at: inbox

Endocrinology - Thyroid Disorders - Fast Facts | NEJM Resident 360

Thyroid disorders are often encountered in both inpatient and outpatient settings. Problems related to thyroid disease can range from benign thyroid nodules to emergencies such as thyroid storm or myxedema coma. In this section, we review approaches for evaluating and managing:

• Thyroid Nodules

• Hypothyroidism

• Hyperthyroidism

• Thyroiditis

• Sick Euthyroid Syndrome

Thyroid Nodules

Thyroid nodules are a common finding and may be detected on physical examination or incidentally on imaging. Only about 8% to 16% of thyroid nodules are thyroid cancer. Upon finding a thyroid nodule, the following questions need to be answered:

1. Is this nodule functional? (e.g., Is the patient euthyroid or hyperthyroid?)
2. Is this nodule malignant?

Workup

Workup of a thyroid nodule includes:

1. A thorough history:

• Check for a family history of thyroid disease and thyroid cancer or other malignancies.

• Ask if there’s a personal history of neck irradiation or incidental exposure to ionizing radiation.

• Look for red-flag symptoms (e.g., recent hoarseness, weight loss).

2. A physical examination:

• Evaluate the thyroid and central and lateral neck for signs of lymphadenopathy.

• Assess for signs of hyper- and hypothyroidism.

3. Laboratory testing to evaluate for hormonal function:

• Screen with thyroid-stimulating hormone (TSH) concentration.

• Consider measuring thyroxine (T4) and triiodothyronine (T3) concentration if TSH level is abnormal.

• If laboratory results are consistent with thyrotoxicosis, a radioactive iodine uptake scan should be performed. If the uptake of radioiodine in the nodule is increased (hyperfunctioning, or “hot”, nodule), then the risk of malignancy is exceedingly low and further evaluation for malignancy is not needed, however treatment of the thyrotoxicosis may still be indicated.

4. Imaging to characterize cold (hypofunctioning) nodules and to evaluate cytology when needed:

• Ultrasound (US): All patients with clinically identified thyroid nodules should undergo neck US to evaluate the number, size, and characteristics of the thyroid nodules.

• • Findings on US that are suspicious for malignancy include microcalcifications, irregular margins, extrathyroidal extension, taller than wide shape. Findings that indicate a lower risk of malignancy include cystic nodules and isoechogenicity or hyperechogenicity (compared with surrounding thyroid tissue).

• Fine-needle aspiration (FNA) under US guidance: perform based on the radiological features of the nodule; consider for high- or intermediate-suspicion nodules with widest diameter ≥1 cm.

Management

Generally, the cytological findings on FNA are used to determine management of a thyroid nodule.

• Benign lesions can be managed with regular US follow-up every 1 to 2 years and regular clinical review in case of change.

• When thyroid cancer is detected, lobectomy or thyroidectomy with or without adjuvant treatment is indicated.

Algorithm for Evaluation of Thyroid Nodules

This algorithm is devised mainly for thyroid nodules 1 cm or larger in greatest dimension and is for general application; decision making depends on clinical and radiologic-imaging risk stratification.****(Source: Thyroid Nodules. N Engl J Med 2015.)

Hypothyroidism

Hypothyroidism is one of the most common endocrine disorders; it is more common in women than in men, and it can present in several forms:

• Overt primary hypothyroidism: laboratory findings of elevated TSH and reduced T4

• • The most common presentation of hypothyroidism is high TSH on screening labs.

  • The range of causes include chronic autoimmune (Hashimoto) thyroiditis, thyroidectomy or radioiodine therapy, iodine deficiency or excess, drugs (e.g., lithium, amiodarone, tyrosine kinase inhibitors, immune checkpoint inhibitors), infiltrative diseases (e.g., hemochromatosis, sarcoidosis), thyroiditis, and congenital diseases.

• Subclinical hypothyroidism: laboratory findings of elevated TSH and normal T4

• • Higher incidence is associated with increasing age, female sex, and suboptimal iodine intake.

  • Up to 46% of patients with TSH <7 IU/L have a normalized TSH within 2 years.

• Secondary (central) hypothyroidism: laboratory findings of low or normal TSH and low or low–normal T4

• • This is the least-common type and is caused by pituitary or hypothalamic disease.

  • It is often associated with abnormalities of other pituitary hormones.

Symptoms

Thyroid hormone plays a crucial role in maintaining thermogenic and metabolic homeostasis and is active in all tissues in the body. Overall, the symptoms of hypothyroidism reflect reduced thermogenesis and a slowing of metabolic rate. Symptom onset is usually insidious, and patients may not be aware of them until euthyroid status is restored. Symptoms can include:

• fatigue

• cold intolerance

• weight gain

• constipation

• dry skin

• myalgia

• menstrual irregularities

Diagnosis

Diagnosis hinges on evaluation of laboratory thyroid studies (TSH and T4). A thorough patient history will help determine underlying causes of hypothyroidism. Thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb) can be evaluated in suspected autoimmune (Hashimoto) thyroiditis. 

Treatment

Overt hypothyroidism: Treatment is almost always with synthetic T4 (levothyroxine). The usual full daily replacement dose is around 1.6 µg/kg, but lower doses may be sufficient in patients with residual thyroid function. Treatment goals are to resolve symptoms and normalize the TSH concentration. TSH should be checked 4 to 6 weeks after starting levothyroxine due to its long half-life, with appropriate adjustment of dosing based on results. Patients should be counseled to take thyroid hormone in the morning on an empty stomach and wait 45–60 minutes before eating and taking other medications. Alternative thyroid preparations (e.g., T3 or desiccated porcine thyroid) should not be routinely used without consultation with an endocrinologist.

Subclinical hypothyroidism: No universally accepted recommendations for treatment of subclinical hypothyroidism exist. In general, patients with TSH >10 mIU/L or women wishing to conceive should receive treatment with levothyroxine. The following table outlines different treatment recommendations for subclinical hypothyroidism:

(Source: Subclinical Hypothyroidism. N Engl J Med 2017.)

Hyperthyroidism

The clinical constellation of signs and symptoms of hyperthyroidism is termed thyrotoxicosis.** As with hypothyroidism, hyperthyroidism is more common in women and typically affects them during the reproductive years.

Like hypothyroidism, hyperthyroidism can present in primary, subclinical, and secondary forms:

• Overt primary hyperthyroidism: laboratory findings of suppressed TSH (<0.4 mU/L) and elevated T4

• • Primary hyperthyroidism develops when the thyroid gland produces excessive thyroid hormone.

  • Graves disease, an autoimmune disorder, is the most common cause.

  • Other causes include thyroiditis, toxic nodular goiter, and exogenous thyroid hormone supplementation.

• Subclinical hyperthyroidism: laboratory findings of suppressed TSH (<0.4 mU/L) and normal T4

• • The causes of subclinical hyperthyroidism are similar to those of primary hyperthyroidism.

  • It can progress to primary hyperthyroidism, particularly when TSH <0.1 mU/L.

  • It can be associated with adverse cardiovascular events even without progression.

• Secondary (central) hyperthyroidism: laboratory findings of elevated TSH with elevated T4

• • Secondary hyperthyroidism is a very rare presentation and classically associated with TSH-producing pituitary adenomas.

Symptoms

The symptoms of thyrotoxicosis represent upregulation of thermoregulatory and metabolic homeostasis. These include:

• hyperactivity, irritability

• tremor

• heat intolerance and sweating

• palpitations

• weakness

• diarrhea

• oligomenorrhea

Elderly patients can present with more-subtle signs and symptoms; fatigue, anorexia, depression, and unintentional weight loss or atrial fibrillation may be the only presentations.

Patients with Graves disease can present with specific signs and symptoms related to the cytokine and inflammatory response, including Graves ophthalmopathy with lid retraction and proptosis, pretibial myxedema with skin changes over the anterior and lateral aspects of the lower legs, and thyroid acropachy (finger clubbing).

Cachexia and Muscle Wasting Due to Graves Disease

(Source: Graves’ Disease. N Engl J Med 2011.)

Clinical Manifestations of Graves Disease

Panel A shows a diffuse, moderately enlarged goiter in a woman with Graves’ hyperthyroidism. Panel B shows moderate-to-severe, thyroid-associated ophthalmopathy characterized by bilateral proptosis, periorbital edema, scleral injection, and lid retraction. Panel C shows the plaque form of pretibial dermopathy. Panel D shows acropachy with clubbing of the fingers. (Source: Graves’ Disease. N Engl J Med 2016.)

Diagnosis

Diagnosis of hyperthyroidism is again based on laboratory thyroid studies (TSH and T4). A positive thyrotropin-receptor antibodies (TRAb) has 99% sensitivity and specificity for identifying Graves disease. A radioiodine uptake scan may be helpful in patients with negative antibodies when clinical suspicion is high. In patients with evidence of Graves ophthalmopathy, consider CT or MRI of the orbit to help differentiate from other mimics. The following algorithm is a common approach for investigating Graves disease:

Algorithm for Investigating the Clinical Suspicion of Graves Disease

(Source: Graves’ Disease. N Engl J Med 2016.)

Treatment

Primary hyperthyroidism: Treatment of hyperthyroidism involves both management of symptoms and treatment of the underlying disease. In general, with most etiologies, treatment options include:

• stop or decrease thyroid hormone supplementation

  • for treatment of exogenous thyrotoxicosis

• propranolol or longer-acting beta-1 selective-receptor blocker

• • blocks the stimulatory adrenergic effects of thyroid hormone excess

  • useful while waiting for antithyroid medication to work

• antithyroid medication (methimazole, carbimazole, and propylthiouracil)

• • blocks thyroid peroxidase and thyroid hormone synthesis

  • dose can be titrated as symptomatic control is achieved

• radioactive iodine

• • irradiates thyroid cells; patients will often require lifelong levothyroxine replacement

  • treatment of choice for hyperfunctioning nodule; tends to be second-line treatment for Graves disease

  • contraindicated in Graves ophthalmopathy

• thyroidectomy

• • achieves rapid euthyroidism but patients will require lifelong levothyroxine replacement

The treatment details for Graves disease are outlined in the following table:

(Source: Graves’ Disease. N Engl J Med 2016)

Subclinical hyperthyroidism: Although data are lacking from randomized clinical trials to guide treatment in patients with subclinical hyperthyroidism, professional organizations recommend treatment in the following patient groups due to the association with cardiovascular disease, bone loss, fractures, and dementia:

• Treat subclinical hyperthyroidism in adults >65 years old and postmenopausal women with TSH <0.1 mU/L.

• Consider treatment in premenopausal woman and younger patients <65 years with TSH <0.1 mU/L and coexisting conditions (e.g., osteopenia, osteoporosis, cardiovascular disease).

Thyroiditis

Thyroiditis is an umbrella term for a range of conditions that cause inflammation of the thyroid gland. Common causes include viral illness, underlying autoimmunity, and immune checkpoint inhibitors that are used in cancer treatment. The different types of thyroiditis can be distinguished based on chronicity and whether there is associated thyroid pain:

• Chronic thyroiditis is commonly associated with autoimmunity (e.g., Hashimoto thyroiditis) and usually presents with the insidious onset of hypothyroidism.

• Painless thyroiditis includes postpartum and drug-induced thyroiditis. The usual presentation is with transient thyrotoxicosis as preformed thyroid hormone is released, followed by hypothyroidism, and sometimes with eventual restoration of a euthyroid state. The entire triphasic response can take months.

• Painful thyroiditis, characterized by prominent pain of the anterior neck**,** can either represent a suppurative thyroiditis due to bacterial infection, or a subacute thyroiditis (also referred to as de Quervain thyroiditis) that is associated with viral upper respiratory tract infections (e.g.,  coxsackie virus). In addition to neck pain, patients with suppurative thyroiditis often present with prominent symptoms of the bacterial infection, including fever and sepsis. On the other hand, subacute thyroiditis is characterized by viral prodrome and symptoms of thyrotoxicosis due to the triphasic response described above.

Diagnosis

Thyroid function tests will vary at time of diagnosis, depending on the phase of disease at presentation. Therefore, the diagnosis of thyroiditis and type cannot be made based on thyroid-function testing alone but requires the full clinical scenario, including temporal changes in thyroid function tests. Diagnosis of thyroiditis in a patient with lab results showing thyrotoxicosis is confirmed by a high erythrocyte sediment rate (ESR) and low radioiodine uptake.

Treatment

Treatment of bacterial thyroiditis involves antibiotics and surgical drainage of suppurative complications. Most other cases of thyroiditis do not require any specific treatment other than monitoring of thyroid function tests to ensure resolution of any abnormalities. Beta-blockers can be used to control symptoms of thyrotoxicosis and relatively high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to control pain***.*** If pain persists, consider systemic glucocorticoids tapered over 4 to 6 weeks. If permanent hypothyroidism develops, then thyroid hormone replacement is indicated.   

Sick Euthyroid Syndrome

During any acute illness, changes can occur to circulating thyroid hormone concentration, hormone-binding proteins, and TSH concentration. Proinflammatory cytokines that are released in response to the acute illness are responsible for these changes and can lead to abnormalities in thyroid-function tests in the absence of thyroid disease. Avoid thyroid-function testing in acutely unwell patients unless you have a strong suspicion of primary thyroid disease.

Changes in Thyroid-Function Tests during Acute Illness

Illness Severity	TSH	fT4	T4	fT3	T3	Reverse T3*
Mild-to-moderate	Normal	Normal	Normal	Low	Low	High
Severe	Normal or low	Low	Low	Low	Low	High
Recovery phase	Normal or high	Low to normal	Low to normal	Low to normal	Low to normal	Low

*High reverse T3 is useful for differentiating between central hypothyroidism and nonthyroidal illness.

inbox