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Controversy Continues Over Treating Symptomatic People with Normal TSH Levels
A Look at Weetman's July 2002 Commentary in Clinical Endocrinology

by Mary Shomon

July 2002 -- In the July 2002 issue of Clinical Endocrinology, well-known thyroid expert A.P. Weetman tackles the question of whether or not thyroxine treatment should be used in people who are “biochemically euthyroid” (have normal TSH test values) but “clinically hypothyroid” (have thyroid symptoms.)

In a commentary, Weetman claims that he suspects the practice of thyroxine treatment in euthyroid people “is quite widespread” and he quotes the Health World Online website (www.healthy.net), which in an article titled The Diagnosis and Treatment of Hypothyroidism, by Michael Schachter M.D., F.A.C.A.M., says that:

“If a patient has a normal TSH and a normal free T4, he is told by the conventional physician that he does not have hypothyroidism, no matter how many symptoms or signs of hypothyroidism he has. This is the fatal error because these tests only pick up the most severe cases of hypothyroidism and miss virtually all of the milder cases that would respond favorably to thyroid hormone treatment.“
Weetman dismisses this idea, claiming that “we would do well to use every possible means to reassure patients that thyroid hormone replacement is not the answer to nonspecific symptoms suggestive of hypothyroidism when biochemical euthyroidism is demonstrated.”

In defense of his argument, Weetman references the recent Pollock study, which gave 100 mcg. of thyroxine every day (or placebo) for 3 months to 25 symptomatic patients and 19 controls. With a six week “washout period” of no drugs in between, the patients and controls were then switched. Cognitive, psychological and physical symptoms were measured. To qualify for the study, the 25 symptomatic patients had to have at least three symptoms from among a list that included: fatigue, lethargy, problems with excess body weight, intolerance to cold, hair loss, dry skin/hair.

According to the researchers, thyroxine had no benefit in the symptomatic people. Of particular interest was the fact that the symptomatic group responded to placebo better than controls on 3 of 15 psychological measures, versus no improvement in the control group. These findings suggest that those symptomatic patients who felt they had improvement were demonstrating a true psychological “placebo” effect.

Weetman concludes his commentary:
"For now, though, a normal TSH and free T4 rule out hypothyroidism and thyroid hormone treatment is not indicated for suggestive symptoms in such individuals.”
Beyond Weetman’s Commentary

It is certainly possible that it could be proven that thyroid hormone treatment offers no therapeutic or symptomatic benefits to people who are euthyroid. But the Pollock study is not sufficient enough to rely on as a guide in any clinical decision making. Because, while Weetman may be satisfied that a normal TSH and free T4 rule out hypothyroidism or further treatment, he has overlooked a number of obvious issues that call the study results into question, as well as a number of unresolved questions that are at the real heart of the controversy.

Dosage Size

100 mcg. of thyroxine was the standard dosage provided to all the symptomatic people in the Pollock study. A key question is how was this dosage determined? According to many thyroid experts, hypothyroidism patients require on average a dose of approximately 1 microgram per pound of body weight. 100 mcg. then, would correlate with a 100 lb. body weight. It's likely that most of the symptomatic patients had body weight far exceeding this level. Would study results have been different had the dosage been 150 mcg? How was this particular dosage determined, and how do the results at this dosage somehow preclude that another dosage -- perhaps a smaller or larger dose -- might not have different results?

T3 Levels and Drug Used

The February 11, 1999 issue of the New England Journal of Medicine reported on the results of research that found that “treatment with thyroxine plus triiodothyronine improved the quality of life for most [hypothyroid] patients.” Since T3 levels were not considered in the Pollock study, nor was any T3 drug given, it’s conceivable that some of the patients might have had hypothyroidism symptoms that represented insufficient T3 (cellular hypothyroidism), or some dysfunction in the process of conversion from T4 to T3 (thyroid resistance). Without testing of T3 levels, there is no way to know if these patients had low or out of range T3 levels. And without provision of T3, it’s impossible to know if that would have resolved symptoms more than thyroxine alone.

Study Length

It can take a long time to become hypothyroid, and get properly diagnosed, and as most thyroid patients know, it can take an equally long time to see any notable improvements in symptoms. After a diagnosis of hypothyroidism, treatment begins, and many patients find that blood levels return to normal, making them "euthyroid," weeks or months before symptoms resolve. So patients may be biochemically euthyroid, but it can be many months before any noticeable improvement in symptoms is felt.

One endocrinologist regularly counsels her patients to wait at least four months after achieving euthyroidism before exploring additional options, supplemental or alternative drugs, or dosage changes to deal with their unresolved symptoms.

Given that information, how was it determined that three months is a sufficient time in which to assess response– or lack thereof – to thyroxine in the symptomatic patients? This length of time seems utterly inadequate if even one endocrinologist will decide to make important diagnostic decisions based on the findings of this research.

Weetman admits that some effects of the thyroxine may have been missed during the study, but since no “trends” were observed, he is satisfied that there is no benefit to treating euthyroid but symptomatic people with thyroxine. It’s not clear how a definite “trend” could be identified in such a short amount of time.

Study Size

In his commentary, Weetman asks whether there are any problems with the study, then proceeds to identify one concern that would typically be raised by most researchers -- the study’s very small size – then summarily dismisses that concern, claiming that the small size was a function of limited resources.

Compounded with the issue of a short duration, the extremely small size of this study calls the results of the study even further into question. With an estimated 10 million+ people in the U.S. alone estimated to be hypothyroid, and many more subclinically, or with high-normal TSH levels and antibodies, a study of sufficient size would seem to be essential before anyone makes important clinical decisions about how and when to treat patients.

What is a “Normal” TSH Level?

In the United States, most laboratories have as the normal TSH reference range from approximately 0.5 to 5.5. Yet, in early 2001, the American Association of Clinical Endocrinologists (AACE) made what constituted a fairly dramatic reversal of its previous doctrine, stating that a "Even though a TSH level between 3.0 and 5.0 uU/ml is in the normal range, it should be considered suspect since it may signal a case of evolving thyroid underactivity."

A groundbreaking study published in the February 2002 issue of the Journal of Clinical Endocrinology and Metabolism examined levels of undiagnosed thyroid disease in different U.S. populations between 1988 and 1994. In addition to discovering that nearly five percent of Americans suffer from often undiagnosed thyroid disease, the Centers for Disease Control and Prevention (CDC) report on the National Health and Nutritional Survey (NHANES) found that among the disease-free population (those who did not have any presence of thyroid antibodies, or diagnosed thyroid disease), the mean TSH level was 1.5. This finding could bolster the assertions of some practitioners and many patients that the optimal TSH levels are between 1 and 2, and that levels above that may in fact represent an abnormality. It certainly points up the need to reconsider the basis for most U.S. labs measuring hypothyroidism as only at levels of approximately 5.0 and above.

And reporting in the Journal of Clinical Endocrinology & Metabolism earlier in 2002, Danish researchers summarized an interesting study that looked at the monthly thyroid levels -- T4, T3, free T4 index, and TSH -- of 16 healthy men with over a period of 12 months. What they found was that each of the individuals had different variations of their thyroid function, around unique levels - or “set points.” Each person had his own individual thyroid function and normal level, and people tended to fluctute slightly within their own range. These findings led the researchers to conclude that a thyroid test result within a laboratory’s reference limits - or “normal range” -- is not necessarily normal for a particular individual. In fact, the researchers also concluded that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T4 and/or T3) is somewhat arbitrary, because the patient’s normal set point for T4 and T3 within the laboratory reference range is actually illustrative and needs to be taken into account.

Weetman himself appears to have overlooked his own study of the subject of TSH levels, which appeared in the 19 April 1997 issue of the British Medical Journal, in which he said:
". . . even within the reference range of around 0.5-4.5 mU/l, a high thyroid stimulating hormone concentration (>2 mU/l) was associated with an increased risk of future hypothyroidism. The simplest explanation is that thyroid disease is so common that many people predisposed to thyroid failure are included in a laboratory's reference population, which raises the question whether thyroxine replacement is adequate in patients with thyroid stimulating hormone levels above 2 mU/l."
With agreement as to what a normal TSH level is so ambiguous at present, it is imprudent to declare that patients can be ruled out for treatment on the basis of “a normal TSH,” when there are serious questions as to what constitutes a normal TSH level. It's clear that this is a topic that urgently needs further research.

The Role of Antibodies

Simply testing TSH and T4 levels is not enough to accurately diagnose a thyroid problem. If relying on blood tests for diagnostic purposes, to fully assess whether or not someone should receive thyroid treatment, complete testing for thyroid antibodies should also be performed.

In the March, 2001 issue of the journal Thyroid, German researchers reported that use of levothyroxine treatment for cases of Hashimoto's autoimmune thyroiditis where TSH had not yet elevated ("euthyroid") beyond normal range could reduce the incidence and degree of autoimmune disease progression. In the study of 21 patients with euthyroid Hashimoto's Thyroiditis, who had normal range TSH, but elevated antibody levels, half of the patients were treated with levothyroxine for a year, the other half were not treated. After 1 year of therapy with levothyroxine, the antibody levels and lymphocytes (evidence of inflammation) decreased significantly only in the group receiving the medication. Among the untreated group, the antibody levels rose or remained the same. The researchers concluded that preventative treatment of normal TSH range patients with Hashimoto's disease reduced the various markers of autoimmune thyroiditis, and speculated that that such treatment might even be able to stop the progression of Hashimoto's disease, or perhaps even prevent development of the hypothyroidism.

It’s not clear why Weetman would choose to entirely overlook the issue of antibodies, their role in thyroid health, and the use of antibody testing as part of the decision-making process for treatment with thyroid hormone. But this oversight is a major one, one that ignores some of the most cutting-edge research into the autoimmune process and its role in hypothyroidism, and continues to call his conclusions into serious question.

Into the Future

If even Weetman himself, a bastion of conventional endocrinology like AACE, and other researchers are all claiming that levels above 2 or 3 may in fact represent people with evolving thyroid problems, and that the normal TSH level of someone without any thyroid disease is under 2, and it’s acknowledged that the current reference population may in fact be invalid in the first place, then it's premature to make categorical pronouncements about treating or not treating people with a "normal" TSH.

If Weetman believes that the use of blood testing is in fact the gold-standard, then he would be doing a service to thyroid patients and the practice of endocrinology to call for a complete re-evaluation of the reference ranges for normal TSH levels, so that the numbers he and his colleagues wish to rely so heavily on are in fact valid. Given the research, he should also be advocating the inclusion of antibodies tests as part of any standard thyroid panel to uncover thyroid disease and hypothyroidism.

All in all, while Weetman offers his opinions in his Commentary, it's important to remind readers that they are just that -- opinions, and should not guide the diagnostic technique or practice of physicians.

Because ultimately, the validity of research on the fundamental way hypothyroidism is treated rests on an outdated TSH reference range that calls out for a complete re-evaluation and revamping. This re-evaluation of the TSH reference range is the first priority among many much-needed and essential reforms to conventional thyroid doctrine and practice.



Sources:

Bunevicius, Robertas M.D. et. al. "Effects of Thyroxine as Compared with Thyroxine plus Triiodothyronine in Patients with Hypothyroidism," New England Journal of Medicine, Volume 340:424-429 February 11, 1999 Number 6 http://content.nejm.org/cgi/content/short/340/6/424

“Narrow Individual Variations in Serum T4 and T3 in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease,” The Journal of Clinical Endocrinology & Metabolism, Vol. 87, No. 3 1068-1072, 2002.

Pollock, M.A., Sturrock, A., Marshall, K., Davidson, K.M., Kelly, C.J.G., McMahon, A.D. & McLaren, E.H. (2001), "Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range; randomised double blind placebo controlled crossover trial." British Medical Journal , 323, 891-895.
See Medline reference
Read full article in British Medical Journal

Schachter, Michael, M.D., F.A.C.A.M. “The Diagnosis and Treatment of Hypothyroidism,” HealthyNet
Read article online

"Serum TSH, T4, and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III)," "A Population-Based Study on the Frequency of Additional Congenital Malformations in Infants with Congenital Hypothyroidism: Data from the Italian Registry for Congenital Hypothyroidism (1991-1998)" Journal of Clinical Endocrinology and Metabolism, February 2002

"One-year prophylactic treatment of euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benefit?" Thyroid, 2001 Mar;11(3):249-55

Weetman, A.P. "Fortnightly review: Hypothyroidism: screening and subclinical disease," British Medical Journal, 1997;314:1175 (April 1997)
Read article online

Weetman, A.P., “Thyroxine treatment in biochemically euthyroid but clinically hypothyroid individuals,” Clinical Endocrinology, Volume 57 Issue 1 Page 25 - July 2002



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