Hypothyroidism and associated symptoms—lethargy, weight gain, sensitivity to cold, constipation, and dry skin—are common, especially in women. While thyroxine (T4), often taken for many years, effectively treats most hypothyroid patients, up to 20% still report symptoms even after T4 has brought their thyroid-stimulating hormone (TSH) concentration within reference ranges. Outside the U.S., more clinicians are prescribing liothyronine (T3) in combination with the usual T4, but the strategy remains controversial in this country. However, interest in and use of combination T3-T4 therapy is growing.

Meanwhile, some clinicians and laboratorians contend that current free T4 and free T3 immunoassays are unsuitable for measuring these analytes, arguing that these commonly used tests sometimes can be inaccurate, thereby contributing to continued suffering among millions of patients. “Immunoassays are precise, but they give you precisely the wrong results [for free T4 and free T3],” said Steven Soldin, PhD, senior scientist in the Department of Laboratory Medicine at the National Institutes of Health. He holds two patents related to measurement of thyroid hormones by mass spectrometry and advocates wider use of this method and combination therapy for hypothyroid patients who continue to feel unwell on T4 monotherapy.

Guideline Recommendations

The American Thyroid Association (ATA), the European Thyroid Association (ETA), and the American Association for Clinical Endocrinology (AACE) recommend T4 as first-line therapy for hypothyroid patients, noting the lack of randomized clinical trial data on both the efficacy and safety of combination therapy, and formulations of T3 that mirror natural physiology. However, the guidelines all say combination therapy might be indicated in hypothyroid patients without comorbid conditions who report no relief from T4.

If they hold out the possibility of combination T3-T4 therapy in certain circumstances, the guidelines differ on the specifics. ETA says trials for individual patients should be conducted under specialist supervision, preferably with evaluations of response with standardized quality-of-life tools. ATA goes a step further by recommending that individual patient trials be subject to formal ethical and governance approvals like larger clinical trials. The British Thyroid Association (BTA) concurs that combination therapy should not be used routinely, but states that if a trial is offered to patients who haven’t benefited from T4 therapy, the decision to move forward should be made after “an open and balanced discussion of the uncertain benefits, likely risks of over-replacement, and lack of long-term safety data.” The BTA goes on to caution that many clinicians don’t agree with this approach, and their “clinical judgement must be recognized as being valid given the current understanding of the science and evidence of the treatments” (Clin Endocrinol 2016;84:799–808).

Meanwhile, the Italian Thyroid Association’s (ITA) 2016 consensus statement also calls combination therapy “experimental,” but gives more specifics on how and to whom it should be given. ITA wants T3-T4 therapy limited to non-pregnant, overtly hypothyroid adults, and lists specific contraindications. ITA also recommends measuring T3 in the morning before daily administration and suggests assessing cardiac and osteoporosis markers during long-term combination therapy (Endocrinol Invest 2016; doi:10.1007/s40618-016-0511-z).

The Downsides of T3 Therapy

The guidelines’ caution about combination therapy reflects clinicians’ worries that high blood T3 concentration can cause rapid and irregular heartbeat and decreased bone density, particularly in older individuals and women already at risk of osteoporosis, explained Jacqueline Jonklaas, MD, PhD, MPH, first author of the ATA guidelines and an associate professor of endocrinology at Georgetown University Medical Center in Washington, D.C. T3 overtreatment also can cause behavioral issues, infertility, weight loss, and diarrhea, added William Winter, MD, a professor of pathology and pediatrics at University of Florida College of Medicine in Gainesville.

Without a slow-release L-T3 formulation added to once-daily T4 administration available in the U.S., patients have to take T3 3 times per day in order to maintain constant blood levels. This schedule means T3 “is not really a viable medication for people who might potentially take it for the rest of their lives,” Jonklaas noted.

T3 Measurement Issues

Free T3 testing issues compound the debate over combination therapy. While Soldin and some others prefer mass spectrometry, immunoassay is cheaper and far more common. However, immunoassay may overestimate T3 values at high and especially low concentrations that spur treatment decisions (Eur J Endocrinol 2016;175:R1–9).

A recent editorial by endocrinologists Leonard Wartofsky, MD, and Leonidas Duntas, MD, maintains that inadequate thyroid hormone monitoring tends to justify the ETA/ATA contention that combination therapy should remain an experimental approach. Unconvincing studies have had variable ratios of T4 to T3 relative to the normal molar ratio secreted by the intact thyroid gland, the editorial adds (Metabolism 2016;65:428–31).

Studies by Soldin point to immunoassay shortcomings. In one, 45% of samples deemed within reference range by immunoassay tested low by mass spectrometry. In another, false normal results occurred in 50% of T3 samples tested by immunoassay and in 65% of T4 tests (Clin Biochem 2016;49:846–9 and Clin Chim Acta 2014;430:121–4).

Soldin placed partial blame for this situation on the Food and Drug Administration’s (FDA) approval of immunoassay platforms without requiring evidence that results generated by T3 and T4 immunoassays are in line with TSH concentrations or patients’ clinical condition. The mismatch between lab results and symptoms likely stems from TSH’s inability to indicate whether T3 concentration is adequate, he said. “T4 is a prehormone and has poor affinity for its nuclear receptor. When given therapeutically in treatment of hypothyroidism, it normalizes the previously elevated TSH. In contrast, T3 is the active hormone and is mostly below the 2.5th percentile when measured by mass spectrometry in the approximately 20 percent of patients still manifesting symptoms of hypothyroidism after being treated by T4 monotherapy,” Soldin explained.

A recent review paper by Soldin notes that it is possible to have TSH within the normal reference range while simultaneously having insufficient T3 in tissue. Additionally, immunoassays for free T4 are affected by serum binding proteins that can be disrupted by pregnancy, cardiac surgery, common illnesses like kidney disease, and frequently taken medications including heparin, furosemide, salicylates, and anti-epileptic drugs.

“We have been telling FDA and manufacturers for a decade-and-a-half that . . . free T4 needs to be measured after removal of the binding proteins and that is not what the latter are doing,” Soldin added. Until immunoassays are improved, mass spectrometry provides much more accurate measurement at lower concentrations because it better detects hormones found at important high and very low concentrations, he maintained.

Jonklaas agreed that mass spectrometry is a better assay in general as it is not subject to some of the artifacts that affect immunoassays. Winter, however, would like to see more data. Before millions of women have their therapy changed, he called for multicenter, randomized, controlled trials to confirm Soldin’s finding that immunoassays are not robust for low levels of T3.

The Genetic Connection

Genetic variations may also drive T4 monotherapy’s failure to bring relief to some hypothyroid patients. At least one polymorphism in D2, a gene which codes for a deiodinase enzyme that helps maintain the euthyroid state, has been associated with reduced T4 to T3 activation in skeletal muscle and thyroid, obesity, alterations in thyroid-pituitary feedback, and responses to thyroid hormone treatment, notes a review article by Wartofsky (Curr Opin Endocrinol Diabetes Obes 2013;20:460–6). A higher than normal free L-T4/free L-T3 ratio may suggest a patient has the polymorphism, Wartofsky noted.

While some physicians advocate combination T3-T4 therapy for certain hypothyroid patients, Winter said that such a strategy can be complicated. One reason is that TSH values within reference intervals do not indicate absence of disease. Rather, they show how a patient compares to others believed to be without disease. Patient reports of symptoms are subjective, so “you can’t make a one-to-one correlation between test results and clinical findings,” he explained.

Winter does not entirely dismiss T3 testing and combination therapy, however. “If T3 were to be used therapeutically in patients with TSH and free T4 levels within the reference intervals who continue to be symptomatic of hypothyroidism, adding a small dose of L-T3 and titrating it up to see if the patient improves, while monitoring his or her thyroid function, might be reasonable,” he suggested.

Jonklaas also said that combination therapy might be a practical option for symptomatic patients with free T4 and TSH within reference intervals, but only after ruling out other conditions, informing patients of risks, and under close monitoring. Still, she added that combination therapy is a very long way from becoming a first-line treatment. “We don’t know about the effects after five or ten years,” she explained, noting that the longest study of combination therapy only lasted 12 months, with most lasting just 12 weeks.

“We have so much to try and understand about what is causing patients to have symptoms despite a normal TSH,” she emphasized.

Deborah Levenson is a freelance writer based in College Park, Maryland. +Email: [email protected]