Before beginning therapy with thyroid hormone, the hypothyroid patient requires at least a clinical assessment for adrenal insufficiency and angina. The presence of either condition requires further evaluation and management.
A. Treatment for Hypothyroidism
Synthetic levothyroxine is the preferred preparation for treating hypothyroidism. Intestinal absorption can vary by up to 15% with different levothyroxine preparations, so ideally, the patient should receive a consistent manufacturer’s preparation. Most generic and brand levothyroxine preparations are tablets, although capsules and a liquid preparation (Tirosint) are available. Lyophilized preparations of levothyroxine are available for reconstitution and intravenous administration, when indicated.
Otherwise healthy young and middle-aged adults with hypothyroidism may be treated initially with levothyroxine in average doses of about 1.6 mcg/kg/day. Lower doses can be used for very mild hypothyroidism, while full doses are given for more symptomatic hypothyroidism. Pregnant women with overt hypothyroidism or myxedema should be treated immediately with levothyroxine at full replacement doses of 1.6 mcg/kg/day (about 100–150 mcg daily). For initial titration, the levothyroxine dosage may be increased according to clinical response and serum TSH, measuring serum TSH every 4–6 weeks and trying to keep the serum TSH level in the lower half of the reference range (0.4–2.0 milli-international units/L) during pregnancy.
The initial hormonal goal of levothyroxine replacement therapy should be to normalize serum TSH levels. Bedtime levothyroxine administration results in somewhat higher serum T4 and lower TSH levels than morning administration. Therefore, the administration timing for levothyroxine should be kept constant. After beginning daily administration, significant increases in serum T4 levels are seen within 1–2 weeks, and near-peak levels are seen within 3–4 weeks.
Patients with stable coronary artery disease or those who are over age 60 years are treated with smaller initial doses of levothyroxine, 25–50 mcg orally daily; higher initial doses may be used if such patients are severely hypothyroid. The dose can be increased by 25 mcg every 1–3 weeks until the patient is euthyroid. Ideally, patients with hypothyroidism and unstable coronary artery disease or uncontrolled atrial fibrillation should begin levothyroxine replacement following medical or interventional therapy.
Myxedema crisis requires larger initial doses of levothyroxine intravenously, since myxedema itself can interfere with intestinal absorption of oral levothyroxine. Levothyroxine sodium 500 mcg is given intravenously as a loading dose, followed by 50–100 mcg intravenously daily; the lower dose is given to patients with suspected coronary artery disease. In patients with severe myxedema crisis, liothyronine (T3, Triostat) can be given intravenously with a loading bolus of 10–20 mcg, followed by 10 mcg intravenous boluses every 8–12 hours for the first 48 hours. The hypothermic patient is warmed only with blankets, since faster warming can precipitate cardiovascular collapse. Hypoglycemic patients are given 5% dextrose intravenously. Hyponatremic patients with a serum sodium 120–130 mEq/mL are administered 0.9% NaCl intravenously, while patients with a serum sodium below 120 mEq/mL are treated with boluses of 100 mL of 3% NaCl intravenously with intravenous furosemide 20–40 mg to promote water diuresis; serum sodium levels must be followed closely and boluses of 3% NaCl can be repeated about every 6 hours until the serum sodium rises to 120 mmol/L or higher. When giving intravenous saline to myxedematous patients, care must be taken to avoid fluid overload.
Patients with hypercapnia require mechanical assistance with ventilation. Opioid medications must be stopped or used in very low doses. Infections must be detected and treated aggressively. Patients in whom concomitant adrenal insufficiency is suspected are treated with hydrocortisone, 100 mg intravenously, followed by 25–50 mg every 6–8 hours.
B. Monitoring and Optimizing Treatment of Hypothyroidism
Regular clinical and laboratory monitoring is critical to determine the optimal levothyroxine dose for each patient. After initiating levothyroxine replacement, serum TSH, FT4, and FT3 levels are monitored monthly, and the dose is adjusted with an aim to normalize the serum TSH within 2 months of commencing thyroid replacement therapy. The patient should be prescribed sufficient levothyroxine to restore a clinically euthyroid state; this can usually be attained by maintaining the serum TSH, FT4, and FT3 within their reference ranges.
Different levothyroxine preparations vary in their bioavailability by up to 14% and such differences may have a subtle but significant clinical impact. It is optimal for patients to consistently take the same manufacturer’s brand of levothyroxine.
Pregnancy usually increases the levothyroxine dosage requirement; an increase in levothyroxine requirement has been noted as early as the fifth week of pregnancy. Adequate levothyroxine is critical to the health of the fetus. Therefore, it is prudent to increase levothyroxine dosages by approximately 20–30% as soon as pregnancy is confirmed. The fetus is at least partially dependent on maternal T4 for its CNS development—particularly in the second trimester. By mid-pregnancy, women require an average of 47% increase in their levothyroxine dosage. The increased levothyroxine dosage requirement during pregnancy is believed to be due to several factors: (1) Rising estrogen levels during pregnancy increase thyroxine binding globulin (TBG) serum concentrations, reducing FT4 levels. (2) Placental deiodinase promotes the turnover of T4. (3) Supplemental iron and prenatal multivitamins containing iron can bind to oral T4 and reduce its intestinal absorption. It is therefore important to carefully monitor hypothyroid pregnant women with serum TSH (FT4I or T4 concentrations in hypopituitarism) determinations every 4–6 weeks and to increase levothyroxine progressively as required (see Chapter 19). Serum TSH levels normally drop while FT4I rises during the first trimester of pregnancy. This probably results from high levels of hCG (with structural homology to TSH) that stimulates thyroid hormone production. Most women with a low serum TSH in the first trimester are euthyroid. Serum FT4I is helpful in evaluating the thyroid status of pregnant women, particularly in the first trimester. Postpartum, levothyroxine replacement requirement ordinarily returns to prepregnancy level.
Decreased levothyroxine dose requirements occur in women after delivery, after bilateral oophorectomy or natural menopause, after cessation of oral estrogen replacement, or during therapy with GnRH agonists. Levothyroxine dosage may need to be titrated downward for patients who start taking teduglutide for short bowel syndrome.
1. Elevated serum TSH level
For patients with coronary artery disease or recurrent atrial fibrillation, it may be prudent to administer lower doses of levothyroxine to keep serum TSH in the high-normal or even slightly elevated range. For most other patients, though, a high serum TSH indicates underreplacement with levothyroxine. However, patient nonadherence to prescribed levothyroxine is surprisingly common; before increasing the levothyroxine dosage, it is important to confirm that the patient is taking the prescribed dosage of levothyroxine consistently. It is sometimes necessary to contact the patient’s pharmacy to confirm prescription renewal.
Increased levothyroxine dosage requirements (low serum T4 levels) can occur with drugs that increase the hepatic metabolism of levothyroxine (Table 26–3). Amiodarone can increase or decrease levothyroxine dose requirements. Malabsorption of levothyroxine can be caused by coadministration of binding substances, such as iron (eg, in multivitamins); fiber; raloxifene; sucralfate; aluminum hydroxide antacids; sevelemer; orlistat; bile acid–binding resins (cholestyramine and colesevelam); and calcium, magnesium, milk, coffee, and soy milk, or formula. Therefore, it is important that patients take their levothyroxine replacement at least 4 hours before or after such dietary supplements.
Proton pump inhibitors interfere slightly with the absorption of levothyroxine. Gastrointestinal disorders can interfere with levothyroxine absorption, including celiac disease, inflammatory bowel disease, lactose intolerance, Helicobacter pylori gastritis, and atrophic gastritis. Nephrotic syndrome can increase the required dose of oral levothyroxine. Women with hypothyroidism may require increased doses of levothyroxine after commencing oral estrogen therapy.
Serum TSH may be elevated transiently in acute psychiatric illness, with antipsychotics and phenothiazines, and during recovery from nonthyroidal illness. Autoimmune disease can cause false elevations of TSH by interfering with the assay. Very rarely, a high TSH can be caused by a thyrotropin-secreting pituitary tumor or hyperplasia.
2. Normal serum TSH level
For most patients, the goal of levothyroxine replacement is to maintain the serum TSH in the low normal range (0.4–2.0 milli-international units/L). However, treated patients with normal serum TSH levels have higher serum LDL cholesterol levels, lower average basal metabolic rate, and lower serum T3 levels compared to matched euthyroid controls. This appears to explain why some treated patients continue to have subjective symptoms suggestive of mild hypothyroidism, despite normal serum TSH levels. Such patients must be assessed for concurrent conditions, such as an adverse drug reaction, Addison disease, depression, hypogonadism, anemia, celiac disease, or gluten sensitivity. If such conditions are not present or are treated and hypothyroid-type symptoms persist, a serum T3 or free T3 level is often helpful. Low serum T3 levels may reflect inadequate peripheral deiodinase activity to convert inactive T4 to active T3. Unless contraindicated by unstable angina, such patients with continued hypothyroid-type symptoms may be carefully administered a slightly higher dose of levothyroxine to suppress the serum TSH while achieving clinical euthyroidism and a serum FT3 near the low-normal range. For most patients with hypothyroidism, an ideal stable maintenance dose of levothyroxine can usually be found.
Some clinicians have found success with other strategies, such as using desiccated natural porcine thyroid preparations containing both T4 and T3 (eg, Armour Thyroid, Nature-Throid, NP Thyroid). For product conversion purposes, 100 mcg of levothyroxine is equivalent to about 65 mg (1 grain) of desiccated thyroid. The use of desiccated thyroid preparations has been discouraged by several professional medical societies, but some patients prefer them. A possible explanation is that a common genetic variant in deiodinase type 2 gene (deiodinase type 2 converts T4 to active T3) is associated with worse quality of life scores in hypothyroid patients taking levothyroxine and a better response to therapy with thyroid preparations containing a mixture of T4 and T3.
3. Low or suppressed serum TSH level
A serum TSH level-below the reference range (adults 0.4–4.0 milli-international units/L) is either “low” (0.1–0.39 milli-international units/L) or “suppressed” (less than 0.1 milli-international units/L). Clinically euthyroid patients receiving levothyroxine who have “low” TSH levels do not have increased morbidity. However, a “suppressed” serum TSH often indicates over-replacement with levothyroxine, and such patients may have symptoms of hyperthyroidism with an increased risk for atrial fibrillation, osteoporosis, and clinical hyperthyroidism. A suppressed serum TSH can occur with hypopituitarism, severe nonthyroidal illness, and some medications such as nonsteroidal anti-inflammatory drugs, biotin, opioids, nifedipine, verapamil, and high-dose [short-term] corticosteroids). Aside from the latter circumstances, when the serum TSH is suppressed, the dosage of levothyroxine is reduced. However, some patients feel unmistakably hypothyroid while taking the reduced dose of levothyroxine and have low serum T3 or free T3 levels. For such patients, a higher levothyroxine dose may be resumed with close surveillance for atrial fibrillation, osteoporosis, and manifestations of subtle hyperthyroidism.