Definition: Hypothyroidism Primary hypothyroidism is characterized biochemically by a high serum thyroidstimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration. Subclinical hypothyroidism is characterized biochemically by a high serum TSH concentration and a normal serum free T4 concentration. Most patients are asymptomatic. Secondary or tertiary (Central) hypothyroidism caused by hypothalamic or pituitary disease is characterized by a low serum T4 concentration and a serum TSH concentration that is not appropriately elevated. TSH may be low, normal, or even slightly elevated (up to approximately 10 mu/l). The clinical manifestations of central hypothyroidism are similar to but sometimes milder than those of primary hypothyroidism.
Diagnosis: Primary hypothyroidism Primary thyroid disease accounts for over 95 percent of cases of hypothyroidism. In most patients with symptoms or signs suggestive of hypothyroidism, the serum TSH should be the initial test. If the serum TSH concentration is elevated, the TSH measurement should be repeated along with a serum free T4 to make the diagnosis of hypothyroidism. All patients with overt primary hypothyroidism require treatment (regardless of symptoms), unless the hypothyroidism is transient (as after painless thyroiditis or subacute thyroiditis) or reversible (due to a drug that can be discontinued).
We define an elevated serum TSH as a TSH concentration above the upper limit of the normal TSH reference range, which is typically 4 to 5 mu/l in most laboratories. The upper limit of normal could be as high as 6 to 8 mu/l in healthy octogenarians (a person who is from 80 to 89 years old), or as high as 7.5 mu/l in morbid obesity. Secondary and tertiary (central) hypothyroidism Central hypothyroidism is much less common than primary hypothyroidism. Secondary and tertiary hypothyroidism should be suspected in the following circumstances: There is known hypothalamic or pituitary disease. A mass lesion is present in the pituitary. When symptoms and signs of hypothyroidism are associated with other hormonal deficiencies. In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase appropriately as T4 secretion falls. As a result, the symptoms and the serum free T4 value must be used to make the diagnosis. Thus, we measure both serum TSH and free T4 if pituitary or hypothalamic disease is suspected. We also measure free T4 if the patient has convincing symptoms of hypothyroidism despite a normal TSH result. In patients with central
hypothyroidism, the serum free T4 value is low-normal to low and serum TSH may be frankly low, inappropriately normal (for the low T4), or slightly high (7 to 15 mu/l) due to secretion of biologically inactive TSH. In pregnancy For women in the first trimester of pregnancy with a TSH above 4.0 mu/l, we also measure a free T4 (or total T4, if free T4 measurements appear discordant with TSH measurements). In addition, we agree with the American Thyroid Association (ATA) recommendation to measure thyroid peroxidase (TPO) antibodies in pregnant women with TSH >2.5 mu/l to inform treatment considerations 3. Treatment: Goals of therapy The goals of therapy are: Amelioration of symptoms Normalization of serum TSH secretion Reduction in the size of the goiter in patients with goitrous autoimmune thyroiditis (Hashimoto's disease) Avoidance of overtreatment (iatrogenic thyrotoxicosis) The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4, levothyroxine), which is a prohormone with very little intrinsic activity. It is deiodinated in peripheral tissues to form T3, the active thyroid hormone. We aim to keep TSH within the normal reference range (approximately 0.5 to 5.0 mu/l). Goals of therapy in pregnancy: Newly diagnosed hypothyroidism: a goal TSH of <2.5 mu/l is reasonable. Preexisting hypothyroidism: The goal preconception serum TSH level is between the lower reference limit and 2.5 mu/l. However, some experts prefer a lower preconception TSH level (<1.2 mu/l) 3. Dosage 2 : Oral: Adults (healthy) who have been hypothyroid for only a few months:
Initial: 1.6 mcg/kg/day; adjust dose by 12.5 to 25 mcg/day every 4 to 6 weeks as needed. Usual doses are 200 mcg/day (range: 100 to 125 mcg/day [70 kg adult]); doses 300 mcg/day are rare (consider poor compliance, malabsorption, and/or drug interactions). Adults >50 years of age without evidence of coronary heart disease (off-label): Lower starting doses (eg, 50 mcg/day) may be preferred (ATA/AACE [Garber 2012]). Adults with cardiac disease: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg increments at 6- to 8- week intervals as needed. Adults with severe longstanding hypothyroidism: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg/day every 2 to 4 weeks as appropriate. Pregnant patients: Dosage requirements may increase during pregnancy in patients with preexisting disease (35%-50% increase of weekly dose). If new onset hypothyroidism occurs general dosing guidance is as follows: TSH >4 mu/l (or above population and trimester-specific upper limit of normal), with low free T4 (using assay method and trimester-specific reference range): Close to full replacement dose (approximately 1.6 mcg/kg body weight per day) TSH >4 mu/l, with normal free T4: Intermediate dose (approximately 1 mcg/kg per day) TSH 2.6 to 4 mu/l: If a decision has been made to treat, low dose (typically 50 mcg daily) 3. Timing of dose T4 should be taken on an empty stomach with water, ideally an hour before breakfast. T4 should not be taken with other medications that interfere with its absorption, such as bile acid resins, calcium carbonate, and ferrous sulfate.
Initial monitoring and dose adjustments Patients who are treated with T4 usually begin to improve symptomatically within two weeks, but complete recovery can take several months in those with severe hypothyroidism. Although symptoms may begin to resolve after two to three weeks, steady-state TSH concentrations are not achieved for at least six weeks. Serum thyroid hormone concentrations increase first and then TSH secretion begins to fall because of the negative feedback action of T4 on the pituitary and hypothalamus. After initiation of T4 therapy: The patient with symptomatic improvement should be reevaluated and serum TSH measured in six weeks. If the TSH remains above the reference range, the dose of T4 can be increased by 12 to 25 mcg/day. The patient will require a repeat TSH measurement in six weeks. The patient with persistent symptoms after two to three weeks should be reevaluated and a serum free T4 and TSH measured in three weeks. If the serum free T4 is below normal, the dose can be increased at three weeks without additional testing, but it should be recognized that serum T4 (and TSH) concentrations at this time are not steady-state values, and serum TSH levels may still be falling despite normal (or even high) serum T4 concentrations. Given the one-week plasma half-life of T4, it takes approximately six weeks (six half-lives) before a steady state is attained after therapy is initiated or the dose is changed. This process of increasing the dose of T4 every three to six weeks (depending upon the patient's symptoms) should continue, based upon periodic measurements of serum TSH (and free T4 if steady-state conditions have not yet been achieved), until the high values of TSH in patients with primary hypothyroidism return to the reference range. We suggest that patients remain on the same formulation of T4. Either a generic or a brand-name formulation is acceptable. If a switch from one manufacturer to another is made by the pharmacy and there is concern regarding equivalent efficacy of the preparations, we measure a serum TSH six weeks after changing preparations to document that the serum TSH is still within the therapeutic target. Adjustment of maintenance dose After identification of the proper maintenance dose, the patient should be examined and serum TSH measured once yearly or more often if there is an abnormal result or a change in the patient's status. Further dose adjustment is usually not required, but there are situations in which a different dose may be needed. When drugs that affect the absorption of T4 are begun for coexisting medical conditions, serum TSH should be measured four to six weeks later to confirm that the T4 dose is still adequate. The dose should be increased if the serum TSH value
is high. Medications that interfere with T4 absorption should be taken several hours after the T4 dose. In addition, increases in dose may be required in the following settings: Pregnancy, and if increased, the dose should be reduced to the prepregnancy maintenance dose postpartum. Weight gain of more than 10 percent of body weight. Diminished thyroid hormone absorption (patients with impaired acid secretion or other gastrointestinal disorders [eg, uncontrolled celiac disease]). Increased thyroid hormone excretion (nephrotic syndrome). Increased rate of thyroid hormone metabolism (therapy with rifampin, carbamazepine, phenytoin, or phenobarbital). If the TSH is slightly elevated (eg, 5 to 15 mu/l), a small increase of 12 to 25 mcg/day is usually sufficient. The serum TSH should be remeasured six to eight weeks after any change in dose. Decreases in dose may be required in the following settings: Normal aging Weight loss of roughly more than 10 percent of body weight Initiation of androgen therapy If the TSH is slightly below normal (eg, 0.05 to 0.3 mu/l), a small dose reduction of 12 to 25 mcg/day is usually sufficient. Lower TSH values may require larger dose reductions. The serum TSH should be remeasured after six to eight weeks. Combination therapy with T4 and T3 The majority of patients do well on T4 monotherapy, and we do not suggest the routine use of combined T4 and T3 therapy for the treatment of hypothyroidism. Candidates for combined therapy include patients who have not felt well on T4 monotherapy: Since thyroidectomy Since ablative therapy with radioiodine Who have serum T3 at or below the lower end of the T3 reference range We discourage the use of combined therapy in older patients, patients with underlying cardiovascular disease in whom excessive T3 levels might precipitate an arrhythmia, and in pregnant women. When T4-T3 therapy is used, the T4-to- T3 ratio should be approximately 13:1 to 16:1
SPECIAL TREATMENT SITUATIONS There are several situations in which therapy should be more conservative or the dose may need modification: 1. Older patients or those with coronary heart disease Doses are mentioned in the dosage part. 2. Pregnancy Women need more thyroid hormone during pregnancy and, unlike normal women, those with hypothyroidism are unable to increase thyroidal T4 and T3 secretion. The increase in T4 requirements occurs as early as the fifth week of gestation and plateaus by week 16 to 20. T4 dose requirements may increase during pregnancy in women with preexisting overt or subclinical hypothyroidism. For treated hypothyroid women who are newly pregnant, we suggest preemptively increasing their levothyroxine dose at the time of the positive pregnancy test. We typically accomplish this by increasing the dose from once-daily dosing to a total of nine doses per week (double the daily dose two days each week) 3. Doses are mentioned in the dosage part. 3. Estrogen therapy In women receiving T4 therapy, estrogens increase serum thyroxine-binding globulin (TBG) concentrations, as they do in normal women, and may increase the need for T4. 4. Surgical patients Patients receiving chronic T4 therapy who undergo surgery and are unable to eat for several days need not be given T4 parenterally. If oral intake cannot be resumed in five to seven days, then T4 should be given intravenously. The dose should be approximately 70 to 80 percent of the patient's usual oral dose because that is approximately the fraction of oral T4 that is absorbed. We typically give 80 percent. 5. Poorly compliant patients Some patients do not take their T4 regularly and do not respond to efforts to improve compliance. These patients may be given their total weekly dose of T4 once per week. 6. Thyroid cancer Patients who have had a thyroidectomy for thyroid cancer, with or without additional treatment with radioiodine (I-131), need to take T4 not only for treatment of hypothyroidism but also to prevent recurrence of their thyroid cancer, especially those with higher risk disease.
7. Selenium deficiency Selenium is required for deiodinase activity (the enzyme is a selenoprotein), and it has important effects on immune function. Selenium supplementation reduces antithyroid peroxidase antibody levels, improves the ultrasound structure of the thyroid gland, and reduces the occurrence of postpartum thyroiditis in pregnant women with thyroid peroxidase antibodies. Monitoring Parameters: Adults: TSH 4 to 6 weeks after treatment initiation or dose changes, 4 to 6 months after adequate replacement dose determined, followed by every 12 months thereafter (or more frequently depending on clinical situation). T 4 ; heart rate, blood pressure, clinical signs of hypo- and hyperthyroidism. TSH is the most reliable guide for evaluating adequacy of thyroid replacement dosage in primary thyroid dysfunction. TSH may be elevated during the first few months of thyroid replacement despite patients being clinically euthyroid. In cases where T 4 remains low and TSH is within normal limits, an evaluation of free (unbound) T 4 is needed to evaluate further increase in dosage. Free T 4 (not TSH) should be monitored to guide treatment in patients with central hypothyroidism. Bone mineral density (particularly with long term use in postmenopausal women). References: 1. Ross,D. (2017). Treatment of primary hypothyroidism in adults. In J. E. Mulder, (Ed.), UpToDate. Retrieved December 26, 2018, from https://www.uptodate.com/contents/treatment-of-primary-hypothyroidism-inadults? 2. Levothyroxine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/multinat_f/4669428. Accessed December 26, 2018.
3. Ross,D. (2018). Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment. In J. E. Mulder, (Ed.), UpToDate. Retrieved December 26, 2018, from https://www.uptodate.com/contents/hypothyroidism-duringpregnancy-clinical-manifestations-diagnosis-and-treatment? Done by PharmD Students: Lina Aburrub, Hana a Abujuma a. Supervised by clinical pharmacist : Eshraq Al-Abweeny.