June 2004
Update on the Management of Hypothyroidism
Irwin Klein, MD

Dr. Klein serves on the editorial boards of several endocrine journals and is the author of more than 150 original articles, editorials, and book chapters. Dr. Klein’s clinical and basic science research interest is thyroid hormone action on the heart. Dr. Klein is a consultant for King PharmaceuticalsTM, Inc.

Introduction We have developed this supplement to clarify various issues relating to the treatment of hypothyroidism in light of new developments and the recent Food and Drug Administration (FDA) regulations regarding levothyroxine sodium products.1 I am certain that most of you are currently managing a number of patients with thyroid dysfunction and will likely be identifying more cases of hypothyroidism in the near future. Therefore, I will also discuss current management choices related to thyroid disease and risk factors for comorbid conditions, presenting four key points you should find useful in managing your patients with hypothyroidism.

Epidemiology Hypothyroidism, or underproduction of human thyroid hormone, has a significant impact on health care today, both in terms of the prevalence of the disorder and in the complications and management challenges it presents. The prevalence of hypothyroidism is markedly higher for women than for men; however, as the incidence increases with age, the difference is less obvious.2 Current data indicate that 3-4% of the adult American population has overt hypothyroidism, as defined by a thyroid-stimulating hormone (TSH) level above 15 mU/L and a low thyroxine or T4 level. These individuals usually present with the typical symptoms that clearly suggest hypothyroidism (Table I), and so you would normally order the confirming diagnostic tests. There is no disagreement among physicians and specialists that this population needs to be treated. The standard of therapy is replacement of the deficiency with synthetic levothyroxine sodium.3

However, there has been considerable debate over the necessity for treatment of subclinical hypothyroidism, commonly referred to as mild hypothyroidism. I am referring to those patients with a TSH above the upper limit of normal, yet less than the standard 12-15 mU/L that is considered overt hypothyroidism, and with a free T4 level in the normal range. This condition affects some 10-12% of adults, with perhaps three times as many patients having subclinical rather than overt disease. That translates to 3-4 million Americans who may have mild hypothyroidism and remain undiagnosed.4 Before continuing the discussion of the subclinical population, I will review the current standards for diagnosing hypothyroidism; it is pertinent at this point to review the symptoms with which patients present (Table I).

Diagnosis The American Thyroid Association guidelines for detection of thyroid dysfunction state that serum TSH assay is the single best screening test for both hypothyroidism and hyperthyroidism.5 Prior to the late 1980s, the TSH assay was limited in sensitivity and therefore used primarily to detect hypothyroidism. The third generation of TSH assay available today is proven to be sufficiently sensitive and specific to diagnose thyroid disease in essentially every case.6 For initial diagnosis, many physicians and specialists choose to order additional assays, such as T4 and T3 levels. Because it yields high levels of accuracy, the TSH assay is also the standard test for regular monitoring of patients.

Often, we repeat diagnostic tests because we are not certain of the accuracy of the result, so you may be wondering just how reliable an individual TSH may be. In a study of 15 males with euthyroidism, monthly TSH testing over a 1-year period shows a high degree of consistency.7 The study further demonstrates that the hormone concentration for individual patients is maintained within relatively narrow limits, and therefore, a single TSH test is both sensitive and sufficient to establish a diagnosis.

As data accumulate, it becomes apparent that the TSH reference ranges we have previously considered to be normal may need to be re-evaluated and refined. The National Health and Nutrition Examination Surveys (NHANES) were designed to establish normal estimates of health and nutritional status in the noninstitutionalized U.S. population. Using data from the NHANES III survey, we can more precisely define the TSH range that accurately depicts a normal functioning thyroid.2

The survey, conducted from 1988 to 1994, established a TSH normal range of 0.33-5.8 mU/L for a representative total population of 17,353 individuals ≥ 12 years of age.2

Establishing a normal range requires defining two standard deviations on either side of the median. Also, the normal range should be calculated from a population of completely disease-free individuals. If you remove those patients with thyroid disease who are receiving thyroid hormone replacement, as well as those with a family history or with thyroid antibodies, the upper limit of normal moves closer to 4.0 mU/L. So, we see a refined range of normal at about 0.5-2.5 mU/L.2,8

A few issues must be considered in monitoring TSH levels. First, TSH levels pulse diurnally: they peak during the night, reducing to lower levels during the day. Ideally, samplings should be conducted at the same time of day, or between the hours of 8:00 am and 6:00 pm. You should also be aware that the range of normal can vary with ethnicity and with advancing age. Finally, in women, estrogen and progesterone cycling and oral contraceptives can affect the binding capacity of thyroid hormone, and pregnancy can alter thyroid hormone metabolism.6

Levels below the lower limit of normal are of diagnostic value, as are those above the upper limit. A TSH level below 0.1 mU/L could represent endogenous hyperthyroidism (Grave’s disease) or excess thyroxine replacement, and the development of iatrogenic hyperthyroidism. This situation is associated with an increased risk of complications such as reduced bone density, atrial fibrillation, and increased cardiovascular mortality.8

The first key point of this supplement can be summarized as follows:

• TSH is the primary diagnostic tool for thyroid disease. • The TSH range of normal is narrower than has been previously considered. • The goal of treatment for primary hypothyroidism should be to restore TSH levels to the optimum range (0.5-2.5 mU/L) using FDA-approved preparations of levothyroxine sodium. • Levothyroxine sodium is a drug with a narrow therapeutic window, and it must be precisely titrated to avoid persistent hypothyroidism and to prevent iatrogenic hyperthyroidism.

Risk Factors of Mild Hypothyroidism As I previously mentioned, there is controversy about the need to treat subclinical or mild hypothyroidism. By definition, patients with subclinical hypothyroidism do not have the classic hypothyroid symptoms (subclinical). Yet, it may be that the symptoms are simply unobserved and/or unreported by patients. How do we identify these individuals? The American Thyroid Association recommends that adults be screened for thyroid dysfunction with serum TSH assay beginning at age 35 and every 5 years thereafter.5 Additionally, if you specifically question your patients, you may turn up complaints that cause you to suspect mild thyroid dysfunction. The question then becomes, “What would be the benefit of diagnosing and treating mild hypothyroidism?”

There is evidence that the closer the TSH level is to the upper limit of normal, the greater the risk is for developing overt hypothyroidism. The Whickham Survey, conducted in Great Britain, documented prognostic risk factors for thyroid disease in a large representative sample of adults.9 Twenty years later a follow-up survey was conducted in this cohort to determine the incidence and history of thyroid disease. It revealed that individuals who originally tested with a TSH of > 2.0 were at increased risk for progression to overt hypothyroidism, and that risk further increased in the presence of antithyroid antibodies.9

We already know that overt hypothyroidism can be associated with cardiovascular disease. It has been suggested that risk factors begin to present with mild hypothyroidism.10 In the Rotterdam Study, clinicians compared 1159 elderly women who were either euthyroid (normal TSH and T4) or subclinically hypothyroid (elevated TSH and normal T4) to determine if mild hypothyroidism may increase the risk for cardiovascular disease (Figure 1).11 Women with subclinical hypothyroidism had a twofold increase of atherosclerosis and myocardial infarction over the group with euthyroidism.11 This study first answered the question and provided population-based data that individuals with subclinical hypothyroidism are at increased risk for untoward cardiac events.

If you screen a larger population, you get essentially the same results. In the Colorado Thyroid Disease Prevalence Study, over 25,000 patients were screened for thyroid disease and grouped as having euthyroidism, mild thyroid failure, or overt hypothyroidism (Figure 2).4 All patients were evaluated for dyslipidemia, and while the cholesterol levels of patients with mild hypothyroidism were not as high as those with overt disease, there is definitely an elevation over the group with euthyroidism. Furthermore, cholesterol levels increased incrementally with TSH level.4 More important is the observation in clinical practice that reducing TSH levels to normal appears to have an effect on normalizing cholesterol metabolism.

My colleagues and I have been examining the risk that mild hypothyroidism poses on cardiovascular disease in five different spheres, and we too conclude that in addition to increased cholesterol levels, serum levels of homocysteine are increased, as is abdominal aortic calcification. Blood pressure, specifically diastolic pressure, is frequently elevated and endothelial function is impaired. Yet, these known cardiovascular risk factors are reversible with diagnosis and treatment of hypothyroidism.10

It appears that there may be a significant cardiovascular benefit to treating mild as well as overt hypothyroidism. Normalizing thyroid status in peripheral tissues can be achieved by maintaining TSH levels in the range of 0.5-2.5 mU/L. The simplicity and cost-effectiveness of TSH monitoring gives you the ability to provide adequate therapy while minimizing undertreatment and overtreatment.3

In conclusion, the second key point of this supplement is that overt and subclinical hypothyroidism are both associated with increased risk factors for cardiovascular disease, and there is compelling support for routine TSH screening of the adult populations as well as treatment of mild and overt disease to promote cardiovascular risk reduction.

Initiating and Monitoring Thyroxine Therapy Endocrine specialists advocate the use of a high-quality brand preparation of levothyroxine for the treatment and management of clinical hypo¬thy¬roi¬d¬ism.5,6 The initiation guidelines are largely dependent on age. We know that older patients (> 60 years) generally require less medication, and older patients with an established cardiac history present an additional challenge. Table II provides initiating and monitoring recommendations relevant to younger patients and older patients with and without a cardiac history.12

Patients younger than age 60 with no cardiac history or significant metabolic or clinical illness should start at a dose of 1.2-1.6 mcg/kg/day. Of course you would start a patient with mild disease on a lower dose, and you should perform repeat TSH testing at 8-12 weeks. The half-life of levothyroxine sodium is 7 days, so good pharmacologic principles require 6 weeks on any given dosage before a new steady state is reached. The dosage is increased or decreased in 25-mcg increments until normal TSH is established. For about 90% of these patients, the total dose falls somewhere between 100 and 150 mcg/day.

Patients over the age of 60 with no cardiac history usually require 20-30% less medication. The starting dose would be 50 mcg/day with TSH monitoring every 6-8 weeks. The dosage is increased in 12- to 25-mcg increments every 2-3 months. Patients over 60 with a history of angina, heart failure, hypertension, or myocardial infarction are initiated and titrated more carefully. Begin with only 25 mcg/day, monitor the TSH every 6 weeks, and progress slowly to titrate at 12.5-mcg increments.

Once the TSH falls within the normal range, I recommend monitoring every 6-12 months. Anytime you change the dosage for any reason, follow up with TSH monitoring. This is also critical in evaluating patients who have undergone generic substitution or a change in brand or formulation.

Much of the bioavailability of levothyroxine is determined by absorption. Between 60% and 70% of the dose is absorbed. The degree of absorption can be affected by gastrointestinal motility, gastrointestinal disease states, interactions with other drugs, minerals, and foods. Calcium, iron, soy, fiber, sucralfate, and phosphate binders, for example, are known to affect absorption. Even minor variations in bioavailability can affect therapy significantly for a drug with a narrow therapeutic window.

Despite the progress we have gained in effectively managing hypothyroidism, there could be improvement in the overall status of treated patients. Among the 1500 patients in the Colorado study who were taking thyroid medication, only 60% were within the normal TSH range.4 Nearly 18% had subclinical hypothyroidism, and a little over 20% had subclinical hyperthyroidism. By using good management principles and appropriate TSH testing, I think we could get the populations with subclinical hypothyroidism and hyperthyroidism down to essentially none.

The myth and the reality of the adverse effects of thyroxine need to be discussed. In educating our patients about risks and benefits, they’ve been told that decreased bone mineral density and osteoporosis can accompany levothyroxine treatment. In fact, it has categorically been demonstrated that as long as the TSH is in the normal range, there is no adverse bone effect from levothyroxine sodium replacement. There are patients, however, who are on excess amounts of medication. The result is that the excess medication then pushes the TSH levels into iatrogenic hyperthyroidism. This is the situation that potentially promotes excess bone loss, as well as anxiousness, nervousness, palpitations, and atrial arrhythmias.8

The effect of low serum TSH levels on atrial fibrillation is supported by the Framingham Heart Study, in which 2000 patients were evaluated for serum thyrotropin concentrations, and followed for a 10-year period to determine the frequency of fibrillation occurrence.13 Those patients with a TSH of ≤ 0.1 mU/L, in the range of chemical hyperthyroidism, had a 30% increase in the cumulative incidence of atrial fibrillation over the 10-year period.13 So, it is very much incumbent upon us that we regularly monitor patients to be certain their TSH levels remain within normal limits.

The third key point of this supplement is that optimal therapy for hypothyroidism is to maintain TSH levels consistently within the narrow, normal range. Variations of as little as 15-20% can result in changes in TSH levels. In order to maintain consistent normal levels, we must choose therapeutic preparations that demonstrate reliable, reproducible bioavailability based on established criteria for absorption and in vivo drug metabolism; we must initiate and titrate treatment with careful consideration of individual patient differences; and we must monitor TSH levels at regular intervals and anytime there is a change in dosage, formulation, or patient condition.

Regulatory Aspects of Levothyroxine Preparations The clinical aspects of hypothyroidism are the basis for the recent regulatory activity regarding levothyroxine sodium therapy for hypothyroidism. Levothyroxine sodium was introduced in the 1950s. Its clinical efficacy is well established, and until recently it was available as an unapproved marketed drug. However, by 1997 there were at least 37 manufacturers or repackagers of the product, and problems began to surface due to product stability (levothyroxine degrades quickly when exposed to light, moisture, oxygen, and carbohydrate excipients), product formulation consistency, and bioequivalence among brands.14 By requiring New Drug Application (NDA) approval, the FDA is providing oversight of these conditions so that physicians can be assured that their patients are receiving consistent formulation of their medication.

Guidelines have been established for assessing the pharmacokinetics and bioavailability of levothyroxine sodium products based on established criteria for dissolution, absorption, and in vivo drug metabolism. These guidelines apply to both the NDAs and to the approval of generic preparations (Abbreviated New Drug Applications [ANDAs]). The protocols utilize healthy volunteers with normal thyroid function tests, which can be a challenge because in normal individuals endogenous hormones are present in significant concentrations. Consequently, a single oral dose, much higher than the normal therapeutic dose, is administered to overcome various issues related to endogenous secretions and metabolism.

In addition to the potential differences in pharmacokinetics and bioavailability already discussed here, there are differences is dissolution properties of the various levothyroxine preparations. For example, one preparation was almost completely dissolved within 2.5 minutes, while another took 30 minutes to achieve the same degree of dissolution. Direct comparative studies in bioequivalence were not required for the NDA approval process, so the currently approved preparations cannot be used interchangeably. According to the FDA Orange Book, branded levothyroxine sodium products are rated BX and cannot be substituted.6

Six branded levothyroxine sodium preparations have been FDA-approved. Three of them (Levoxyl®, Synthroid®, and Unithroid™) are actively marketed at this time. Each is available in 12 strengths from 25-300 mcg, and is designed to be taken once daily on an empty stomach. Remember, they have not been tested for bioequivalence, so if you switch brands you cannot assume the 100-mcg dose of each will yield the same result in your patient.

In June 2002, the FDA approved a generic equivalent specifically for the branded formulation, Unithroid™. According to FDA generic testing guidelines, a levothyroxine preparation can be considered equivalent to an established branded preparation if the rate and extent of absorption for the test falls between -20% and +25% of the referenced branded drug. Figure 3 is a graphic representation of this condition. The clear circles represent the entire 12 tablet strengths of Levoxyl® with the -20% and +25% variations shown as the vertical lines. The 100-mcg tablet of Levoxyl® (a commonly prescribed dose) would be considered equivalent to a generic substitute that could range anywhere from 80-125 mcg. For a variety of reasons, three major professional organizations, the American Thyroid Association, the American Association of Clinical Endocrinologists, and the Endocrine Society, have jointly expressed their concerns regarding this testing to the FDA.15

That brings us to the final point of this supplement. The management goals for hypothyroidism in 2004 are to avoid cardiovascular risks by maintaining TSH levels within a tight range of normal (0.5-2.5 mU/L), utilizing FDA approved preparations of levothyroxine sodium, regularly monitoring with TSH assay, and understanding the potential pitfalls in the use of generic equivalents for levothyroxine sodium.

REFERENCES 1. U.S. Department of Health and Human Services, Food and Drug Administration CDER. Guidance for Industry: Levothyroxine Sodium Products Enforcement of August 14, 2001 Compliance Date and Submission of New Applications. July 2001. 2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87: 489-499. 3. Brent GA, Larsen PR. Treatment of hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:853-858. 4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000;160:526-534. 5. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 2000;160: 1573-1575. 6. Klein I, Danzi S. Evaluation of the therapeutic efficacy of different levothyroxine preparations in the treatment of human thyroid disease. Thyroid 2003;13(12):1127-1132. 7. Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: A clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002;87(3):1068-1072. 8. Demers LM, Spencer CA. Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease [published guidelines]. National Academy of Clinical Biochemistry. Available at: http://www.nacb.org/ lmpg/thyroid_LMPG_PDF.stm. Accessed May 19, 2004. 9. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43(1):55-68. 10. Danzi S, Klein I. Thyroid hormone and blood pressure regulation. Curr Hypertens Rep 2003;5(6):513-520. 11. Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med 2000;132: 270-278. 12. Klein I. Endocrine disorders and cardiovascular disease. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, PA: W.B. Saunders. In press. 13. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331(19):1249-1252. 14. Johnson SB. Endogenous substance bioavailability and bioequivalence: Levothyroxine sodium tablets. Food and Drug Administration; March 2003. Available at: http://www.fda.gov/ohrms/ dockets/ac/03/slides/3926S2_07_Johnson.ppt. Accessed May 19, 2004. 15. Letter to the FDA: ATA, AACE, and TES respond to FDA postponement of workshop. American Thyroid Association; 2004. Available at: http://www.thyroid.org/professionals/advocacy/ 04_03_19_fda.html. Accessed May 26, 2004.

This special report was produced by MultiMedia HealthCare/Freedom, LLC, under an unrestricted educational grant from King Pharmaceuticals™, Inc. The views expressed in this publication are not necessarily those of King Pharmaceuticals or the publishers.

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(June 2004)