Articles

Hypothyroid Disorder

By Paul Hueseman, R.Ph, Pharm.D. & A. Cornille, R.Ph.

It is estimated that approximately 20 million Americans have a thyroid disorder which means 1 in every 10 people6. Hypothyroidism is caused from decreased production of thyroid hormone which results in decreased metabolism6. Hypothyroidism occurs more commonly in women 1.2-2% as compared to men 0.2 %. Hypothyroidism is also more common in menopausal women. People at high risk for thyroid dysfunction include post-partum women, people with high levels of radiation exposure (< 20mGy), elderly, and people with Down Syndrome4. The elderly are often undiagnosed because symptoms mimic aging6. Also as a person ages, the incidence also increases.1

The primary cause of hypothyroidism is the failure of the thyroid gland termed primary hypothyroidism. There are several causes of primary hypothyroidism such as Hashimoto’s disease (inflammation of the thyroid by an autoimmune mechanism)6, iatrogenic hypothyroidism such as after radioactive iodine therapy, iodine deficiency, enzyme defects, underdevelopment of the thyroid gland, and substances that cause goiters. Another cause of thyroid disorder is Wilson’s Syndrome. A less common cause of hypothyroidism is from pituitary or hypothalamic disease called secondary hypothyroidism. This article will focus primarily on the role of the thyroid hormones, symptoms, and treatment of hypothyroidism, with additional information on Wilson’s Syndrome.

The thyroid is a gland in the body which is composed of two lobes on either side of the trachea2. The thyroid produces hormones that are involved in almost every part of the body. In adults, the major role is to maintain metabolic stability. Thyroid hormones are stored in the thyroid gland and in the blood. The hypothalamic-pituitary-thyroid axis is designed to monitor levels of the hormones in the body and to maintain levels in a very specific narrow range.1

The synthesis of thyroid hormone occurs when the thyroid hormones thyroxine (T4) and triiodothyronine (T3), the more biologically active hormone, are formed on thyroglobulin. The thyroid cell is the site where the synthesis of the large glycoprotein thyroglobulin takes place. Iodinated tyrosine, which is present in the glycoprotein, binds together to make the active thyroid hormones. Iodine is an important element for the functioning of the thyroid gland and an adequate supply is needed2.

Three proteins are involved in the transport of T4 and T3: thyroid-binding globulin (TBG), thyroid-binding prealbumin (TBPA) and albumin. The secretion of T4 occurs primarily in the thyroid although this is not the case for T3. T3 is formed from the breakdown of T4 in the peripheral tissues. In comparing the two hormones, T3 is the more active, therefore T3 plays the primary role in regulating metabolic activity within the body. The thyroid’s growth and function is maintained by TSH (thyroid stimulating hormone). The thyroid is regulated by several mechanisms. First the anterior pituitary gland secretes TSH which regulates the thyroid hormones. Also the process of removing iodine from T4 and T3 is regulated by many factors which include nutrition, drugs, illness, and other non-thyroid hormones.1

In Wilson’s syndrome there is a problem converting T4 to T3. In normal thyroid function, T4 converts to T3 in the active form and reverse T3 (RT3) in an inactive form. The enzyme that is used to convert T4 to T3 is inhibited by stress, acute and chronic illness, fasting and the stress hormone cortisol. In times of stress, the body produces more T4 to RT3 to conserve energy for stress. A vicious cycle then occurs with more RT3 than T3 being produced.8

In Wilson’s Syndrome, the thyroid levels appear normal although the patient is still experiencing symptoms of low thyroid. Symptoms include hair loss, weight gain, cold extremities, low body temperature, low blood pressure, irregular menstrual cycles, infertility, premenstrual syndrome, unexplained and chronic fatigue, osteoporosis, hypoglycemia, constipation, and muscle cramps7. These symptoms worsen in periods of physical or emotional stress. Possible stressors include childbirth, surgery, divorce, death in family, or job and family stress. These symptoms persist even when the stressors have passed.

Nonpharmacologic treatment includes getting plenty of rest, eliminating as much emotional stress as possible, moderate exercise for stress control, and eating a well balanced diet. Pharmacologic treatment includes reducing T4 by giving T3. In this fashion, the body senses it has enough hormones and decreases production of T4, which decreases production of RT3. Treatment only lasts for a couple of weeks or months. Sustained release T3 seems to be best tolerated in twice daily dosing. Immediate release T3 is marketed under liothyronine (Cytomel), but does not appear to work as well as sustained release T3, which a compounding pharmacy would have to prepare. Dessicated thyroid (Armour thyroid) has also been used since its main constituent is T3 although it has T4 as well. Levothyroxine (Synthoid) is not as good of an option because it is only T4.8

In hypothyroidism, patients can have a wide variety of symptoms but generally there is slowing of metabolic processes3. There is a range of hypothyroidism that consists of subclinical to overt hypothyroidism to myxedema2. Patient who are older have fewer signs and symptoms and in both young and old patients there is little correlation between clinical and biochemical manifestations2. Early and nonspecific symptoms consist of lethargy and decreased energy, cold intolerance, muscle cramps, muscle pain and stiffness, constipation, and weight gain6. Over time, symptoms of hypothyroidism consist of dry skin, mental slowing, course hair and skin6. Depression is also common in untreated hypothyroidism.

Decreased levels of thyroid hormone result in swelling around the eyes and decreased heart rate. A patient’s speech is often slow and the voice is hoarse. Also decreased reflexes are also common. In the later stages, there is also accumulation of glycoaminoglycans into interstitial tissues and this accumulation results in edema of skin, muscle, heart, and striated muscles, which results in symptoms of a round puffy face, loss of hair and dry skin. Patients also can experience hearing loss, numbness in the extremities, and day time sleepiness6. There is also a decrease in the conversion of carotene to vitamin A which causes the skin to have a yellowish color3. Also hypothyroidism is involved in decreased conversion of estrogen precursors into estrogen which can result in infertility3.

Lab tests performed in diagnosing and monitoring primary hypothyroidism are serum TSH and Free Thyroxine Index (FT4I)6. The first step in evaluation is to measure serum TSH and free T4 index or serum free T42. Overt primary hypothyroidism reveals a rise in TSH and free serum T4 level is low2. If the serum free T4 is low and the TSH is normal or low then diagnosis of central hypothyroidism or nonthyroidal disease can be made2. Additional tests might include free T4, thyroid autoantibodies such as antithyroglobulin autoantibodies and anti-thyroid peroxidase, and in the case of suspicious thyroid structure then a thyroid scan and/or ultrasonography5. Less common but very important tests also include total T3 and free T3 as TSH is often normal indicating euthyroid despite adequate T3 levels which could be indicative of Wilson’s Syndrome.

Goals of therapy include the restoration of thyroid hormone in tissues and to provide relief from symptoms. Patients should be educated about life long treatment and the need for follow-up to evaluate the response. Compliance should also be assessed at each visit2. Thyroid hormone replacement is either natural or synthetic. Dosing of thyroid medications depends on patient’s age, the addition of other disorders, and the severity and length of time of hypothyroidism. T4 replacement (L-thyroxine) is the main stay of treatment2. In middle- aged and young adults the dose should be 0.075- 0.1mg/day. In the elderly, the initial dose should be 0.05 mg/day2. There are many factors that alter the dosage needs of patients. Patient should be instructed to tell their doctor of all your medical conditions and medications they are currently taking2. Treatment pace depends on the severity and length of time the patient has had hypothyroidism and on other comorbid medical conditions5. If converting T4 to T3 is a problem, then other options include T3/T4 supplementation with Armour as well as custom compounding of T3/T4 or T3 as extended release.

In an article published in the journal Endocrine, researchers looked at the treatment of thyroiditis. Patients were women who had Grave’s Disease, but who now had hypothyroidism due to thyroidectomy. The authors compared thyroxine (T4) to thyroxine plus triiodothryonine (T3) treatment. The author’s substituted 10 mcg of T3 for 50 mcg of T4. There was a significant decrease in free T4, but there was no significant change in T3 or TSH concentration. The authors’ concluded that treatment with T4 plus T3 increased mental functioning, but not on cognitive functioning. Also symptoms of hypothyroidism and hyperthyroidism decreased on the symptom scale after combination therapy was used. 9 In another journal article in the New England Journal of Medicine in which the researchers compared thyroxine with thyroxine plus triiodothyronine in patients with hypothyroidism, the researchers concluded that partial substitution of the T3 for the T4 may improve mood and neuropsychologic function.10

The measurement of free and total thyroid hormone levels and TSH are important in monitoring the patient for the correct dose. Signs and symptoms should resolve within 4-8 weeks, although some symptoms may continue for 4-6 months2. The goal of therapy is euthyroidism. For monitoring, TSH and T4 levels should check every 4- 6 weeks until euthyroidism occurs2. The correct maintenance dose should allow TSH to be in the normal range. For patients who have secondary hypothyroidism monitoring should occur with the following of T4 levels. For monitoring Wilson’s Syndrome, T3 and free T3 should be used. Monitoring is very important since over-dosing can result in heart failure, chest pain, or heart attack. Patients who are chronically on T4 should have TSH reassessed every 6-12 months to ensure proper medication dosage2. If hypothyroidism is managed correctly the symptoms should be reversible3.

References:
1. Reasner CA, Ralbert RL. Thyroid disorders. In: Pharmacotherapy a pathophysiologic approach. 5th ed. Dipiro JT, Talbert RL, Yee GC, etal., eds. New York: McGraw-Hill;2002:1359-1378.
2. Felig P, Frohman LA. The thyroid:physiology, thyrotoxicosis, hypothyroidism, and painful thyroid. In:Endocrinology and metabolism. 4th ed. New York: McGraw-Hill; 2001:261-329.
3. Greenspan FS. The thyroid glan. In: Basic and clinical endocrinology. 7th ed. Greenspan FS, Gardner DG. New York: Lange Medical Books/McGraw-Hill; 2004:215-251.
4. Screening for thyroid disease: recommendation statement. 2004 National Guideline Clearinghouse [resource on World Wide Web}. URL: http://www.guideline.gov. Available from Internet. Accessed 2004 Sept 16.
5. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. 2002 National Guideline Clearinghouse [resource on World-Wide Web].URL: http://www.guideline.gov . Available from Intenet. Accessed 2004 Sept 16.
6. Armour thyroid web site. Hypothyroidism. [resource World Wide Web]. URL: http://www.armourthyroid.com. Available from internet. Accessed 2004 Sept 16.
7. Diamonte, M. The new approach to low thyroid conditions. To your health: the magazine of healing and hope [online]. 1997 Sept/Oct [cited 2004 Sept 22]. Available from : database Alt HealthWatch
8. Wilson’s Syndrome [resource World Wide Web]. URL:http://www.wilsonsthyroidsyndrome.com. Available from internet.
9. Bunevicous R, Jakubonien N, Jurkevivius R, et al. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Grave’s Disease. Endocrine. 2002;18:129-33.
10. Bunevivius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triidothyronine in patients with hypothyroidism. New England Journal of Medicine. 1999;340 (6):424-70 .