Hyperthyroidism or thyrotoxicosis comprises a spectrum of clinical findings consistent with thyroid hormone excess. The former describes excess from the thyroid gland, whereas the latter can be produced from any other source or not identified.

• Graves disease (GD): The most common form; diffuse goiter and thyrotoxicosis are common characteristics. Infiltrative orbitopathy is seen in 50% of patients. Infiltrative dermopathy is rare. Autoantibodies are directed at the thyrotropin-stimulating hormone (TSH) receptors.
• Toxic multinodular goiter (TMNG): Second most common; a TSH receptor mutation has been found in 60% of patients; patients older than age 40, insidious onset, frequent in iodine-deficient areas.
• Toxic adenoma: Younger patients, autonomously functioning nodules
• Iodine-induced hyperthyroidism
• Thyroiditis: Transient autoimmune process:
  • Subacute thyroiditis/De Quervain: Granulomatous giant cell thyroiditis, benign course; viral infections have been involved.
  • Postpartum thyroiditis
  • Drug-induced thyroiditis: Amiodarone, interferon alpha, interleukin 2, lithium
  • Miscellaneous: Thyrotoxicosis factitia, TSH-secreting pituitary tumors, and functioning trophoblastic tumors
• Subclinical hyperthyroidism: Suppressed TSH with normal thyroxine (T₄); may be associated with osteoporosis and atrial fibrillation (1)
• Thyroid storm: Rare hyperthyroidism; fever, tachycardia, systolic hypertension, CNS dysfunction (e.g., coma); up to 50% mortality

ALERT
Geriatric Considerations

• Characteristic symptoms and signs may be absent.
• Atrial fibrillation is common when TSH <0.1 mU/L.

Pediatric Considerations

• Neonates and children are treated with antithyroids for 12–24 months.
• Radioactive iodine is controversial in patients under the ages of 15–18 years.

Pregnancy Considerations
Propylthiouracil (PTU) is currently the drug of choice during pregnancy. Treat with lowest effective dose. Avoid treatment-induced hypothyroidism. Radioiodine therapy is contraindicated.

• 1.3% of population
• Predominant sex: Female > Male (7–10:1).
• Predominant age: Autoimmune thyroid disease in second and third decades. TMNG presents in patients older than age 40. GD is seen between 40 and 60 years of age.

Incidence

• Female 1:1,000
• Male: 1:3,000

• Positive family history, especially in maternal relatives
• Female
• Other autoimmune disorders
• Iodide repletion after iodide deprivation, especially in TMNG

Genetics The concordance rate for GD among monozygotic twins is 35%.

• GD: Autoimmune disease
• TMNG: 60% TSH receptor gene abnormality; 40% unknown
• Toxic adenoma: Point mutation in TSH receptor gene with increased hormone production
• Thyroiditis:
  • Hashitoxicosis: Autoimmune destruction of the thyroid; antimicrosomal antibodies present
  • Subacute/De Quervain thyroiditis: Granulomatous reaction; genetic predisposition in specific human leukocyte antigens (HLAs); viruses such as coxsackievirus, adenovirus, echovirus, and influenza virus have been implicated; self-limited course, 6–12 months
  • Suppurative: Infectious
  • Drug-induced thyroiditis: Amiodarone produces an autoimmune reaction and a destructive process. Lithium, interferon-alpha, and interleukin 2 cause an autoimmune thyroiditis.
  • Postpartum thyroiditis: Autoimmune thyroiditis that lasts up to 8 weeks, and in 60% of patients, hypothyroidism manifests in the future.

• Autoimmune diseases
• Down syndrome
• Iodine deficiency

• Thyrotoxicosis is a hypermetabolic state where energy production exceeds needs, causing increased heat production, diaphoresis, and even fever.
• Thyrotoxicosis affects several different systems:
  • Constitutional: Fatigue, weakness, increased appetite, weight loss
  • Neuropsychiatric: Agitation, anxiety, emotional lability, psychosis, coma, and poor concentration and memory
  • GI: Increased appetite, hyperdefecation
  • Gynecologic: Oligomenorrhea, amenorrhea
  • Cardiovascular: Tachycardia (most common) and chest discomfort that mimics angina

ALERT
Geriatric Considerations
Apathetic hyperthyroidism in the elderly

• Adults:
  • Skin: Warm, moist, pretibial myxedema (GD only)
  • Head, eye, ear, nose, throat (HEENT): Exophthalmos, lid lag
  • Endocrine: Hyperhidrosis, heat intolerance, goiter, gynecomastia, low libido, and spider angiomata (males)
  • Cardiovascular: Tachycardia, atrial fibrillation, cardiomegaly
  • Musculoskeletal: Skeletal demineralization, osteopenia, osteoporosis, fractures
  • Neurologic: Tremor, proximal muscle weakness, anxiety and lability, brisk deep tendon reflexes
  • Rarely: Thyroid acropathy (clubbing), localized dermopathy
• Children:
  • Linear growth acceleration
  • Ophthalmic abnormalities more common

Lab

• 95% have suppressed TSH and elevated free T₄. Total T₄ and triiodothyronine (T₃) represent the bound hormone and can be affected by pregnancy and hepatitis.
• T₃: Elevated especially in T₃ toxicosis or amiodarone-induced thyrotoxicosis
• T₄: Elevated; TSH autoantibodies rarely needed
• Free thyroxine index (FTI): Calculated from T₄ and thyroid hormone–binding ratio; corrects for misleading results caused by pregnancy and estrogens
• Inappropriately normal or elevated TSH with high T₄ suspicious for pituitary tumor or thyroid hormone resistance
• Drugs may alter lab results: Estrogens, heparin, iodine-containing compounds (including amiodarone and contrast agents), phenytoin, salicylates, steroids (e.g., androgens, corticosteroids)
• Drug precautions: Amiodarone and lithium may induce hyperthyroidism; MMI may cause warfarin resistance.
• Other findings that can occur: Anemia, granulocytosis, lymphocytosis, hypercalcemia, transaminase, and alkaline phosphate elevations.

Initial Labs

• TSH, free T₄, T₄, T₃, TSI
• TSH-receptor (-R) antibodies (Abs): The routine assay is the TSH-binding inhibitor immunoglobulin assay (TBII). TSH-R Abs are useful in the prediction of postpartum Graves thyrotoxicosis and neonatal thyrotoxicosis.
• Thyroxine/triiodothyronine ratio: The T₄:T₃ ratio may be a useful tool when the iodine uptake testing is not available/contraindicated. ∼2% of thyrotoxic patients have “T₃ toxicosis.”

Follow-Up and Special Considerations In severe cases, such as thyroid storm, hospitalize until stable, especially if >60 years of age, because of the risk of atrial fibrillation.

Imaging

• Nuclear medicine scanning (¹²³I or ¹³¹I): The reference-range values for 24-hour radioiodine uptake is between 5% and 25%.

• Increased thyroid iodine uptake is seen with TMNG, toxic solitary nodule, and GD.
• GD shows a diffuse uptake and can have a paradoxical finding of high uptake at 4–6 hour but normal uptake at 24 hour because of the rapid clearance (2).
• TMNG will show a heterogeneous uptake, whereas solitary toxic nodule will show a warm or “hot” nodule.
• In iodine-deficient areas, an increased uptake is associated with low urine iodine levels.
• Hashimoto's thyroiditis can have an increased uptake at an early stage but no increased thyroid hormone production.
• Causes of thyrotoxicosis with low iodine uptake:
  • Acute thyroiditis, thyrotoxicosis factitia, and iodine intoxication with amiodarone or contrast material can cause low-uptake transient thyrotoxicosis. After thyroiditis resolves, the patient can become euthyroid or hypothyroid.
  • Iodine loading can cause iodine trapping and decreased iodine uptake (Wolff-Chaikoff effect).
  • Thyrotoxicosis factitia: Thyroglobulin levels are low in exogenous intake and high in endogenous production.
  • Other extrathyroidal causes include struma ovarii and metastatic thyroid carcinoma.
  • Technetium-99m scintigraphy: Controversial because it has a 33% discordance rate with radioactive iodine scanning.

Diagnostic Procedures/Other Neck ultrasound will show increased diffuse vascularity in GD.

Pathological Findings

• GD: Hyperplasia
• Toxic nodule: Nodule formation

• Anxiety
• Malignancy
• Diabetes mellitus
• Pregnancy
• Menopause
• Pheochromocytoma
• Depression
• Carcinoid syndrome

• Radioactive iodine therapy (RAIT): Most common definitive treatment used in the US for GD and TMNG
• Pretreatment with antithyroid drugs is preferred to avoid worsening thyrotoxicosis. MMI is preferred over PTU as pretreatment because of decreased relapse, but it is held 3–5 days before therapy.
• There is concern for a slightly higher risk of lymphoma and leukemia in patients treated with RAIT.
• Usually patients become hypothyroid 2–3 months after therapy; therefore, antithyroid medications are continued after ablation.
• Glucocorticoids: Reduce the conversion of active T₄ to the more active T₃. In Graves ophthalmopathy, the use of prednisone before and after RAIT improves outcome.
• After RAIT, the release of antigens can worsen the inflammatory reaction and the ophthalmopathy.
• Smoking in GD patients is a risk factor for ophthalmopathy when treated with RAIT.
• For TMNG, the treatment of choice is RAIT. Medical therapy with antithyroid medications has shown a high recurrence rate. Surgery is considered only in special cases.
• Treatment for subacute thyroiditis is supportive with NSAIDs and beta blockers. Steroids can be used for 2–3 weeks.
• For amiodarone-induced thyrotoxicosis (AIT) type I, the treatment is antithyroid drugs and beta blockers. Potassium perchlorate also can be used as an iodine uptake inhibitor. Thyroidectomy is the last option. AIT type II is self-limited.
• Graves dermopathy: Difficult to treat in the chronic phase. Topical steroids with occlusive dressing may help in acute phase.

First Line

• Antithyroid drugs: MMI and PTU are thionamides that inhibit iodine oxidation, organification, and iodotyrosine coupling. PTU can block peripheral conversion of T₄ to active T₃. Both can be used as primary treatment for GD and prior to RAIT or surgery (3)[A].
• Duration of treatment: 6 months to 2 years; 50–60% relapse after stopping; treatment beyond 18 months did not show any further benefit. The most serious side effects are hepatitis (0.1–0.2%), vasculitis, and agranulocytosis:
  • MMI: Adults: 10–15 mg q12h; children aged 6–10 years: 0.4 mg/kg/d PO once daily
  • PTU: Adults (preferred in thyroid storm and pregnant and lactating women): 100–150 mg PO q8h, not to exceed 200 mg/d during pregnancy
• β-adrenergic blocker: Propranolol in high doses (>160 mg/d) inhibits T₃ activation by up to 30%. Atenolol, metoprolol, and nadolol can be used.
• Glucocorticoids: Reduce the conversion of active T₄ to the more active T₃
• Cholestyramine: Anion exchange resin that decreases thyroid hormone reabsorption in the enterohepatic circulation; dose: 20–30 g/d
• Other agents:
  • Lithium: Inhibits thyroid hormone secretion and iodotyrosine coupling; can be dosed at 300 mg q8h with close monitoring of levels to avoid toxicity
  • Lugol solution: Saturated solution of potassium iodide (SSKI); blocks release of hormone from the gland but should be administered at least 1 hour after thionamide was given; acts as a substrate for hormone production (Jod-Basedow effect)
  • Potassium perchlorate: Especially for amiodarone-induced thyrotoxicosis
  • RAIT: See “Treatment” section.

Second Line Ipodate sodium (Oragrafin): 0.5 g PO q.i.d. most effectively prevents conversion of T₄ to T₃ and thyroid hormone release; also useful in thyroid storm.

Issue for Referral Patients with Graves ophthalmopathy should be referred to an experienced ophthalmologist.

Thyroidectomy for compressive symptoms, masses, and thyroid malignancy may be performed in the second trimester of pregnancy only.

Patient Monitoring

• Repeat thyroid tests once a year, CBC and LFTs on thionamide therapy; continue therapy with thionamides for 12–18 months (3).
• After RAIT, thyroid function tests at 6 weeks, 12 weeks, 6 months, and annually thereafter if euthyroid; TSH may remain undetectable for months if patient is euthyroid; follow T₃ and T₄.

Sufficient calories to prevent weight loss

Good (with early diagnosis and treatment)

• Surgery: Hypoparathyroidism, recurrent laryngeal nerve damage, and hypothyroidism
• RAIT: Postablation hypothyroidism
• GD: High relapse rate with antithyroid drug as primary therapy
• Graves ophthalmopathy, worsening heart failure if cardiac condition, atrial fibrillation, muscle wasting, proximal muscle weakness, increased risk of cerebrovascular accident (CVA) and cardiovascular mortality

• 242.00 Toxic diffuse goiter without mention of thyrotoxic crisis or storm
• 242.10 Toxic uninodular goiter without mention of thyrotoxic crisis or storm
• 242.20 Toxic multinodular goiter without mention of thyrotoxic crisis or storm
• 242.30 Toxic nodular goiter, unspecified type, without mention of thyrotoxic crisis or storm
• 242.90 Thyrotoxicosis without mention of goiter or other cause, and without mention of thyrotoxic crisis or storm
• 245.2 Chronic lymphocytic thyroiditis
• 245.1 Subacute thyroiditis

• E05.90 Thyrotoxicosis, unspecified without thyrotoxic crisis or storm
• E05.00 Thyrotoxicosis with diffuse goiter without thyrotoxic crisis or storm
• E05.01 Thyrotoxicosis with diffuse goiter with thyrotoxic crisis or storm
• E05.10 Thyrotoxicosis with toxic single thyroid nodule without thyrotoxic crisis or storm
• E05.11 Thyrotoxicosis with toxic single thyroid nodule with thyrotoxic crisis or storm
• E05.20 Thyrotoxicosis with toxic multinodular goiter without thyrotoxic crisis or storm
• E05.21 Thyrotoxicosis with toxic multinodular goiter with thyrotoxic crisis or storm
• E05.80 Other thyrotoxicosis without thyrotoxic crisis or storm
• E05.81 Other thyrotoxicosis with thyrotoxic crisis or storm
• E05.91 Thyrotoxicosis, unspecified with thyrotoxic crisis or storm
• E06.9 Thyroiditis, unspecified
• E05.40 Thyrotoxicosis factitia without thyrotoxic crisis or storm
• E05.41 Thyrotoxicosis factitia with thyrotoxic crisis or storm
• E06.0 Acute thyroiditis
• E06.1 Subacute thyroiditis
• E06.3 Autoimmune thyroiditis
• E06.5 Other chronic thyroiditis
• E06.9 Thyroiditis, unspecified

• 34486009 hyperthyroidism (disorder)
• 237498007 toxic goiter (disorder)
• 90739004 thyrotoxicosis (disorder)
• 21983002 Hashimoto thyroiditis (disorder)
• 57777000 toxic nodular goiter (disorder)
• 26389007 toxic multinodular goiter (disorder)
• 38727009 subacute thyroiditis (disorder)

• Not all thyrotoxicoses are secondary to hyperthyroidism.
• GD presents with hyperthyroidism, ophthalmopathy, and goiter.
• Medical treatment for GD has a high relapse rate after stopping medications.
• Thyroid storm is a medical emergency that needs hospitalization and aggressive treatment.

Anup K. Sabharwal, MD, FACE
Atil Kargi, MD

1. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295:1033–41.  [PMID:16507804]
2. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am. 2007;36:617–56.  [PMID:17673122]
3. Abraham P, Avenell A, Watson WA, et al. A systematic review of drug therapy for Graves’ hyperthyroidism. Cochrane Database Sys Rev. 2005;153(4):489–98.

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