April 23, 2015Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.
I want to talk with you today about the vexing question of whether to routinely screen asymptomatic nonpregnant women for thyroid dysfunction, and if subclinical hypo- or hyperthyroidism is found, whether to routinely treat these conditions. This is a controversial issue. Moreover, given how common these conditions are, we have surprisingly little clear guidance from randomized clinical trials and other research studies to balance the benefits and risks.
The US Preventive Services Task Force (USPSTF) recently released its updated guidelines on this subject, published in March 2015 in Annals of Internal Medicine. They concluded that there is insufficient evidence to advise for or against routine screening. This is based largely on the absence of clear guidance from randomized clinical trials as to the balance of benefits and risks of treatment of subclinical or preclinical disease. I want to mention, however, that other professional societies do recommend either routine screening for thyroid dysfunction or else a screening of high-risk subgroups.
The American Thyroid Association (ATA) recommends routine screening beginning at age 35 and then every 5 years. The American Association of Clinical Endocrinologists (AACE) recommends[2,3] an aggressive case-finding approach with screening of several high-risk groups. These groups include:
Finally, the ATA and AACE emphasize the importance of continued screening of newborns for congenital hypothyroidism, which seems very reasonable.
Overall, I believe that an aggressive case-finding approach and targeting high-risk groups for thyroid dysfunction screening is reasonable. I believe that it is tremendously important to conduct randomized clinical trials and additional research to answer these questions and clarify the balance of benefits and risks of routine screening or screening high-risk groups for thyroid disease, and whether it is advisable to treat subclinical or preclinical hypo- or hyperthyroidism.
Hopefully, 10 years from now, or whenever the next USPSTF guidelines are released, we will have moved beyond the “insufficient evidence” conclusion and will be given clear guidance from the USPSTF as well.
Thank you so much for your attention. This is JoAnn Manson.
March 04, 2015
Hypothyroidism is a clinical disorder frequently encountered by primary care providers (PCPs). The latest estimates suggest that hypothyroidism occurs in 4.6% of the US population aged 12 years or older, 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) and the American Academy of Family Physicians (AAFP), 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.
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, 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, a position that appears to remain unchanged. The AACE, which recommended routine TSH measurement in older patients (age unspecified), especially women, later reported “compelling evidence” to screen in certain groups at increased risk, a position supported by the ACP. The AAFP has concluded that evidence is insufficient to recommend for or against routine screening for thyroid disease in adults, a conclusion also recently reached by US Preventive Services Task Force (USPSTF). Dr Burman agrees that this area is controversial and should be examined thoroughly using a more recent analysis.
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.
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.”
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. 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.” 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.
Guidelines support measuring both TSH and T4 levels 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 T3 may 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. (The ATA guidelines recommend a therapeutic target of 0.4-4.0 IU/L.)
“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.
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. “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.
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.”
December 18, 2014
“To T3 or not to T3?” That was the question posed in the title of a talk at the 2014 Annual Meeting of the American Thyroid Association addressing the group’s new hypothyroidism guidelines and one of their key controversial issues — combination therapy.
The conclusion — that evidence is still insufficient to choose ‘to T3’ — specifically, to routinely combine triiodothyronine (L-T3) with synthetic thyroxine and levothyroxine (L-T4) in the treatment of hypothyroidism — was not, in the minds of some, the nobler of choices, and the ATA subsequently found itself the target of more than a few slings and arrows.
The use of combination therapy is clearly a very emotive issue.
“The use of combination therapy is clearly a very emotive issue,” said presenter Jacqueline Jonklaas, MD (Georgetown University Medical Center, Washington, DC), head of the ATA task force on the new hypothyroidism guidelines, underscoring her point with a sampling of postings on the ATA’s Facebook page following the recommendation: some calling the decision “shameful,” others accusing the ATA of being in the pockets of the pharmaceutical industry, and at least one battle cry for a class-action lawsuit.
Dr Jonklaas noted that even some of the guidelines’ own reviewers questioned the decision. She shared a couple of their comments, including: “I do not understand why the authors would not recommend a therapeutic trial of low-dose T3, even though the benefits may be unproven,” and “I (personally) think that not mentioning a therapeutic trial with low doses of T3 is unnecessarily rigid, if these guidelines are for practicing physicians.”
In a stance seen as somewhat bolder than the ATA, the European Thyroid Association (ETA) has specifically addressed combination therapy in guidance published in 2012 (Eur Thyroid J. 2012;1:55–71) , which opened the door for L-T4 and L-T3 combination therapy “as an experimental treatment modality” for hypothyroidism in compliant L-T4–treated hypothyroid patients who have persistent complaints despite serum thyroid-stimulating-hormone (TSH) values within the reference range.
Guidelines Recommend Only Against “Routine” Use of Combo
But among the most important phrases in the new ATA guidelines that should be underscored — loud and clear — is that they “recommend only against the routine use of combination therapy,” said ATA president elect Antonio C Bianco, MD, PhD (chief, division of endocrinology and metabolism; executive vice chair, department of internal medicine, Rush University Medical Center, Chicago, Illinois), who cochaired the hypothyroidism task force along with Dr Jonklaas.
“At the same time, there are multiple instances in which combination therapy is supported,” he told Medscape Medical News.
Those instances include when patients’ serum TSH levels are normal but they are still symptomatic — which is when most clinicians are likely to consider the option.
In such cases, “acknowledgment of the patients’ symptoms and evaluation for alternative causes is recommended,” the guidelines state.
With L-T4 monotherapy effective in treating approximately 80% to 90% of hypothyroid patients, however, the recommendation that monotherapy should stand as the routine treatment in primary hypothyroidism is reasonable, Dr Bianco stressed.
Dr Jonklaas agrees and defended the stance taken by the 11-member task force, explaining that evidence is weak regarding combination therapy: few studies have directly compared the two regimens of combination and monotherapy, and the 13 combination-therapy trials that were evaluated had too many inconsistencies to collectively provide the kind of conclusive support needed for a recommendation for routine use.
“The studies included diverse causes of hypothyroidism, different dosing recommendations, different outcomes measures, and different durations of treatment,” she explained.
Some studies also had flaws such as nonvalidated outcome measures, and the studies did not address the important concern of overtreatment when L-T3 is combined with L-T4.
“We don’t have a good sense of how many people are over- or undertreated in these combination-therapy regimens,” Dr Jonklaas said. “We also do know there were some reports of side effects and concern about cardiac arrhythmia, with one report of atrial fibrillation.”
“All of these are reasons arguing against ‘just giving people L-T3.’ ”
Dr Bianco concurs: “Given that this is a lifelong therapy, ideally we would like to know that this is safe [and] that it [will not harm] patients in 10, 20, or 30 years before we make the recommendation that all patients can routinely use combination therapy. In contrast, safety data do exist for L-T4 tablets.”
The take-home message, Dr Jonklaas told Medscape Medical News, is that “levothyroxine remains the best therapy that we have for patients with hypothyroidism; however, we should not be complacent, as we want 100% of our patients to feel well.”
“We definitely need more research. We should try to design better studies that examine benefits and risks in both male and female patients of all ages and that examine these benefits and risks over longer periods of treatment.”
Could Genetic Variation Play a Role in Response to Therapy?
One theory as to why some patients may indeed continue to experience hypothyroid symptoms such as fatigue, weight gain, and “brain fog” despite achieving normal TSH levels with L-T4 monotherapy was recently proposed with the discovery of common variations in the deiodinase 2 (DIO2) gene (J Clin Endocrinol Metab. 2009;94:1623-1629). The latter was found to be associated with reduced ability to convert T4 to T3, potentially leading to a lack of response to monotherapy with T4.
According to Leonard Wartofsky, MD (Georgetown University School of Medicine, Washington Hospital Center, Washington, DC), this information could make a big difference in improving hypothyroidism treatment.
“Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a DIO2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage-achieving low-normal serum thyroid-stimulating-hormone levels,” he wrote in an editorial last year (Curr Opin Endocrinol Diabetes Obes. 2013;20:460-466).
One place to look for such evidence could be in patients’ free T4 and free T3 levels, he added. “A…clue to the presence of this polymorphism could be a higher-than-normal free-T4/free-T3 ratio.”
Dr Wartofsky told Medscape Medical News that while he recognized the ATA’s need to make the recommendation it did on combination therapy, he personally leans more toward the ETA guidelines, which allow greater experimentation.
I think that the ATA guidelines’ recommendation regarding combination therapy is appropriately cautious.
“I think that the ATA guidelines’ recommendation regarding combination therapy is appropriately cautious,” given the available data on this, said Dr Wartofsky. “But because the data from studies ostensibly showing no benefit of combination therapy may be viewed as flawed, I personally consider the ETA guidelines on this particular issue to be both more reasonable and patient-centered.”
The ATA task force did address the genetic data in its guidelines, agreeing that controlled confirmatory studies are needed.
But the task force noted that genetic testing for the specific deiodinase polymorphisms is currently available only in a research setting, and it added that there is likely much more to the picture than is realized.
“The small effect of the type 2 deiodinase gene variants identified so far that do affect thyroid-hormone concentrations suggests that other factors (eg, yet-unidentified genetic variants) may play a far greater role in determining an individual patient’s thyroid-hormone concentrations,” the task force noted.
Meanwhile, Desiccated Thyroid Lives On
While the debate among clinicians continues over combined therapy, online posting and blogs from patients and patient advocates show a continued interest in treatment with desiccated-thyroid extracts, despite their being generally considered obsolete since the introduction of synthetic formulations during the early 1960s.
Containing a combination of T4 and T3, desiccated thyroid, made from porcine thyroid and also referred to as natural desiccated thyroid, is currently available under such brand names as Armour (Forest Laboratories) or Naturethroid (RLC Labs).
Long the first-line treatment for hypothyroidism, the treatment still represents, for some, the ideal combination therapy.
“I suggest Armour to patients because it’s economical and it’s simple,” said Gary Pepper, MD (Palm Beach Diabetes and Endocrinology Specialists, Jupiter, Florida), a strong proponent of the use of desiccated thyroid.
I suggest Armour to patients because it’s economical and it’s simple.
“One problem with combination therapy [with synthetic T4 and T3] is that people find it to be very hard to take three pills a day, and you only have to take one Armour,” he told Medscape Medical News.
“Furthermore, the synthetic T3 is very expensive, so I’m really looking at it from a more practical point of view.”
In a study he published this year, Dr Pepper described satisfaction ratings among 154 of his own patients who were still symptomatic while on L-T4 for hypothyroidism and who were switched to Armour (J Endocrinol Diabetes Obes. 2014;2:1055).
After a minimum of 4 weeks on Armour, 78% expressed a preference for Armour compared with L-T4, with no serious adverse events noted, even with 30 of the subjects aged 65 years or older.
“The key is, if you pinpoint the subgroup of patients who still have symptoms while taking T4 in your research, you get a more accurate picture of efficacy,” Dr Pepper explained.
The only randomized, double-blind trial to compare desiccated thyroid with L-T4 therapy for hypothyroidism, a crossover study published last year, showed that about half of patients preferred the desiccated-thyroid therapy (J Clin Endocrinol Metab. 2013;98:1982-1990).
The study involved 70 patients, aged 18 to 65, who were treated for 16 weeks with either desiccated-thyroid extract or L-T4 and then crossed over for the same duration.
Patients treated with desiccated thyroid had an average weight loss of 3 lb, and there was no difference in thyroid-function blood tests between the two groups after treatment.
In terms of patient satisfaction, 48% of patients expressed preference for the desiccated-thyroid extract over L-T4.
“It was interesting to find out that nearly half of the study patients preferred desiccated-thyroid extract over L-T4 therapy, and desiccated-thyroid extract caused modest weight loss,” lead author Thanh D Hoang, DO (Naval Medical Center, San Diego, California) told Medscape Medical News.
“No study patient experienced significant adverse effects from desiccated-thyroid extract or L-T4; therefore, desiccated-thyroid–extract therapy can be considered for some hypothyroid patients who do not do well with L-T4,” he noted.
This study is important in light of the fact that patients clearly are continuing to look for alternative therapies and are turning to desiccated thyroid, and it is not clear whether studies comparing synthetic T4 and synthetic T4/T3 combination “can be extrapolated to desiccated thyroid,” he added.
“Therefore, it is imperative to further investigate the effects and efficacy of desiccated thyroid in hypothyroid patients.”
ATA Task Force: More Evidence Needed for Desiccated Thyroid
The ATA guidelines acknowledge Dr Hoang’s study on desiccated thyroid and have removed a recommendation that products such as Armour “should not be used.”
But they still “strongly recommend” levothyroxine over the use of desiccated-thyroid extracts in the routine care of primary hypothyroidism.
“Although there is preliminary evidence from a short-duration study that some patients may prefer treatment using thyroid extracts, high-quality controlled long-term outcome data are lacking to document superiority of this treatment [over] levothyroxine therapy.”
And desiccated-thyroid formulations present two key safety concerns, the guidelines assert — the first being that their ratio of T4 to T3 is 4.2 to 1, significantly lower than the 14:1 ratio the human thyroid normally secretes.
“This relative excess of T3 leads to supraphysiologic levels of T3,” the guidelines state.
In addition, a shorter half-life of T3 results in peak levels after dosing followed by fluctuations throughout the day, thereby posing a risk for thyrotoxicosis if the therapy isn’t adjusted to serum TSH levels.
Dr Pepper, who regularly treats patients with Armour — but underscored that he has no relationship with the makers — responded that the T4:T3 ratio is not as fixed a ratio as the guidelines suggest.
“It’s important to remember that the ratio is just an average, and anyone who has done research on this knows that the ratio doesn’t apply to everyone,” he said. “There are some, particularly patients who don’t create T3 as well, who don’t fit into those margins, so the argument is extremely weak.
“Furthermore, we are specialists, after all,” he added. “You monitor the patient’s blood levels and adjust the dose as is appropriate.”
The same applies to the risk for thyrotoxicosis, Dr Pepper said.
“Regarding the theory that it could be dangerous — where are the case reports of people getting sick? You will not find a single scientific paper stating any real danger from desiccated thyroid, and as far as I’m concerned, the [medical societies] are scaring people away from this.”
“I have patients who are 60 and 70 years old who are taking this medication, and I can tell you they are delighted with it.”
ATA President Elect: Thyroid Community Voices Should Be Heard
Whether the topic is desiccated thyroid, combination therapy, or the host of other hypothyroid issues raised by the often-outspoken online thyroid community, the opinions deserve recognition, Dr Bianco stressed.
[Some] patients are very vocal about this, and I can only sympathize with them. They are symptomatic, sometimes depressed, and actively seeking a way to improve quality of life.
“I agree that (some) patients are very vocal about this, and I can only sympathize with them,” he said. “They are symptomatic, sometimes depressed, and actively seeking a way to improve quality of life.”
“Physicians, professional societies, and pharmaceutical companies should listen and help.”
Dr Jonklaas noted that she and coinvestigator Kenneth D Burman, MD, have conducted a study of a T3 product funded by IPE; however, the study was designed only to look at blood levels of T3, and the product was not discussed in the guidelines. Dr Bianco is director of a research laboratory at Rush University Medical Center funded exclusively by the National Institutes of Health and the ATA to study thyroid-hormone metabolism and action. He is on a board of scientific counselors of the National Institute of Diabetes and Digestive and Kidney Diseases and from 2013 to 2014 he was on the scientific board for Fondazione Institut Biochimique for scientific research. Dr Wartofsky is the editor in chief of the Journal of Clinical Endocrinology & Metabolism. He is a consultant for Asurogen, Genzyme, and IBSA and is on the speaker’s bureau for Genzyme. Dr Pepper and Dr Hoang report they have no relevant financial relationships.