DETANGLING CONFLICTING GUIDELINES
HYPOTHYROIDISM IN PRIMARY CARE
Hypothyroidism is a clinical disorder frequently encountered by primary care providers (PCPs).[1]The latest estimates suggest that hypothyroidism occurs in 4.6% of the US population aged 12 years or older,[2] and most of these cases can be effectively and safely managed in primary care.
US guidelines for the management of hypothyroidism by PCPs, such as those provided by the American College of Physicians (ACP)[3]and the American Academy of Family Physicians (AAFP),[4] are generally based on the specialist guidelines drawn up by such organizations as the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE). Recently, however, as reported by Medscape,[5-8] these guidelines have differed in their interpretations of the clinical evidence to date.
To try to clarify guidance for PCPs in the diagnosis and treatment of hypothyroidism, Medscape spoke with Kenneth D. Burman, MD, director of the Endocrine Section at MedStar Washington Hospital Center in Washington, DC. Dr Burman is also professor of medicine and director of the Georgetown University Hospital/Washington Hospital Center Endocrinology Fellowship Program. He is a past president of the ATA (2008-2009) and was a coauthor of the ATA’s most recent guideline on the treatment of hypothyroidism.[9]
Universal Screening for Hypothyroidism?
Opinions differ on screening for thyroid dysfunction. Hypothyroid patients can present with a variety of symptoms that are also seen in patients with normal thyroid function. In a recent study, almost 6% of overtly hypothyroid patients were free of symptoms,[10] implying that screening only symptomatic patients would miss a significant proportion of hypothyroid patients.
In 2000, the ATA recommended assessing thyroid-stimulating hormone (TSH) levels every 5 years in all adults starting at 35 years of age,[11] a position that appears to remain unchanged.[12] The AACE, which recommended routine TSH measurement in older patients (age unspecified), especially women,[13] later reported “compelling evidence” to screen in certain groups at increased risk,[14] a position supported by the ACP.[3] The AAFP has concluded that evidence is insufficient to recommend for or against routine screening for thyroid disease in adults,[4] a conclusion also recently reached by US Preventive Services Task Force (USPSTF).[15] Dr Burman agrees that this area is controversial and should be examined thoroughly using a more recent analysis.
DIAGNOSING AND IDENTIFYING THE CAUSE OF HYPOTHYROIDISM
Dr Burman agrees that PCPs can successfully diagnose most patients with hypothyroidism. “The proper context would include symptoms of lethargy, neck pain, trouble swallowing, inability to concentrate, and cold intolerance, to name a few,” he explains. “Most centers diagnose on the basis of serum TSH level with a free thyroxine (FT4) level as well. If the TSH is elevated with a FT4 that is either normal or low, then the patient should be considered for treatment.”
The symptoms are nonspecific, but the laboratory tests are very specific, he says. “Many patients will have symptoms that are consistent with hypothyroidism, but in fact do not have hypothyroidism confirmed by laboratory testing.” points out Dr Burman. “Neither a PCP nor an endocrinologist should treat a patient for hypothyroidism unless it is clear that the patient has biochemical support for that diagnosis,” he stresses. Most patients with hypothyroidism have Hashimoto thyroiditis or have had thyroid surgery, but other, more unusual causes, such as subacute thyroiditis and postpartum thyroiditis, can be more difficult to diagnose. Dr Burman advises referring these patients to an endocrinologist.
Levothyroxine Only?
In most cases, patients can be reassured that a PCP can successfully treat their hypothyroidism, Dr Burman believes. “Family practitioners and PCPs do a very nice job in treating and monitoring hypothyroidism,” he says. The drug of choice for treatment—a strong recommendation by all current guidelines—is levothyroxine, also called “L-thyroxine” (LT4), “owing to its efficacy in resolving the symptoms of hypothyroidism, long-term experience of its benefits, favorable side effect profile, ease of administration, good intestinal absorption, long serum half-life, and low cost.”[9]
Approved levothyroxine preparations are available as brand-name and generic products, which according to the US Food and Drug Administration (FDA) are bioequivalent, although this position is not supported by the AACE or the ATA.[16] It remains a controversial area, Dr Burman acknowledges. Stressing that he is expressing his personal opinion, he says that “In our practice, we would believe that the majority of times we consider them bioequivalent, but not every generic preparation has been subjected to rigorous control in comparison with other preparations. So it is possible that there are some preparations that are not totally bioequivalent, and they have not been tested for bioequivalence.”
The latest ATA treatment guidelines recommend maintaining a patient on the same identifiable formulation of levothyroxine, on the basis of concerns that “even products judged to be bioequivalent do not have therapeutic equivalence, and that switching of products could lead to perturbations in serum TSH.”[9] Dr Burman believes that these are issues that need to be explored further. “It’s difficult to know whether every generic is bioequivalent, whether brands are equivalent, or whether every brand is equivalent to every generic,” he says, adding, “The FDA indicates that it is appropriate for pharmacists in the United States to substitute different generic products, and even substitute a generic product for a brand-name product, unless ‘do not substitute’ (DNS) is specifically stated on the prescription.” Although Dr Burman would not go as far as advising physicians to write “DNS” on every prescription for levothyroxine to avoid unexpected substitutions, he acknowledges that it is a legitimate concern.
Adding liothyronine (LT3) in patients with a poor response to levothyroxine is not recommended in guidelines addressing the primary care setting; specialist guidelines also advise against doing so.[9,14] The recent ATA treatment guidelines concluded that evidence is insufficient to recommend routine use of LT3 in primary hypothyroidism, but suggested that future trials might identify subgroups who could benefit from a combination of levothyroxine and liothyronine. This has occasionally been interpreted as support for the possibility of treating patients—or for patients to self-treat—with liothyronine.[6-8] “That is a much more controversial area,” stated Dr Burman. He admitted that further research is indicated in this area.
MONITORING THE EFFECTS OF TREATMENT
Guidelines support measuring both TSH and T4levels as the best way to monitor therapy. “In terms of frequency of monitoring, a patient with hypothyroidism who is relatively stable should be monitored every 6-12 months. Depending on the circumstance, this involves blood tests for TSH and FT4, examination of the patient, and taking a good history,” Dr Burman says. “If the patient has symptoms that could be related to altered thyroid levels, blood tests and a physical exam should be done.” Although neither the AACE nor the ATA recommends routine monitoring of free or total triiodothyronine (T3), the ATA acknowledges an interest in data from preliminary human and animal research studies. “In unusual or exceptional circumstances, it is possible that T3may be useful, but if we measure T3, it is usually total T3, not free T3,” Dr Burman says.
Although the goal of treatment, in addition to alleviating symptoms, is to maintain the patient’s TSH level within the normal range, the definition of the normal reference range has been the subject of debate in past years. Dr Burman believes that the generally accepted reference range for normal serum TSH in healthy adults is now 0.40-4.2 mIU/L, as used in the National Health and Nutrition Examination Survey III.[2] (The ATA guidelines recommend a therapeutic target of 0.4-4.0 IU/L.[9])
“However, selective circumstances apply to individuals over the age of about 70 years. In older patients, the TSH level normally goes up. The normal range for this group is unknown, but it is probably 1-7 mIU/L,” Dr Burman cautions. “Controversy still revolves around what is normal in a young individual,” he adds. “Some people say it should be 0.5-2.5 mIU/L, because the TSH level is not normally distributed and most younger patients have a TSH level below 2.5 mIU/L, but we don’t consider treatment with a TSH level of 2.5 mIU/L,” he states.
There are also some patients in whom it is more difficult to monitor treatment because they have persistently low values on thyroid function tests (eg, FT4) when they are on their medication. “They may have associated celiac disease, or there may be some other factor interfering with the assay or the absorption of thyroid hormone; certainly, these patients should be considered for a consult with an endocrinologist,” Dr Burman advises.
PATIENT AWARENESS
Increased emphasis is being placed on patient thyroid awareness, with such efforts as the AACE’s thyroid awareness campaign and such publications as the ATA’s Clinical Thyroidology for the Public. Patients are being encouraged to discuss their condition and treatment with their clinicians and also with their pharmacists.[17]“Pharmacists are part of the healthcare team, and they are very knowledgeable about medications and how to take them,” Dr Burman asserts. “In general, levothyroxine should be taken alone, separated from other medications and food by approximately 2 hours. Some people take it early in the morning, and some people take it at night; it doesn’t make that much difference, as long as you are following the guidelines in terms of not interacting with any other medications you are taking. There are many medications (such as calcium) that if taken at about the same time would inhibit the absorption of levothyroxine,” he warns. Patients who are just starting on treatment should discuss this issue with their physician and pharmacist.
On the subject of self-medication, Dr Burman stresses, “Not only should PCPs and pharmacists advise patients not to try this, they should stress the side effects of changing the thyroid medication on the heart and on the bones. Thyroid hormone levels should be within the normal range; if they are not, that puts the patient at increased risk for atrial fibrillation and enhanced bone loss.” “Self-medication” refers to taking thyroid hormone when not needed, or altering the dose frequently on the basis of subjective symptoms rather than thyroid function tests.
Physician Awareness
Dr Burman cautions that “although hypothyroidism is extremely common and most of the time it is caused by Hashimoto thyroiditis, PCPs should keep in the back of their minds the fact that hypothyroidism can have other causes, such as infiltrative diseases of the thyroid; postpartum thyroiditis; silent thyroiditis; subacute thyroiditis; and, rarely, pituitary tumors. Of course, pituitary tumors would be associated with a low TSH level, but it is a little more complicated than that, because TSH in pituitary tumors as measured in an assay may include TSH that is biologically inactive (as a result of abnormal glycosylation of the TSH molecule). The patient with a pituitary tumor can have a normal TSH level because TSH is actually inactive and the T4 and T3 could be low,” he explains.
Dr Burman continues, “The major take-home message is that if someone has symptoms of a pituitary tumor, with vision abnormalities and other endocrine abnormalities that are consistent with a tumor, the PCP should consider that as a possible diagnosis. Probably even more common is the association of Hashimoto thyroiditis with adrenal disease, because adrenal insufficiency (Addison disease) occurs more frequently in patients with primary hypothyroidism. If a patient is tired and being treated with thyroid hormone, that patient may actually have adrenal insufficiency as well, or sometimes even alone. Celiac disease (sprue) also occurs at a higher frequency in patients with Hashimoto thyroiditis, so if a patient on LT4 has difficult-to-control disease, the PCP should consider that the medication may be being absorbed irregularly because of celiac disease.”