eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hypothyroidism: Differential Diagnoses & Workup

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Coauthor(s): Andrew J Bauer, MD, Program Director, Department of Pediatrics, Division of Pediatric Endocrinology, Uniformed Services University of the Health Sciences
Contributor Information and Disclosures

Updated: Jul 10, 2008

Differential Diagnoses

Constipation
Malabsorption Syndromes
Constitutional Growth Delay
Malnutrition
Growth Hormone Deficiency
Mood Disorder: Depression
Hyposomatotropism
Short Stature

Workup

Laboratory Studies

For all measures of thyroid function, age must be considered to interpret the results. In the term neonate, laboratory tests best reflect true thyroid function when performed in infants older than 24 hours.

  • Serum thyrotropin (TSH) concentration remains the most sensitive screening test for hypothyroidism and for establishing the diagnosis of primary hypothyroidism. The sample can be obtained at any time of day. A value within the reference range does not exclude TSH deficiency or TRH deficiency.
    • A physiologic surge of TSH occurs within the first 30 minutes of life and appears to be related to the stress of delivery and exposure to the cold temperature of the extrauterine environment. Serum TSH levels peak at levels as much as 70 mIU/L within the first 24 hours of life and then rapidly drop to less than 10 mIU/L within the first 3 days of life. Beyond the neonatal period, healthy serum levels of TSH are less than 6 mIU/L. Serum TSH levels are elevated in primary hypothyroidism or compensated hypothyroidism and should be low or within the reference range in cases of pituitary (TSH deficiency) or hypothalamic (TRH deficiency) etiologies. Isolated TSH deficiency is far less common than multiple anterior pituitary hormone deficiencies.
    • Serum TSH is the optimal parameter to guide dosing of thyroid hormone replacement, except in patients with secondary or tertiary hypothyroidism. In these patients, measuring serum free T4 by means of equilibrium dialysis is the superior testing method. Adequate thyroid hormone replacement results in normalization of serum TSH. In the rare syndromes of thyroid hormone resistance, serum TSH levels are elevated in the presence of normal-to-high serum total T4 concentration.
    • Serum TSH levels are often mildly abnormal (£ 7 mIU/L) in children and adolescents who are morbidly obese (>20 lb overweight). If the serum free T4 level is normal, the growth velocity has been normal for at least 6 months, the serum TSH level remains stable (not rising) over at least 3 months, and no other signs of hypothyroidism are present, these children and adolescents do not require routine T4 therapy.
  • T4 is present in both the free state and bound to TBG. Total T4 assays measure T4 in both states and are useful to establish the diagnosis of primary hypothyroidism and to assess response to treatment. Free T4 should be directly measured with the equilibrium dialysis method. Many laboratories report a calculated value termed the free T4 index, which is an estimate of the free T4 concentration, not a measurement. The free T4 index is calculated by multiplying the T4 by the T3 resin uptake. Serum free T4 by equilibrium dialysis should be measured when secondary hypothyroidism (pituitary TSH deficiency) or tertiary hypothyroidism (hypothalamic TRH deficiency) is suggested.
  • Measurement of serum T3 concentration, free or total, is not required to confirm the diagnosis of hypothyroidism.
  • Newborn screening for congenital hypothyroidism includes the following:
    • Required by US law in all 50 states, these programs measure total T4 levels using a filter paper–based assay. In those neonates whose serum T4 level falls within the lowest 10th percentile for newborns screened that day by the program, T4 is reassayed, and TSH is simultaneously determined. Remember that, even with the best screening programs, infants with hypothyroidism can be missed. Therefore, the occurrence of a normal screening result must not preclude thyroid function testing in any infant with signs or symptoms of hypothyroidism.
    • Infants with abnormal or borderline screening results should have total T4 and TSH obtained for definitive testing. Thyroid hormone replacement may be empirically initiated while awaiting the confirmatory studies.
    • In infants, if the serum total T4 is less than 85 nmol/L (<7 mg/dL), with TSH more than 40 mIU/L, congenital hypothyroidism is likely. If total T4 is low, and serum TSH is not elevated, TBG deficiency, central hypothyroidism, or euthyroid sick syndrome should be considered, and repeat testing may be needed. Serum free T4 concentration is normal in TBG deficiency. Normal TSH (<20 mIU/L) in the presence of low total T4 and free T4 concentrations suggest secondary or tertiary causes of hypothyroidism. In the latter, signs of associated hypopituitarism (eg, poor feeding, hypoglycemia) and physical findings (eg, midline defects, micropenis) support the diagnosis. All such infants should be screened for other pituitary hormone deficiencies (see Hypopituitarism).
  • Serum antithyroid antibody test findings do not facilitate the diagnosis of hypothyroidism and only serve to establish a diagnosis of CLT and indicate the risk of subsequent development of hypothyroidism. Antithyroid peroxidase and antithyroglobulin antibody titers are elevated in 90-95% of children with CLT. A small proportion of children with test results that are initially negative become positive later. As many as 20% of individuals who have antibody-positive test results do not develop hypothyroidism or hyperthyroidism.
  • Serum total T4 levels and serum free T4 levels are both low in patients with hypothyroidism. In compensated hypothyroidism, total T4 may remain within the reference range in the presence of elevated TSH.
  • Newborns with an elevated TSH should be treated empirically with thyroid hormone replacement until they are aged 2 years to eliminate any possibility of permanent cognitive deficits as a result of hypothyroidism.
  • Low or low-normal serum total T4 levels in the setting of a serum TSH within the reference range suggests TBG deficiency. This congenital disorder causes no pathologic consequence; however, it should be recognized to avoid unnecessary thyroid hormone administration. TBG deficiency affects 1 individual per 3000 population; therefore, occurrence is nearly as frequent as that in congenital hypothyroidism. TBG deficiency results in low serum total T4; however, serum TSH and serum free T4 concentrations are normal. Assessment of the serum TBG concentration, preferably with simultaneous serum free and serum total T4 concentrations, confirms the diagnosis.

Imaging Studies

  • In vivo radionucleotide studies: The iodide-trapping or concentrating mechanism of normal thyroid tissue can be evaluated by radioisotope (iodine-123 or technetium-99m pertechnetate). In children, technetium-99m is a useful radioisotope because it is trapped by the thyroid but not organified; thus, the child is exposed to lower amounts of radiation.
  • In congenital organification defects and lymphocytic thyroiditis, the amount of radioisotope uptake is within reference range; however, the half-life of the radioisotope within the thyroid is decreased because of the lack of organification. This can be demonstrated by means of a perchlorate washout study.
  • Radioisotope-based thyroid scanning is useful to detect the absence or ectopic location of healthy thyroid tissue in congenital hypothyroidism.
  • Iodine-123 scanning of the thyroid can be used to identify ectopic thyroid tissue, such as lingual thyroid. Absence of a signal on this study confirms athyreosis.

Procedures

Fine-needle aspiration is generally not necessary in children with hypothyroidism.

  • This study, which is designed to evaluate a thyroid nodule, should only be performed by a physician experienced with this procedure.
  • This procedure is most strongly indicated in adolescents or young adults who have a single cold nodule detected by means of iodine-123 scanning.

Histologic Findings

The histologic appearance of CLT includes lymphocytic infiltration, formation of lymphoid follicles, and follicular cell hyperplasia.

More on Hypothyroidism

Overview: Hypothyroidism
Differential Diagnoses & Workup: Hypothyroidism
Treatment & Medication: Hypothyroidism
Follow-up: Hypothyroidism
References
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References

  1. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007;92(8 Suppl):S1-47. [Medline].

  2. Ayala AR, Danese MD, Ladenson PW. When to treat mild hypothyroidism. Endocrinol Metab Clin North Am. Jun 2000;29(2):399-415. [Medline].

  3. Bongers-Schokking JJ, Koot HM, Wiersma D, et al. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr. Mar 2000;136(3):292-7. [Medline].

  4. Brown RS, Bellisario RL, Botero D, et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab. Mar 1996;81(3):1147-51. [Medline].

  5. Brown RS, Keating P, Mitchell E. Maternal thyroid-blocking immunoglobulins in congenital hypothyroidism. J Clin Endocrinol Metab. May 1990;70(5):1341-6. [Medline].

  6. Daliva AL, Linder B, DiMartino-Nardi J, Saenger P. Three-year follow-up of borderline congenital hypothyroidism. J Pediatr. Jan 2000;136(1):53-6. [Medline].

  7. DeBoer MD, Lafranchi SH. Pediatric thyroid testing issues. Pediatr Endocrinol Rev. 2007;5 Suppl 1:570-7. [Medline].

  8. Dubuis JM, Glorieux J, Richer F, et al. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J Clin Endocrinol Metab. Jan 1996;81(1):222-7. [Medline].

  9. Dussault JH. Childhood primary hypothyroidism and endemic cretinism. Curr Ther Endocrinol Metab. 1997;6:107-9. [Medline].

  10. Dussault JH. The anecdotal history of screening for congenital hypothyroidism. J Clin Endocrinol Metab. Dec 1999;84(12):4332-4. [Medline].

  11. Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism. J Pediatr. Mar 2000;136(3):273-4. [Medline].

  12. Fisher DA, Schoen EJ, La Franchi S, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab. Aug 2000;85(8):2722-7. [Medline].

  13. Franceschi R, Camilot M, Teofoli F. Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes. Clin Endocrinol (Oxf). 2005;63:146-151. [Medline].

  14. Garcia-Filion P, Epport K, Nelson M, et al. Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study. Pediatrics. 2008;121:e653-9. [Medline].

  15. Glinoer D, Delange F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid. Oct 2000;10(10):871-87. [Medline].

  16. Gruneiro-Papendieck L, Chiesa A, Mendez V. Efficacy of congenital hypothyroidism neonatal screening in preterms less than 32 weeks of gestational age: more evidence. J Pediatr Endocrinol Metab. 2005;18:373-377. [Medline].

  17. Guarnieri GF, Laforgia N, Mautone A, Balducci G. Delayed closure of ductus arteriosus in term newborns with congenital hypothyroidism: effect of L-thyroxine therapy. Pediatr Cardiol. 2008;29:455-6. [Medline].

  18. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine. 1999;341(8):549-555. [Medline].

  19. Hanukoglu A, Perlman K, Shamis I, et al. Relationship of etiology to treatment in congenital hypothyroidism. J Clin Endocrinol Metab. Jan 2001;86(1):186-91. [Medline].

  20. Hardy O, Worley G, Lee MM, et al. Hypothyroidism in Down syndrome: screening guidelines and testing methodology. Am J Med Genet A. 2004;124:436-7. [Medline].

  21. Hashimoto K, Curty FH, Borges PP, et al. An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci U S A. Mar 27 2001;98(7):3998-4003. [Medline].

  22. Hopwood NJ, Kelch RP. Thyroid masses: approach to diagnosis and management in childhood and adolescence. Pediatr Rev. Dec 1993;14(12):481-7. [Medline].

  23. Hsiao PH, Chiu YN, Tsai WY, et al. Intellectual outcome of patients with congenital hypothyroidism detected by neonatal screening. J Formos Med Assoc. Jan 2001;100(1):40-4. [Medline].

  24. Hsiao PH, Chiu YN, Tsai WY, et al. Intellectual outcomes of patients with congenital hypothyroidism not detected by neonatal screening. J Formos Med Assoc. Jul 1999;98(7):512-5. [Medline].

  25. Ishikawa N, Eguchi K, Ohmori T, et al. Defective organification of iodide causing congenital goitrous hypothyroidism. J Clin Endocrinol Metab. Jan 1996;81(1):376-83. [Medline].

  26. Kempers MJ, van Trotsenburg AS, van Rijn RR, et al. Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease. J Clin Endocrinol Metab. 2007;92:2984-91. [Medline].

  27. Kordonouri O, Hartmann R, Riebel T, Liesenkoetter KP. Early treatment with L-thyroxine in children and adolescents with type 1 diabetes, positive thyroid antibodies, and thyroid gland enlargement. Pediatr Diabetes. 2007;8:180-4. [Medline].

  28. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid. Jul 1999;9(7):735-40. [Medline].

  29. LaFranchi S. Thyroid function in the preterm infant. Thyroid. Jan 1999;9(1):71-8. [Medline].

  30. Lomenick JP, El-Sayyid M, Smith WJ. Effect of levo-thyroxine treatment on weight and body mass index in children with acquired hypothyroidism. J Pediatr. 2008;152:96-100. [Medline].

  31. McElduff A, McElduff P, Wiley V. Neonatal TSH as measured in a congenital hypothyroidism screening program: influence of the mode of delivery. J Clin Endocrinol Metab. 2005;[Medline].

  32. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia?. J Clin Endocrinol Metab. Nov 2000;85(11):3975-87. [Medline].

  33. Muller AF, Berghout A, Wiersinga WM, Kooy A, Smits JW, Hermus AR. Thyroid function disorders - Guidelines of the Netherlands Association of Internal Medicine. Neth J Med. 2008;66:134-42. [Medline].

  34. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005;42:379-389. [Medline].

  35. Rovet JF. Congenital hypothyroidism: long-term outcome. Thyroid. Jul 1999;9(7):741-8. [Medline].

  36. Ruiz M, Rajatanavin R, Young RA, et al. Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis. N Engl J Med. 1982;306:635-9. [Medline].

  37. Sakata S, Matsuda M, Ogawa T, et al. Prevalence of thyroid hormone autoantibodies in healthy subjects. Clin Endocrinol (Oxf). Sep 1994;41(3):365-70. [Medline].

  38. Sbrocchi AM, Chédeville G, Scuccimarri R, Duffy CM, Krishnamoorthy P. Pediatric hypothyroidism presenting with a polymyositis-like syndrome and increased creatinine: report of three cases. J Pediatr Endocrinol Metab. 2008;21:89-92. [Medline].

  39. Screening for congenital hypothyroidism: US Preventive Services Task Force reaffirmation recommendation. Ann Fam Med. 2008;6:166. [Medline].

  40. Topaloglu AK. Athyreosis, dysgenesis, and dyshormonogenesis in congenital hypothyroidism. Pediatr Endocrinol Rev. 2006;3 Suppl 3:498-502. [Medline].

  41. van der Sluijs Veer L, Kempers MJ, Last BF, Vulsma T, Grootenhuis MA. Quality of life, developmental milestones, and self-esteem of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab. May 6 2008;[Medline].

  42. van Tijn DA, de Vijlder JJ, Verbeeten B Jr. Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab. 2005;90:3350-3359. [Medline].

  43. Van Vliet G. Neonatal hypothyroidism: treatment and outcome. Thyroid. Jan 1999;9(1):79-84. [Medline].

  44. Veasey SC, Guilleminault C, Strohl KP, Sanders MH, Ballard RD, Magalang UJ. Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 2006;29:1036-44. [Medline].

  45. Vela M, Gamboa S, Loera-Luna A, et al. Neonatal screening for congenital hypothyroidism in Mexico: experience, obstacles, and strategies. J Med Screen. 1999;6(2):77-9. [Medline].

  46. Vigone MC, Fugazzola L, Zamproni I. Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum Mutat. 2005;26:395. [Medline].

  47. Woeber KA. Subclinical thyroid dysfunction. Arch Intern Med. May 26 1997;157(10):1065-8. [Medline].

  48. Working Group on Neonatal Screening of the European Society for Paediatric Endo. Revised guidelines for neonatal screening programmes for primary congenital hypothyroidism. Horm Res. 1999;52(1):49-52. [Medline].

  49. Zamproni I, Grasberger H, Cortinovis F, et al. Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab. 2008;93:605-10. [Medline].

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Further Reading

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Keywords

hypothyroidism, congenital hypothyroidism, acquired hypothyroidism, chronic lymphocytic thyroiditis, CLT, autoimmune thyroiditis, Hashimoto thyroiditis, Hashimoto's thyroiditis, Hashimoto disease, Hashimoto's disease, lymphadenoid goiter, infantile hypothyroidism, cretinism, secondary hypothyroidism, transient hypothyroidism, tertiary hypothyroidism, dietary iodine deficiency, goiter, obstructive sleep apnea, constipation, heat intolerance, hyperthyroidism, toxic thyroiditis, Graves disease, Graves' disease, short stature, sexual pseudoprecocity, precocious puberty, galactorrhea, bradycardia, umbilical hernia, thyroid carcinoma, 21 syndrome, Ulrich-Turner syndrome, Klinefelter syndrome, type 1 diabetes mellitus, histiocytosis X, cystinosis

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching

Coauthor(s)

Andrew J Bauer, MD, Program Director, Department of Pediatrics, Division of Pediatric Endocrinology, Uniformed Services University of the Health Sciences
Andrew J Bauer, MD is a member of the following medical societies: American Academy of Pediatrics, American Thyroid Association, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School
George P Chrousos, MD, FAAP, MACP, MACE is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfiser, Inc. Honoraria Consulting

 
 
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