Unit4 Hypothyroidism Book summary

Hypothyroidism diagnosis

A rise in TSH level is the first evidence of primary hypothyroidism. Many patients have a free T4 level within the normal range (compensated hypothyroidism) and few, if any, symptoms of hypothyroidism. As the disease progresses, the free T4 drops below normal. The T3 concentration is often maintained in the normal range despite low T4. Antithyroid peroxidase antibodies and antithyroglobulin antibodies are usually elevated. The RAIU is not useful in evaluation of hypothyroidism because it can be low, normal, or elevated. Pituitary failure (secondary hypothyroidism) should be suspected in patients with decreased T4 levels and inappropriately normal or low TSH levels

hypothyroidism clinical presentation-general

General Hypothyroidism can lead to a variety of end-organ effects with a wide range of disease severity, from entirely asymptomatic individuals to patients in coma with multisystem failure. In the adult, manifestations of hypothyroidism are varied and nonspecific. In the child, thyroid hormone deficiency may manifest as growth or intellectual retardation

levothyroxine dosing in special populations-hypothyroidism during

Hypothyroidism during pregnancy leads to an increased rate of stillbirths and possibly lower neuropsychological scores in infants born of women who received inadequate replacement during pregnancy.50,119 Thyroid hormone is necessary for fetal growth and must come from the maternal side during the first 2 months of gestation. Although liothyronine may cross the placental membrane slightly better than levothyroxine, the latter is considered the drug of choice. The objective of treatment is to decrease TSH to normal, based on the normal reference range for pregnancy. Current guidelines suggest a TSH below 2.5 milli-international units/L during the first trimester and a TSH below 3 milli-international units/L during the remainder of pregnancy.50,51 Based on elevated TSH levels during pregnancy, it was found in one study that the mean dose of levothyroxine had to be increased by 48% to decrease TSH into the normal range. However, in individual women the dosage increase needed may vary from approximately 10% to 80%. Increased production of binding proteins, a marginal decrease in free hormone concentration, modification of peripheral thyroid hormone metabolism, and increased T4 metabolism by the fetal-placental unit all may contribute to increased thyroid hormone demand. As these changes regress after delivery the need for increased levothyroxine will decline.50,51 Up to 60% of women need to have levothyroxine dose adjustment during pregnancy. Upward adjustment will usually be needed by the eighth week of pregnancy. The etiology of the hypothyroidism affects the magnitude of the required increase in levothyroxine dose.107 After delivery the levothyroxine dose can be reduced based on T4 concentrations and measurement of TSH, typically about 6 to 8 weeks after delivery. Many patients can return to their pre-pregnancy dose requirement.

Epidemiology of Hypothyroidism

Hypothyroidism is defined as the clinical and biochemical syndrome resulting from decreased thyroid hormone production.56 Overt hypothyroidism occurs in 1.5% to 2% of women and 0.2% of men, and its incidence increases with age. In the Third National Health and Nutrition Examination Survey (NHANES III), levels of serum TSH and total T4 were measured in a representative sample of adolescents and adults (age 12 or older). Among 16,533 people who neither were taking thyroid medication nor reported histories of thyroid disease, 3.9% had subclinical hypothyroidism (serum TSH more than 4.5 milli-international units/L, and T4 normal), and 0.2% had "clinically significant" hypothyroidism (TSH more than 4.5 milli-international units/L, and T4 less than 4.5 mcg/dL).

TREATMENT OF MYXEDEMA COMA

Immediate and aggressive therapy with IV bolus levothyroxine, 300 to 500 mcg, has traditionally been used. Initial treatment with IV liothyronine or a combination of both hormones has also been advocated because of impaired conversion of T4 to T3. Give glucocorticoid therapy with IV hydrocortisone 100 mg every 8 hours until coexisting adrenal suppression is ruled out. Consciousness, lowered TSH concentrations, and improvement in vital signs are expected within 24 hours. Maintenance levothyroxine doses are typically 75 to 100 mcg IV until the patient stabilizes and oral therapy is begun. Provide supportive therapy to maintain adequate ventilation, euglycemia, BP, and body temperature. Diagnose and treat underlying disorders such as sepsis and MI.

levothyroxine dosing in special populations-congenital hypothyroidism

In congenital hypothyroidism, full maintenance therapy should be instituted early to improve the prognosis for mental and physical development.116,117 The average maintenance dose in infants and children depends on the age and weight of the child. Several studies demonstrate that aggressive therapy with levothyroxine is important for normal development, and current recommendations are for initiation of therapy as soon as possible after birth at a dose of 10 to 15 mcg/kg/day.61,118 This dose is used to keep T4 concentrations at about 10 mcg/dL within 30 days of starting therapy and is associated with improved IQs in treated infants. The dose is progressively decreased to a typical adult dose as the child ages, the adult dose being given in the age range of 11 to 20 years

evaluation of therapeutic outcomes-hypothyroidism

Patients with idiopathic hypothyroidism and Hashimoto's thyroiditis on optimal thyroid hormone replacement therapy should have TSH and free T4 serum concentrations in the normal range.21 Those who are being treated for thyroid cancer should have TSH suppressed to low levels, with the appropriate TSH concentration being determined based on the patient's risk of recurrence or progression, and TG should be undetectable.119 Given the half-life of T4 of 7 days, the appropriate monitoring interval is no more often than 4 weeks. The signs and symptoms of hypothyroidism should be improved or absent (see Clinical Presentation of Hypothyroidism discussed earlier), although it may take several months for the full benefit of therapy to manifest.

release of thyroid hormone into the bloodstream

Proteolysis within thyroid cells releases thyroid hormone into the bloodstream. T4 and T3 are transported by thyroid-binding globulin (TBG), transthyretin, and albumin. Only the unbound (free) thyroid hormone can diffuse into cells, elicit biologic effects, and regulate thyroid-stimulating hormone (TSH) secretion from the pituitary

levothyroxine dosing and administration

Recent studies suggest that the average maintenance dose of levothyroxine for most adults is about 125 mcg/day.56 The replacement dose of levothyroxine is affected by body weight. Estimates of weight-based doses for replacement in hypothyroid patients include 1.6 and 1.7 mcg/kg/day.21 There is, however, a wide range of replacement doses, necessitating individualized therapy and appropriate TSH monitoring to determine an adequate but not excessive dose. In addition to alleviation of symptoms, the goal of treatment for patients with hypothyroidism is to maintain the patient's TSH within the normal range. Some clinicians are of the opinion that the traditional reference range of approximately 0.5 to 4.5 milli-international units/L includes at its upper end some individuals who have unrecognized thyroid disease.99 Thus, some believe that the reference range should be modified downward to 0.5 to 3.5 milli-international units/L or even 0.5 to 2.5 milli-international units/L.100 If this premise is accepted, both the TSH values that trigger l-thyroxine treatment and the TSH treatment goal could potentially be altered. There are cogent arguments on both sides of the issue. Those who suggest maintaining current reference ranges believe that lowering the upper limit of the reference range could result in treating many individuals with thyroid hormone who would not necessarily benefit from such treatment.101 Those who favor narrowing the reference range suggest that additional patients would, in fact, derive benefit from thyroid hormone treatment.100 TSH reference ranges also differ for different populations, such as those who are pregnant, specific ethnic groups, and older individuals.21 The required dose of levothyroxine is dependent on the patient's age102 and the presence of associated disorders, as well as the severity and duration of hypothyroidism.21 Most patients will require approximately 1.7 mcg/kg/day once they reach steady state for full replacement. Dose requirement may be better estimated based on ideal body weight, rather than actual body weight.103 In patients with long-standing disease and older individuals without known cardiac disease, therapy should be initiated with 50 mcg daily of levothyroxine and increased after 1 month. The recommended initial daily dose for older patients with known cardiac disease is 25 mcg daily titrated upward in increments of 25 mcg at monthly intervals to prevent stress on the cardiovascular system. Some patients may experience an exacerbation of angina with higher doses of thyroid hormone. Although the TSH is an indicator of underreplacement or overreplacement, clinicians often fail to alter the dose based on TSH values clearly outside of the normal range. Patients with subclinical or mild hypothyroidism (seen more commonly in the elderly and women) have no or few signs or symptoms, normal serum T3 and T4 concentrations, and an elevated basal TSH concentration.38 The prevalence of this disorder in the NHANES III study was found to be 4.3%.10 Untreated individuals with moderate degrees of subclinical hypothyroidism and negative TPOAb may revert to euthyroidism during followup.104 Increased mortality may be associated with moderate, but not mild subclinical hypothyroidism.105 Spontaneous recovery of thyroid function and uncertainties about which patient groups may benefit from therapy contribute to the debate about treatment of subclinical hypothyroidism. Although the treatment of subclinical hypothyroidism is controversial, patients presenting with marked elevations in TSH (more than 10 milli-international units/L) and high titers of TPOAb or prior treatment with 131I may be most likely to benefit from treatment. It should be noted that some studies find that only one of four treated patients experienced improvement. Other patients who may improve with replacement include those with mild symptoms of hypothyroidism and depression. Reduction of events due to ischemic heart disease was only observed in younger patients in one study.106 If treatment is pursued, reasonable goals in this situation would be to maintain serum T4 and T3 levels in the normal range and reduce TSH to a value of 0.5 to 2.5 milli-international units/L in younger patients and 4 to 6 milli-international units/L in older patients.38 Once euthyroidism is attained, the daily maintenance dose of levothyroxine does not fluctuate greatly. As patients age, the dosing requirement may be reduced.21,102 Third-generation TSH assays improved the accuracy with which thyroid hormone replacement can be monitored. The TSH concentration is the most sensitive and specific monitoring parameter for adjustment of levothyroxine dose. Plasma TSH concentrations begin to fall within hours and are usually normalized within 2 weeks, but they may take up to 6 weeks for some patients, depending on the baseline value. Both TSH and T4 concentrations are used to monitor therapy, and they should be checked every 6 weeks until a euthyroid state is achieved.21,68 Laboratory assessment of thyroid function should be performed approximately 6 weeks after levothyroxine dose initiation or change. This time frame allows achievement of steady state, as the half-life of levothyroxine is approximately 1 week. Serum T4 concentrations can be useful in detecting noncompliance, malabsorption, or changes in levothyroxine product bioequivalence. An elevated TSH concentration indicates insufficient replacement. The appropriate dose maintains the TSH concentration in the normal range. T4 disposal is accelerated by nephrotic syndrome, other severe systemic illnesses, and several antiseizure medications (phenobarbital, phenytoin, and carbamazepine) and rifampin. Pregnancy increases the T4 dose requirement for 75% of women, probably because of factors such as increased degradation by the placental deiodinase, increased T4 pool size, and transfer of T4 to the fetus. The etiology of hypothyroidism also affects the magnitude of the dosage increase.107 Initiating postmenopausal hormone replacement therapy increases the dose needed in 35% of women, perhaps due to an increased circulating TBG level. Patient noncompliance with prescribed T4, the most common cause of inadequate treatment, might be suspected for patients with a dose that is higher than expected, variable thyroid function test results that do not correlate well with prescribed doses, and an elevated serum TSH concentration with serum free T4 at the upper end of the normal range, which can suggest improved compliance immediately before testing, with a lag in the thyrotropin response. For patients with central hypothyroidism caused by hypothalamic or pituitary failure, the serum TSH cannot be used to assess adequacy of replacement. Alleviation of the clinical syndrome and restoration of serum T4 to the normal range are the only criteria available for estimating the appropriate replacement dose of l-thyroxine. Keeping free T4 values in the upper part of the normal laboratory reference range is a reasonable approach,108 with modification of this goal to the middle of the normal range in older patients or patients with comorbidities. Concurrent use of dopamine, dopaminergic agents (bromocriptine), somatostatin or somatostatin analogs (octreotide), and corticosteroids suppresses TSH concentrations in individuals with primary hypothyroidism and may confound the interpretation of this monitoring parameter.21,68 TSH-suppressive levothyroxine therapy can be given to patients with nodular thyroid disease and diffuse goiter, and to patients with a history of thyroid irradiation. It is also usually given to patients with papillary or follicular thyroid cancer. The rationale for suppression therapy is to reduce TSH secretion, which promotes growth and function of abnormal thyroid tissue. However, such management, other than for patients with thyroid cancer or with elevated TSH levels, is quite controversial. Some clinicians rarely recommend or use such therapy; others will recommend a trial of levothyroxine as suppressive therapy in some patients. Three meta-analyses concluded that suppressive therapy for nodules was associated with a small decrease in nodule growth,109 a statistically nonsignificant reduction in nodule growth,110 and a significant reduction in nodule growth with longer-term treatment.111 l-thyroxine may be given in nontoxic MNG to suppress the TSH to low-normal levels of 0.5 to 1 milli-international unit/L if the baseline TSH is more than 1 milli-international unit/L. Goiter size and thyroid volume may be reduced with suppression therapy. Diffuse goiter associated with autoimmune thyroiditis may also be treated with levothyroxine to reduce goiter size and thyroid volume. If suppressive therapy with levothyroxine is pursued, the age, gender, and menopausal status of the patient need to be considered, along with the risk of cardiac arrhythmias and reduced bone mineral density. Levothyroxine suppression therapy is of benefit to all but the lowest-risk thyroid cancer patients and is generally used in the management of patients with differentiated thyroid cancer, with the TSH goal being influenced by the patient's thyroid cancer stage and other risk factors.112,113 Current guidelines from the American Thyroid Association suggest suppressing the TSH to below 0.1 milli-international unit/L in higher-risk patients, but keeping TSH around the lower limit of normal (0.1-0.5 milli-international unit/L) in low-risk patients.

Hypothyroidism goals of treatment

Restore thyroid hormone concentrations in tissue, provide symptomatic relief, prevent neurologic deficits in newborns and children, and reverse the biochemical abnormalities of hypothyroidism

conversion of T4 to T3

T4 is secreted solely from the thyroid, but less than 20% of T3 is produced there; most T3 is formed from breakdown of T4 catalyzed by the enzyme 5′-monodeiodinase in peripheral tissues. T3 is five times more active than T4. T4 may also be acted on by 5′-monodeiodinase to form reverse T3, which has no significant biologic activity

hypothyroidism clinical presentation-other tests

TPOAbs and anti-TG antibodies are likely to be elevated in autoimmune thyroiditis.

Thyroid hormone formation

Thyroid hormones: thyroxine (T4) and triiodothyronine (T3) are formed on thyroglobulin, a large glycoprotein synthesized within the thyroid cell. Inorganic iodide enters the thyroid follicular cell and is oxidized by thyroid peroxidase and covalently bound (organified) to tyrosine residues of thyroglobulin. Iodinated tyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) combine (couple) to form iodothyronines in reactions catalyzed by thyroid peroxidase. Thus, two molecules of DIT combine to form T4, and MIT and DIT join to form T3.

hypothyroidism clinical presentation-diagnosis

diagnosis In primary hypothyroidism, TSH serum concentration should be elevated. In secondary hypothyroidism, TSH levels may be within or below the reference range; when TSH bioactivity is altered, the levels reported by immunoassay may even be elevated. Free and/or total T4 and T3 serum concentrations should be low

hypothyroidism clinical presentation-signs

signs Objective weakness is common, with proximal muscles being affected more than distal muscles. Slow relaxation of deep tendon reflexes is common. The most common signs of decreased levels of thyroid hormone include coarse skin and hair, cold or dry skin, periorbital puffiness, and bradycardia. Speech is often slow and the voice may be hoarse. Reversible neurologic syndromes such as carpal tunnel syndrome, polyneuropathy, and cerebellar dysfunction may also occur. Galactorrhea may be found in women.

thyroid hormone synthesis

The thyroid hormones thyroxine (T4) and triiodothyronine (T3) (Fig. 75-1) are formed within thyroglobulin (TG), a large glycoprotein synthesized in the thyroid cell. Because of the unique tertiary structure of this glycoprotein, iodinated tyrosine residues present in TG are able to bind together to form active thyroid hormones. Iodide is actively transported through the basolateral membrane via a Na+/I- symporter from the extracellular space into the thyroid follicular cell against an electrochemical gradient, driven by the coupled transport of sodium.1 Structurally related anions such as thiocyanate (SCN-), perchlorate (ClO4-), and pertechnetate (TcO4-) are competitive inhibitors of iodine transport.1 In addition, bromine, fluorine, and, under certain circumstances, lithium block iodide transport into the thyroid (Table 75-1). Inorganic iodide that enters the thyroid follicular cell is ushered through the cell to the apical membrane, where it is transported into the follicular lumen by pendrin, and possibly other transport proteins.1 Located on the luminal side of the apical membrane, thyroid peroxidase oxidizes iodide and covalently binds the organified iodide to tyrosine residues within TG (Fig. 75-2). It is interesting that although salivary glands and the gastric mucosa are able to actively transport iodide, they are unable to effectively incorporate iodide into proteins given the lack of similar oxidizing machinery. The iodinated tyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) combine to form iodothyronines (Fig. 75-3). Thus, two molecules of DIT combine to form T4, whereas MIT and DIT constitute T3. In addition to its role in iodine organification, the hemoprotein thyroid peroxidase also catalyzes the formation of iodothyronines (coupling) Iodine deficiency causes an increase in the MIT:DIT ratio in TG and leads to a relative increase in the production of T3.2 Because T3 is more potent than T4, the increase in T3 production in iodine-deficient areas may be beneficial. The thionamide drugs used to treat hyperthyroidism inhibit thyroid peroxidase and thus block thyroid hormone synthesis. Thyroglobulin is stored in the follicular lumen and must reenter the cell, where the process of proteolysis liberates thyroid hormone into the bloodstream. Thyroid follicles active in hormone synthesis are identified histologically by columnar epithelial cells lining a follicular lumen, which is depleted of colloid. Inactive follicles are lined by cuboidal epithelial cells and are replete with colloid. Both iodide and lithium block the release of preformed thyroid hormone, through poorly understood mechanisms. T4 and T3 are transported in the bloodstream primarily by three proteins: (1) thyroxine-binding globulin (TBG), (2) transthyretin (TTR), and (3) albumin. It is estimated that 99.96% of circulating T4 and 99.5% of T3 are bound to these proteins. However, only the unbound (free) thyroid hormone is able to diffuse into the cell, elicit a biologic effect, and regulate thyroid-stimulating hormone (TSH; also known as thyrotropin) secretion from the pituitary. Multiple functions have been ascribed to these transport proteins, including (a) assuring minimal urinary loss of iodide, (b) providing a mechanism for uniform tissue distribution of free hormone, and (c) transport of hormone into the central nervous system. Whereas T4 is secreted solely from the thyroid gland, less than 20% of T3 is produced in the thyroid. The majority of T3 is formed from the breakdown of T4 catalyzed by the 5′-monodeiodinase enzymes found in extrathyroidal peripheral tissues. Because the binding affinity of nuclear thyroid hormone receptors (TRs) is 10 to 15 times higher for T3 than for T4, the deiodinase enzymes play a pivotal role in determining overall metabolic activity. Three different monodeiodinase enzymes are present in the body. Of the enzymes that catalyze 5′-monodeiodination, type I enzymes are present in peripheral tissues such as the liver and kidney, whereas type II enzymes are found in the CNS, pituitary, and thyroid. Type III enzymes, found in the placenta, skin, and developing brain, inactivate T4 and T3 by deiodinating the inner ring at the 5 position. The principal characteristics of these enzymes are listed in Table 75-2. T4 may also be acted on by the enzyme 5′-monodeiodinase to form reverse T3, but this accounts for a small component of hormone metabolism. Polymorphisms in the deiodinase genes may prove to be of clinical significance. For example, a polymorphism in the type I deiodinase leading to increased activity seems to be associated with an increased circulating ratio of free T3 to free T4.3 Reverse T3 has no known biologic activity. T3 is removed from the body by deiodinative degradation and through the action of sulfotransferase enzyme systems converting to T3 sulfate and 3,3-diiodothyronine sulfates, thus facilitating enterohepatic clearance. Thyronamines are derivatives of thyroid hormone that are present in low concentrations in human serum.4 The most studied thyronamine, 3-iodothyronamine, can theoretically be made from T4 by decarboxylation and deiodination. Administration of pharmacologic amounts of 3-iodothyronamine to animals has profound effects on temperature regulation and cardiac function, and shifts fuel metabolism from carbohydrates to lipids. However, a possible physiologic role for thyronamines has yet to be determined, although altered levels may be associated with some disease states

Hypothyroidism Levothyroxine treatment

Levothyroxine (L-thyroxine, T4) is the drug of choice for thyroid hormone replacement and suppressive therapy because it is chemically stable, relatively inexpensive, active when given orally, free of antigenicity, and has uniform potency. Because T3 (and not T4) is the biologically active form, levothyroxine administration results in a pool of thyroid hormone that is readily and consistently converted to T3. In patients with long-standing disease and older individuals without known cardiac disease, start therapy with levothyroxine 50 mcg daily and increase after 1 month. The recommended initial dose for older patients with known cardiac disease is 25 mcg/day titrated upward in increments of 25 mcg at monthly intervals to prevent stress on the cardiovascular system. The average maintenance dose for most adults is ~125 mcg/day, but there is a wide range of replacement doses, necessitating individualized therapy and appropriate TSH monitoring to determine an appropriate dose. Although treatment of subclinical hypothyroidism is controversial, patients presenting with marked elevations in TSH (>10 mIU/L) and high titers of thyroid peroxidase antibody or prior treatment with sodium iodide-131 may be most likely to benefit from treatment. Levothyroxine is the drug of choice for pregnant women, and the goal is to decrease TSH to the normal reference range for pregnancy. Cholestyramine, calcium carbonate, sucralfate, aluminum hydroxide, ferrous sulfate, soybean formula, dietary fiber supplements, and espresso coffee may impair the GI absorption of levothyroxine. Drugs that increase nondeiodinative T4 clearance include rifampin, carbamazepine, and possibly phenytoin. Selenium deficiency and amiodarone may block conversion of T4 to T3 Excessive doses of thyroid hormone may lead to heart failure, angina pectoris, and myocardial infarction (MI). Hyperthyroidism leads to reduced bone density and increased risk of fracture.

pharmacologic therapy for hypothyroidism

Levothyroxine is the drug of choice for thyroid replacement and suppressive therapy because it is chemically stable, relatively inexpensive, active when orally administered, free of antigenicity, and has uniform potency. Whereas T3 is the biologically more active form of thyroid hormone, levothyroxine administration results in a pool of thyroid hormone that is readily and consistently converted to T3; in this regard, levothyroxine may be thought of as a prohormone. The ability of levothyroxine to achieve normal T3 concentrations was illustrated in a study of recently athyreotic patients in whom levothyroxine monotherapy produced similar T3 levels to those documented prior to the patient's thyroidectomy.71 Several other studies, however, suggest that athyreotic individuals taking T4 may have low or low-normal T3 levels.72,73,74 Liothyronine (T3) is chemically pure with known potency and has a shorter half-life of 1.5 days. Although it can be used diagnostically in the T3 suppression test, T3 has some clinical disadvantages, including a higher incidence of cardiac adverse effects, higher cost, and difficulty in monitoring with conventional laboratory tests. If used, T3 needs to be administered three times a day and it may take a prolonged period of adjustment to achieve stable euthyroidism.70 Liotrix is a combination of synthetic T4 and T3 in a 4:1 ratio. It is chemically stable and pure and has a predictable potency. The major limitations to this product are high cost and lack of therapeutic rationale, because most T3 is peripherally converted from T4. In addition, the T4:T3 ratio is much higher than the 14:1 molar ratio produced by the thyroid gland in humans. Image not available. Trials comparing levothyroxine alone with a combination of levothyroxine plus partial replacement with liothyronine (T3) have generally shown that combinations of T4 + T3 are no better than T4 alone. At least 13 such trials with varying designs have been performed to date.21 Four of these trials have found that patients expressed a preference for combination therapy. By way of illustration, in one trial of combination therapy, Clyde et al.75 compared levothyroxine alone for treatment of primary hypothyroidism with combination therapy using levothyroxine plus liothyronine. These investigators demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a health-related quality-of-life questionnaire, and standard measures of cognitive performance.75 As discussed in recent guidelines,21 three meta-analyses and a systematic review have also suggested no benefits.76,77,78,79 A secondary analysis, however, suggested that individuals harboring a specific deiodinase polymorphism may have a poorer psychological response to levothyroxine therapy and a better response to combination therapy with both T4 and T3. However, no prospective study investigating whether the presence of these polymorphisms affects satisfaction with replacement therapy has yet been reported.80 A recent study conducted in rats suggested impairment of type 2 deiodinase activity in the whole body during levothyroxine monotherapy due to deiodinase inactivation, compared with maintenance of deiodinase activity in the hypothalamus.81 The lesser activation in the hypothalamus lead to efficient T3 production in the hypothalamus and normalization of TSH before T3 normalized in the rest of the body. Accompanying the inactivation of type 2 deiodinase in other tissues, lower serum T3 and higher T4/T3 ratios were seen in rats during monotherapy with l-thyroxine, compared with combination therapy employing a subcutaneous slow release T3 pellet. Clinical trials of a slow release T3 preparation, other than a pharmacokinetic study of T3 sulfate in profoundly hypothyroid individuals,82 has yet to be conducted. Desiccated thyroid has historically been derived from pig, beef, or sheep thyroid glands, although pigs are currently the usual source. The United States Pharmacopeia, requires thyroid USP to contain 38 mcg (±15%) of l-thyroxine and 9 mcg (±10%) of liothyronine for each 60 to 65 mg (one grain). Thyroid USP, as an animal protein-derived product, may be antigenic in allergic or sensitive patients. Even though desiccated thyroid is inexpensive, its limitations preclude it from being considered as a drug of choice for hypothyroid patients.

hypothyroidism liothyronine treatment

Liothyronine (synthetic T3) has uniform potency but has a higher incidence of cardiac adverse effects, higher cost, and difficulty in monitoring with conventional laboratory tests Excessive doses of thyroid hormone may lead to heart failure, angina pectoris, and myocardial infarction (MI). Hyperthyroidism leads to reduced bone density and increased risk of fracture.

hypothyroidism Liotrix treatment

Liotrix (synthetic T4:T3 in a 4:1 ratio) is chemically stable, pure, and has a predictable potency but is expensive. It also lacks therapeutic rationale because most T3 is converted peripherally from T4. Excessive doses of thyroid hormone may lead to heart failure, angina pectoris, and myocardial infarction (MI). Hyperthyroidism leads to reduced bone density and increased risk of fracture.

levothyroxine dosing in special populations-myxedema coma

Myxedema coma is a rare consequence of decompensated hypothyroidism.27,115 Clinical features include hypothermia, advanced stages of hypothyroid symptoms, and altered sensorium ranging from delirium to coma. Mortality rates of 60% to 70% necessitate immediate and aggressive therapy. Traditionally, the initial treatment has been IV bolus levothyroxine 300 to 500 mcg.21 However, as deiodinase activity is markedly reduced, impairing T4 to T3 conversion, initial treatment with IV T3, or a combination of both hormones has also been advocated.27 Glucocorticoid therapy with IV hydrocortisone 100 mg every 8 hours should be given until coexisting adrenal suppression is ruled out.21 All therapies must be administered parenterally as cessation of gastrointestinal peristalsis occurs, preventing absorption of orally administered medications. Consciousness, lowered TSH concentrations, and improvement in vital signs are expected within 24 hours. Maintenance doses of levothyroxine are typically 75 to 100 mcg given IV until the patient stabilizes and oral therapy is begun. Supportive therapy must be instituted to maintain adequate ventilation, blood pressure, and body temperature, and ensure euglycemia. Any underlying disorder, such as sepsis or myocardial infarction, obviously must be diagnosed and treated.

levothyroxine adverse effects

Serious untoward effects are unusual if dosing is appropriate and the patient is carefully monitored during initial treatment. A cross-sectional study showed that of a population of 1,525 individuals taking levothyroxine, 40% actually had abnormal TSH values.87 A recent study showed that 57% of individuals 65 years or older receiving thyroid hormone treatment had abnormal TSH values.88 Both of these studies suggest failure to keep a patient's TSH at goal is common. Levothyroxine replacement in athyreotic hypothyroid patients restores systolic and diastolic left ventricular performance within 2 weeks, and the use of levothyroxine may increase the frequency of atrial premature beats but not necessarily ventricular premature beats. Excessive doses of thyroid hormone may lead to heart failure, angina pectoris, and myocardial infarction; rarely, the latter may be caused by coronary artery spasm. Allergic or idiosyncratic reactions can occur with the natural animal-derived products such as desiccated thyroid, but these are extremely rare with the synthetic products used today. The 0.05 mg (50 mcg) Synthroid tablet is the least allergenic (due to a lack of dye and few excipients) and should be tried for the patient suspected to be allergic to thyroid hormone tablets. Hyperremodeling of cortical and trabecular bone due to hyperthyroidism leads to reduced bone density and may increase the risk of fracture. Compared with normal controls, excess exogenous thyroid hormone results in histomorphometric and biochemical changes similar to those observed in osteoporosis and untreated hyperthyroidism.89,90 The risk for this complication seems to be related to the dose of levothyroxine, patient age, and gender. Markers for bone turnover include urinary N-telopeptides, pyridinoline crosslinks of type I collagen, osteocalcin, and bone-specific alkaline phosphatase. When doses of levothyroxine are used to suppress TSH concentrations to below-normal values (eg, less than 0.3 milli-international unit/L) in postmenopausal women, this adverse effect is more likely to be seen. Cortical bone is affected to a greater degree than trabecular bone at suppressive doses of l-thyroxine. In contrast, it appears to be much less likely in men and in premenopausal women. Maintaining the TSH between 0.7 and 1.5 milli-international units/L does not alter bone mineral density in premenopausal women. Although not all studies have shown consistent results, a recent cohort study suggests that there is no adverse effect on bone density with treatment with l-thyroxine to achieve a normal TSH.

Hypothyroidism EVALUATION OF THERAPEUTIC OUTCOMES

Serum TSH concentration is the most sensitive and specific monitoring parameter for adjustment of levothyroxine dose. Concentrations begin to fall within hours and are usually normalized within 2 to 6 weeks. Check both TSH and T4 concentrations every 6 weeks until a euthyroid state is achieved. An elevated TSH level indicates insufficient replacement. Serum T4 concentrations can be useful in detecting noncompliance, malabsorption, or changes in levothyroxine product bioequivalence. TSH may also be used to help identify noncompliance. In patients with hypothyroidism caused by hypothalamic or pituitary failure, alleviation of the clinical syndrome and restoration of serum T4 to the normal range are the only criteria available for estimating the appropriate replacement dose of levothyroxine

hypothyroidism clinical presentation-symptoms

Symptom Common symptoms of hypothyroidism include dry skin, cold intolerance, weight gain, constipation, and weakness. Complaints of lethargy, depression, fatigue, exercise intolerance, or loss of ambition and energy are also common but are less specific. Muscle cramps, myalgia, and stiffness are frequent complaints of hypothyroid patients. Menorrhagia and infertility may present commonly in women.

hypothyroidism clinical presentation

Symptoms of hypothyroidism include dry skin, cold intolerance, weight gain, constipation, weakness, lethargy, fatigue, muscle cramps, myalgia, stiffness, and loss of ambition or energy. In children, thyroid hormone deficiency may manifest as growth or intellectual retardation. Physical signs include coarse skin and hair, cold or dry skin, periorbital puffiness, bradycardia, and slowed or hoarse speech. Objective weakness (with proximal muscles affected more than distal muscles) and slow relaxation of deep tendon reflexes are common. Reversible neurologic syndromes such as carpal tunnel syndrome, polyneuropathy, and cerebellar dysfunction may also occur. Most patients with secondary hypothyroidism due to inadequate TSH production have clinical signs of generalized pituitary insufficiency, such as abnormal menses and decreased libido, or evidence of a pituitary adenoma, such as visual field defects, galactorrhea, or acromegaloid features. Myxedema coma is a rare consequence of decompensated hypothyroidism manifested by hypothermia, advanced stages of hypothyroid symptoms, and altered sensorium ranging from delirium to coma. Mortality rates of 60% to 70% necessitate immediate and aggressive therapy.

Thyroid Hormone Regulation and Action

The growth and function of the thyroid are stimulated by activation of the thyrotropin receptor by TSH.5 The receptor belongs to the family of G-protein-coupled receptors. The thyrotropin receptor is coupled to the α subunit of the stimulatory guanine-nucleotide-binding protein (Gsα), activating adenylate cyclase and increasing the accumulation of cyclic adenosine monophosphate. Through this mechanism, TSH stimulates the expression of Na+/I- symporter, TG, and thyroid peroxidase genes as well as increases apical iodide efflux. Somatic activating mutations in the receptor are commonly seen in autonomously functioning thyroid nodules.6 Rarely, germline-activating mutations of the TSH receptor have been reported in kindreds with Leclere's syndrome, and thyrotoxicosis can result from germline-activating mutations in G-protein signaling in McCune-Albright syndrome. Conversely, thyrotropin resistance results from point mutations that prevent TSH binding, leading to abnormalities in the thyrotropin receptor-adenylate cyclase system and congenital hypothyroidism.5 Individuals with this abnormality have high levels of TSH but decreased TG levels and a normal or small gland. Thyroid hormone nuclear receptors regulate the transcription of target genes in the presence of physiologic concentrations of T3.7 Unlike most other nuclear receptors, TRs also actively regulate gene expression in the absence of hormone, typically resulting in an opposite effect. TRs translocate from the cytoplasm to the nucleus, interact in the nucleus with T3, and target genes and other proteins required for basal and T3-dependent gene transcription. TRs exist in several isoforms, including TRβ1, TRβ2, and TRα1.7 Thyroid hormone has different actions in different tissues based on tissue-specific expression of the different TR isoforms. There is interest in developing thyroid hormone analogs that selectively activate specific TR isoforms. Such agents could theoretically have targeted desirable effects such as stimulating energy expenditure without having adverse effects on other tissues.8 The production of thyroid hormone is regulated in two main ways. First, thyroid hormone is regulated by TSH secreted by the anterior pituitary. The secretion of TSH is itself under negative feedback control by the circulating level of free thyroid hormone and the positive influence of hypothalamic thyrotropin-releasing hormone (TRH). Second, extrathyroidal deiodination of T4 to T3 is regulated by a variety of factors including nutrition, nonthyroidal hormones, ambient temperatures, drugs, and illness.

hypothyroidism levothyroxine pharmacokinetics

The half-life of levothyroxine is approximately 7 days. This long half-life is responsible for a stable pool of prohormone and the need for only once-daily dosing with levothyroxine. Older studies with levothyroxine suggested that bioavailability was low and erratic; however, this product has been reformulated, and the average bioavailability improved to approximately 80%.83 Different levothyroxine preparations contain different excipients such as dyes and fillers. The bioavailabilities of Synthroid, Levoxyl, and generic levothyroxine preparations were compared in a blinded, randomized, four-way crossover trial.84 The study was sponsored by the manufacturers of Synthroid, who have challenged the authors' conclusions that the levothyroxine preparations are bioequivalent and should be interchangeable for the majority of patients. However, because the relationship between T4 concentration and TSH is not linear, very small changes in T4 concentration can lead to substantial changes in TSH, which is a more accurate reflection of hormone replacement status. Currently, the FDA mandates that l-thyroxine bioequivalency testing be done using normal volunteers (600 mcg in the fasted state) and three baseline free T4 concentrations be used to correct for endogenous T4 production. Bioequivalency is based on the area under the curve (AUC) and maximum concentration (Cmax) of T4 out to 48 hours. Approximately 70% of the AUC is derived from endogenous production. TSH is not considered, and it is now very clear that T4 is too insensitive as a measure of bioequivalency.85,86 To avoid overtreatment and undertreatment, once a product is selected, therapeutic interchange should be discouraged. Currently, there are several levothyroxine products available, and a number of permutations for interchange are available considering that there are AB1, AB2, AB3, and AB4 products available, and since no reference listed drug is mandated in bioequivalency testing.

levothyroxine drug-drug and drug-food interactions

The time to maximal absorption of levothyroxine is about 2 hours and this should be considered when T4 concentrations are determined. Ingestion of l-thyroxine with food can impair its absorption.21,92 This can potentially affect the TSH concentration achieved if levothyroxine timing with respect to food is varied.93 Mucosal diseases, such as celiac sprue, diabetic diarrhea, and ileal bypass surgery, can also reduce absorption. Cholestyramine, calcium carbonate, sucralfate, aluminum hydroxide, ferrous sulfate, soybean formula, dietary fiber supplements, and espresso coffee may also impair the absorption of levothyroxine from the gastrointestinal tract (reviewed extensively in recent treatment of hypothyroidism guidelines21). Acid suppression with histamine blockers and proton pump inhibitors may also reduce levothyroxine absorption.94 Drugs that increase nondeiodinative T4 clearance include rifampin, carbamazepine, and possibly phenytoin. Selenium deficiency and amiodarone may block the conversion of T4 to T3. Several non-randomized studies have suggested that liquid formulations of levothyroxine or formulations in which the levothyroxine is dissolved in glycerin and encased in a gelatin capsule may circumvent the impaired absorption of levothyroxine that may occur with tablet preparations. For patients receiving enteral feeding, liquid levothyroxine added directly to the feeding tube was associated with a similar serum TSH to that seen in another group of patients in whom the feeding was interrupted in order to administer crushed tablets.95 The former procedure was found to be more convenient by providers. In a study of patients taking proton pump inhibitors, switching to an oral solution was associated with a decrease in serum TSH from a mean of 5.4 milli-international units/L to 1.7 milli-international units/L, suggesting better absorption of the liquid preparation in these patients.96 A study of patients with gastritis who had a stable serum TSH while taking levothyroxine tablets and were then switched to a lower dose of levothyroxine gel capsules, showed that two-thirds of patients had a similar TSH on the lower dose, again suggesting better absorption of the gel capsule formulation.97 Another study suggested that the serum TSH achieved by levothyroxine gel capsules was not affected by the timing with respect to breakfast.98 If the findings of these studies are bolstered by randomized controlled studies in the future, these levothyroxine formulations may prove very convenient for hypothyroid patients.

Etiology of Hypothyroidism

The vast majority of patients have primary hypothyroidism due to thyroid gland failure due to chronic autoimmune thyroiditis. Special populations with higher risk of developing hypothyroidism include postpartum women, individuals with a family history of autoimmune thyroid disorders and patients with previous head and neck or thyroid irradiation or surgery, other autoimmune endocrine conditions (eg, type 1 diabetes mellitus, adrenal insufficiency, and ovarian failure), some other nonendocrine autoimmune disorders (eg, celiac disease, vitiligo, pernicious anemia, Sjögren's syndrome, and multiple sclerosis), primary pulmonary hypertension, and Down's and Turner's syndromes. Secondary hypothyroidism due to pituitary failure is uncommon but should be suspected in a patient with decreased levels of T4 and inappropriately normal or low TSH levels. Most patients with secondary hypothyroidism due to inadequate TSH production will have clinical signs of more generalized pituitary insufficiency, such as abnormal menses and decreased libido, or evidence of a pituitary adenoma, such as visual field defects, galactorrhea, or acromegaloid features, but isolated TSH deficiency can be congenital or acquired as a result of autoimmune hypophysitis.57 Generalized (peripheral and central) resistance to thyroid hormone is extremely rare

hypothyroidism pathophysiology

The vast majority of patients have primary hypothyroidism due to thyroid gland failure from chronic autoimmune thyroiditis (Hashimoto disease). Defects in suppressor T lymphocyte function lead to survival of a randomly mutating clone of helper T lymphocytes directed against antigens on the thyroid membrane. The resulting interaction stimulates B lymphocytes to produce thyroid antibodies. Autoimmune thyroiditis (Hashimoto's disease) is the most common cause of spontaneous hypothyroidism in the adult. Patients may present either with goitrous thyroid gland enlargement and mild hypothyroidism or with thyroid gland atrophy and more severe thyroid hormone deficiency. Both forms of autoimmune thyroiditis probably result from cell- and antibody-mediated thyroid injury. The bulk of evidence suggests that the presence of specific defects in suppressor T-lymphocyte function leads to the survival of a randomly mutating clone of helper T lymphocytes, which are directed against normally occurring antigens on the thyroid membrane. Once these T lymphocytes interact with thyroid membrane antigen, B lymphocytes are stimulated to produce thyroid antibodies. Antithyroid peroxidase (antimicrosomal) antibodies are present in virtually all patients with Hashimoto's thyroiditis and appear to be directed against the enzyme thyroid peroxidase.59 These antibodies are capable of fixing complement and inducing cytotoxic changes in thyroid cells. Antibodies that are capable of stimulating thyroid growth through interaction with the TSH receptor may occasionally be found particularly in goitrous hypothyroidism; conversely, antibodies that inhibit the trophic effects of TSH may be present in the atrophic type Iatrogenic (relating to illness caused by medical examination or treatment) hypothyroidism follows exposure to destructive amounts of radiation, after total thyroidectomy, or with excessive thionamide doses used to treat hyperthyroidism. Other causes of primary hypothyroidism include iodine deficiency, enzymatic defects within the thyroid, thyroid hypoplasia, and ingestion of goitrogens. Iatrogenic hypothyroidism follows exposure to destructive amounts of radiation (radioiodine or external radiation) or surgery. Hypothyroidism occurs within 3 months to a year after 131I therapy in most patients treated for Graves' disease. Thereafter, it occurs at a rate of approximately 2.5% each year. External radiation therapy to the region of the thyroid using doses of greater than 2,500 centigray (cGy) for therapy of neck carcinoma also causes hypothyroidism. This effect is dose dependent, and more than 50% of patients who receive more than 4,000 cGy to the thyroid bed develop hypothyroidism. Total thyroidectomy causes hypothyroidism within 1 month. Excessive doses of thionamides used to treat hyperthyroidism can also cause iatrogenic hypothyroidism. Secondary hypothyroidism due to pituitary failure is uncommon. Pituitary insufficiency may be caused by destruction of thyrotrophs by pituitary tumors, surgical therapy, external pituitary radiation, postpartum pituitary necrosis (Sheehan syndrome), trauma, and infiltrative processes of the pituitary (eg, metastatic tumors and tuberculosis). Iodine deficiency, enzymatic defects within the thyroid gland, thyroid hypoplasia, and maternal ingestion of goitrogens during fetal development may cause cretinism. Early recognition and treatment of the resultant thyroid hormone deficiency is essential for optimal mental development.60 Large-scale neonatal screening programs in North America, Europe, Japan, and Australia are now in place.61 The frequency of congenital hypothyroidism in North America and Europe is 1 per 3,500 to 4,000 live births. In the United States, there are racial differences in the incidence of congenital hypothyroidism, with whites being affected seven times as frequently as blacks. In the adult, hypothyroidism is rarely caused by iodine deficiency and goitrogens. Iodine ingestion in the form of expectorants can lead to hypothyroidism. In sensitive persons (particularly those with autoimmune thyroiditis), the iodide blocks the synthesis of thyroid hormone, leading to an increased secretion of TSH and thyroid enlargement. Thus, both iodine excess and iodine deficiency can cause decreased secretion of thyroid hormone. An example of a goitrogen that can induce hypothyroidism is raw bok choy.62 Several medications can cause hypothyroidism, including lithium, amiodarone, interferon-alfa, interleukin-2, tyrosine kinase inhibitors, and perchlorate. Thyroid-stimulating hormone is required for normal thyroid secretion. Thyroid atrophy and decreased thyroid secretion follow pituitary failure. Pituitary insufficiency may be caused by destruction of thyrotrophs by either functioning or nonfunctioning pituitary tumors, surgical therapy, external pituitary radiation, postpartum pituitary necrosis (Sheehan's syndrome), trauma, and infiltrative processes of the pituitary such as metastatic tumors, tuberculosis, histiocytosis, and autoimmune mechanisms.63,64 In all these situations, TSH deficiency most often occurs in association with other pituitary hormone deficiencies. The identification of secondary hypothyroidism due to bexarotene use has led to recognition of the role of rexinoids and retinoids to cause dysregulation of TSH production.65,66 Note that pituitary enlargement in hypothyroidism does not invariably indicate the presence of a primary pituitary tumor. Pituitary enlargement is seen in patients with severe primary hypothyroidism due to compensatory hyperplasia and hypertrophy of the thyrotrophs.67 With thyroid hormone replacement therapy, serum TSH concentrations decline, indicating that the TSH secretion is not autonomous, and the pituitary resumes a more normal configuration. These patients are easily separated from patients with primary pituitary failure by measuring a TSH level. Thyrotropin-releasing hormone deficiency also causes a rare form of central hypothyroidism. In both adults and children it may occur as a result of cranial irradiation, trauma, infiltrative diseases, or neoplastic diseases.

hypothyroidism thyroid USP treatment

Thyroid USP (or desiccated thyroid) is usually derived from pig thyroid gland. It may be antigenic in allergic or sensitive patients. Inexpensive generic brands may not be bioequivalent Excessive doses of thyroid hormone may lead to heart failure, angina pectoris, and myocardial infarction (MI). Hyperthyroidism leads to reduced bone density and increased risk of fracture.

thyroid hormone production regulation

Thyroid hormone production is regulated by TSH secreted by the anterior pituitary, which in turn is under negative feedback control by the circulating level of free thyroid hormone and the positive influence of hypothalamic thyrotropin-releasing hormone (TRH). Thyroid hormone production is also regulated by extrathyroidal deiodination of T4 to T3, which can be affected by nutrition, nonthyroidal hormones, drugs, and illness.

role of TH in children vs. adults

Thyroid hormones affect the function of virtually every organ system. In a child, thyroid hormone is critical for normal growth and development. In an adult, the major role of thyroid hormone is to maintain metabolic stability. Substantial reservoirs of thyroid hormone in the thyroid gland and blood provide constant thyroid hormone availability. In addition, the hypothalamic-pituitary-thyroid axis is exquisitely sensitive to small changes in circulating thyroid hormone concentrations, and alterations in thyroid hormone secretion maintain peripheral free thyroid hormone levels within a narrow range. Patients seek medical attention for evaluation of symptoms due to abnormal thyroid hormone levels or because of diffuse or nodular thyroid enlargement

hyper and hypo thyroidism key concepts

Thyrotoxicosis is most commonly caused by Graves' disease, which is an autoimmune disorder in which thyroid-stimulating antibody (TSAb) directed against the thyrotropin receptor elicits the same biologic response as thyroid-stimulating hormone (TSH). Hyperthyroidism may be treated with antithyroid drugs such as methimazole (MMI) or propylthiouracil (PTU), radioactive iodine (RAI: sodium iodide-131 [131I]), or surgical removal of the thyroid gland; selection of the initial treatment approach is based on patient characteristics such as age, concurrent physiology (eg, pregnancy), comorbidities (eg, chronic obstructive lung disease), and convenience. MMI and PTU reduce the synthesis of thyroid hormones and are similar in efficacy, although their dosing ranges differ by 10-fold. Overall, PTU may have a greater incidence of side effects. Response to MMI and PTU is seen in 4 to 6 weeks and therefore β-blocker therapy may be concurrently initiated to reduce adrenergic symptoms. Maximal response is typically seen in 4 to 6 months; treatment usually continues for 1 to 2 years, and therapy is monitored by clinical signs and symptoms and by measuring the serum concentrations of TSH and free thyroxine (T4). . Adjunctive therapy with β-blockers controls the adrenergic symptoms of thyrotoxicosis but does not correct the underlying disorder; iodine may also be used adjunctively in preparation for surgery and acutely for thyroid storm. Many patients choose to have ablative therapy with 131I rather than undergo repeated courses of MMI or PTU treatment; most patients receiving RAI eventually become hypothyroid and require thyroid hormone supplementation. Hypothyroidism is most often due to an autoimmune disorder known as Hashimoto's thyroiditis. The drug of choice for replacement therapy in hypothyroidism is levothyroxine. Studies of combination therapy with levothyroxine and liothyronine have not shown reproducible benefits. This approach to treatment of hypothyroidism requires further study. Monitoring of levothyroxine replacement therapy is achieved by observing clinical signs and symptoms and by measuring the serum TSH level. An elevated TSH indicates under-replacement; a suppressed TSH indicates over-replacement

conclusion-hypothyroidism

Untreated hypothyroidism is a devastating disease that if unrecognized eventually progresses into myxedema coma in the absence of any endogenous thyroid reserve. Levothyroxine is a readily available and efficacious hormone that rapidly reverses the biochemical and clinical abnormalities that characterize hypothyroidism. Serum TSH and thyroid hormone levels are useful measures for adjusting the levothyroxine dose during therapy. Until regeneration of thyroid cells from pluripotent stem cells has been fully realized, levothyroxine is the most effective treatment for this common disorder.