Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
87-1 HYPOTHYROIDISM Trying to Have a Baby Is Making Me Tired! . . . . . . . Level II Michael D. Katz, PharmD A 31-year-old African-American woman who has been undergoing an infertility workup by her OB-GYN is referred to an endocrinologist for consultation. She complains of fatigue which the patient ascribes to stress, and she also has some menstrual changes, constipation, weight gain, difficulty in concentrating at work, and dry skin. The infertility workup showed no male factor causes. Additionally, the patient has no evidence of structural reproductive tract problems or endometriosis, and sex hormone and gonadotropin levels are normal. Her thyroid stimulating hormone (TSH) is elevated at 9.8 mIU/L, and her free T4 level is low normal at 0.72 ng/dL. She has evidence of thyroid autoimmunity with a positive antithyroid peroxidase (anti-TPO) antibody level. Her low-density lipoprotein (LDL) cholesterol is slightly elevated at 142 mg/dL. Two years ago, the patient had a TSH of 4.2 mIU/L, which was within the reference range for that laboratory. While the patient’s TSH is in the range usually considered as “subclinical” or mild hypothyroidism, her infertility, thyroid autoimmunity, symptoms, and elevated LDL cholesterol are evidence of overt hypothyroidism and indications for thyroid replacement therapy. Levothyroxine (LT4) is the drug of choice. Therapy may be initiated with a relatively low LT4 dose (~50–75 mcg daily) that is titrated if necessary over time to the target TSH range (TSH target is midnormal, range 0.5–2.5 mIU/L, not the laboratory-defined reference range). The calculated full replacement dose (1.6 mcg/kg per day, ~100 mcg daily) also may be used, though this dose may be higher than necessary in patients with relatively mild hypothyroidism who have some residual gland function. After thyroid function tests have normalized, evaluation of therapy with TSH measurements every 6–12 months is sufficient in most patients to monitor therapy. However, if the patient successfully becomes pregnant, she will need monthly monitoring of her TSH, and she likely will need a higher dose of LT4. Over-replacement of thyroid hormone should be avoided, as it may lead to hyperthyroidism, which can result in decreased bone density and increased fracture risk, as well as adverse cardiac effects. QUESTIONS Problem Identification 1.a. Identify this patient’s drug therapy problems. • Hypothyroidism, not currently being treated; “subclinical” (mild) by TSH criteria but the patient likely has overt hypothyroidism based on unexplained infertility, is symptomatic, and has an elevated LDL cholesterol level. • Infertility, possibly due to hypothyroidism • Elevated LDL cholesterol, possibly related to hypothyroidism; not receiving intervention with diet or drug therapy. • Constipation, possibly due to hypothyroidism, but could alternatively be due to or exacerbated by iron and calcium supplements 1.b. What information (signs, symptoms, and laboratory values) indicates the presence of hypothyroidism? • Signs. Unexplained infertility, dry skin. • Symptoms. Fatigue, cognitive impairment, menstrual changes, constipation, and weight gain in the face of elevated TSH consistent with hypothyroidism. • Laboratory values. Elevated TSH, and low-normal serum free T4 level. In addition, hypercholesterolemia (total cholesterol = 212 mg/dL, LDL-C = 142 mg/dL) may be the result of or may be worsened by existing hypothyroidism. • Other. The patient is a 31-year-old woman who, 2 years ago, had a TSH near the upper limit of the TSH reference range. The incidence of hypothyroidism increases with age and is more common in women than men, and in whites and Hispanics than blacks.1,2 Patients with mild hypothyroidism due to autoimmune thyroiditis (ie, Hashimoto’s thyroiditis) often will progress to overt hypothyroidism after several years, especially if serum antithyroid peroxidase antibodies are present in serum. 1.c. Could hypothyroidism be a cause of her infertility? • Hypothyroidism has a variety of effects on the female reproductive axis,3,4 including changes in estrogens, androgens, gonadotropins, and prolactin. Hypothyroidism often is associated with menstrual changes, including changes in the amount of bleeding and cycle length. Hypothyroidism has been linked to infertility in women, particularly in those with evidence of thyroid autoimmunity and concomitant endometriosis. LT4 replacement therapy has been shown to increased conception rates in infertile women with subclinical hypothyroidism. 1.d. List examples of medications that are known to cause hypothyroidism. Could any of the patient’s complaints have been caused by drug therapy? • Several medications can cause hypothyroidism. Examples include amiodarone, lithium, interferon-α, antithyroid drugs (propylthiouracil, methimazole, and tyrosine kinase inhibitors), and others. While the patient does not appear to be receiving any of these agents, it would be important to confirm that she is not taking any unreported prescription or nonprescription medications or complementary/alternative products. Exposure to internal or external radiation can precipitate hypothyroidism. Iodine excess and deficiency can interfere with TSH synthesis and result in hypothyroidism, but this is uncommon in adults in North America. Certain foods (cassava, lima beans, maize, bamboo shoots, sweet potatoes, and cruciferous vegetables) can have an antithyroid effect if ingested in large quantities, so it would be reasonable to obtain more information regarding the patient’s diet. • This patient’s constipation could be the result of her hypothyroid state, ferrous sulfate therapy, and/or calcium therapy. 1.e. What was the significance, if any, of her previous TSH of 4.2 mIU/L? • The current reference range for TSH does not have a normal distribution.1 Further, the upper limit of the reference range for TSH is skewed in patients with subclinical hypothyroidism. Many experts feel that the upper limit of the TSH reference range should be reduced to 2.5 or 3.0 mIU/L.5 It would have been reasonable 2 years ago to have assessed the patient for thyroid autoimmunity, since patients with positive antithyroid Copyright © 2017 by McGraw-Hill Education. All rights reserved. Hypothyroidism CASE SUMMARY • History of iron deficiency anemia as a teenager; not currently anemic on low-dose iron. CHAPTER 87 87 • Menstrual changes, possibly due to hypothyroidism 87-2 SECTION 8 antibodies have a greater likelihood of rapidly progressing to overt hypothyroidism. refills. Bioequivalent products are not necessarily therapeutically equivalent.9,10 • Many patients with “subclinical” hypothyroidism (TSH <10 mIU/L) do, in fact, have symptoms that may improve with LT4 therapy. If she was completely asymptomatic 2 years ago, it was reasonable to withhold LT4 therapy, but she should have received more frequent TSH monitoring (every 6–12 months). • Liothyronine (T3) is also a synthetic product, but it has clinical disadvantages that include a higher incidence of cardiac side effects, difficulty in monitoring with conventional laboratory tests, and higher cost than levothyroxine. There is strong evidence that combined LT4/T3 therapy provides no outcome advantage over LT4 monotherapy.11 Desired Outcome Endocrinologic Disorders 2.What are the goals of pharmacotherapy for this patient? • Alleviate the clinical signs and symptoms of hypothyroidism. • Normalize thyroid laboratory tests and maintain long-term control. The target TSH level is the mean normal value (1.4 mIU/L, range 0.5–2.5 mIU/L).6 • Facilitate conception and successful pregnancy; appropriately monitor and dose LT4 during pregnancy. • Prevent complications of overtreatment and undertreatment with LT4. • Assure adherence with the pharmacotherapy regimen. Therapeutic Alternatives 3.a. What nondrug therapies might be useful for this patient? • Dry skin may be improved by using a nonallergenic lotion to provide moisture until she is euthyroid. The patient can also avoid using harsh soaps to avoid contributing to the itchiness and dryness. • This patient’s constipation may be secondary to her hypothyroid state, ferrous sulfate, and/or calcium. As her thyroid status improves, the constipation may also improve. In addition, reassessment of her need for ferrous sulfate therapy is indicated. Increased dietary fiber may also help her constipation. • Exercise and improved diet could help her level of stress and assist in losing the weight she has gained, as well as reduce her LDL cholesterol level. 3.b. What feasible pharmacotherapeutic alternatives (including complementary/alternative medicine products) are available for treatment of hypothyroidism? • There are several natural or synthetic thyroid preparations that may be used; refer to the section on hypothyroidism in the textbook chapter on thyroid disorders for a complete listing. • Thyroid USP is a natural T4/T3 product that is nonphysiologic for humans, may have an unpredictable biologic response, may be allergenic, and can be expensive. Products containing thyroid USP should no longer be used for thyroid replacement therapy. • Liotrix (a combination product containing T4 and T3 in a nonphysiologic 4:1 ratio) is a high-cost product that lacks therapeutic rationale. • Levothyroxine (LT4) is the drug of choice for thyroid replacement therapy because it is a synthetic formulation that is most physiologic, chemically stable, has more uniform potency, is not allergenic, and is relatively inexpensive. There is evidence that the FDA-specified methodology for bioequivalence testing is faulty for endogenous substances such as LT4 and cannot distinguish relatively large differences in bioavailability among different products.7 Products deemed bioequivalent may differ in bioavailability by as much as 25%. Since small changes in LT4 dose can cause clinically significant changes in a patient’s TSH,8 it is recommended that a brand name LT4 product be prescribed to assure that product not be switched at subsequent Copyright © 2017 by McGraw-Hill Education. All rights reserved. • There are many products marketed on the Internet and in health food stores that are claimed to be more effective and “natural” than LT4 therapy. Many of these products do, in fact, contain active thyroid hormone products. Patients should be advised not to use these products since they are unregulated and have not been tested for safety and efficacy. Optimal Plan 4.What drug, dosage form, product, dose, schedule, and duration of therapy are best for this patient? • The standard therapy used for thyroid replacement is LT4. Its advantages include once-daily dosing, stability, predictable potency, and a variety of dosage strengths to allow for easy dosage titration. • In this patient, brand name LT4 therapy should be initiated with 50–75 mcg once daily on an empty stomach. Prescribers should be educated to write LT4 prescriptions in mcg (eg, 50 mcg) doses rather than mg (eg, 0.05 mg) doses to reduce the chance of a medication error. The TSH should be reevaluated in 6–8 weeks. If the TSH is not in the target range (0.5–2.5 mIU/L), the dose should be increased or decreased by 10–20% and the TSH rechecked in another 6–8 weeks. This process may be repeated until the patient’s TSH is at target and she is no longer symptomatic. Some patients have the best clinical result when the TSH is at a low-normal level. However, overtreatment with a below normal TSH should be avoided. A variety of factors can alter LT4 dose requirements over time, including many drugs, diet, aging, and pregnancy. • In elderly patients and patients with known cardiac disease, therapy should be initiated with a lower LT4 dose of 12.5–25 mcg daily and titrated slowly upward. Clinical and biochemical evaluation should be performed 6–8 weeks after initiation of treatment. If the TSH is not in the target range, the dose may be titrated as described above. If the patient’s cardiac condition worsens during the titration phase, the dose should be reduced, and then retitrated in smaller increments. • Pharmacologic treatment for her elevated LDL cholesterol should not be considered until she is/has been euthyroid for at least several months. If her LDL cholesterol remains elevated, statin medications should not be used since she is trying to become pregnant, and these medications are teratogenic. • Significant drug interactions should be avoided and monitored. Both iron and calcium have been shown to significantly reduce the bioavailability of oral LT4. This problem can be avoided by the patient taking the iron and calcium at least 3–4 hours apart from the LT4. Outcome Evaluation 5.What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse effects? • Perform clinical and biochemical re-evaluation at 6- to 8-week intervals with dosage increased until the serum TSH is in the target range and the patient has resolution of symptoms. 87-3 • The patient should obtain relief from her symptoms of fatigue within 2–3 weeks of beginning therapy. However, dry skin may take several months to subside. • Under-replacement with LT4 and long-term mild hypothyroidism has been associated with infertility, elevated serum cholesterol, elevated BP, increased risk of coronary disease, altered cardiac function, and cognitive impairment. • If the patient becomes pregnant, monthly TSH monitoring will be necessary to assure that she is receiving an adequate LT4 dose. The majority of women who become pregnant while receiving LT4 will quickly require a dose increase, averaging a 50% increase over the prepregnancy dose. The LT4 dose should be titrated to a mid- to low-normal TSH level. Undertreatment and maternal hypothyroidism may result in significant adverse sequelae to the baby, including an increased risk of obstetrical complications, and impaired development and intellectual function after birth. Patient Education 6.What information should be provided to the patient to enhance adherence, ensure successful therapy, and minimize adverse effects? • The reason for taking this medication is to replace the hormone that your thyroid gland is not producing in adequate amounts. Replacing the thyroid hormone may improve your chances of becoming pregnant. In doing so, your symptoms should improve and your abnormal lab values should return to normal. • Make sure you receive the same brand of this medication each time the prescription is filled. While all the brands on the market are good, they are not the same. If the brand is switched, your blood tests may change and will need to be checked more often. If the tablets look different when the prescription is refilled, make sure to ask your pharmacist about it. • Take this medication once a day exactly as your healthcare provider directed. • Space this medicine from the time you take your iron and calcium tablets by at least 3–4 hours. The iron and calcium tablets may reduce the amount of thyroid hormone your body will absorb. If you become pregnant and are taking prenatal vitamins, the same recommendation applies since those products contain calcium and iron. In addition, you should not take your thyroid pill with foods that are high in fiber or with fiber supplements. • Since taking this medication with food can decrease its absorption, it is best to take it on an empty stomach. • If you miss a dose, take it as soon as you remember, unless it is within 12 hours of your next dose. If it is too close to your next • You should begin to feel better within 2–3 weeks of starting this medication. You will initially notice an improvement in your energy and mood. Other symptoms, such as dry skin, may take longer to disappear. • Blood tests will need to be checked periodically (every 6–8 weeks) until your healthcare provider determines the best dose for you. After that, you will only need to have a blood test once or twice a year unless there is a change in your condition, or if the brand of medication is changed. If you become pregnant, your TSH test will be checked on a monthly basis, and your thyroid dose changed to make sure that both you and your baby are receiving the right amount of medication. • If the dose of your medication is too high, you may experience diarrhea, sweating, tremors, palpitations, or intolerance to heat. Call your healthcare provider if you notice these side effects. Over a long period of time, taking too much of this medication can cause problems with your bones and heart. Taking too little of the medication can make you have the same symptoms you started with, plus you can develop high blood pressure, high cholesterol levels, and an increased risk of heart disease. This is a very safe medication, and these problems will not occur if you take the medication as directed, and if your thyroid blood tests are checked periodically and stay in the desired range. • Call your healthcare provider immediately if you experience any chest pain, palpitations, or irregular heartbeats. • Because your thyroid gland is not producing enough thyroid hormone, you will likely need to take this medication for the rest of your life. • It is very important to keep regular appointments with your healthcare provider(s) to monitor your therapy so that you can gain the full benefit of this therapy while avoiding potential side effects. ■■ FOLLOW-UP QUESTIONS 1.How should this patient’s elevated LDL cholesterol be managed now? What if her cholesterol continues to be elevated after she becomes euthyroid? • The patient’s elevated LDL may be caused by her hypothyroid state. Her lipid panel should be rechecked after she has been euthyroid for several months. Most patients will have a significant reduction on LDL with initiation of LT4 therapy, though the high-density lipoprotein (HDL) usually is not significantly increased. Pharmacologic lipid-lowering therapy should only be considered if her LDL remains significantly elevated after she becomes euthyroid, per evidence-based guidelines. However, since she is trying to become pregnant, it is best to withhold any medications that may be harmful to the fetus, including statins. The patient should be counseled regarding a healthy diet as part of overall health maintenance. 2.What changes in her thyroid therapy might be necessary if she does become pregnant? • Pregnancy increases the need for thyroid hormone, due to the needs of the developing fetus, increased thyroid hormone clearance, and protein binding.13–15 The fetus is completely dependent on maternal thyroid hormone during the first trimester. The majority of women who become pregnant while receiving LT4 therapy will require a dose increase, averaging 50% above the prepregnancy dose. Since TSH levels normally drop during pregnancy due to the TSH receptor stimulating Copyright © 2017 by McGraw-Hill Education. All rights reserved. Hypothyroidism • Over-replacement of thyroid hormone can lead to signs and symptoms of hyperthyroidism. Hyperthyroidism is also associated with menstrual problems and infertility. Long-term over-replacement can lead to reduced bone density, which can increase the risk of fractures, especially in postmenopausal women. Mild or subclinical hyperthyroidism also has been associated with increased rate of atrial fibrillation and cardiovascular mortality.12 Even during maintenance therapy, the dose of LT4 should be adjusted, if necessary, to keep the TSH level in the target range. dose, forget about the dose you missed and continue with your regular regimen. Do not double doses. CHAPTER 87 • Once the TSH is at target, evaluate response to therapy with TSH measurements every 6–12 months, unless there is a change in the patient’s clinical condition (eg, pregnancy) or the product is switched. 87-4 SECTION 8 effect of β-HCG, the target TSH during pregnancy is low- to mid-normal (0.5–1.5 mIU/L). TSH is monitored monthly during pregnancy. Upon delivery, the LT4 dose may be reduced to the prepregnancy dose. 3.Evaluate this patient’s continued need for iron and calcium. Should they be discontinued? If not, what potential problems (if any) might be expected once thyroid replacement therapy is started? Endocrinologic Disorders • It is not clear from the information provided if she has had iron deficiency anemia since she was a teenager. If she has not and she has no current risk of iron deficiency (very heavy periods), it would be reasonable to discontinue the iron. However, if she becomes pregnant, iron supplementation in the form of a prenatal vitamin will be necessary. If the iron therapy is continued or restarted, the potential absorption interaction with iron and LT4 must be addressed. It is not clear why she is taking calcium, so it would be reasonable to obtain more information regarding her reasons for using and potential risk factors for osteoporosis. If she does continue taking calcium, the potential absorption interaction with LT4 must be addressed. REFERENCES 1. Aoki Y, Belin RM, Clickner R, Jeffries R, Phillips L, Mhafey KR. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999–2002). Thyroid 2007;17:1211–1223. 2. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526–534. 3. Stagnaro-Green A, Pearce E. Thyroid disorders in pregnancy. Nat Rev Endocrinol 2012;8:650–658. 4. Poppe K, Velkeniers B, Glinoer D. The role of thyroid autoimmunity in fertility and pregnancy. Nat Clin Pract Endocrinol Metab 2008;4:394–405. Copyright © 2017 by McGraw-Hill Education. All rights reserved. 5. Laurberg P, Andersen S, Carle A, et al. The TSH upper reference limit: where are we at? Nat Rev Endocrinol 2011;7:232–239. 6.Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis and management. Med Clin North Amer 2012;96:203–221. 7. Blakesley V, Awni W, Locke C, Ludden T, Granneman GR, Braverman LE. Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable? Thyroid 2004;14:191–200. 8. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotropin releasing hormone test using a sensitive thyrotropin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol 1988;28:325–333. 9.Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997;277:1205–1213. 10. Mayor GH, Orlando T, Kurtz NM. Limitations of levothyroxine bioequivalence evaluation: an analysis of an attempted study. Am J Ther 1995;2:417–432. 11. Grozinsky-Glasberg S, Fraser A, Nahashoni E, Weizman A, Leibovici L. Thyroxine triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: a meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006;91:2592–2599. 12. Franklyn KA. The thyroid—too much and too little across the ages. The consequences of subclinical thyroid dysfunction. Clin Endocrinol 2013;78:1–8. 13. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081–1125. 14.De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543–2565. 15. Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E. Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev 2013;(5):CD007752. doi:10.1002/14651858.CD007752.pub3.