treatment hypothyroid
TRANSCRIPT
NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1717
ation of the thyroid subsequent toGraves’ disease and surgical removal ofthe thyroid gland.
Long-term thyroid dysfunction aftersubacute granulomatous thyroiditis (de Quervain’s thyroiditis) or subacutelymphocytic thyroiditis (silent or pain-less thyroiditis) is fairly rare. Full thyroidfunction is regained in 90 percent ofpatients with these conditions.6
Hypothyroidism can also develop sec-ondary to hypothalamic and pituitarydisorders. These endocrine conditionsoccur primarily in patients who haveundergone intracranial irradiation orsurgical removal of a pituitary adenoma.
Signs and SymptomsThe signs and symptoms of hypothy-
roidism are nonspecific and may be con-fused with those of other clinical condi-tions, especially in postpartum womenand the elderly. Because of the variety ofpossible manifestations, family physi-cians must maintain a high index of sus-picion for the disorder, especially inhigh-risk groups.
Patients with severe hypothyroidism
Hypothyroidism is secondonly to diabetes mellitusas the most commonendocrine disorder inthe United States, and its
prevalence may be as high as 18 cases per1,000 persons in the general population.1
The disorder becomes increasingly com-mon with advancing age, affecting about2 to 3 percent of older women.2 Becausehypothyroidism is so common, familyphysicians need to know how to diag-nose the disorder and select appropriatethyroid hormone replacement therapy.
EtiologyA number of conditions can lead to
hypothyroidism (Table 1).3 Of noniatro-genic causes, Hashimoto’s thyroiditis, orchronic lymphocytic thyroiditis, is themost common inflammatory thyroiddisorder and the most frequent cause ofgoiter in the United States.4 For anunknown reason, the prevalence ofHashimoto’s thyroiditis has been in-creasing dramatically in this countryover the past 50 years.5 Other commoncauses of hypothyroidism include irradi-
Thyroid disease affects up to 0.5 percent of the population of the United States. Itsprevalence is higher in women and the elderly. The management of hypothy-roidism focuses on ensuring that patients receive appropriate thyroid hormonereplacement therapy and monitoring their response. Hormone replacement shouldbe initiated in a low dosage, especially in the elderly and in patients prone to car-diac problems. The dosage should be increased gradually, and laboratory valuesshould be monitored six to eight weeks after any dosage change. Once a stabledosage is achieved, annual monitoring of the thyroid-stimulating hormone (TSH)level is probably unnecessary, except in older patients. After full replacement ofthyroxine (T4) using levothyroxine, the addition of triiodothyronine (T3) in a lowdosage may be beneficial in some patients who continue to have mood or memoryproblems. The management of patients with subclinical hypothyroidism (a highTSH in the presence of normal free T4 and T3 levels) remains controversial. In thesepatients, physicians should weigh the benefits of replacement (e.g., improved car-diac function) against problems that can accompany the excessive use of levothy-roxine (e.g., osteoporosis). (Am Fam Physician 2001;64:1717-24.)
Treatment of HypothyroidismWILLIAM J. HUESTON, M.D., Medical University of South Carolina, Charleston, South Carolina
COVER ARTICLEPRACTICAL THERAPEUTICS
Members of various fam-ily practice departmentsdevelop articles for“Practical Therapeutics.”This article is one in aseries coordinated by theDepartment of FamilyMedicine at the MedicalUniversity of South Car-olina, Charleston. Guesteditor of the series isWilliam J. Hueston, M.D.
generally present with a constellation of signsand symptoms that may include lethargy,weight gain, hair loss, dry skin, forgetfulness,constipation and depression. Not all of thesesigns and symptoms occur in every patient,and many may be blunted in patients withmild hypothyroidism. The most commonmanifestations of hypothyroidism are listedin Table 2.7
In older patients, hypothyroidism can beconfused with Alzheimer’s disease and otherconditions that cause cognitive impairment.Because depression can be a manifestationof hypothyroidism, patients with this endo-crine condition may be treated as depressed,and other signs and symptoms of the disor-der may be overlooked. This is particularlytrue with hypothyroidism that develops orworsens during pregnancy, or with postpar-
tum thyroiditis, which has many of the samesymptoms as postpartum depression.
Physical findings in patients with hypothy-roidism are also nonspecific. These findingscan include lowered blood pressure withbradycardia, nonpitting edema, generalizedhair loss (especially along the outer third ofthe eyebrows), dry skin and a diminishedrelaxation phase of reflexes.
A primary challenge is to differentiate thegeneralized symptoms of early hypothy-roidism from the similar symptoms offatigue and depression that occur in manyother conditions.
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TABLE 1
Causes of Hypothyroidism
Primary hypothyroidism (95% of cases)Idiopathic hypothyroidism*Hashimoto’s thyroiditisIrradiation of the thyroid subsequent to Graves’
diseaseSurgical removal of the thyroidLate-stage invasive fibrous thyroiditisIodine deficiencyDrug therapy (e.g., lithium, interferon)Infiltrative diseases (e.g., sarcoidosis, amyloidosis,
scleroderma, hemochromatosis)
Secondary hypothyroidism (5% of cases)Pituitary or hypothalamic neoplasmsCongenital hypopituitarismPituitary necrosis (Sheehan’s syndrome)
*—Probably old Hashimoto’s thyroiditis (i.e., a“burned out” thyroid from Hashimoto’s thyroiditis).
Adapted with permission from Hueston WJ. Thyroiddisease. In: Rosenfeld JA, Alley N, Acheson LS,Admire JB, eds. Women’s health in primary care. Bal-timore: Williams & Wilkins, 1997:617-31.
TABLE 2
Common Signs and Symptoms of Hypothyroidism*
Sign or symptom Affected patients (%)
Weakness 99
Skin changes 97(dry or coarse skin)
Lethargy 91
Slow speech 91
Eyelid edema 90
Cold sensation 89
Decreased sweating 89
Cold skin 83
Thick tongue 82
Facial edema 79
Coarse hair 76
Skin pallor 67
Forgetfulness 66
Constipation 61
*—Only signs and symptoms that occur in 60 per-cent or more of patients with hypothyroidism arelisted in this table.
Adapted with permission from Larsen PR, Davies TF,Hay ID. The thyroid gland. In: Wilson JD, Foster DW,Kronenberg HM, Larsen PR, eds. Williams Textbookof endocrinology. 9th ed. Philadelphia: Saunders,1998:461.
DiagnosisThe evaluation of patients with new-onset
hypothyroidism is quite limited. In patientswith primary hypothyroidism, the thyroid-stimulating hormone (TSH) level is elevated,indicating that thyroid hormone productionis insufficient to meet metabolic demands,and free thyroid hormone levels are depressed.In contrast, patients with secondary hypothy-roidism have a low or undetectable TSH level.
TSH results have to be interpreted in lightof the patient’s clinical condition. A low TSHlevel should not be misinterpreted as hyper-thyroidism in the patient with clinical mani-festations of hypothyroidism. When symp-toms are nonspecific, a follow-up assessmentof the free thyroxine (T4) level can help distin-guish between primary and secondary hypo-thyroidism. A guide to the laboratory diagno-sis of hypothyroidism and the interpretationof TSH, T4 and triiodothyronine (T3) levels isprovided in Table 3.
Once the diagnosis of primary hypothy-roidism is made, additional imaging or sero-logic testing is unnecessary if the thyroidgland is normal on examination. In patients
with secondary hypothyroidism, furtherinvestigation with provocative testing of thepituitary gland can be performed to deter-mine if the underlying cause is a hypothala-mic or pituitary disorder. In patients withpituitary dysfunction, imaging is indicated todetect microadenomas, and levels of otherhormones that depend on pituitary stimula-tion should also be measured. In general, evi-dence of decreased production of more thanone pituitary hormone is indicative of panhy-popituitary problems.
Thyroid Hormone ReplacementSELECTING THE APPROPRIATE AGENT
Thyroid medications were once preparedfrom desiccated samples of ground thyroid
Hypothyroidism
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TABLE 3
Laboratory Values in Hypothyroidism
TSH level Free T4 level Free T3 level Likely diagnosis
High Low Low Primary hypothyroidism
High (>10 µU per mL Normal Normal Subclinical hypothyroidism with high risk for future [10 mU per L]) development of overt hypothyroidism
High (6 to 10 µU per mL Normal Normal Subclinical hypothyroidism with low risk for future [6 to 10 mU per L]) development of overt hypothyroidism
High High Low Congenital absence of T4-T3–converting enzyme; amiodarone (Cordarone) effect on T4-T3 conversion
High High High Peripheral thyroid hormone resistance
Low Low Low Pituitary thyroid deficiency or recent withdrawal of thyroxine after excessive replacement therapy
TSH = thyroid-stimulating hormone; T4 = thyroxine; T3 = triiodothyronine.
In primary hypothyroidism, the thyroid-stimulating hormone(TSH) level is elevated, and free thyroid hormone levels aredepressed. In secondary hypothyroidism, the TSH level is lowor undetectable. A follow-up assessment of the free thyrox-ine level can help distinguish between primary and secondaryhypothyroidism.
glands from cows, and standardization wasbased on the iodine content of the extractrather than its T3 or T4 content. The actualthyroid hormone content of the productsvaried considerably from manufacturer tomanufacturer, and even within products fromthe same manufacturer, depending on thethyroid status of the cows. Fortunately, thismethod of preparing thyroid hormone hasbeen abandoned, and replacement is nowaccomplished primarily with synthetic thy-roid hormones.
A recent analysis8 of four levothyroxinepreparations, including two brand-nameproducts (Synthroid and Levoxyl) and twogeneric preparations, demonstrated relativebioequivalence. Patients switched from anyone of the four preparations to anothershowed insignificant variations in their thy-roid function tests. Among the four products,the only difference noted was that Synthroidproduced a more rapid and higher rise in theT3 level after administration. However, thedifference was not statistically significant andis of questionable clinical importance.
INITIATING TREATMENT
Most otherwise healthy adult patients withhypothyroidism require thyroid hormonereplacement in a dosage of 1.7 µg per kg perday, with requirements falling to 1 µg per kgper day in the elderly. Thus, levothyroxine ina dosage of 0.10 to 0.15 mg per day is neededto achieve euthyroid status. For full replace-ment, children may require up to 4 µg per kgper day.9
In young patients without risk factors forcardiovascular disease, thyroid hormonereplacement can start close to the target goal.
In most healthy young adults, replacement isinitiated using levothyroxine in a dosage of0.075 mg per day, with the dosage increasedslowly as indicated by continued elevation ofthe TSH level.
Levothyroxine should be initiated in a lowdosage in older patients and those at risk forthe cardiovascular compromise that couldoccur with a rapid increase in resting heartrate and blood pressure.9 In these patients,the usual starting dosage is 0.025 mg per day.This dosage can be increased in increments of0.025 to 0.050 mg every four to six weeksuntil the TSH level returns to normal.
Thyroid hormone is usually given oncedaily, but some evidence suggests that weeklydosing may also be effective. In a small study10
of 12 patients with hypothyroidism, a bolusdose of thyroid hormone equal to seven timesthe usual daily dose was well tolerated. Beforeweekly replacement can be recommended,however, more investigation is required,including definitions of the populations inwhich this approach is indicated.
In a study11 of 33 middle-aged patients(mostly women) with stable hypothyroidismwho were already receiving levothyroxine,small improvements in mood, memory andcold tolerance occurred after triiodothyro-nine was added, in a dosage of 0.0125 mg perday, with a concomitant 0.05-mg decrease inthe usual levothyroxine dosage. Although thisstudy was small, it suggests that some patientswho are chemically euthyroid but have linger-ing neuropsychiatric problems might benefitfrom triiodothyronine. Further investigationis required to determine the role of tri-iodothyronine in these patients, as well as thelong-term consequences of its use.
MONITORING THYROID FUNCTION
In patients with an intact hypothalamic-pituitary axis, the adequacy of thyroid hor-mone replacement can be followed with ser-ial TSH assessments. However, changes in theTSH level lag behind serum thyroid hormonelevels. Thus, the TSH level should be evalu-
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Because levothyroxine can cause increases in the resting heartrate and blood pressure, replacement should begin at a lowdosage in older patients and patients at risk for cardiovascularcompromise.
ated no earlier than four weeks after anadjustment in the levothyroxine dosage. Thefull effects of thyroid hormone replacementon the TSH level may not become apparentuntil after eight weeks of therapy.12
In patients with pituitary insufficiency,measurements of free T4 and T3 levels can beperformed to determine whether patientsremain euthyroid. In these patients, the goal isto maintain free thyroid hormone levels inthe middle to upper ranges of normal toensure adequate replacement.
TSH or free T4 levels are monitored annu-ally in most patients with hypothyroidism, al-though no data support this practice. Gener-ally, once a stable maintenance dosage oflevothyroxine is achieved, that dosage will re-main adequate until patients are 60 to 70 yearsof age. With age, thyroid binding maydecrease, and the serum albumin level maydecline. In this setting, the levothyroxinedosage may need to be reduced by up to 20 percent.13,14 Although less frequent thanannual monitoring could be justified inyounger adult patients whose weight is stable,annual monitoring in older patients is neces-sary to avoid overreplacement.15
A guideline for initiating and monitoringthyroid hormone replacement therapy is pro-vided in Figure 1.
INTRAVENOUS REPLACEMENT
Because thyroid hormone has a large vol-ume of distribution and long half-life, par-enteral replacement is unnecessary inpatients who are unable to take medicationorally for a few days to a week. However,some patients may be unable to take oralmedications for much longer periods. Intra-venous administration is advised in thesepatients and in those who need to begin thy-roid hormone replacement but cannot takeoral medications. Only about 70 to 80 per-cent of an oral dose of replacement medica-tion is absorbed. Therefore, parenteralreplacement should be initiated at 70 to 80percent of the usual oral dose.16
SUBCLINICAL HYPOTHYROIDISM
The TSH level can be mildly elevated whenthe free T4 and T3 levels are normal, a situationthat occurs most often in women and becomesincreasingly common with advancing age.This condition has been termed “subclinicalhypothyroidism,” based on the suppositionthat it reflects early failure of the thyroid hor-mone and eventual development of hypothy-roidism.17 However, it appears that patientswith a TSH level between 6 and 10 µU per mL
Hypothyroidism
NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1721
Treatment of Hypothyroidism
Is there a documented need forthyroid hormone replacement?
Is the patient >50 years of age and/or at risk for cardiac disease?
Start levothyroxine, 0.075 mg per day.
Start levothyroxine, 0.025 to 0.05 mg per day.
Monitor TSH level (if primary hypothyroidism) or free T4 level (if secondary hypothyroidism)every 6 to 8 weeks; adjust levothyroxinedosage until laboratory tests are normal.
Does the patient still have lethargy or memory problems?
Continue to monitor TSHor T4 levels annually.
Consider adding triiodothyronine,0.0125 mg per day (althoughlong-term effects are not known).
NoYes
NoYes
FIGURE 1. Initiation and monitoring of treatment for hypothyroidism. (TSH = thyroid-stimulating hormone; T4 = thyroxine)
(6 to 10 mU per L) are not at risk for subse-quent hypothyroidism.1 In contrast, patientswith a higher TSH level (above 10 µU per mL)progress to overt hypothyroidism at a rate of1 to 20 percent per year.1
Thyroid hormone replacement may havesome benefits in patients with subclinicalhypothyroidism, but there is also a potentialfor adverse effects, particularly in olderpatients. Some studies have shown that sup-plementation of thyroid hormone acceleratesbone mineral loss in older women with sub-clinical hypothyroidism, and that estrogenreplacement therapy does not counteract thiseffect.17 Bone-wasting effects have not beenobserved in patients who are clinically hypo-thyroid and receive adequate thyroid hor-mone replacement therapy.18
Thyroid hormone replacement has alsobeen reported to decrease serum homocys-teine levels.19 Along with changes in lipids,hyperhomocysteinemia may be one of themechanisms through which hypothyroidismis associated with an increased risk for cardio-vascular disease.20
At this time, the approach to patients withsubclinical hypothyroidism must be individ-ualized. In patients at higher risk for osteo-porosis or fractures, the deleterious effects ofexcessive thyroid hormone can be avoided bywithholding replacement until the free T4
and T3 levels drop below normal. In patientswith hyperhomocysteinemia, existing car-diac disease or risk factors for heart disease,early thyroid hormone replacement mayoffer more advantages. Right now, consensusis lacking on how to manage patients with
subclinical hypothyroidism. More research isneeded to sort out the most appropriatemanagement.
Conditions Affecting Thyroid HormoneReplacement Requirements
Because thyroid hormone is highly proteinbound, medical conditions that alter theamount of binding hormones and drugs thatcompete for binding may change the amountof available free thyroid hormone. The thy-roid replacement dosage must be changed inresponse to alterations in binding status.
With conditions that cause an increase inserum binding proteins, such as high estro-gen states (e.g., pregnancy), oral contracep-tive use or postmenopausal estrogen replace-ment, the dosage of levothyroxine must beincreased. In contrast, androgens decreaselevels of thyroid binding proteins, necessitat-ing a reduction in the dosage. Older patientsalso have lower serum protein levels and mayrequire reductions in their maintenancedosage over time. Nephrosis, protein-losingenteropathies and cirrhosis are other condi-tions that require a reduced thyroid hor-mone dosage.
A number of medications reduce theabsorption of thyroid hormone from theintestines, necessitating an increase in thereplacement dosage (Table 4).21 Other drugsaccelerate the metabolism of thyroid hor-mone, and an increase in the replacementdosage is then required. When these medica-tions are started or adjusted, the TSH valueshould be monitored to determine whetheradditional thyroid hormone replacement isindicated.
Persistently Elevated TSH Despite Thyroid Hormone Replacement
Poor compliance is the most common rea-son for continued elevation of the TSH levelin patients receiving presumably adequatethyroid hormone replacement. Patients whodo not regularly take their replacement med-ication and then try to “catch up” just before
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The Author
WILLIAM J. HUESTON, M.D., is professor and chair of the Department of Family Medi-cine at the Medical University of South Carolina, Charleston. He received his medicaldegree from Case Western Reserve University School of Medicine, Cleveland, and com-pleted a family practice residency at Riverside Methodist Hospital, Columbus, Ohio.
Address correspondence to William J. Hueston, M.D., Department of Family Medicine,Medical University of South Carolina, P.O. Box 250192, Charleston, SC 29425 (e-mail:[email protected]). Reprints are not available from the author.
a physician visit may restore their free T4 lev-els to normal but continue to have an elevatedTSH level.
Very rarely, patients have tissue-level unre-sponsiveness to thyroid hormone. This con-dition reflects a mutation in the gene thatcontrols a receptor for T3, rendering it unableto bind with the hormone. The genetic muta-tion has been identified in only 300 families.22
In these patients, adequate amounts of thy-roid hormone are produced but are ineffec-tive. Consequently, the TSH level remains ele-
vated, and the patients continue to havesymptoms of hypothyroidism. These patientsshould be referred to an endocrinologist forfurther evaluation and management.
Screening for HypothyroidismThe U.S. Preventive Services Task Force23
does not recommend routine screening forhypothyroidism in asymptomatic persons.Recently, some expert panels24 noted thatscreening may be beneficial in high-risk pop-ulations such as elderly women. However,widespread screening is not likely to be cost-effective. Because of the nonspecific symp-toms of hypothyroidism, many patientswould be tested because of their symptoms.This practice should not be confused withasymptomatic screening.
The author indicates that he does not have any con-flicts of interest. Sources of funding: none reported.
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Hypothyroidism
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TABLE 4
Drugs Potentially Altering Thyroid Hormone Replacement Requirements
Increase replacement requirementsDrugs that reduce thyroid hormone production
LithiumIodine-containing medicationsAmiodarone (Cordarone)
Drugs that reduce thyroid hormone absorptionSucralfate (Carafate)Ferrous sulfate (Slow Fe)Cholestyramine (Questran)Colestipol (Colestid)Aluminum-containing antacidsCalcium products
Drugs that increase metabolism of thyroxineRifampin (Rifadin)PhenobarbitalCarbamazepine (Tegretol)Warfarin (Coumadin)Oral hypoglycemic agents
Increase thyroxine availability and may decrease replacement requirements
Drugs that displace thyroid hormone from protein bindingFurosemide (Lasix)Mefenamic acid (Ponstel)Salicylates
Adapted with permission from Surks MI, Sievert R.Drugs and thyroid function. N Engl J Med 1995;333:1688-94.
Hypothyroidism
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