Primary Care Update
Psychiatric illness or thyroid disease? Don’t be misled by false lab tests
Thyroid dysfunction is often in the differential diagnosis of psychiatric disorders. The author reviews the practical aspects of workup, diagnosis, and patient management, and addresses how to distinguish findings of a true thyroid illness from false readings.
Psychiatrists commonly order thyroid testing and are often the first to confront abnormal thyroid test results. As thyroid testing has become more sophisticated and sensitive (Box 1), the interpretation and management of abnormal or slightly abnormal results has become increasingly complex. What’s more, older individuals, hospitalized patients, and those with psychiatric illness often present with subtle laboratory abnormalities.
Hyperthyroidism and hypothyroidism are highly prevalent disorders, especially in women and the elderly. Thyroid dysfunction is the second most common endocrine disorder after diabetes among elders. In the three cases that follow, some of the problems and solutions in dealing with thyroid testing are presented.
Case 1: Depression and thyroid abnormalities
J.R., 67, has a history of hypertension. She was referred for evaluation of depressive symptoms. She reports 3 months of increasing fatigue, lethargy, and poor motivation. Her weight has increased by 10 pounds over this period. Her physical exam, ECG, and chest x-ray are normal. She is well groomed and slightly overweight. Her medications have not changed recently and include hydrochlorothiazide 25 mg/d and an aspirin a day.
J.R. reports no history of treatment for psychiatric illness, denies current use of alcohol, tobacco, or illicit drugs, exhibits no abnormal movements or psychomotor changes, and her speech is articulate. Her mood is depressed, and her affect is restricted. She is not suicidal or homicidal, and her exam reveals no psychotic features.
Challenge Patients with thyroid abnormalities often present with psychiatric complaints. Classically, hypothyroidism can present like a depressive episode with similar symptoms of fatigue, anhedonia, weight gain, and sleep disturbance. Patients with hypothyroidism, however, may have physical complaints as well, which should alert the clinician to an underlying thyroid disorder. Typical physical complaints include hair loss, weight gain, dry skin, cold intolerance, constipation, muscle cramps, and joint pains. Women may also complain of menstrual disturbances such as menorrhagia, and may have trouble with fertility.
SCREENING FOR HYPOTHYROIDISM AND HYPERTHYROIDISM
An elevated or decreased TSH suggests thyroid dysfunction and should always be evaluated.
A low free T4 confirms the diagnosis of hypothyroidism. A low total T3 or free T3 is not always present but is associated with severe forms of hypothyroidism. The hallmark of hyperthyroidism is an elevated free T4 level or free T3 level or both. In a primary thyroid disorder, the TSH is below 0.1 U/L or undetectable.
Here is a description of these tests and what they mean:
- TSH (thyroid-stimulating hormone) is a pituitary hormone that acts on the thyroid gland to increase thyroid hormone secretion. Measurement of TSH is the most sensitive test to screen for hypothyroidism and hyperthyroidism as long as a second-generation assay is used (0.05 mIU/L). Thyroid testing should always begin just with the TSH test. Ordering a free T4 test at the same time is redundant and costly.
- T4 (thyroxine) is best and most accurately measured in its unbound free form. Of all the tests that measure thyroxine, free T4 most accurately reflects unbound thyroid hormone, which is physiologically active. Also, several variables (e.g. pregnancy, disease states, medications) alter total T4 levels by increasing or decreasing thyroid binding hormones. A free T4 test should always follow an abnormal TSH.
- T3 (triiodothyronine) is produced in the thyroid and in peripheral tissues via the enzymatic conversion of T4. Like T4, it is bound and unbound in the serum by thyroid binding globulin, and either form can be measured. T3 should be measured when the TSH is abnormal but the free T4 is within normal limits.
- T3 resin uptake is used to calculate indirectly free T4 and should only be ordered if a free T4 test is unavailable.
- Thyroid antibody tests can help uncover the underlying cause of thyroid dysfunction. These tests lack sensitivity and specificity and should not be used to rule out cancer. Thyroid peroxidase antibodies (antithyroglobulin) and antimicrosomal antibodies are associated with Hashimoto’s thyroiditis and Graves’ disease. Thyroid-stimulating immunoglobulin (TSI) or thyroid-stimulating hormone receptor antibodies are almost always unique to Graves’ disease.
- A radioactive iodine uptake thyroid scan (RAIU) is the best test to determine the cause of hyperthyroidism. Uptake is elevated in most common conditions causing hyperthyroidism, but the pattern of uptake differs. In the context of hyperthyroidism, absent uptake should raise a red flag for nonfunctioning nodules that can be either benign or malignant. A thyroid scan is unhelpful and should not be ordered in working up hypothyroidism.
- Thyroid ultrasound can characterize gland size and nodularity but cannot distinguish benign from malignant masses.
- Fine-needle aspiration biopsy (FNAB) is the best test to distinguish benign and malignant nodules.
What makes the diagnosis difficult and often missed is that some patients have hypothyroidism with minimal or no symptoms. This is especially true in elders because many of the signs and symptoms of hypothyroidism are attributed to “normal” aging. In one recent review of women older than 70 who were screened in an office-based setting, 2% were diagnosed with unsuspected overt hypothyroidism.1 Because classical exam and laboratory findings associated with hypothyroidism tend to present later in the disorder, many patients with thyroid dysfunction have “normal” exams.
Exam findings associated with a hypo-functioning thyroid may include an enlarged thyroid gland (goiter) or nonpalpable gland, non-pitting edema (myxedema), sinus bradycardia, decrease in body temperature, and delayed relaxation of the deep tendon reflexes. Secondary laboratory abnormalities associated with hypothyroidism include normacytic anemia and elevated lipoproteins. Without specific thyroid testing, a “normal” physical does not rule out thyroid dysfunction.
Hyperthyroidism can also manifest as a depression in elders, known as “apathetic hyperthyroidism.” Patients report decreased cognition, depression, and fatigue, and often experience unexplained weight loss, muscle weakness, or atrial fibrillation. Therefore, elderly patients presenting with depression may have a hyper- or hypo-functioning thyroid.
Case 1 concluded The treating psychiatrist diagnosed the patient with major depression. In addition to treatment with an antidepressant, the patient underwent laboratory testing, including a complete blood count, metabolic panel, and TSH (thyroid stimulating hormone). Test results were normal except for a TSH of 64 mU/L, consistent with hypothyroidism. The patient was referred to her primary care physician to begin thyroid hormone replacement.
Comment Although psychiatric symptoms may be caused by clinically important thyroid dysfunction, thyroid function testing may uncover abnormalities of questionable clinical significance. The prevalence of abnormal thyroid hormone levels in hospitalized psychiatric patients ranges from 3% to 32%.2 High thyroid levels (free T4 index and total T4) are associated with acutely psychotic patients such as those with schizophrenia, affective psychosis, and amphetamine abuses. Most studies show that these changes are transient and often normalize with correction of the psychiatric condition, usually within 10 days. Many researchers believe these findings are consistent with euthyroid sick syndrome (Box 2).3
Depressed patients and those with bipolar disorder often present with altered measures of the hypothalamic-pituitary-thyroid (HPT) axis. These abnormalities include mildly elevated or depressed T3, T4 and TSH levels and are not indicative of true thyroid dysfunction (Table 1). It has been debated whether these patients differ in prognosis from psychiatric patients without such abnormalities, although data in depressed patients suggest equivalent outcomes. 4 Furthermore, there is no clear evidence that thyroid supplementation benefits depressed patients with mildly elevated TSH with normal T4 and T3 values.5
The prevalence of thyroid disorders in the general population depends largely on the age, sex, and iodine consumption of the population studied. Women in general face a greater risk of overt thyroid dysfunction than do men, and elders face a greater risk than do the young. High dietary iodine consumption is associated with autoimmune hypothyroidism, especially in the aged. Iodine deficiency facilitates the development of hyperthyroidism secondary to toxic nodular goiter.
INTERPRETING TEST RESULTS
Normal or decreased
Euthyroid sick syndrome
Normal or decreased
Normal or decreased
Hypothalamic pituitary disorder
Normal or decreased
Hypothalamic pituitary disorder
Normal or decreased
A number of other risk factors should also clue the clinician to thyroid dysfunction (Table 2).
Case 2: Subclinical thyroid abnormalities
S.J., 34, has a history of panic disorder that has been well controlled with a selective serotonin reuptake inhibitor (SSRI). He is referred to a primary care physician for an annual physical exam. His blood pressure is elevated as it has been on several occasions over the past year. His physical exam is otherwise normal. Laboratory and ECG test results are normal, except for an elevated TSH at 12 mU/L. Follow-up free T4 and free T3 tests are within normal limits. S.J. agrees to eat less salt to address his hypertension.
Challenge An elevated or decreased TSH with a normal thyroxine level (Table 1) is referred to as a “subclinical” thyroid disorder, which is more common than overt thyroid disorders. Women and elders are at greatest risk for subclinical hypothyroidism. In patients older than 60, the rate can be as high as 17% in women and 15% in men.6 The rate largely depends on the number of patients receiving exogenous thyroid hormone—16% in populations including individuals receiving exogenous thyroid hormone and as low as 0.6-1.1% in populations without such patients.1 Chronic subclinical hypothyroidism or mild thyroid failure is the most common condition found in thyroid function screening.
WHEN TO CONSIDER THYROID DYSFUNCTION
Although patients with subclinical abnormalities appear to be symptom-free, there are clinical implications for these patients. Subclinical hyperthyroidism in the elderly increases the risk for atrial fibrillation and osteoporosis. Postmenopausal women with chronically low TSH measures have lower bone density, especially in cortical bone (e.g., the forearm and hip). Subclinical hypothyroidism is associated with lipid abnormalities and progression to overt hypothyroidism. More recently it has become apparent that this “subclinical” syndrome is not as symptom-free as once assumed, with dry skin, cold intolerance, and easy fatigability more common than in euthyroid patients.7
Case 2 concluded Three months later, repeat testing reveals a negative thyroid antibody test, a TSH elevated to 9 mU/L, and a free T4 and fasting lipid profile within normal limits. S.J. and his physician discuss the pros and cons of thyroid replacement and decide to retest his thyroid function in 6 months with a repeat TSH.
Comment Should individuals with subclinical disorders be treated? How frequently should their thyroid function tests be monitored? The answers vary greatly among clinicians.
Some experts argue that treatment improves behavioral function and decreases lipid levels. Some clinicians take a “wait and see” approach because values can normalize in approximately 10% of patients.6,8 Others treat based on presence of symptoms and risk of progression to overt thyroid failure (Table 2). If treatment is elected, only partial supplementation is usually needed. Most clinicians will start with a dose of 25 ug/d of T4 with adjustment every 6 to 8 weeks until the TSH is normalized.
Unless subclinical hyperthyroidism is secondary to over-replacement with exogenous thyroid hormone, this condtion can be more difficult to treat than subclinical hypothyroidism. Antithyroid therapy should be discussed with patients who have symptoms suggestive of hyperthyroidism, osteoporosis, recurrent atrial fibrillation, or thyroid gland nodules. Consultation with an endocrinologist can help clarify the risks and benefits and determine the specific antithyroid treatment appropriate for each patient.
Case 3: Medications and thyroid abnormalities
R.K., 56, has a long history of bipolar disorder. Upon presenting to his psychiatrist for routine follow-up, he reports a lack of energy but denies other symptoms of mania or depression. He periodically leaves work early or takes a short nap in his office to combat the fatigue. He feels that this may simply be part of “getting old.” He denies any new medical problems and has seen his family physician in the last year. He states that he has been compliant with his medications, lithium and olanzapine. He appears slightly withdrawn and blunted but otherwise there are no abnormal features.