Hypothyroidism, Acquired

Descriptive text is not available for this imageBASICS

DESCRIPTION

Hypothyroidism that occurs after the neonatal period

EPIDEMIOLOGY

  • May develop at any age
  • Autoimmune thyroid disorders occur more frequently in children and adolescents with type 1 diabetes and other autoimmune conditions.
  • Chronic lymphocytic thyroiditis prevalence correlates with iodine intake; countries with the highest dietary iodine also have the highest prevalence.
  • Subclinical hypothyroidism (thyroid-stimulating hormone [TSH] concentrations between the upper limit of normal reference range and 10 mIU/L, with normal free thyroxine [T4] levels) found in 7–23% of children living with obesity and 0.3–2% of normal weight controls. It seems to be a consequence rather than cause of the obesity and can normalize with weight loss.

ETIOLOGY

  • Myriad causes (See “Differential Diagnosis” section.)
  • Can result from thyroid gland dysfunction (primary hypothyroidism) or from pituitary/hypothalamic dysfunction leading to understimulation of the thyroid gland (secondary and tertiary hypothyroidism)

RISK FACTORS

Genetics

  • Family history of thyroid disease or other autoimmune endocrinopathies increases risk.
  • Genetic predisposition in patients with chronic lymphocytic thyroiditis; 30–40% of patients have a family history of thyroid disease, and up to 50% of their 1st-degree relatives have thyroid antibodies.
  • Weak associations of chronic lymphocytic thyroiditis with certain human leukocyte antigen haplotypes; also associated with genotypes of cytotoxic T lymphocyte–associated 4 (CTLA4) and interleukin-18 (IL-18) genes, and with DNA hypermethylation of the PTPN22 gene promoter (encodes inhibitor of T-cell activation).
  • Autoimmune thyroid disease may be part of type 2 (Schmidt disease) and type 3 autoimmune polyglandular syndrome.
  • Genetic syndromes associated with higher incidence of autoimmune thyroiditis include:
    • Trisomy 21
    • Turner syndrome (especially isochromosome Xq)
    • Klinefelter syndrome
    • 22q11.2 deletion syndrome

COMMONLY ASSOCIATED CONDITIONS

  • Type 1 diabetes
  • Celiac disease
  • Pernicious anemia, chronic atrophic gastritis
  • Vitiligo
  • Alopecia areata
  • Obesity. Although hypothyroidism can lead to increased weight gain, obesity, via leptin, can also lead to mild TSH elevations that correct with weight loss.

Descriptive text is not available for this imageDIAGNOSIS

ALERT

Decompensated hypothyroidism (a.k.a. myxedema coma) is the most severe presentation of primary or secondary hypothyroidism. It is exceedingly rare, involves multiple organ abnormalities, and progressive mental status deterioration.

HISTORY

  • Linear growth failure can be the first sign of thyroid dysfunction.
  • Declining school performance is a sensitive marker for lethargy and reduced focus.
  • Radiation exposure, history of type 1 diabetes, family history of other autoimmune disorders
  • Signs and symptoms:
    • Early primary hypothyroidism can be asymptomatic.
    • Hypothyroid-related symptoms indicate progression from compensated to uncompensated hypothyroidism.
    • Hypothyroidism may be preceded in some cases by temporary hyperthyroidism (hashitoxicosis).
    • Goiter may be the presenting sign of acquired hypothyroidism; tenderness suggests an infectious process.

PHYSICAL EXAM

  • Bradycardia: Thyroid hormone has cardiac effects.
  • Short stature (or fall-off on growth curve) and increased upper/lower segment ratio: Euthyroidism is required to maintain normal growth.
  • Goiter: Note consistency, symmetry, nodularity, signs of inflammation:
    • May give a clue regarding cause of hypothyroidism
    • May provide a clinical marker to follow during therapy
  • Myxedema (water retention) is not limited to subcutaneous tissue; it may also lead to cardiac failure, pleural effusions, and coma.
  • Muscle hypertrophy, yet muscle weakness
    • Most obvious in arms, legs, and tongue
    • Hypothyroidism causes disordered muscle function.
  • Delayed relaxation phase of deep tendon reflexes due to slowed muscle contraction.
  • Pale, cool, dry, carotenemic (yellow-colored) skin due to decreased cell turnover.
  • Increased lanugo hair in children; can be reversed with treatment.
  • Sexual development is an important factor. Hypothyroidism may be associated with either of the following:
    • Delayed puberty (due to low thyroid hormone levels)
    • Precocious puberty and galactorrhea (due to elevated TSH)

DIFFERENTIAL DIAGNOSIS

  • Immunologic
    • Chronic lymphocytic thyroiditis (Hashimoto thyroiditis)
    • Autoimmune polyglandular syndrome type II (Schmidt syndrome)
  • Infectious
    • Postviral subacute thyroiditis
    • Associated with congenital infections
      • Rubella
      • Toxoplasmosis
  • Environmental
    • Goitrogen ingestion
      • Iodides
      • Expectorants
      • Thioureas
    • Exposure to polybrominated diphenyl ethers (PBDEs; flame retardants) was associated with an increased prevalence of hypothyroidism in Canadian women.
    • Low selenium intake
  • Iatrogenic
    • Following surgical thyroidectomy for thyroid cancer, hyperthyroidism, or extensive neck tumors
    • Following radioiodine ablative therapy for hyperthyroidism or thyroid cancer
    • Following head or neck irradiation for cancer treatment or hematopoietic stem cell transplantation
    • Medications: lithium, amiodarone, iodine contrast dyes, tiratricol (an over-the-counter [OTC] fat-loss supplement), antiepileptics (valproate and carbamazepine but not levetiracetam)
  • Metabolic
    • Cystinosis
    • Histiocytosis X
  • Congenital
    • Late-onset congenital, large ectopic gland
  • Genetic syndromes
    • Trisomy 21
    • Turner syndrome
  • Secondary or tertiary hypothyroidism
    • Hypothalamic or pituitary disease
  • Consumptive hypothyroidism
    • Due to increased type 3 iodothyronine deiodinase activity in hemangiomas

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (screening, lab, imaging)

  • T4 (low) and TSH (elevated): Elevated TSH with normal T4 indicates compensated (subclinical) primary hypothyroidism.
  • Free T4: The most sensitive marker for secondary/tertiary hypothyroidism (TSH elevation lost; total T4 may still be low normal.)
  • Thyroglobulin antibodies and thyroid peroxidase (microsomal) antibodies are markers for chronic lymphocytic thyroiditis.
  • The following conditions may test false positive for acquired hypothyroidism:
    • Thyroid-binding globulin deficiency: low total T4 but normal free T4 and TSH
    • Peripheral resistance to thyroid hormone: normal/high total T4
    • “Euthyroid sick” syndrome: low T4 and T3; normal/low TSH; increased shunting to reverse T3
  • The following tests may be affected in acquired hypothyroidism:
    • Serum creatinine: elevated due to reduced glomerular filtration rate
    • Low-density lipoprotein (LDL) cholesterol level: elevated due to decreased LDL receptor expression
    • Creatine kinase: increased; hypothyroidism is a rare cause of rhabdomyolysis.
  • Imaging: Head magnetic resonance imaging (MRI) for cases of suspected secondary/tertiary hypothyroidism or pituitary or hypothalamic lesion
ALERT

The 2023 American Academy of Pediatrics (AAP) Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity recommended against routine lab screening for hypothyroidism unless height deceleration is evident.

Descriptive text is not available for this imageTREATMENT

GENERAL MEASURES

Weight loss may normalize subclinical hypothyroidism seen in obese children.

MEDICATION

LT4 (levothyroxine; synthetic thyroid hormone) replacement

  • Indicated for the treatment of overt or compensated hypothyroidism
  • 10 to 15 mcg/kg PO once daily
  • Monitor T4 and TSH and titrate doses to maintain normalized thyroid function tests.
  • Duration of therapy:
    • Lifetime
    • In 30% of the cases, children with chronic lymphocytic thyroiditis will undergo spontaneous remission.
    • Need for treatment can be reassessed after growth is completed.

Descriptive text is not available for this imageONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • Whenever starting medication or adjusting dose, check T4 and TSH at 4- to 6-week intervals to assess adequacy of the new dose. Need to wait this long to reach equilibrium given to long half-life of T4 (5 to 7 days).
  • Once dose established, 6-monthly monitoring until linear growth completed; annually thereafter
  • Monitor response to treatment by measuring T4 and TSH levels to assess adequacy of therapy and compliance.

PATIENT EDUCATION

  • Pharmacies have been recommending that LT4 be administered on an empty stomach.
  • The Drugs and Therapeutics Committee of the Pediatric Endocrine Society recommended that consistency in administration, coupled with regular dose titration based on thyroid function laboratory tests, is more important than improving absorption by restricting intake to only times of empty stomach.

PROGNOSIS

  • If patients are adherent, prognosis is excellent.
  • Adherence to LT4 is lower in pubertal than prepubertal children and in children self-administering their medication than those administered by their parents.
  • Treated patients often resume growth at a rate greater than normal (catch-up growth).
  • In children with severe hypothyroidism or in whom treatment has been delayed, catch-up growth may not fully normalize height to predicted values.
  • Other signs and symptoms resolve at a variable rate.
  • Goiters in chronic lymphocytic thyroiditis may not completely regress with treatment (enlargement due to persistent inflammation does not correct, although TSH-mediated hypertrophy will).

COMPLICATIONS

  • Most significant complication is impaired linear growth.
  • Puberty can also be affected.
  • Myxedema coma may occur.
  • Encephalopathy of varied clinical presentation has been associated with high titers of thyroid antibodies, especially antimicrosomal; this condition responds well to corticosteroid treatment.

ADDITIONAL READING

  • Barrett B , Bauer AJ . The effects of amiodarone on thyroid function in pediatric and adolescent patients. Curr Opin Pediatr. 2021;33(4):436-441. doi:10.1097/MOP.0000000000001040  [PMID:34117173]
  • Chaker L , Razvi S , Bensenor IM , Azizi F , Pearce EN , Peeters RP . Hypothyroidism. Nat Rev Dis Primers. 2022;8(1):30. doi:10.1038/s41572-022-00357-7  [PMID:35589725]
  • De Sanctis V , Soliman A , Daar S , et al. The myxedema coma in children and adolescents: a rare endocrine emergency—personal experience and review of the literature. Acta Biomed. 2021;92(5):e2021481. doi:10.23750/abm.v92i5.12252  [PMID:34738556]
  • Ilia TS , Dragoumi P , Papanikolopoulou S , Goulis DG , Pavlou E , Zafeiriou D . Is the prevalence of thyroid disease higher in children receiving antiepileptic medication? A systematic review and meta-analysis. Seizure. 2022;94:117-125. doi:10.1016/j.seizure.2021.11.010  [PMID:34896814]
  • Kyritsi EM , Kanaka-Gantenbein C . Autoimmune thyroid disease in specific genetic syndromes in childhood and adolescence. Front Endocrinol (Lausanne). 2020;11:543. doi:10.3389/fendo.2020.00543  [PMID:32973676]
  • Rodriguez L , Dinauer C , Francis G . Treatment of hypothyroidism in infants, children and adolescents. Trends Endocrinol Metab. 2022;33(7):522-532. doi:10.1016/j.tem.2022.04.007  [PMID:35537910]
  • Sharifi M , Goodman AB , Chua KP . Assessment of underuse and overuse of screening tests for co-occurring conditions among children with obesity. JAMA Netw Open. 2022;5(7):e2222101. doi:10.1001/jamanetworkopen.2022.22101  [PMID:35834247]
  • Zeitler P , Solberg P ; Pharmacy and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Food and levothyroxine administration in infants and children. J Pediatr. 2010;157(1):13.e1-14.e1. doi:10.1016/j.jpeds.2010.05.025  [PMID:20547262]

CODES

ICD 10

  • E03.9 Hypothyroidism, unspecified
  • E03.8 Other specified hypothyroidism
  • E06.3 Autoimmune thyroiditis
  • E03.4 Atrophy of thyroid (acquired)

FAQ

  • Q: What happens if my child forgets a dose?
  • A: Give the dose as soon as you remember. If it is the next day, give 2 doses.
  • Q: How long will my child have to take these pills?
  • A: Probably for life.
  • Q: Are there any side effects from the medication?
  • A: No. The medication contains only the hormone that your child’s thyroid gland is not making. The hormone is made synthetically, so there is also no infectious risk.
  • Q: If my child takes twice the dose, will his or her growth catch up faster?
  • A: Your child may grow a little faster in the short term but will also have symptoms (such as fast heart rate, tremors, sleep issues) from having too much thyroid hormone.
  • Q: Does the medication have to be taken at any particular time of day?
  • A: No, but consistently choosing the same time of day helps to remember to take it. Do not take simultaneously with soy products, iron-containing medication, calcium supplements, or raloxifene (an antiestrogen medication) because they can cause malabsorption of levothyroxine.
  • Q: What if my child needs surgery?
  • A: Treatment of hypothyroidism such that the patient is euthyroid (normal thyroid status) prior to surgery is preferable whenever possible (only exception is ischemic heart disease requiring surgery). Euthyroid sick syndrome, which is common in very ill patients, should not be treated.

Authors

Adda Grimberg, MD


© Wolters Kluwer Health Lippincott Williams & Wilkins