Graves Disease

Basics

Description

Multisystem autoimmune disorder that presents with the classic triad of hyperthyroidism (goiter), exophthalmos, and dermopathy (rare in children)

Epidemiology

  • Female > male (4 to 5:1)
  • 10–15% of all childhood thyroid disorders
  • Incidence increases with age, peaking in adolescence and in the 3rd to 4th decades.
  • Rising incidence of pediatric cases in several countries over the past 15 years
  • Higher prevalence of thyrotoxicosis among non-Hispanic blacks in the United States, age 12 to 49 years

Risk Factors

Genetics

  • No simple hereditary pattern (i.e., genetic susceptibility plus environmental factors)
    • Up to 60% of patients have a family history of autoimmune thyroid disease (hyperthyroidism or hypothyroidism).
    • Concordance rates of Graves disease: 17% in monozygotic twins (of note, another 17% had chronic lymphocytic thyroiditis and 10% had other nonthyroid autoimmune conditions), 2% in dizygotic twins, 4% of 1st-degree relatives
  • Often associated with HLA-DR3
  • Increased incidence in genetic syndromes
    • Down syndrome: presents at a younger age, no female predominance unlike the general population; usually milder course
    • Turner syndrome

Pathophysiology

  • Autoimmune process that includes production of immunoglobulins against antigens in the thyroid, orbital tissue, and dermis
  • IgG1 anti–thyroid-stimulating hormone (TSH) receptor autoantibody and thyroid-stimulating immunoglobulin (TSI) activates the TSH receptor, causing constitutive stimulation, leading to increased thyroid follicular cell production and release of thyroid hormone.

Commonly Associated Conditions

  • Increased risk for celiac disease, associated with HLA-DQ2 haplotype, early onset of Graves disease, and family history of autoimmune disorders
  • Prevalence of hyperthyroidism is higher among children <18 years with type 1 diabetes than without.

Diagnosis

ALERT
Thyroid storm can constitute an endocrinologic medical emergency.

History

  • Growth acceleration that can be associated with precocious puberty (Hyperthyroidism can accelerate the bone age.)
  • Declining school performance, mind racing, difficulty concentrating; may be mistaken for ADHD
  • Symptoms of hyperthyroidism and their duration (if child complains of these symptoms, evaluate for possible hyperthyroidism):
    • Restlessness, emotional lability, nervousness
    • Fine tremor
    • Disturbed sleep pattern and insomnia; may result in daytime fatigue
    • Weight loss despite increased appetite
    • Palpitations or chest pain with minimal exertion or at rest; low exercise tolerance
    • Heat intolerance
    • Increased urination and diarrhea
    • Muscle weakness (proximal)
    • Plummer nails (separation of nail from bed)
    • Menstrual irregularities
  • Thyroid gland enlargement: Graves disease can present with goiter. Tenderness suggests infectious cause.
  • Exophthalmos (bulging of the eyes), increased staring, change in vision or in facial appearance: Exophthalmos due to retro-orbital immune depositions is a hallmark of Graves disease.
  • Familial history: increased incidence of Graves disease in families with thyroid disease

Physical Exam

  • Accelerated growth or height above expected genetic potential due to bone age advancement
  • Symmetrically enlarged, smooth, nontender goiter in >95% of cases
  • Auscultate the thyroid gland for bruit while patient holds his or her breath (glandular hyperperfusion is associated with hyperthyroidism).
  • Resting tachycardia with widened pulse pressure; hyperdynamic precordium: cardiac effects of excessive thyroid hormone
  • Slightly elevated temperature: Thyroid hormone controls basal metabolic rate and upregulates catecholamine-induced thermogenesis.
  • Lid lag/stare; exophthalmos and proptosis: Severe ophthalmopathy is rare.
  • Fine tremor, especially visible in hands and tongue in ~60% of children with Graves disease
  • Proximal muscle weakness is common but seldom severe.
  • Exaggerated deep tendon reflexes are variable.
  • Skin warmth and moisture: heat intolerance and excessive sweating in >30% of children

Differential Diagnosis

  • Infectious
    • Acute suppurative thyroiditis (i.e., transient thyroxine elevations)
    • Subacute thyroiditis after viral illness (also transient)
  • Environmental
    • Thyroid hormone ingestion
    • Ingestion of excess iodine (escape from Wolff-Chaikoff block due to impaired autoregulation)
  • Tumors (all rare in childhood)
    • TSH-producing pituitary adenoma
    • Thyroid adenoma/hyperfunctioning autonomous thyroid nodule (Most pediatric patients are euthyroid; incidence of nodule hyperfunctioning rises with patient age.)
    • Thyroid carcinoma (rarely presents with hyperthyroidism)
  • Congenital
    • Neonatal Graves disease (transplacental antibody transfer from mothers with Graves disease or chronic thyroiditis)
  • Genetic and developmental
    • Pituitary resistance to thyroid hormones (dominant negative thyroid-receptor gene mutations causing loss of pituitary negative feedback loop and inappropriately elevated TSH concentrations; can be isolated, with clinical hyperthyroidism, or associated with peripheral thyroid resistance and clinical euthyroidism or hypothyroidism)
    • TSH-receptor gene mutations (rare; germline activating TSH-receptor mutations cause autosomal dominant nonautoimmune hereditary hyperthyroidism)
    • McCune-Albright syndrome: Activating G-protein mutation can lead to indolent hyperthyroidism in addition to the classic features of this syndrome.
    • Ectopic thyroid tissue
  • Other causes of hyperthyroidism: See “Goiter.”

Diagnostic Tests and Interpretation

Initial Tests

  • Total or free thyroxine: elevated
  • Triiodothyronine assessment by radioimmunoassay: elevated (triiodothyronine radioimmunoassay, as direct measurement of triiodothyronine, and not triiodothyronine resin uptake, which indirectly evaluates thyroid hormone–binding capacity)
  • TSH: significantly suppressed or undetectable
  • TSI titer: positive in 90% of children
  • False-positive test results: Elevated total thyroxine levels can also be caused by increased protein binding and so are not necessarily diagnostic for hyperthyroidism: Increased estrogen states (e.g., pregnancy and oral contraceptive use) lead to augmented hepatic thyroxine-binding globulin (TBG) production. Familial dysalbuminemic hyperthyroxinemia: Mutation affecting thyroxine binding affinity leads to increased protein-bound pool.
  • I123 scan: not needed to diagnose Graves disease. If done, shows diffuse increased uptake at 6 and 24 hours. If palpation suggests nodule, scan may reveal a hot nodule within a suppressed gland.
  • 99mTc uptake assessment is a good second-line test for hyperthyroidism of unclear etiology and negative TSI.

Treatment

General Measures

Avoid caffeine.

Medication (Drugs)

ALERT
  • Antihistamines and cold medications may worsen sympathetic nervous system symptoms.
  • Stopping antithyroid drugs because of low thyroxine values when TSH is still suppressed, reflecting continued TSI activity, will likely result in relapse. Antithyroid medication dosage should be decreased, or L-thyroxine should be added.
  • FDA issued a black box warning (June 4, 2009) against propylthiouracil (PTU) use in treating Graves disease owing to risk of severe liver injury including life-threatening acute liver failure.

First Line Medication

  • Drug therapy is the first-line choice in children. Antithyroid medications (thiourea derivatives): 65–95% effective: Medications block thyroid hormone synthesis but not the release of existing hormone.
    • Methimazole
    • PTU: Note black box warning. Limited, short-term use of PTU may be considered for patients requiring antithyroid medication (neither I131 ablation nor prompt surgery are options) or after a toxic reaction to methimazole. PTU is preferred during first trimester of pregnancy (teratogenic effects of methimazole).
  • Propranolol and atenolol block adrenergic symptoms; should be used with antithyroid medications at start of treatment and whenever cardiac symptoms are prominent
  • Duration of treatment:
    • Antithyroid medications can be tapered and potentially discontinued after 2 to 3 years of therapy, depending on the patient’s course.
    • β-Blockers: Continue until thyroxine and triiodothyronine are under control (~6 weeks).
    • If remission not achieved in 1 to 2 years, ablation with I131 or total or subtotal thyroidectomy may be considered.

Issue for Referral

Treatment for severe ophthalmopathy: must refer patient to an ophthalmologist:

  • Three options: high-dose glucocorticoids, orbital radiotherapy, or surgical orbital decompression
  • Rehabilitative surgery for eye muscles or eyelids is often needed after the ophthalmopathy has been treated.

Diagnostic Procedures/Other

  • Radiotherapy: I131 ablation therapy
    • 90–100% effective; safe and definitive, with predictable outcome
    • Results in permanent hypothyroidism requiring lifelong thyroxine replacement
    • Adequate dose should be used (>150 μCi/g of thyroid tissue) to prevent residual tissue that would be at risk of developing thyroid cancer.
    • Current recommendations advise avoiding I131 ablation in children <5 years of age owing to theoretical concerns relating radiation exposure and cancer risks.
    • Radioiodine ablation may exacerbate ophthalmopathy, but this effect can be prevented with concomitant glucocorticoid administration.
  • Total or near-total thyroidectomy
    • Effective, rapid, and definitive (vs. 30% recurrence rate for subtotal thyroidectomy)
    • Lifelong thyroxine replacement needed
    • Surgical complication rates higher for children <6 years and for children treated in lower volume centers

Ongoing Care

Patient Teaching

Stop exercising immediately if palpitations develop; patients may need letters for their physical education teachers or coaches.

Prognosis

  • Good, if adherent with treatment
  • Mortality in severe thyrotoxicosis is possible from cardiac arrhythmias or cardiac failure.
  • Spontaneous remission occurs in 20–30% of children after 1 to 2 years but can relapse in 30%. Large thyroid gland size (by ultrasound) and high titers of TSH-receptor antibody (TRAb) predict lower chance of remission.
  • Neonatal hyperthyroidism remits by 48 weeks and more commonly by 20 weeks.
  • Propranolol or atenolol should result in rapid relief of symptoms of sympathetic hyperactivity.
  • 4 to 6 weeks of medical treatment should result in normalization of thyroxine and triiodothyronine concentrations, although TSH levels may remain suppressed owing to persistent underlying activity of the thyroid-stimulating Ig.
  • Persistent suppression of TSH is associated with pretreatment presence of thyrotropin-binding inhibitory Ig, severity of thyrotoxicosis, and time to recovery of thyroid hormone levels.
  • Duration and type of treatment depend on patient age and remission and relapse pattern.

Complications

  • Endocrine disturbances: delayed/early puberty, menstrual irregularity, hypercalcemia
  • Ophthalmologic: 3–5% of patients develop severe ophthalmopathy, including eye muscle dysfunction and optic neuropathy, requiring specific treatment by an ophthalmologist. Pediatric ophthalmologic findings (lid lag, soft tissue involvement, and proptosis) are more common but usually less severe than in adults.
  • Bone: low bone mineral density for age/sex common at diagnosis due to high bone turnover. Corrects with Graves disease therapy and return to euthyroid status. Osteoporosis and pathologic fractures may occur in undiagnosed hyperthyroidism.
  • Fetal/neonatal: intrauterine growth retardation (IUGR), nonimmune hydrops fetalis, craniosynostosis, intrauterine death, goiter that complicates labor and can cause life-threatening airway obstruction at delivery, hyperkinesis, failure to thrive, diarrhea, vomiting, cardiac failure and arrhythmias, systemic and pulmonary hypertension, hepatosplenomegaly, jaundice, hyperviscosity syndrome, thrombocytopenia
  • Medication side effects: agranulocytosis (in 0.2–0.5% of patients), rash (most common side effect), gastrointestinal upset, headache, transient transaminitis/hepatitis and life-threatening liver failure with PTU, vasculitis with PTU (frequently associated with perinuclear antineutrophil cytoplasmic antibody [p-ANCA] titers)

Additional Reading

  1. Aversa T, Valenzise M, Salerno M, et al. Metamorphic thyroid autoimmunity in Down syndrome: from Hashimoto’s thyroiditis to Graves’ disease and beyond. Ital J Pediatr. 2015;41:87.  [PMID:26558364]
  2. Bahn RS, Burch HB, Cooper DS, et al; for American Thyroid Association, American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17(3):456–520.  [PMID:21700562]
  3. Baskaran C, Misra M, Levitsky LL. Diagnosis of pediatric hyperthyroidism: technetium 99 uptake versus thyroid stimulating immunoglobulins. Thyroid. 2015;25(1):37–42.  [PMID:25257665]
  4. Correia MF, Maria AT, Prado S, et al. Neonatal thyrotoxicosis caused by maternal autoimmune hyperthyroidism. BMJ Case Rep. 2015;2015:bcr2014209283. doi:10.1136/bcr-2014-209283.  [PMID:25750228]
  5. Harvengt J, Boizeau P, Chevenne D, et al. Triiodothyronine-predominant Graves’ disease in childhood: detection and therapeutic implications. Eur J Endocrinol. 2015;172(6):715–723.  [PMID:25766047]
  6. Havgaard Kjær R, Smedegård Andersen M, Hansen D. Increasing incidence of juvenile thyrotoxicosis in Denmark: a nationwide study, 1998–2012. Horm Res Paediatr. 2015;84(2):102–107.  [PMID:26111962]
  7. Hodax JK, Reinert SE, Quintos JB. Autonomously functioning thyroid nodules in patients <21 years of age: the Rhode Island Hospital experience from 2003–2013. Endocr Pract. 2016;22(3):328–337.  [PMID:26574789 ]
  8. Marcocci C, Marinò M. Treatment of mild, moderate-to-severe and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab. 2012;26(3):325–337.  [PMID:22632369]
  9. Matheis N, Lantz M, Grus FH, et al. Proteomics of orbital tissue in thyroid-associated orbitopathy. J Clin Endocrinol Metab. 2015;100(12):E1523–E1530.  [PMID:26451909]
  10. McLeod DS, Cooper DS, Ladenson PW, et al. Race/ethnicity and the prevalence of thyrotoxicosis in young Americans. Thyroid. 2015;25(6):621–628.  [PMID:25744381]
  11. Nandi-Munshi D, Taplin CE. Thyroid-related neurological disorders and complications in children. Pediatr Neurol. 2015;52(4):373–382.  [PMID:25661286]
  12. Okawa ER, Grant FD, Smith JR. Pediatric Graves’ disease: decisions regarding therapy. Curr Opin Pediatr. 2015;27(4):442–447.  [PMID:26087421]
  13. Sarezky MD, Corwin DJ, Harrison VS, et al. Hyperthyroidism presenting with pathologic fractures. Pediatrics. 2016;137(2):e20150169.  [PMID:26746406]
  14. Srinivasan S, Misra M. Hyperthyroidism in children. Pediatr Rev. 2015;36(6):239–248.  [PMID:26034254]
  15. Wilhelm SM, McHenry CR. Total thyroidectomy is superior to subtotal thyroidectomy for management of Graves’ disease in the United States. World J Surg. 2010;34(6):1261–1264.  [PMID:20033406]
  16. Zirilli G, Velletri MR, Porcaro F, et al. Hyperthyroidism in childhood: peculiarities of the different clinical pictures. Acta Biomed. 2015;86(3):220–225.  [PMID:26694148]

Codes

ICD-9

  • 242.00 Toxic diffuse goiter without mention of thyrotoxic crisis or storm
  • 242.01 Toxic diffuse goiter with mention of thyrotoxic crisis or storm
  • 775.3 Neonatal thyrotoxicosis

ICD-10

  • E05.00 Thyrotoxicosis w diffuse goiter w/o thyrotoxic crisis
  • E05.01 Thyrotoxicosis w diffuse goiter w thyrotoxic crisis or storm
  • P72.1 Transitory neonatal hyperthyroidism

SNOMED

  • 353295004 Graves’ disease (disorder)
  • 60216004 Toxic diffuse goiter with thyrotoxic crisis
  • 59957008 Neonatal Graves’ disease (disorder)
  • 237499004 thyrotoxicosis due to Graves’ disease (disorder)
  • 55807009 Toxic diffuse goiter with exophthalmos (disorder)

FAQ

  • Q: Does Graves disease lead to thyroid cancer?
  • A: No, although controversy surrounds the role of TSH and the closely related TSH-receptor antibodies of Graves disease in thyroid cancer’s incidence and aggressiveness. There is an increased incidence of benign thyroid adenoma from 0.6% to 1.9% after therapy involving I131 ablation.
  • Q: Does hyperthyroidism affect long-term growth or final adult height?
  • A: No. Hyperthyroidism can cause tall stature and acceleration of skeletal maturity but does not typically affect final adult height.
  • Q: Should WBC counts be monitored routinely while patients are on antithyroid medications?
  • A: No. Routine monitoring is not cost-effective because agranulocytosis is rare and sudden in onset. WBC counts should be checked when a patient on antithyroid medication develops fever.
  • Q: Will the ophthalmopathy correct with antithyroid treatment?
  • A: Not necessarily. It may require specific intervention by an ophthalmologist.
  • Q: Can a mother breastfeed while being treated for Graves disease?
  • A: Yes. PTU has a lower milk/serum concentration ratio than methimazole (0:1 and 1:0, respectively). In one study, 3 of 11 infants exclusively breastfed by women on 300 to 750 mg daily PTU had high levels of TSH; of these 3, 1 was just above the normal range and the other 2 completely corrected while the mother was still being medicated.

Authors

Adda Grimberg, MD


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