Excess production (or ingestion) of thyroid hormone.
II. Diagnostic Approach
A. What is the differential diagnosis for this problem?
- Autoimmune Disease: Graves’ disease, Hashitoxicosis
- Thyroid Nodules: Toxic multinodular goiter, thyroid adenoma
- Thyroiditis: de Quervain’s (subacute granulomatous) thyroiditis, painless (including postpartum), radiation, amiodarone
- Exogenous thyroid hormone
- Central (TSH-mediated) hyperthyroidism
- Ectopic hyperthyroidism: Metastatic follicular thyroid cancer, struma ovarii
B. Describe a diagnostic approach/method to the patient with this problem
In a patient with symptoms suggestive of hyperthyroidism, thyroid-stimulating hormone (TSH) is the best screening test. In nearly all patients with hyperthyroidism, the TSH will be low (often undetectable). If the TSH is low, free T4 and T3 should be checked to verify that the patient has overt hyperthyroidism (as opposed to subclinical hyperthyroidism where the T4 and T3 levels will be normal). To elucidate the cause of a patient’s hyperthyroidism, further testing would include serum autoantibodies and a 24-hour radioiodine uptake scan.
1. Historical information important in the diagnosis of this problem.
- Symptoms of hyperthyroidism: unintentional weight loss, tremor, palpitations, heat intolerance, increased perspiration, anxiety/emotional lability, hyperdefecation, oligo-/amenorrhea
- Medications: Amiodarone, herbal medications (some of which contain thyroid hormone)
- History of radiation exposure
- Changes in vision (suggestive of Graves’ ophthalmopathy)
- Family history of thyroid disease (associated with increased incidence of Graves’ and younger age of onset)
- Recent contrast study (can induce hyperthyroidism in those with multinodular goiter or iodine deficiency)
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- Thyroid palpation: Enlarged thyroid suggestive of Graves’ disease, although thyroid may be normal in size.
- Presence of a single nodule suggests hyperfunctioning adenoma, while multiple nodules suggestive of toxic multinodular goiter. A painful thyroid is seen in subacute (granulomatous) thyroiditis.
- Thyroid auscultation: Thyroid bruit can sometimes be heard in Graves’ disease.
- Eyes: Graves’ disease is associated with multiple eye findings, including exophthalmos, periorbital/conjunctival edema, and limited eye movements. Lid retraction and lid lag can be seen with all causes of hyperthyroidism.
- Cardiac: Tachycardia, often with atrial arrhythmias.
- Neurologic: Hyperreflexia, proximal muscle weakness.
- Psychiatric: Rapid speech, emotional lability.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
Most cost-effective screening test for hyperthyroidism. Hyperthyroidism is associated with suppressed levels of TSH (typically, <0.5 mU/L). Rarely, an elevated TSH level can be associated with hyperthyroidism if there is a pituitary adenoma secreting TSH. If the TSH is normal (0.5-5 mU/L in most labs), a diagnosis of hyperthyroidism is very unlikely.
Free T4 and T3
In most cases of hyperthyroidism, both T4 and T3 levels will be elevated. A low TSH with normal free T4 and T3 levels is consistent with subclinical hyperthyroidism. Some patients with nodular goiter and Graves’ disease, particularly early in the disease course, will have predominant elevations in T3 due to increased conversion of T4 to T3 and a disproportionate increase in T3 secretion. Patients with amiodarone toxicity will have higher T4 concentrations (as amiodarone inhibits T4 to T3 conversion), as will patients taking exogenous thyroxine.
TSI (thyroid-stimulating immunoglobulin) and/or thyrotropin-receptor antibodies positive in Graves’ disease. Other causes of hyperthyroidism typically do not have associated autoantibodies, except for painless thyroiditis (positive thyroid peroxidase antibodies).
24-hour radioiodine uptake
Imaging study of choice in hyperthyroidism. Increased uptake of radioiodine seen in Graves’ (diffuse, homogenous distribution) and nodular diseases (diffuse, patchy distribution in toxic multinodular goiter or focal uptake with a hyperfunctioning adenoma). Decreased uptake is seen with thyroiditis and exogenous ingestion of hormone.
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- Clinical features: Typically, subacute or chronic presentation (symptoms over weeks to months). May also have ocular symptoms.
- Test results: Low TSH, elevated T4/T3, positive autoantibodies (TSI or thyrotropin-receptor), increased uptake on radioiodine scan with homogenous distribution.
Toxic multinodular goiter
- Clinical features: Seen in younger patients in iodine-deficient areas. Length of symptoms and severity are variable.
- Test results: Low TSH, elevated T3 (T4 level variable), increased uptake on radioiodine scan with patchy distribution.
- Clinical features: More common in women and the elderly. Length of symptoms and severity are variable.
- Test results: Low TSH, elevated T3 (T4 level variable), increased uptake on radioiodine scan in single area with decreased uptake elsewhere.
- Clinical features: More common in postpartum women. Symptoms tend to be less severe and of shorter duration.
- Test results: Low TSH, elevated T4/T3, positive TPO antibodies, decreased uptake on radioiodine scan.
Painful subacute thyroiditis
- Clinical features: Often follows a viral illness. Symptoms of shorter duration. Significant thyroid tenderness.
- Test results: Low TSH, elevated T4/T3, decreased uptake on radioiodine scan.
- Clinical features: Seen in patients moving from iodine-deficient to iodine-abundant areas (Jod-Basedow phenomenon). Also can be seen in patients receiving high doses of iodine, typically in radiographic contrast.
- Test results: Low TSH, elevated T3 (T4 level variable), variable uptake on radioiodine scan.
- Clinical features: Can be associated with other hormonal abnormalities.
- Test results: Elevated TSH, elevated T4/T3.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- Free T4/T3 by dialysis: Limited availability and is more expensive than other tests without significant benefit.
- Neck CT scan: Useful if there is a concern for airway or thoracic-inlet obstruction, but not useful in general management. If ordered prior to other studies, can actually cause delay in diagnosis (if patient receives IV contrast, limits ability to perform radioiodine-uptake scan over the next several months).
III. Management while the Diagnostic Process is Proceeding
A. Management of hyperthyroidism.
An uncommon presentation of thyrotoxicosis, but one that is associated with high mortality (>20%). Most often it is caused by Graves’ disease. There is no clear definition of thyroid storm (to separate it from severe thyrotoxicosis), although Burch and Wartofsky did devise a scoring system that can aid in delineating severity.
- Medications – Initial anti-thyroid treatment is with propylthiouracil or methimazole (to prevent new hormone production) followed by iodine therapy (to inhibit thyroid hormone release). Cardiovascular manifestations are managed with beta-blockers, most commonly oral propranolol titrated to keep the pulse less than 100 beats/minute (commonly 60mg every four to six hours). If intravenous (IV) medications are needed, esmolol (50-100 microgram/kilogram/minute) can be used. As patients can also be relatively adrenally insufficient, hydrocortisone 100 mg IV every 8 hours is commonly given (steroids also decrease the T4 to T3 conversion).
- Identification of precipitants – Many precipitants are obvious (surgery, trauma, etc.,), but others require thorough history, physical and diagnostic testing (myocardial infarction, pulmonary embolism, ketoacidosis, infection, recent iodine administration).
Typically treated by medication, radioiodine, or surgery.
- Medication – Methimazole and propylthiouracil are used to interfere with thyroid hormone synthesis. Methimazole offers more convenient dosing (once daily vs three times daily) and may have less side effects. Improvement in symptoms takes about one month with the dose adjusted as needed to normalize T4 and T3 levels. Length of treatment varies (usually at least 6 months), but relapse occurs in over 50% of patients.
- Radioiodine – May be used as initial therapy, or after treatment with antithyroid medications. Induces hypothyroidism, so patients need lifelong hormone replacement.
- Surgery – Induces hypothyroidism, so patients need lifelong hormone replacement.
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem
- Non-thyroidal illness syndrome – Levels of TSH, T4 and T3 can all drop during acute illness. Therefore, it is recommended that thyroid function tests not be checked during hospitalization unless there is concern for significant thyroid dysfunction. If thyroid function tests are checked during hospitalization, a full panel (TSH, free T4, total T4 and T3) should be ordered since one test on its own is unreliable in this setting.
- Subclinical hyperthyroidism – Diagnosed when serum TSH is low but free T4 is normal. There is controversy over whether treatment should be initiated in these patients, but observational studies have suggested an increased risk of fractures and heart disease (coronary disease and atrial fibrillation) in patients with subclinical hyperthyroidism.
- Medications – Side effects include weight gain, transaminitis, rash, and joint pain. The most concerning side effect is a granulocytosis (0.1 to 0.3% of patients). Advise patients to discontinue antithyroid medications for symptoms (such as fever or mouth ulcerations) that suggest cytopenia. Agranulocytosis can occur at any time during therapy but tends to present acutely so routine monitoring of complete blood chemistry (CBC) is not recommended.
- Radioiodine – Induces hypothyroidism. Other side effects include neck pain and worsening of Graves’ ophthalmopathy (there is some evidence that treatment with steroids reduces the risk of worsening eye disease). Radioiodine should not be used in pregnant women or in those wishing to become pregnant soon (recommended that women not attempt to conceive for 6-12 months following treatment).
- Surgery – Induces hypothyroidism. Risks are lower when procedure is performed by an experienced surgeon, but complications include hypoparathyroidism and recurrent laryngeal nerve damage.
What’s the Evidence?
Adler, SM, Wartofsky, L. “The nonthyroidal illness syndrome”. Endocrinol Metab Clin North Am. vol. 36. 2007. pp. 657-72.
Brent, GA. “Graves’ disease”. NEJM. vol. 358. 2008. pp. 2594-2605.
Kharlip, J, Cooper, DS. “Recent developments in hyperthyroidism”. Lancet. vol. 373. 2009. pp. 1930-32.
Nayak, B, Burman, K. “Thyrotoxicosis and thyroid storm”. Endocrinol Metab Clin N Amer. vol. 35. 2006. pp. 663-686.
Blum, MR. “Subclinical thyroid dysfunction and fracture risk”. JAMA.. vol. 313. 2015. pp. 2055-65. (Observational study showing increased risk of fractures in those with subclinical disease.)
Collet, TH. “Subclinical hyperthyroidism and the risk of coronary heart disease and mortality”. Arch Intern Med.. vol. 172. 2012. pp. 799-809. (Observational study showing increased risk of heart disease in those with subclinical thyroid disease.)
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- I. Problem/Condition.
- II. Diagnostic Approach
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding
- A. Management of hyperthyroidism.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem