Thyroid Disease • 45
consistent with hormone release from an inflamed thyroid gland (Figure 1). An RAIU should not be performed if a patient is sus- pected or confirmed to be pregnant or is breast-feeding. Patients with acute nonthyroidal illness may have TSH suppression that is part of the “euthyroid sick syndrome” and not due to underlying thyrotoxicosis. The free-T4 may be normal, elevated, or low.
Additional testing is sometimes required to make the diagnosis of “euthyroid sick syndrome.”
Thyroid storm is defined as a life-threatening condition man- ifested by an exaggeration of the clinical signs and symptoms of thyrotoxicosis accompanied by systemic decompensation. It is usually caused by rapid release of thyroid hormone (e.g., large iodine load, withdrawal of antithyroid drugs, or treatment with radioactive iodine) in the setting of other illness such as surgery, infection, or trauma. Early recognition, prompt hospitalization, and consultation with endocrinology are the keys to a successful outcome. In hyperthyroid patients, thyroid storm is a clinical diag- nosis; there is no concentration of thyroid hormone elevation that is diagnostic.
The risks of hyperthyroidism are primarily related to cardiac function and arrhythmias, bone loss and osteoporosis, and a hypermetabolic state. Graves’ ophthalmopathy (soft tissue inflam- mation, proptosis, extraocular muscle dysfunction, and optic neu- ropathy) is present in 10%-25% of affected patients, although sub- clinical enlargement of extraocular muscles may be present in up to 70% of patients without overt eye disease. Pretibial myxedema (infiltrative dermopathy characterized by nonpitting scaly thick- ening and induration of the skin) is a rare complication of Graves’ disease. Once treated effectively, the overall risk associated with hyperthyroidism can be substantially diminished.
Hypothyroidism has a wide range of clinical symptoms and signs (see Table 1). The serum TSH is elevated (>10 µU/mL)
in primary hypothyroidism (thyroid gland failure), and is low or normal in conjunction with a low free-T4in rare cases of hypothy-
roidism due to pituitary or hypothalamic disease (secondary hypothyroidism). Patients with a mildly elevated TSH (5-10 µU/mL) and a normal free-T4have subclinical hypothyroidism.
This distinction is important because patients with subclinical hypothyroidism may not require treatment if asymptomatic and not desiring pregnancy (or not currently pregnant).
The most common causes of hypothyroidism are chronic lym- phocytic thyroiditis (Hashimoto’s disease), post-thyroidectomy, and radioactive iodine administration (Table 2). Hashimoto’s dis- ease is an autoimmune disease that may present at any time but increases in prevalence with age. Onset is usually insidious and is usually associated with a goiter. The presence of thyroid peroxi- dase (TPO) antibody is highly correlated with the presence of Hashimoto’s disease and can be useful in confirming the disease or assessing the risk of developing hypothyroidism in the future. Subacute and painful thyroiditis are other illnesses that can lead to hypothyroidism. Most patients demonstrate a triphasic thyroid hormone response once activated: mild hyperthyroidism, followed by mild hypothyroidism, followed by a return to normal thyroid function. If the final phase of thyroid normalization is not attained, TSH will remain elevated and hypothyroidism will persist.
Therapy
Early in the treatment of thyrotoxicosis, iodine avoidance (such as the contrast agent used in CT scans) and exercise restriction are recommended. Thyroidectomy is a reasonable choice in thyro- toxic patients with concomitant suspicious (malignant) nodules and in patients who cannot tolerate or refuse radioactive iodine or antithyroid drugs.
Table 1. Signs and Symptoms of Hyperthyroidism and Hypothyroidism Hyperthyroidism Hypothyroidism
Common symptoms Common symptoms
Nervousness or emotional lability Fatigue Increased sweating Weight gain
Heat intolerance Alopecia
Palpitations Cold intolerance and constipation Fatigue Sluggish affect or depression Weight loss Fluid retention
Hyper-defecation Delayed deep tendon reflexes
Menstrual irregularity Loss of the lateral portion of the eyebrow
Common signs Common signs
Tremors Dry, coarse skin and hair Tachycardia or evidence of atrial fibrillation Periorbital puffiness Proptosis of the eyes or extraocular muscle palsy Bradycardia
Stare, lid lag, or signs of optic neuropathy Slow movements and speech
Goiter Hoarseness
Pretibial myxedema Diastolic hypertension Goiter
Thyrotoxicosis due to thyroiditis is managed conservatively because it is often self-limited. Repeated measurements of thyroid function (monthly) are indicated over a 3-4 month period.
β-blockers can be used for sympathomimetic symptoms (tachy- cardia, tremor, and anxiety). Nonsteroidal anti-inflammatory drugs and, rarely, corticosteroids, are administered to reduce inflammation and discomfort. For patients with Graves’ disease and autonomously functioning thyroid nodules, antithyroid drugs or radioiodine can be used, although patient preference, patient age, comorbidity, severity of thyrotoxicosis, and the presence of Graves’ ophthalmopathy must be taken into account.
Antithyroid drugs are used for primary therapy of thyrotoxi- cosis, attainment of euthyroidism in preparation for thyroidecto- my, and for use in conjunction with radioiodine therapy in select- ed patients. Antithyroid drugs are also preferred to radioactive iodine in the presence of severe Graves’ ophthalmopathy and thy- roid storm. Most patients, however, ultimately select radioiodine as therapy for thyrotoxicosis caused by Graves’ disease, toxic multinodular goiter, or autonomously functioning thyroid nod- ules. Radioiodine is also indicated in patients failing to achieve a remission after a course of antithyroid drugs. When antithyroid drugs are prescribed, methimazole is effective for most patients.
46 • Endocrinology and Metabolism
Alternatively, propylthiouracil is preferred in pregnant patients and in those with an allergy to methimazole. With either drug, patients should be counseled for the risk of hepatitis, vasculitis, and agranulocytosis, rare but potentially severe side effects. If immediate control of severe thyrotoxicosis is required, inorganic iodine (SSKI) can be administered orally and is highly effective. This therapy, however, is self-limited in duration (3 weeks) and precludes further use of radioactive iodine for months thereafter. The response of Grave’s ophthalmopathy to the treatment of hyperthyroidism is complex and requires consultation with an ophthalmologist and endocrinologist.
Levothyroxine is the preferred treatment of hypothyroidism, and it safely, effectively, and reliably relieves symptoms and nor- malizes lab tests in hypothyroid patients. Levothyroxine is con- verted to T3(the active hormone) primarily in peripheral tissues
at an appropriate rate for overall metabolic needs. Treatment with a combination of T4 and T3 is not recommended. While all
patients with overt hypothyroidism (TSH >10 µU/mL) should be treated, there is limited evidence that treatment of subclinical hypothyroidism is beneficial in non-pregnant patients. At present, most patients can be safely monitored with TSH measurements every 4-6 months, evaluating for progression of disease. This rec- ommendation excludes women seeking pregnancy or currently pregnant, who should be treated once TSH is outside the normal range because of greater maternal and fetal risk.
Follow-Up
Following treatment for thyrotoxicosis, TSH and free-T4 are
monitored every 3-6 months for the first year, and every 6-12 months thereafter. Radioactive iodine is likely to cause permanent thyroid destruction requiring life-long levothyroxine therapy.
Once initiated for the treatment of hypothyroidism, levothy- roxine therapy is life-long. Serum TSH should be monitored 6-8 weeks after initiating therapy, and adjustments made to obtain a value within the normal range. A full replacement dose of levothyroxine is approximately 1.7 µg/kg, although many patients require less due to partial thyroid dysfunction. Finally, an annual evaluation of serum TSH is recommended in patients receiving levothyroxine therapy; studies have demonstrated that up to 30% of such patients may be unintentionally under- or over-replaced.
Book Enhancement
Go to www.acponline.org/essentials/endocrinology-section.html to view an example of Graves’ ophthalmopathy, cervical goiter, and a nuclear scan of a hyperfunctioning nodule and to access a classification of thyrotoxicosis based upon radioactive scan results and a table of important facts on hypothyroidism. In MKSAP for
Students 4, assess yourself with items 21-26 in the Endocrinology
and Metabolismsection.
Bibliography
Brent GA. Graves’ disease. N Eng J Med. 2008;358:2594-605. [PMID: 18550875]
Burch HB.Hyperthyroidism (Thyrotoxicosis). http://pier.acponline.org/ physicians/diseases/d175. [Date accessed: 2008 Feb 27] In: PIER [online database]. Philadelphia: American College of Physicians; 2008.
McDermott MT.Hypothyroidism. http://pier.acponline.org/physicians/ diseases/d238. [Date accessed: 2008 Feb 27] In: PIER [online data- base]. Philadelphia: American College of Physicians; 2008.
Nayak B, Hodak SP.Hyperthyroidism. Endocrinol Metab Clin North Am. 2007;36:617-56. [PMID: 17673122]
Thyroid Disease • 47
Table 2. Differential Diagnosis of Hypothyroidism Disease Notes
Hashimoto's disease TSH high; positive family history for hypothyroidism; TPO antibodies present; slowly progressive Iodine deficiency TSH high; urine iodine low; iodine- deficient area; rare in United States
Postpartum thyroiditis TSH triphasic (low, high, normal) over 2-4 months but often ultimately elevated; recent pregnancy Silent thyroiditis TSH triphasic (low, high, normal) over 2-4 months; self-limited in most cases
Subacute thyroiditis TSH triphasic (low, high, normal) over 2-4 months; ESR elevated; painful thyroid
Drug induced TSH high; use of amiodarone, lithium, sunitinib, interferon, iodine, or thioamides in past 1-6 months
Pituitary/hypothalamic mass TSH low or normal; FT4low; headaches; most often a pituitary or sellar lesion noted on MRI/CT scan, or evidence of prior pituitary surgery
Pituitary/hypothalamic TSH low or normal; FT4low; history of cranial radiation therapy radiation therapy
48