: Subclinical hypothyroidism 31. Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab 2000;85:2993–3001. 32. Tagami T, Tamanaha T, Shimazu S, Honda K, Nanba K, et al. Lipid profiles in the untreated patients with Hashimoto thyroiditis and the effects of thyroxine treatment on subclinical hypothyroidism with Hashimoto thyroiditis. Endocr J 2010;57:253–8. 33. Goswami B, Singh B. Role of surrogate markers in assessment of insulin resistance in females with thyroid disorders. Diabetes Metab Syndr 2012;6:163–6. 34. Dimitriadis G, Mitrou P, Lambadiari V, Boutati E, Maratou E, et al. Insulin action in adipose tissue and muscle in hypothyroidism. J Clin Endocrinol Metab 2006;91:4930–7. 35. Dimitriadis G, Parry-Billings M, Bevan S, Leighton B, Krause U, et al. The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats. Eur J Clin Invest 1997;27:475–83. 36. Maratou E, Hadjidakis DJ, Kollias A, Tsegka K, Peppa M, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol 2009;160:785–90. 37. Rochon C, Tauveron I, Dejax C, Benoit P, Capitan P, et al. Response of glucose disposal to hyperinsulinaemia in human hypothyroidism and hyperthyroidism. Clin Sci (Lond) 2003;104:7–15. 38. Kapadia KB, Bhatt PA, Shah JS. Association between altered thyroid state and insulin resistance. J Pharmacol Pharmacother 2012;3:156–60. 39. Arikan S, Bahceci M, Tuzcu A, Celik F, Gokalp D. Postprandial hyperlipidemia in overt and subclinical hypothyroidism. Eur J Intern Med 2012;23:e141–e5. 40. Erdogan M, Canataroglu A, Ganidagli S, Kulaksizoglu M. Metabolic syndrome prevalence in subclinic and overt hypothyroid patients and the relation among metabolic syndrome parameters. J Endocrinol Invest 2011;34:488–92. 41. Samuels MH. Cognitive function in subclinical hypothyroidism. J Clin Endocrinol Metab 2010;95:3611–3. 42. Salerno M, Militerni R, Di MS, Bravaccio C, Gasparini N, et al. Intellectual outcome at 12 years of age in congenital hypothyroidism. Eur J Endocrinol 1999;141:105–10. 43. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. J Am Med Assoc 2004;291:228–38. 44. Surks MI, Ocampo E. Subclinical thyroid disease. Am J Med 1996;100:217–23. 45. Ergur AT, Taner Y, Ata E, Melek E, Bakar EE, et al. Neurocognitive functions in children and adolescents with subclinical hypothyroidism. J Clin Res Pediatr Endocrinol 2012;4:21–4. 46. Reuters VS, Teixeira PF, Vigario PS, Almeida CP, Buescu A, et al. Functional capacity and muscular abnormalities in subclinical hypothyroidism. Am J Med Sci 2009;338:259–63. 47. Duyff RF, Van den BJ, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000;68:750–5. 48. Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 2009;84:65–71. 49. Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, et al. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 2006;16:375–80.
50. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501–9. 51. Varma R, Jain AK, Ghose T. Heart in hypothyroidism–an echocardiographic study. J Assoc Physicians India 1996;44:390–2. 52. Erkan G, Erkan AF, Cemri M, Karaahmetoglu S, Cesur M, et al. The evaluation of diastolic dysfunction with tissue Doppler echocardiography in women with subclinical hypothyroidism and the effect of L-thyroxine treatment on diastolic dysfunction: a pilot study. J Thyroid Res 2011:654304. 53. Gupta A, Sinha RS. Echocardiographic changes and alterations in lipid profile in cases of subclinical and overt hypothyroidism. J Assoc Physicians India 1996;44:546, 51-, 53. 54. Meena CL, Meena RD, Nawal R, Meena VK, Bharti A, et al. Assessment of left ventricular diastolic dysfunction in subclinical hypothyroidism. Acta Inform Med 2012;20:218–20. 55. Oner FA, Yurdakul S, Oner E, Uzum AK, Erguney M. Evaluation of the effect of L-thyroxin therapy on cardiac functions by using novel tissue Doppler-derived indices in patients with subclinical hypothyroidism. Acta Cardiol 2011;66:47–55. 56. Ozturk S, Alcelik A, Ozyasar M, Dikbas O, Ayhan S, et al. Evaluation of left ventricular systolic asynchrony in patients with subclinical hypothyroidism. Cardiol J 2012;19:374–80. 57. Mao S, Wang Y, Jiang G, Zhao Z. Effects of levothyroxine therapy on left and right ventricular function in neonates with congenital hypothyroidism: a tissue Doppler echocardiography study. Eur J Pediatr 2007;166:1261–5. 58. Mao SS, Zhao ZY, Jiang GP. [Left ventricular function in congenital hypothyroidism neonates before and after thyroxine substitution therapy]. Zhonghua YiXueZa Zhi 2005;85:538–41. 59. Galderisi M, Vitale G, D’Errico A, Lupoli GA, Ciccarelli A, et al. Usefulness of pulsed tissue Doppler for the assessment of left ventricular myocardial function in overt hypothyroidism. Ital Heart J 2004;5:257–64. 60. Franzoni F, Galetta F, Fallahi P, Tocchini L, Merico G, et al. Effect of L-thyroxine treatment on left ventricular function in subclinical hypothyroidism. Biomed Pharmacother 2006;60: 431–6. 61. Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health Study. J Am Coll Cardiol 2008;52:1152–9. 62. Akcakoyun M, Kaya H, Kargin R, Pala S, Emiroglu Y, et al. Abnormal left ventricular longitudinal functional reserve assessed by exercise pulsed wave tissue Doppler imaging in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2009;94:2979–83. 63. Chen X, Zhang N, Cai Y, Shi J. Evaluation of left ventricular diastolic function using tissue Doppler echocardiography and conventional doppler echocardiography in patients with subclinical hypothyroidism aged
Review article Gonul Catli, Ayhan Abaci*, Atilla Büyükgebiz and Ece Bober
Subclinical hypothyroidism in childhood and adolescense Abstract: Subclinical hypothyroidism (SH) is defined as a serum thyroid-stimulating hormone (TSH) level above the reference range with normal serum free thyroxin (sT4) and free triiodothyronine (sT3) levels. The prevalence of SH in children and adolescents is reported between 1.7% and 9.5%. Hashimoto’s thyroiditis is the most prevalent cause of SH in children. Although it has been suggested that SH is entirely an asymptomatic laboratory diagnosis, typical hypothyroid symptoms as well have been reported in some patients. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); neuromuscular system; and cognitive functions in the long term. The number of studies investigating the effect of childhood SH on growth, bone maturation, lipid parameters, carbohydrate metabolism, neuromuscular system, and cognitive and cardiac function is limited. Knowledge about the natural history of SH is unclear even though there are numerous studies upon this subject. In children and adults, treatment of SH with L-T4 is still a matter of debate, and there is no consensus on this issue yet. Keywords: treatment.
childhood;
subclinical
hypothyroidism;
DOI 10.1515/jpem-2014-0089 Received February 20, 2014; accepted July 22, 2014; previously published online August 25, 2014
*Corresponding author: Dr. Ayhan Abaci, Department of Pediatric Endocrinology, Dokuz Eylul University Faculty of Medicine, İzmir, Turkey, Phone: +90-232-412-6076, Fax: +90-232-412-6076, E-mail: [email protected] Gonul Catli and Ece Bober: Department of Pediatric Endocrinology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey Atilla Büyükgebiz: Department of Pediatric Endocrinology, Bilim University Faculty of Medicine, İstanbul, Turkey
Introduction Subclinical hypothyroidism (SH) is a serum thyroid-stimulating hormone (TSH) level above the reference range with serum free thyroxin (sT4) and free triiodothyronine (sT3) levels within the normal reference range (1, 2). The prevalence of SH ranges between 1% and 12.4% in the general population (1, 3–6). Nevertheless, the prevalence of SH increases with age reaching to 15%– 18% over the age of 60 years (4, 7). Due to the low prevalence rate and inadequacy of long-term studies, SH in childhood has not been well-defined (8). However, in recent years, thyroid function screening is more frequently performed because of presence of family history for thyroid disease, presence of goiter, and as a part of routine laboratory analyses; thus, the prevalence of childhood SH has been considered to be higher than expected (2). Despite insufficient data, the prevalence of SH in children and adolescents is reported between 1.7% and 9.5% (9, 10).
Etiology The etiology of SH is the same as the etiology of overt hypothyroidism. Hashimoto’s thyroiditis is the most prevalent cause of SH in children (9). It is essential to differentiate SH from other causes of physiological, artificial, or transiently increased serum TSH (10, 11). In particular, both healthy individuals and those with SH have a circadian fluctuation in serum TSH concentration, with a nadir in the early afternoon and approximately 30% higher concentrations being present during the evening and the night. Thus, it was suggested serum TSH concentrations should be measured at a 2–3 month interval to rule out a laboratory error or a transient increase caused, for example, by laboratory analytic problems, by drugs that interfere with thyroid function, by thyroiditis, and by possible toxic injury to the thyroid gland (10, 11). Causes of SH are summarized in Table 1 (1, 2, 4, 8, 10–12).
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1050 Catli et al.: Subclinical hypothyroidism
Table 1 Etiology of subclinical hypothyroidism. Persistent causes of SH – Chronic autoimmune thyroiditis (family history of autoimmune thyroid disease, personal or family history of associated autoimmune disorders, Down and Turner’s syndrome) – Subacute thyroiditis – Partial thyroidectomy or other neck surgery – Radioactive iodine therapy (head and neck) – Drugs (impairing thyroid function): iodine and iodine-containing medications (amiodarone, radiographic contrast agents); lithium carbonate; cytokines (interferon); aminoglutetimide; ethionamide; sulfonamides; and sulphonylureas – Increased T4 clearance (phenytoin, carbamazepine, phenobarbital, etc.) – Infiltrative disease of thyroid gland (amyloidosis, sarcoidosis, hemochromatosis, Riedel’s thyroiditis, cystinosis, AIDS, primary thyroid lymphoma) – Toxic substances, industrial and environmental agents – Germline loss of function mutations in the TSH receptor – İdiopatic Transient causes of SH – Obesity (especially, associated with insulin resistance and body mass index [leptin]), improved after weight loss – Laboratory analytic problems (assay variability, abnormal TSH isoform, heterophilic antibodies, etc.) – Elderly patients with small increases in serum TSH level – Pituitary problem (pituitary adenoma, isolated pituitary resistance to thyroid hormone, etc.) – After withdrawal of thyroid hormone therapy in euthyroid patients – Recovery phase of euthyroid sick syndrome – Renal dysfunction – Adrenal insufficiency – Irregular sleep patterns, following vigorous exercise, mood disorders/depression – Overt hypothyroidism receiving inadequate replacement therapy
Subclinical hypothyroidism and clinical symptoms Although it has been suggested that SH is entirely an asymptomatic biochemical diagnosis, typical hypothyroid symptoms as well have been reported in some patients (1). Clinical presentation of SH may vary from asymptomatic to mild nonspecific symptoms, which are probably related to age, individual sensitivity to thyroid hormone deficiency, and severity and duration of SH (4). A randomized study, which evaluated hypothyroid symptom scores in adults with SH demonstrated that the symptom scores significantly decreased after L-thyroxin therapy (13). Cerbone et al. conducted a study in adults with SH and reported no hypothyroidism-related clinical symptom in any of the patients (14). Previously, we have investigated 31 children and adolescents with SH and found higher symptom scores as compared to the control group, and a significant
decrease was observed in the hypothyroid symptom score after treatment. This result suggested that children with SH are, indeed, not asymptomatic, and it is necessary to question the symptoms in more detail (unpublished data). No comprehensive study exists about the effects of childhood SH on the metabolic and cardiovascular systems; the majority of studies are that comprising adult age group. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); and cognitive functions in the long term. In childhood, thyroid hormones have substantial effects on growth, puberty and metabolism. While short stature and retarded bone age are the other important findings in untreated overt hypothyroidism (14), the number of studies investigating the effect of childhood SH on growth and bone maturation is limited. In a study that followed 36 children with untreated SH, no impairment was observed in anthropometric parameters in the long term (2–9.3 years) (height standard deviation score [SDS] at the time of diagnosis: –0.8 ± 02 vs. –0.7 ± 0.2; bone age/chronological age: 0.92 ± 0.6 vs. 0.97 ± 0.03; body mass index [BMI] SDS: –0.1 ± 0.2 vs. 0.1 ± 0.2, respectively). In the same study, no hypothyroidism-related clinical symptom was reported in any of the patients (14). In a multicenter study from Italy, that included 92 children diagnosed with idiopathic SH, it was observed that the heights of patients were within the normal ranges, and no deviation occurred in the 2-year follow-up period (15). Çetinkaya et al. P1 evaluated growth and anthropometric parameters in children with SH and demonstrated that height velocity SDS was increased after L-T4 therapy (16). In a previous study (unpublished data), we determined no significant difference between SH and the control groups in terms of anthropometric parameters (p > 0.05).
Effects of subclinical hypothyroidism on other systems Subclinical hypothyroidism and dyslipidemia Thyroid hormones play an important role on lipid metabolism, regulating the activities of receptors and enzymes involved in lipoprotein metabolism (10, 17). There are several well-known mechanisms for the effect of thyroid status on lipid concentrations. Possible mechanisms are listed below (10). –– Thyroid hormones reduce cholesterol concentration mainly through the increased expression of low-density lipoprotein-cholesterol (LDL-C) receptors in the
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liver and peripheral organs. LDL-C receptor level is mediated by “sterol regulatory element-binding protein-2,” which is regulated by triiodothyronine (T3). A decrease in LDL-C receptor leads to a decrease in the clearance of LDL-C and increases serum LDL-C concentration. –– Thyroid hormone also has an effect on plasma cholesterol ester transfer protein (CETP) activity and a strong correlation has been shown between thyroid hormone and plasma CETP activity (18). CETP enables high-density lipoprotein-cholesterol (HDL-C) to transfer into LDL-C and very low-density lipoproteincholesterol (VLDL-C) (19). CETP activity is increased in hyperthyroidism and decreased in hypothyroidism. This leads to a change in HDL-C levels in thyroid disorders (18). CETP deficiency, caused by mutations in the CETP gene, is associated with high plasma levels of HDL-C. HDL-C tends to be high in patients with hypothyroidism (18). –– Thyroid hormones increase hepatic lipase activity, which lowers triglyceride levels through hydrolysis of triglyceride-enriched lipoproteins and facilitation of cholesterol transfer from these lipoproteins to HDL-C (20). Increased levels of TSH are associated with a decrease in hepatic lipase activity, which leads to a change in the subfractions s of HDL-C (18, 19, 21). It is estimated that 1%–11% of all patients with dyslipidemia have SH; the effects of SH on serum lipid values are less clear (19). While hyperlipidemia has been reported in > 90% of the patients with overt hypothyroidism, elevated total cholesterol (TC) and LDL-C levels have been reported in 30% (22). Triglyceride (TG), HDL-C, and VLDL-C levels are mildly increased or normal in overt hypothyroidism. While it has been reported that lipid disorders due to overt hypothyroidism are reversible with L-T4 therapy, previous adult studies have indicated contradictory results regarding the impact of SH on lipid disorders and the response to L-T4 therapy (13, 23). A population-based adult study reported that TC level was closely associated with TSH. In this study, it was shown that when TSH level increased over 5.5 mIU/L a mean of 9 mg/dL elevation was observed in TC level. On the other hand, as the TSH was suppressed, the mean TC level decreased by 19 mg/dL (24). Posttreatment decrease in serum lipid levels was found to be more significant in those with a serum TSH level > 10 mIU/L (25). In a previous study, a significant decrease in HDL-C level was determined in the children with TSH level > 10 mIU/L, whereas a significant increase was determined in TC and LDL-C levels in the adults with
TSH level > 10 mIU/L. In contrast, no difference was observed in the lipid parameters of children and adults with TSH level 10 mIU/L, treatment is still questionable for a TSH level between 4.5 and 10 mIU/L (14). Effect of L-T4 therapy on lipid abnormalities in SH remains debatable (73). De Vries et al. (84) emphasized that children with a TSH level between 4.1 and 10 mIU/L and goiter need to be treated. The same study recommended treatment regardless of the presence of goiter for the patients with a TSH level > 10 mIU/L. Treatment is recommended in SH patients with the presence of goiter or clinical signs of hypothyroidism, in child or adolescent patients, a TSH level > 8 in at least two measurements, bipolar disorder and depression, infertility (ovulatory dysfunction), positive antithyroid antibodies, gradually increasing TSH levels, young patient age, and presence of hyperlipidemia (Table 2) (48). Wasniewska et al. (70) compared the SH children treated with L-T4 (n = 69) and those receiving no therapy (n = 92) after a treatment period of 24 months and found the number of patients with a TSH level returned to the normal range to be higher in the treated group. In contrast, while the TSH levels of 42 (60.9%) of 69 patients were within the normal ranges 3 months after the discontinuation of therapy, it increased over 5 mIU/L in 27 (39.1%) patients (TSH 5–10 mIU/L in 55.6%, TSH > 10 mIU/L in 44.4%). The authors (70) emphasized that treatment of SH patients has no effect on posttreatment high TSH levels and that Table 2 Indications for the treatment of subclinical hypothyroidism in childhood (TSH 5–10 mIU/L). – Goiter – Presence of hypothyroidism symptoms – Patient’s choice – Child and adolescent age group – TSH > 8 mIU/L in two measurements – Depression and bipolar disorder – Antithyroid antibody positivity – Progressive TSH elevation – Ovulatory dysfunction – Younger patient age – Hyperlipidemia
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TSH levels return to the baseline after discontinuation of therapy. The same study observed that, TSH increased over 10 mIU/L in the majority of these patients (83%) after discontinuation of therapy if the baseline TSH level of the treated group was > 9 mIU/L (70). According to the Cochrane database, results of the randomized studies on SH reveal that L-T4 therapy does not improve survival or reduce cardiovascular morbidity. However, it has been proven that L-T4 therapy provides an improvement in the left ventricle functions and lipid parameters (7).
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