- CONDITION CENTERS
After completing this continuing education article, the pharmacist should be able to:
1. Understand thyroid hormone function and describe the causes and pathophysiology of hypothyroidism.
2. Identify risk factors for mild and overt hypothyroidism.
3. Describe optimal approaches to the treatment of hypothyroidism.
4. Understand side effects relevant to pharmacologic treatment.
5. Describe consequences of minor deficiency or excess of thyroxine dosage in common clinical circumstances.
6. Understand the pharmacist's role in dispensing agents with a narrow therapeutic index and the possible consequences of switching thyroid hormone preparations.
Hypothyroidism is a common endocrine disorder that results from suboptimal thyroid hormone levels. Pharmacotherapy for hypothyroidism is accomplished through hormone replacement with levothyroxine. Recently, the FDA granted AB-rated status to a number of levothyroxine products that were already approved. These classifications have raised issues regarding optimum treatment of patients with thyroid disease. It is the purpose of this article to review the pathophysiology, risk factors, clinical manifestations, and management of hypothyroidism. Current issues related to treatment, including adverse effects and issues surrounding switching of levothyroxine products, which have a narrow therapeutic index (NTI), are also discussed.
Thyroid Hormone Physiology and Function
Thyroid hormones are necessary for normal metabolism, growth, and development, and virtually every tissue of the body is affected either directly or indirectly by them. The main functions of thyroid hormones include regulation of basal metabolic rate and resting oxygen consumption; increased heat production; increased glucose utilization, uptake, and synthesis; and permissive sympathomimetic effects including increased heart rate and force of contraction.
The synthesis of the iodine-containing thyroid hormones thyroxine (T4) and triiodothyronine (T3) is controlled by the hypothalamic-pituitary-thyroid axis. The hypothalamus synthesizes and releases the peptide thyrotropin-releasing hormone (TRH) that travels through a portal blood system to the anterior pituitary, where it stimulates pituitary thyrotrophs to produce and release the peptide thyrotropin (thyroid-stimulating hormone; TSH). The secretion of TSH is pulsatile in the context of a diurnal rhythm, with a peak at night and lower levels during the daytime.1
Thyrotropin enters the systemic circulation, where it travels to and stimulates the thyroid gland, in a trophic manner, to produceT4and T3. The thyroid hormones then act through a powerful negative feedback mechanism at the levels of the hypothalamus and pituitary to inhibit further release of TRH and TSH, respectively. This endocrine axis allows for tight regulation of thyroid hormone production.
The major product of the thyroid gland is T4, whichaccounts for approximately 85% of thyroid hormone output.2 Circulating T4,with a half-life of 7 days, is metabolized by monodeiodination to T3, with a half-life of 1 day, in the liver, kidney, and target tissues, by specific deiodinases.3 Thus, approximately 87% of T3is derived from T4, and the remaining 13% is synthesized by the thyroid gland.4 This conversion of T4 to T3 is critical because T3 is recognized as the more potent, biologically active form of the hormone.2,5 BothT4 and T3 are subject to high levels of plasma protein binding, including to thyroxine-binding globulin, and only the free fraction of hormone is available to bind to thyroid hormone receptors. Three receptors have been identified that are thought to mediate the primary actions of thyroid hormone. The TRa1, TRb1, and TRb2 receptors are members of the nuclear receptor superfamily.6 Interaction of T3 with its receptor promotes the binding of cofactors that can regulate the expression of thyroid-hormone-responsive genes, either through activation or repression of transcription.7,8 This type of receptor interaction explains why the beneficial effects of thyroid hormone replacement may take weeks to occur, because alteration of gene product (eg, enzymes, proteins) levels relies on new synthesis or breakdown of products already present. Some effects of thyroid hormone have been noted to occur more quickly than can be accounted for by this mechanism, and recent evidence suggests nongenomic actions related to the cyclic adenosine monophosphate (cAMP), Ca2+, or protein kinase cascades. This would imply the presence of a membrane-associated receptor for thyroid hormone.9
Hypothyroidism is a common endocrine disorder affecting between 10 million and 14 million Americans2,10,11 that results from a deficiency in secretion of T4 and T3from the thyroid gland. It occurs more often in women than men and increases in incidence with age.8 Hypothyroidism can be defined based on different parameters of the pathophysiology. Primary hypothyroidism describes the state where the defect is located at the thyroid gland itself, whereas secondary (central) hypothyroidism relates to an abnormality in the anterior pituitary or hypothalamus (sometimes the term tertiary hypothyroidism is used to denote a hypothalamic irregularity). Depending on the cause, hypothyroidism may be either congenital, often due to genetic mutations related to dysfunction of thyroid hormone biosynthesis or function, or acquired, as in autoimmune thyroiditis (Hashimoto's thyroiditis). Interestingly, the most common cause of congenital hypothyroidism worldwide is still iodine deficiency.12 Lastly, hypothyroidism is termed clinical or overt when symptoms are present, and subclinical or mild when no overt symptoms associated with clinical hypothyroidism are present. To assist in the diagnosis and determination of the cause of hypothyroidism, TSH levels are measured. In primary clinical hypothyroidism, free T4 and T3 levels will be low and TSH levels will be high due to the lack of feedback from an inadequate amount of thyroid hormone. Subclinical hypothyroidism is biochemically defined as mildly elevated TSH levels with normal T4 and T3 levels.13 Furthermore, assays for thyroid autoantibodies may be performed to determine the cause of the condition. This may be important as the presence of thyroid autoantibodies in the setting of subclinical hypothyroidism may signal increased risk of future development of clinical hypothyroidism.14,15
The clinical manifestations of hypothyroidism are well characterized and include deleterious effects on multiple organ systems; the severity may vary considerably, however.4,8,16 Myxedema refers to the dry, waxy, nonpitting swelling of the skin with distinct facial changes, including swollen lips and thickening of the nose. A goiter may also occur. Patients may complain of cold intolerance, and hypothermia is common. Effects on brain function lead to slow mental processing, impaired memory, and depression. Muscle fatigue and cramping, gastrointestinal (GI) abnormalities such as constipation, weight gain even with decreased food intake, reproductive irregularities such as infertility, menstrual disturbances, diminished libido, and cardiovascular problems including bradycardia, diastolic hypertension, pericardial effusion, hypercholesterolemia, and coronary atheroma may also be present.17
Risk Factors for Hypothyroidism
Hypothyroidism may be caused by or is associated with many risk factors (Table 1).4,8 Patients with these risk factors or other clinical manifestations seen in hypothyroidism should be evaluated for the presence of this disorder.
Management of Hypothyroidism
The American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA) have each published treatment guidelines for hypothyroidism.18,19 According to these guidelines, the pharmacologic treatment of choice for clinical hypothyroidism is synthetic levothyroxine sodium, which is biochemically and physiologically identical to endogenous T4.20 Once absorbed, levothyroxine is converted to the more potent T3. When given properly, levothyroxine is generally safe and effective21; it has an NTI, however, so dosing must be carefully customized to the individual patient.
The mean dose of levothyroxine for oral replacement therapy in adults should be approximately 1.6 to 1.7 mg/kg of body weight per day.18,19 The initial dose is usually at the lower end of the anticipated dose requirement in otherwise healthy adults, but therapy may be initiated at a low dose (12.5 mg per day) and titrated up based on subsequent TSH measurements every 6 weeks in patients older than 50 years of age or those with a history of cardiac disease. Children may require higher doses (up to 4.0 mg/kg per day), and older patients may require reduced doses (<1.0 mg/kg per day). Once the patient's TSH levels are within the normal range, follow-up evaluations including biochemical measurements should be performed every 6 months or annually.
Levothyroxine is well absorbed from the GI tract; this can be diminished, however, in patients with malabsorption profiles22,23 or with foods such as soy24 and fiber.25,26 This suggests the need to take levothyroxine while fasting. In addition, many drugs may interfere with the absorption of levothyroxine, including cholestyramine, ferrous sulfate, sucralfate, calcium carbonate, and aluminum hydroxide.18,19,27,28 This requires that levothyroxine administration be spaced at least 4 hours apart from these agents.19 Moreover, levothyroxine metabolism may be increased by rifampin29 and sertraline,18 and plasma protein binding and metabolism may be altered by the anticonvulsants phenytoin, phenobarbital, and carbamazepine.8
According to the AACE,18 there is insufficient evidence regarding which patients with hypothyroidism may benefit from treatment with a combination of T4 and T3 versus T4 alone. The ATA19 does not recommend liothyronine treatment for chronic hypothyroidism due to the increased likelihood of iatrogenic hyperthyroidism. Furthermore, a randomized controlled trial by Clyde et al30 found no benefit in patients with primary hypothyroidism that were treated with combination levothyroxine and liothyronine versus levothyroxine alone. Combination therapy is also not recommended due to the increased possibility of fluctuation or elevation of T3 concentrations.31 In addition, the use of desiccated thyroid hormone formulations is not recommended.
Because levothyroxine has an NTI, the potential for insufficient treatment or overtreatment, thus inducing iatrogenic hyperthyroidism, must be recognized. It is estimated that 15% to 29% of patients receive inadequate doses of levothyroxine, and 18% to 24% receive excessive doses based on serum TSH levels that are outside of the normal range.11,32,33 Adverse effects related to levothyroxine treatment occur due to doses higher than optimal for the individual patient and include symptomatic thyrotoxicosis (emotional lability, nervousness, irritability, poor concentration, muscular weakness and fatigability, voracious appetite with weight loss, hyperdefecation, proximal muscle tremor, moist skin, heat intolerance),4 subclinical thyrotoxicosis with increased risks of bone loss,34 and atrial fibrillation.35 On the other hand, inadequate treatment with levothyroxine will not sufficiently alleviate the clinical manifestations of hypothyroidism. Such adverse effects and the patient's perception that the drug is not working can result in poor patient compliance. Although allergies to levothyroxine preparations are rare, it is important for the clinician and pharmacist to ascertain whether a patient may have an allergy or adverse reaction to any of the inactive ingredients in the preparation given. For example, lactose intolerance may be a complication that prevents the use of a lactose-containing preparation of levothyroxine such as Synthroid (Abbott Laboratories, Chicago, IL) in some patients.36 If the patient is sufficiently sensitive to the small amount of lactose present in the tablet, abdominal bloating or other symptoms may result in poor patient compliance and inadequate treatment.
Management of Hypothyroidism During Pregnancy
Levothyroxine is safe during pregnancy, and replacement therapy is advisable in all pregnant patients with mild-to-severe hypothyroidism.18,37-39 The fetal thyroid gland does not become active until about 12 weeks' gestation. Therefore during this time the mother is the sole source of thyroid hormones for the fetus. Haddow et al39 report that hypothyroidism in pregnant women can adversely affect their child's subsequent performance on neuropsychological tests and that decreases in performance can occur even when the mother's hypothyroidism is mild. Thus, treating the pregnant patient can benefit the child as well as reduce the morbidity of the mother.39 It is also recommended that TSH levels be measured before pregnancy, if possible, and each trimester.18,19 Measurement of TSH levels is critical because pregnancy can increase the dose requirement of levothyroxine in many patients with hypothyroidism.37 Administration should return to the prepregnancy dose immediately after delivery, however, and serum TSH levels should be ascertained 6 to 8 weeks later.19
Untreated overt hypothyroidism during pregnancy has been associated with increased risk of maternal hypertension, preeclampsia, anemia, postpartum hemorrhage, cardiac ventricular dysfunction, spontaneous abortion, fetal death, and low birth weight, and evidence suggests the potential for abnormal fetal brain development.18,38 Furthermore, slight increases in maternal TSH levels during pregnancy may be associated with increased risk of spontaneous abortion. Whether levothyroxine therapy can prevent this is unknown. However, it has been determined that, in most of these women, thyroid autoantibodies develop that may also contribute to fetal death.18,38,40
The treatment of hypothyroidism in pregnant patients is thus advised, although tight control of dose is necessary through the repeated measurement of TSH levels. Because of the narrow therapeutic window of levothyroxine, too little or too much replacement therapy can result in adverse effects occurring in both the mother and child.
Hypothyroidism in the Elderly
Hypothyroidism in elderly patients often is associated with subtle symptoms, and many are frequently ascribed simply to old age. Symptoms may include deafness, dry skin, hair loss, hoarseness of voice, ataxia, and mental dysfunction (confusion, dementia, depression). Screening for hypothyroidism using TSH measurements is recommended in women more than 60 years of age, anyone with a prior history of treatment for thyroid disease, and those with a history of autoimmune disease, symptoms of cognitive dysfunction, or hypercholesterolemia.19,41
Levothyroxine therapy should be administered at a dose directed at returning TSH levels into the normal range. The elderly tolerate the effects of excess levothyroxine poorly. Thus patient monitoring is critical to achieve optimal therapy.
Hypothyroidism in Patients with Heart Disease
Hypothyroidism is associated with hyperlipidemia and coronary artery disease. Approximately 3% of patients with chronic hypothyroidism report angina, and about the same percentage complain of angina during levothyroxine treatment. In these patients, the angina does not change but may worsen in up to 40% of patients after levothyroxine treatment, thus requiring less than full replacement therapy.17 Thyroid hormone has both positive inotropic and chronotropic effects on the heart and thus may exacerbate myocardial ischemia and precipitate myocardial infarction or sudden death in patients with underlying cardiac disease. It is recommended that in patients with symptomatic heart disease the initial dose of levothyroxine be 25 mg daily, with upward titration in 12.5-to 25-mg increments every 3 to 6 weeks, with vigilant clinical and myocardial monitoring.8 Again, TSH and freeT4assessment is critical in these patients to properly move the patient toward a euthyroid state, without adversely affecting any underlying cardiac issues.
Hypothyroidism in Other Common Clinical Circumstances
Hypothyroidism necessitates special considerations in patients with type 1 diabetes mellitus, infertility, depression, or euthyroid sick syndrome.
Because type 1 diabetes mellitus has an autoimmune component, it increases the risk of acquiring other autoimmune-related disorders including chronic thyroiditis, and it is estimated that 10% of patients with type 1 diabetes will develop this condition, which may initially present subclinically. Furthermore, approximately 25% of women with type 1 diabetes will develop postpartum thyroiditis.42,43 Measurement of TSH and examination for goiter should be performed at regular intervals in patients with diabetes.
Some patients with infertility or menstrual irregularities will in fact have chronic thyroiditis associated with subclinical or clinical hypothyroidism, and the thyroiditis is contributing to the reproductive abnormality. Once chronic thyroiditis is confirmed, proper levothyroxine therapy may restore fertility and normalize menstrual cycles, particularly in patients with high TSH levels.44-46
The AACE states that the diagnosis of subclinical or clinical hypothyroidism must be considered in every patient with depression because a small proportion of patients with depression have primary hypothyroidism.18 If hypothyroidism is found, appropriate levothyroxine treatment should be initiated. Sometimes in psychiatric practice, depressed patients are treated with levothyroxine as well as with antidepressants, but the evidence does not show that levothyroxine alone alleviates depression in these patients.45,47 Patients receiving lithium must be screened periodically because lithium may induce goiter and hypothyroidism.18
Euthyroid Sick Syndrome
Lastly, the evaluation of hypothyroidism in chronically ill individuals is confounded by several factors. Other agents often administered to these patients, such as corticosteroids, may interfere with thyroid function tests. Also, the body tends to compensate by decreasing metabolic rate in states of starvation or illness, which may lower T4 and TSH levels. Often levothyroxine treatment will be deferred until the patient recovers and has been assessed by a clinical endocrinologist.18
Management of Subclinical Hypothyroidism
Subclinical hypothyroidism is defined as mildly increased serum TSH levels with normal T4 and T3. It may represent early thyroid failure, because it often progresses to overt hypothyroidism. Prevalence is common and ranges from 1% to 10% of the adult population, with increasing incidence in women, with advancing age, and in those with high dietary iodine intake. The treatment of subclinical hypothyroidism with levothyroxine is controversial, however. The ATA recommends screening for thyroid dysfunction beginning at 35 years of age and every 5 years thereafter.16 It is during routine screening using TSH measurements that asymptomatic subclinical hypothyroidism is usually discovered. The most common cause is autoimmune thyroiditis, and those patients with thyroid antibodies have a greater risk of progressing to clinical hypothyroidism.14,15
In addition to progression of hypothyroidism, other health problems associated with subclinical hypothyroidism include hyperlipidemia and cognitive deficits.14 The AACE recommends that treatment begin in patients with TSH levels >10 mIU/mL or in patients with TSH levels between 5 and 10 mIU/mL and goiter or positive antithyroid peroxidase antibodies. The target TSH level with treatment should be 0.3 to 3 mIU/mL.18 Initial dosage of levothyroxine should be between 25 and 50 mg per day with follow-up TSH measurement in 6 to 8 weeks. The ATA also states that treatment of subclinical hypothyroidism is advisable, especially if thyroid autoantibodies are positive.19
In contrast, some experts believe that the data do not support the association of subclinical thyroid disease with symptoms or adverse clinical outcomes and do not recommend treatment in patients with TSH levels between 4.5 and 10 mIU/L.48 Furthermore, Gussekloo et al49 state that, in the very elderly, individuals with high serum TSH do not experience adverse effects and may have a prolonged life span, but they recognize that the determination of whether to treat these patients will require a well-designed, randomized, placebo-controlled clinical trial. Whether subclinical hypothyroidism is treated with levothyroxine or not, patients require proper clinical and biochemical monitoring, and dosage adjustments should be made as needed to prevent iatrogenic hyperthyroidism. The importance of this is suggested in a study by Parle et al,50 where a single measurement of low serum thyrotropin in individuals 60 years of age or older was associated with increased mortality, particularly due to circulatory and cardiovascular diseases.
Coma Due to Primary Hypothyroidism
Coma due to primary hypothyroidism is a rare life-threatening condition in which severe hypothyroidism suddenly worsens and is complicated by multiple organ system failure. It predominantly occurs in the elderly and is often precipitated by another illness. Clinical manifestations other than coma include bradycardia, hypothermia, respiratory failure, and cardiovascular dysfunction. Therapy includes a large replacement dose with or without a 500-mg loading dose of intravenous levothyroxine. Liothyronine in divided doses may also be indicated because conversion of T4 to T3 is likely compromised in these patients. Furthermore, glucocorticoids and treatment of underlying or precipitating disorders should be aggressive. Management is in the intensive care unit and with the consultation of a clinical endocrinologist.8,19
Current Issues in Levothyroxine Treatment
The FDA granted AB-rated status to a number of levothyroxine products (Table 2).51 Levothyroxine products have an NTI. Therefore treatment for hypothyroidism should be individualized to the patient, and biochemical monitoring should be used to evaluate the appropriateness of therapy. The determination of bioequivalence of levothyroxine products is challenging because levothyroxine is biochemically and physiologically identical to theT4 produced endogenously.
Blakesley et al20 performed mathematical corrections based on known physiologic principles that were intended to account for the contributions of endogenous T4. They found that, with no baseline correction for endogenous T4,administered levothyroxine doses that differed by 25% to 33% could not be distinguished. Differences in these amounts could be distinguished, however, when T4 levels were mathematically corrected using one of the following methods: (1) the mean of the three T4 values taken at -0.5, -0.25, and 0 hours before dosing subtracted from each concentration after dosing; (2) each T4 concentration corrected for the hypothetical decay of endogenous T4 with a 7-day half-life, beginning with the level obtained immediately before dosing; or (3) the subtraction of T4 concentration measured at the analogous time point on the day prior to administration of the levothyroxine dose from each T4 concentration after dosing. Acknowledging this, the FDA adopted method number 1 as its basis for granting AB ratings to levothyroxine products. Even using this method, however, products with dosages that differed by 12.5% are still deemed bioequivalent.
In response to the FDA's actions, the AACE, the ATA, and the Endocrine Society released a joint position statement on the use and interchangeability of thyroxine products.52 The statement expresses concern about the FDA's method for determining bioequivalence and asserts that the FDA has failed to address questions related to the bioequivalence of thyroxine preparations. Bioequivalence is generically defined as the relative bioavailabilities of the active ingredients of 2 products and is related to the rate and extent of absorption of the active ingredient.20 FDA guidelines for determining bioequivalence of levothyroxine products through pharmacokinetic studies require the administration of a single dose, administered to healthy people (with normal thyroid function) at a strength several times the normal therapeutic dose.53 This should raise the serum concentration significantly above the endogenous level of T4 produced by the person so that pharmacokinetic monitoring is meaningful. It is possible, however, that endogenous T4 contributes in a significant way to the measurement of hormone levels. The FDA's methods employ area under the curve and maximum concentration measurements to determine bioequivalence, and the joint position statement argues that "corrected" values fail to account for the subjects'own endogenous contribution to T4 levels, and thus can still be off by 12.5%. These organizations express concern that TSH levels are not part of the FDA's determinations for equivalence.
When considering switching levothyroxine preparations in a hypothyroid patient, these issues must be considered. Furthermore, the pharmacist must remember that the potential effects of drug substitution are borne by the patient and should counsel the patient to be aware of any changes in symptoms or the appearance of new symptoms. Because levothyroxine has an NTI, iatrogenic hyperthyroidism or the inadequate replacement of thyroid hormone is possible if a switch to a formulation that in vivo has a significantly different therapeutic profile than the previous preparation in an individual patient occurs. For this reason, AACE guidelines18 suggest the use of a high-quality preparation of levothyroxine. Accordingly, the AACE has a Best Physician Practice Statement that reads, "Patients should be maintained on the same brand name levothyroxine product. If the brand of levothyroxine medication is changed, either from one brand to another brand, from a brand to a generic product, or from a generic product to another generic product, patients should be retested by measuring serum TSH in six (6) weeks, and the drug retitrated as needed. Since small changes in levothyroxine administration can cause significant changes in TSH serum concentrations, precise and accurate TSH control is necessary to avoid potential adverse iatrogenic effects."
Because the prescribing physician may not be aware of possible switches in levothyroxine preparations, the pharmacist should recommend to patients that they be evaluated biochemically for TSH levels approximately 6 weeks after a switch and the drug retitrated if necessary. Open communication between the pharmacist and physician is highly recommended. Furthermore, the pharmacist should educate the patient that levothyroxine therapy is often lifelong and that switching formulations, particularly multiple times, may lead to excess medical cost in terms of follow-up examinations as well as the appearance of unwanted adverse effects.
Until the FDA and the societies that have a main focus on hypothyroidism treatment agree on standardized evaluation protocols for levothyroxine products, these issues regarding switching will remain. It is fair to investigate the possibility of some sort of correction for endogenously produced T4 to get a better comparison of whether 2 levothyroxine preparations are truly bioequivalent.
It is the role of the pharmacist to maintain open lines of communication between physician and pharmacy, and pharmacy and patient, and to encourage appropriate interaction between patient and physician. If a preparation of levothyroxine is changed at the pharmacy, the pharmacist should make the patient fully aware of the switch and recommend that the patient follow up with his or her physician for evaluation, especially if symptoms change. In addition, most states have not designated a list of drugs that are not substitutable, eg, NTI drugs,54 and it is the responsibility of pharmacists to understand the regulations within their jurisdiction regarding this matter.
Hypothyroidism is a common endocrine disorder that is managed pharmacologically with thyroid hormone replacement therapy. Levothyroxine preparations have an NTI. Therefore dosage should be individualized to each patient. Levothyroxine negatively feeds back upon the hypothalamus and anterior pituitary to decrease levels of TRH and TSH. Thus measurement of TSH levels is a sensitive assessment of whether the patient is receiving the proper dosage of levothyroxine. Recently the FDA gave AB-rating status to a number of generic formulations of levothyroxine. The endocrine societies disagree with these ratings, because the dosages of these products can differ by as much as 12.5% and still be deemed bioequivalent. Thus, these products should not be treated as true generics. The pharmacist should understand that small dosage changes or switching levothyroxine preparations can have an adverse impact on the patient and should counsel the patient to be mindful of any changes in symptom profile. Furthermore, the pharmacist should encourage patients to maintain good communication with their physician for the proper evaluation and treatment of their hypothyroidism. Lastly, pharmacists should be encouraged to take a more proactive role regarding issues related to NTI agents and possibly influence the FDA and the clinical societies to agree to mandate a universal decision regarding NTI agents.
Mitchell R. Emerson, PhD: Assistant Professor of Pharmaceutical Sciences, Midwestern University, College of PharmacyGlendale
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(Based on the article starting on page 117.) Choose the 1 most correct answer.
1. TSH is produced by which of the following structures?
2. The major thyroid hormone receptors utilize what form of signal transduction?
3. What is the half-life of T4?
4. Subclinical hypothyroidism is defined biochemically by which of the following?
5. Which of the following is not a clinical manifestation of hypothyroidism?
6. Which of the following is not a risk factor for hypothyroidism?
7. The treatment of choice for hypothyroidism is which of the following?
8. Compared with adults, in children the dose of levothyroxine based on body weight is which of the following?
9. Which of the following agents can increase the metabolism of levothyroxine?
10. Which of the following is not an adverse effect of too much levothyroxine?
11. Which of the following is correct regarding levothyroxine dose during pregnancy?
12. What percentage of hypothyroid patients will experience worsened angina with levothyroxine treatment?
13. The American Thyroid Association recommends screening for thyroid disease beginning at what age?
14. The most common cause of subclinical hypothyroidism is which of the following?
15. Which of the following is incorrect regarding myxedema coma?
16. Which of the following has the FDA not determined to be therapeutically equivalent to Levoxyl?
17. Which of the following has the FDA not determined to be therapeutically equivalent to levothyroxine sodium (Mylan)?
18. Which of the following is not associated with subclinical hypothyroidism?
19. Which of the following is incorrect regarding the guidelines the FDA uses for determining bioequivalence of levothyroxine preparations?
20. Which of the following is incorrect regarding levothyroxine?