Valerie Van Beusekom
Pharm D IV Paper Proposal
I. Title: Subclinical hypothyroidism. The importance of screening, treating and management of patients with slightly elevated TSH levels when compared to reference ranges.
II. Problem:
Purpose of the Study: Subclinical hypothyroidism is defined as an elevated serum TSH level with a normal serum free T4 concentration. Whereas hypothyroidism is an elevated serum TSH level along with a decreased serum T4 concentration. In subclinical hypothyroidism the TSH level is usually above 4.5 mIU/L but not greater than 10 mIU/L. Subclinical hypothyroidism is a common condition discovered by thyroid screening. According to the review of Helfand and Redfern, 5% to 10% of adult women have an elevated TSH level.5 Controversy persists about screening for subclinical hypothyroidism and the TSH level at which treatment should be initiated. A 1998 position paper from the American College of Physicians questioned whether there were sufficient data to recommend treatment of patients with subclinical hypothyroidism.6 A 2004 publication from the US Preventive Services Task Force found that the data were insufficient to recommend for or against screening in adults.7In 2002, a consensus development panel sponsored by the American Thyroid Association, the American Association of Clinical Endocrinologists, and the Endocrine Society found insufficient evidence to support screening and recommended against treating patients with a TSH concentration between 4.5 and 10 mIU/L.8 Because endocrinologists cannot agree whether the majority patients with TSH levels of 4.5 to 10 mIU/L require treatment; they do agree that pregnant women within this range should receive treatment because of the adverse effects on the fetus. It is not useful to diagnose subclinical hypothyroidism in the estimated 25 million persons whose TSH concentrations are between 2.5 and 4.5 mIU/L.9
Objectives:
·To define subclinical hypothyroidism.
· To describe the symptoms experienced by patients receiving inadequate thyroid replacement therapy.
· To expose the factors influencing physicians who rely solely on TSH levels.
· To illustrate the different treatment strategies that may improve thyroid replacement patient outcomes.
· To determine the optimal dose in treatment of hypothyroidism.
· To explore the differences between TSH and Free T3, T4 levels; and the sensitivity of these levels in dosing thyroid medications.
III. Literature Review
Introduction:
Most physicians rely on Standard Thyroid tests, such as TSH (Thyroid Stimulating Hormone) levels, to determine the optimal dose for thyroid replacement. A large proportion of patients’ diagnosed with subclinical hypothyroidism, especially the elderly and women, continue to suffer with the disease symptoms of hypothyroidism even though they may or may not be receiving medication therapy. Using the patient’s signs and symptoms are rarely factored in to determine the optimal dose for thyroid replacement.1 This study will examine the positive and negative implications of relying solely on TSH levels for thyroid dosing and if it is possible that more positive results can be achieved by using more diagnostic testing, laboratory testing and also using the patients’ signs and symptoms, for adequate replacement of thyroid.
Causes of Hypothyroidism: Hypothyroidism may be congenital or acquired, primary or secondary, chronic or transient. Hypothyroidism is common in the elderly it affects up to 20% of women and up to 8% of men. Primary hypothyroidism is caused by autoimmune destruction of the thyroid gland, treatment which destroys the thyroid gland through surgery or radioiodine therapy, and treatment which interferes with thyroid hormone synthesis. The clinical features of hypothyroidism are dependent on the patient’s age, the presence of other disease and the rate at which hypothyroidism develops. With regard to primary hypothyroidism the serum content of T4 is low and the TSH level is high. When a diagnosis of primary hypothyroidism is confirmed, treatment with Levothyroxine is started, the initial dose is started low, especially if the patient has heart disease, next it is adjusted for age, general condition of the patient, the duration, and the severity of the hypothyroidism. The goal Levothyroxine therapy to bring the serum TSH level into the normal range. Another cause of hypothyroidism is Hashimoto's Hashimoto's disease. It is the most common cause of hypothyroidism in the United States. It occurs when the immune system produces antibodies that attack the thyroid gland, creating chronic inflammation that damages the gland and interferes with its ability to make enough thyroid hormone. It occurs more often in women than men, and tends to run in families.

Patient Characteristics: Hypothyroidism is increasingly common as we age. Women over 50 should consider being screened for thyroid deficiency every few years. Hypothyroidism affects as many as 15 percent of women over 70 years of age.

Diagnostic and Laboratory Testing:
In a patient with hypothyroidism, the thyroid gland is not making enough of the main hormone, Thyroxine, free T4. The pituitary gland responds by increasing its production of TSH. However this does not increase the free T4 level and the end result is a high level of TSH and a decreased level of free T4.3 It is a blood test that checks the level of TSH in the blood. Normal thyroid function levels of TSH values are between 0.4 and 4.0 mlU/L1. The diagnosis of patients with hypothyroidism is typically done through the repeated measurement of serum thyroid stimulating hormone levels and may be supplemented with measurements of serum levels of Thyroxine, T4, to verify, quantify and sub classify the abnormality.7

Hypothalamic-Pituitary Relationship: When hypothalamic-pituitary function is normal, a linear inverse relationship between serum TSH and free T4 concentrations is produced by negative feedback inhibition of the pituitary TSH secretion by thyroid hormones. Thus, thyroid function can be determined either directly, by measuring the primary thyroid gland product, T4 , preferably as free T4, or indirectly, by assessing the TSH level, which inversely reflects the thyroid hormone concentration sensed by the pituitary. Because serum TSH and free T4 concentrations have a linear inverse relationship, small changes in free T4 will produce a much larger response in TSH. Hypothyroidism is diagnosed with a high TSH level and low FT4 level. While a low TSH level and high FT4 level is characteristic of hyperthyroidism. In fact, now that the sensitivity and specificity of TSH assays have improved, it is recognized that the indirect approach, serum TSH measurement, offers better sensitivity for detecting thyroid dysfunction than does FT4 testing 4. The importance of T3 and T4 levels is by their ability to activate, synthesize and inhibit other physiological processes at the cellular level. For example, reverse T3 has been thought to be an inactive metabolite, but it has been shown to be a competitive inhibitor of T3 which directly decreasing cellular energy production and directly suppress T4 to T3 conversion. Reverse T3 has been shown to be a more potent inhibitor of T4 to T3 conversion than PTU, a medication used to decrease thyroid hormone levels in hyperthyroidism.4
Symptoms:
Hypothyroidism is associated with a wide range or symptoms. They are Fatigue, Mental depression, Sluggishness, Feeling cold or intolerant to cold, Weight gain, Dry skin and hair, Constipation, and Menstrual irregularities.12

Treatment: Hypothyroidism is treated by replacing the thyroid hormone the body needs. This is usually done with an oral tablet or pill of the thyroid hormone thyroxine , T4 or Levothyroxine. A person will usually notice an improvement in his or her health and decreased symptoms of thyroid disease within two weeks. 12

IV. Methods

This project will be accomplished by a review of recent literature published on the topic of treatment regimens in hypothyroidism therapy. PubMed will be used as the primary search engine. MeSH terms such as: subclinical hypothyroidism, hypothyroidism, treatment, therapy, hypothyroidisms, thyroid function tests, and Pharmacotherapy were used to create this proposal and generated approximately 120 results. These results will be further narrowed to include only relevant articles from 2000 to the present. Exclusion criteria will include information concerning pregnant women and newborn’s, this is because there is consensus among professionals that they should receive hormone replacement. Inclusion criteria will include both men and women above the age of 35 years old. Individuals with co morbid diseases such as Diabetes, cardiovascular disease and other metabolic disorders will be included in the literature review.
The American Thyroid Association, The Endocrine Society and American Association of Clinical Endocrinologist’s websites will also be used as they have an extensive search engines specific regarding the treatment of subclinical hypothyroidism. For these databases it is possible to review recent articles using only the terms ‘treatment, hypothyroidism, subclinical hypothyroidism’.
I will rely on the CDC’s website (www.cdc.gov) for accurate epidemiological primary hypothyroidism data. I will also use the websites www.clinicaltrails.gov and www.fda.gov to search and evaluate emerging hypothyroidism therapies and compare their proposed efficacy to current therapies.
V. Timeline
May 2011 – Begin paper introduction. This will include a literature review of current hypothyroidism therapy treatment impact, cost, reference ranges, pathophysiology of serum TSH, and Free T3 and T4 levels.
This will also include an overview of the patient diagnosis, side effects and adverse events associated with hypothyroidism treatment.
July 2011 - Begin research and writing on the pharmacokinetics of hypothyroidism therapy. This will include intense examination of factors in specific medication therapy. This portion of the paper will also summarize the current diagnosis strategies used to confirm hypothyroidism and alternative diagnosis strategies.
September 2011 – Collect information on emerging hypothyroidism treatment and diagnosis therapies from government websites. Prepare a brief monograph-style overview for selected therapies to use as a concluding piece of the project.
October-November 2011 – Finalize first draft and submit to content advisor for revision.
References
1. Clarke N, Kabadi Um. Optimizing treatment of hypothyroidism J Treat Endocrinology. 2004;3(4)217-21.
2. Laurberg P, Anderson S, Bulow Pederson I, Carle A. Hypothyroidism in the elderly: path physiology, diagnosis and treatment. J Drugs Aging . 2005;22(1):23-38.
3. Eisenberg M, DiStefano III J. TSH based protocol, tablet instability, and absoption effects on L-T4 Bioequivalence. J Thyroid. 2009;19(2):103-110.
4. Hannemann A, Friedich N, Haring R, Krebs A, Volzke H, Dietrich A, Nauck M, Kohlmann T, Schober H, Hoffmann W, and Wallaschofski. Thyroid function tests in patients taking thyroid medication in Germany: Results from the population based “Study of Health in Pomerania(SHIP)”. J BMC Res Notes. 2010;10(3):227-235.
5. Surks M, Ortiz E, Daniels G. Sawin C, Col N, Cobin R, Franklyn J, Hershman J, Burman K, Denke M, Gorman C, Cooper R, Weissman N. Subclinical Thyroid Disease. J American Medical Association. 2004;291(2):228-238.
6. Clinical guideline, part 1. Screening for thyroid disease. American College of Physicians. Ann Intern Med. 1998;129:141-143.
7. US Preventive Services Task Force. Screening for thyroid disease: recommendation statement. Ann Intern Med. 2004;140:125-127.
8. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: review and guidelines for diagnosis and management. JAMA. 2004;291:228-238.
9. Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab. 2005;90:5489-5496.
10. Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG et al. American Thyroid
Association Guidelines for detection of thyroid dysfunction. Arch Intern Med 2000;160:1573-5.

11. Helfand M, Redfern CC: Clinical Guideline, Part 2. Screening for thyroid disease: an update. Ann Intern Med 1998; 129:144-58.

12. http://www.hormone.org/Thyroid/hypothyroidism.cfm