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Tests of Gland Function

RADIOACTIVE IODINE UPTAKE

The radioactive iodine uptake (RAIU), a measure of iodine utilization by the gland, is

an indirect measure of hormone synthesis. It is elevated in hyperthyroidism and in

early hypothyroidism when the failing gland is trying to increase hormone synthesis.

A low or undetectable RAIU occurs in hypothyroidism, thyrotoxicosis factitia, and

subacute thyroiditis. Typically, RAIU is used to calculate the dose of RAI therapy for

treatment of Graves’ disease and to determine the activity of one or several nodules

in a gland. The RAIU is not necessary to diagnose classic Graves’ disease or

hypothyroidism.

A tracer dose of iodine-131 (

131

I) is administered, and the radioactivity of the

gland is measured at 5 and 24 hours after ingestion. It is necessary to measure both

the 5- and 24-hour RAIU, so that patients with rapid turnover of iodine will not be

missed. In some hyperthyroid patients, the 5-hour uptake is elevated, but the 24-hour

uptake can fall to normal or subnormal levels. The normal range of the RAIU (Table

52-7) is affected by any condition that alters iodine intake. Iodine depletion caused

by rigorous diuretic therapy or an iodine-deficient diet increases uptake because of

replenishment of depleted total iodide pools. Conversely, dilution of

131

I with

exogenous iodide sources (e.g., contrast dyes) decreases RAIU.

IMAGING STUDIES

Thyroid Scan

A scan of the gland is performed simultaneously with the RAIU or after ingestion of

technetium (

99mTc) pertechnetate. The scan provides information concerning gland

size and shape, and identifies hypermetabolic (“hot”) and hypometabolic (“cold”)

areas. The possibility of carcinoma must be considered if cold areas are present. A

scan is often obtained in the evaluation of a patient with nodular thyroid disease.

Thyroid Ultrasound

A thyroid ultrasound can provide information about gland size and number of

clinically palpable or non-palpable nodules or cysts in the thyroid gland.

Tests of Autoimmunity

THYROID PEROXIDASE AND ANTITHYROGLOBULIN ANTIBODIES

Thyroid peroxidase antibodies (TPOAb) and thyroglobulin autoantibodies (TgAb) to

the thyroid gland indicate an autoimmune process.

31,33 About 60% to 70% of patients

with Graves’ disease and 95% of patients with Hashimoto’s thyroiditis have positive

antibodies to both thyroid antigens. Positive antibodies alone do not indicate thyroid

disease because 5% to 10% of asymptomatic patients, as well as patients with other

non-thyroidal autoimmune disorders, have positive antibodies.

Clinically, the TPOAb is more specific than TgAb in assessing disease activity.

Although both antibodies are elevated during acute flares of the disease, lower titers

of TPOAb remain positive during quiescent periods of the disease, while TgAb

levels revert to negative.

THYROID RECEPTOR–STIMULATING ANTIBODIES OR THYROIDSTIMULATING IMMUNOGLOBULIN

Thyroid receptor–stimulating antibodies (TRAb) or thyroid-stimulating

immunoglobulin (TSI) are IgG immunoglobulins that are present in virtually all

patients with Graves’ disease.

31,33 Like TSH, these immunoglobulins can stimulate the

thyroid gland to produce thyroid hormones. High titers of TSI are useful in

diagnosing otherwise asymptomatic Graves’ disease (i.e., ophthalmopathy), in

predicting the risk of relapse of Graves’ disease after discontinuing medication, and

in predicting the risk of neonatal hyperthyroidism in utero through transplacental

passage of TSI from the pregnant mother. Otherwise, TSI measurement is expensive

and offers no additional information in the patient with a typical Graves’ disease

presentation.

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Clinical Application and Interpretation

EUTHYROIDISM AND NON-THYROIDAL ILLNESS SYNDROME

CASE 52-1

QUESTION 1: R.K., an obese 42-year-old woman, is admitted to the hospital because of increasing fatigue,

sluggishness, shortness of breath (SOB), and pitting edema of the legs during the past 3 weeks. Bilateral pleural

effusions found on her chest radiograph indicate a worsening of her congestive heart failure (CHF). Her other

medical problems include cirrhosis of the liver, type 2 diabetes, and chronic bronchitis, for which she takes

glipizide 10 mg every day and an iodine-containing herbalsupplement 3 times a day (TID).

Pertinent physical findings include a palpable but normal-size thyroid, bibasilar rales, cardiomegaly,

hepatomegaly, 4 + pitting edema, and normal deep tendon reflexes (DTRs). A diagnosis of worsening CHF

secondary to hypothyroidism is suspected based on the following laboratory findings:

Cholesterol, 385 mg/dL

RAIU at 24 hours, 13% (normal, 5%–35%1

)

Scan, normal-size gland with homogenous uptake

TT4

, 1.4 mcg/dL (normal, 4.8–10.4 mcg/dL)

TT3

, 22 ng/dL (normal, 58–201 ng/dL)

TSH, 4 microunits/mL (normal, 0.45–4.1 microunits/mL)

FT4

, 1.0 ng/dL (normal, 0.8–1.4 ng/dL)

TPOAb, 30 WHO units (normal, <100 WHO units)

TgAb, 0.3 IU/mL (normal, <2 IU/mL)

Evaluate and explain R.K.’s thyroid status based on her clinical and laboratory findings.

Although low-output failure can be a presenting sign of hypothyroidism, the normal

TSH and FT4 definitely indicates that R.K. is euthyroid, despite the confusing results

of her other thyroid function tests. The depressed RAIU is consistent with her history

of iodide ingestion and dilution of the

131

I. The low TT4 and TT3 may be explained by

her cirrhosis and non-thyroidal illness syndrome (see Question 2). The negative

thyroid antibodies, the normal scan, and normal DTRs further substantiate the

diagnosis of euthyroidism. In hypothyroidism, a lower rate of cholesterol degradation

can produce an elevated serum cholesterol level. However, because many

extrathyroidal factors influence the serum concentration of cholesterol, this test is an

imprecise reflection of thyroid status. In this case, the elevated cholesterol level is

not related to hypothyroidism.

CASE 52-1, QUESTION 2: Assess the results and explain the significance of R.K.’s TT4

, FT4

I, and TT3

values.

R.K.’s thyroid function test results are consistent with the non-thyroidal illness

syndrome. Abnormal thyroid function tests are commonly found in euthyroid patients

with various serious systemic diseases, including starvation, infections, sepsis, acute

psychiatric disorders, HIV infection, myocardial infarction (MI), bone marrow

transplantation, and severe chronic cardiac, pulmonary, renal, hepatic, and neoplastic

diseases.

21,31,33,37–42

This “euthyroid sick” syndrome occurs in 37% to 70% of chronically ill or

hospitalized patients and must be recognized. In general, the sicker the patient, the

greater the degree of abnormal thyroid function findings, even though the patient has

no thyroid disease.

The most common finding is a low TT3

(e.g., 15–20 ng/dL) and high inactive

reverse T3

levels (rT3

). Other typical changes include a normal or low TT4

, and a

suppressed or normal TSH levels. A borderline-high compensatory TSH occurs as

patients recover from illness. In more serious illness, the TT4

, FT4

I, and FT3 are

often low. Free hormone levels (e.g., FT4

, FT3

) are often normal or slightly low.

However, these inconsistent findings fuel the controversy over whether thyroid

hormone therapy is beneficial or detrimental. These findings are believed to be

explained by a central hypothyroidism caused by reduction in hypothalamic TRH

because of increased hypothalamic T3

, increased peripheral metabolism of T3

, or by

a reduction in serum thyroid hormone–binding proteins.

38

Impaired protein synthesis

of thyroid-binding prealbumin (TBPA) and an increase in the proportion of a lowerbinding-capacity form of TBG might account for the lower bound hormone levels, but

the concomitant increase in the free hormone concentrations would maintain a

euthyroid state. Furthermore, circulating substances that inhibit the binding of T4 and

T3

to the serum-binding proteins might also be present.

Less common changes include a modestly elevated TT4 and FT4

I in patients with

acute viral hepatitis, psychiatric disorders, renal failure, and advanced HIV

infection. The TT3

is usually normal but can be low in critically ill patients. Modest

elevations in hormonal binding affinity and increased synthesis of TBG explain these

findings.

Several studies have shown a strong inverse correlation between mortality and

total serum T4

, T3

, and rT3

levels.

39–41 Of the 86 hospitalized, intensive care patients,

84% of those with a serum T4 of <3 mcg/dL died, whereas 85% of those with a

serum T4 of >5 mcg/dL survived.

40

In 331 patients with acute MI, rT3

levels >0.41

nmol/L were significantly associated with a greater risk of death at 1 year.

41 During

recovery, TSH levels increase and hormone levels start to normalize. Therefore, a

favorable outcome is associated with reversal of the hormone indices.

Thyroid experts are divided about whether non-thyroidal illness should be treated,

and few randomized studies are available to guide therapeutic decisions.

37–42 The few

available studies found no survival benefits or favorable clinical outcomes from

hormone therapy, although cardiac hemodynamics improved. The benefits of hormone

replacement are unproven and might be detrimental. In one trial, the mortality of

patients with acute renal failure treated with T4 was 43% versus 13% in the control

group.

42 Other small trials have shown thyroid hormones to be well tolerated and

safe.

43 Opponents argue that T4

therapy, by inhibiting TSH, may interfere with normal

thyroid recovery and is preferentially converted to inactive rT3.

43,44 Conversely,

proponents argue that there may be cardiovascular benefits and there is no clear

evidence that therapy is toxic.

44

In summary, T4 and T3 measurements are not helpful in the diagnosis of thyroid

dysfunction in patients with significant non-thyroidal illness. A normal or nearnormal TSH is necessary to establish euthyroidism in sick patients with non-thyroidal

illness. The available data are not supportive of starting thyroid hormone treatment

now. The abnormal laboratory findings should reverse with correction of R.K.’s nonthyroid illness. To confirm euthyroidism, the slightly elevated TSH should be

repeated once R.K.’s medical condition improves.

Drug Interference with Thyroid Function Tests

CASE 52-2

QUESTION 1: J.R., a 45-year-old man, complains of fatigue, dry skin, and constipation. His other medical

problems include alcoholism for 10 years, cirrhosis, generalized tonic–clonic seizures treated with phenytoin

(Dilantin) 300 mg/day and phenobarbital 90 mg

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at night, and rheumatoid arthritis for which he takes aspirin 325 mg, 12 tablets/day.

The results of his thyroid function tests are as follows:

TT4

, 4.2 mcg/dL (normal, 4.8–10.4)

FT4

, 0.6 ng/dL (normal, 0.8–1.4)

TSH, 2.5 microunits/mL (normal, 0.45–4.1)

How should these laboratory findings be interpreted? What factors are responsible for the observed

changes?

Despite complaints that could be consistent with hypothyroidism (e.g., fatigue, dry

skin, constipation) and findings of low serum hormone values, J.R. is euthyroid, as

evidenced by the normal TSH level. Secondary hypothyroidism is unlikely at this age

without a history of central nervous system (CNS) trauma or tumor. Some nonthyroidal factors could account for J.R.’s low TT4 and FT4 values.

21 Antiinflammatory doses of salicylates >2 g/day and salicylate derivatives (i.e., Disalcid,

salsalate) can displace T4

from both TBG and TBPA, causing these abnormal

findings.

21,45,46 Elevation in free T4

levels and suppression of TSH below normal

occur transiently (i.e., no longer than first 3 weeks of administration) but normalize

with chronic administration. Cirrhosis, stress, severe infections, and hereditary

factors can also decrease TBG and TBPA synthesis to produce similar TT4

findings.

A medication history for drugs such as androgens or glucocorticoids that can lower

TBG levels, and therefore TT4

levels, should be elicited (Table 52-1).

21

Enzyme inducers, such as rifampin and anticonvulsants (phenytoin, phenobarbital,

valproic acid, carbamazepine), can alter serum thyroid hormone levels.

21,47–52 A 40%

to 60% reduction in total T4 serum concentrations results from an increase in the

metabolism (non-deiodination) of T4 and from hormone displacement in patients

receiving chronic anticonvulsant therapy. Serum T3

levels are normal or slightly

decreased. In addition, therapeutic levels of phenytoin and carbamazepine interfere

with the FT4 assay, causing a 20% to 40% lower FT4

than would be expected in

euthyroid persons.

48 TSH levels remain normal and patients are euthyroid; however,

those who previously required T4

therapy may need a dosage increase to maintain

euthyroidism.

51,52 Valproic acid is reported to have similar but less potent effects on

thyroid function.

47,49 Phenobarbital can increase T4 uptake by the liver and increase

the fecal excretion of T4

. Serum binding of thyroid hormones is unaffected by

phenobarbital.

In summary, J.R. is taking several drugs that can further compromise the already

low serum T4

levels resulting from his liver disease. FT4

remains subnormal in

euthyroid persons receiving phenytoin. For J.R, the normal TSH confirms

euthyroidism, and no thyroid replacement is warranted.

CASE 52-3

QUESTION 1: S.T., a 23-year-old, sexually active woman whose only medication is birth control pills, comes

to the clinic complaining of extreme nervousness, diaphoresis, and scanty menstrual periods. Although she

appears healthy, the possibility of hyperthyroidism is considered on the basis of the following laboratory values:

TT4

, 16 mcg/dL (normal, 4.8–10.4)

FT4

, 1.2 ng/dL (normal, 0.7–1.9)

TSH, 1.2 microunits/mL (normal, 0.45–4.1)

Based on this information, what would be a reasonable assessment of S.T.’s thyroid status?

The normal FT4 and TSH confirm that S.T. is not hyperthyroid. The elevated TT4

is consistent with increased TBG levels observed in patients with acute hepatitis; in

pregnancy; and in persons taking estrogens, estrogen-containing contraceptives,

tamoxifen, raloxifene, heroin, or methadone.

1,2,21,53–55 Because TBG and therefore

bound T4

levels are increased by estrogens in S.T., total serum T4 measurements are

falsely elevated, but free thyroxine levels remain normal. In patients requiring Lthyroxine, the use of estrogens can increase requirements of hormone replacement

because the increased pituitary secretion of TSH cannot increase thyroid production

needed to offset the increased binding of T4

.

1 Thyroid function tests should return to

normal within 4 weeks after estrogen-containing contraceptives are discontinued. A

change to progesterone-only contraceptives that do not affect protein binding, do not

alter thyroid function tests, and do not increase thyroid requirements can be

considered in S.T.

CASE 52-4

QUESTION 1: J.P., a 55-year-old woman, complains of 3 months of progressive tremors, dizziness, and

ataxia. Two months ago, she had a silent MI complicated by malignant ventricular ectopy that was responsive

only to amiodarone therapy. Her other medical problems include Parkinsonism, type 2 diabetes, and diabetic

gastroparesis. Her current medications include amiodarone, insulin, metformin, metoclopramide, pramipexole,

and levodopa/carbidopa. Physical examination of the thyroid was unremarkable. Thyroid function tests yielded

the following results:

TT4

, 14.5 mcg/dL (normal, 4.8–10.4)

FT4

, 2.3 ng/dL (normal, 0.8–1.4)

TSH, 3.8 microunits/mL (normal, 0.45–4.1)

TT3

, 40 ng/dL (normal, 58–201)

TPOAb, 40 WHO units (normal, <100)

How should J.P.’s laboratory values be interpreted?

Although the symptoms of tremors, dizziness, and weight loss are suggestive of

hyperthyroidism, the low TT3

, negative antibodies, normal TSH, and normal thyroid

examination make this diagnosis unlikely. Side effects of amiodarone could be

responsible for J.P.’s symptoms. Her drug therapy could also explain her laboratory

findings.

Amiodarone produces complex changes in thyroid function tests that are confusing

if not properly interpreted.

3,12,56,57 Because amiodarone inhibits both the peripheral

and pituitary conversion of T4

to T3

, FT4

levels are elevated, and TT3

levels are

subnormal in euthyroid patients. Transient elevations in TSH levels occur (usually

<20 microunits/mL) during the first few weeks of therapy but return to normal in

approximately 3 months. If TSH levels do not normalize, then amiodarone-induced

thyroid disease should be considered. Amiodarone can cause either hypothyroidism

or hyperthyroidism in susceptible patients.

The other drugs J.P. is taking—pramipexole, levodopa, metformin, and

metoclopramide—also add to the diagnostic confusion. Although these drugs do not

affect the actual circulating hormone levels, they affect the dopaminergic system that

controls both TSH and TRH secretion.

21,32,33,58

Infusions of dopamine and dobutamine

can decrease both TSH secretion and the TSH response to TRH in euthyroid and

hypothyroid patients.

21,32,33,59 Therefore, dopamine agonists such as pramipexole,

cabergoline, and levodopa can blunt the normal TSH response.

21,32,58,59

In addition,

metformin after 1 year of therapy can cause significant TSH suppression without

changes in free thyroxine levels by as yet an unknown mechanism of action.

60,61

Conversely, dopamine antagonists such as metoclopramide or domperidone can

elevate TSH levels.

21,32 Fortunately, the alterations in TSH caused by these agents are

usually not substantial enough to completely obscure the true thyroid abnormality.

See Table 52-2 and Cases 52-23 and 52-24 for more information about drug effects

on thyroid function.

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J.P.’s thyroid tests present a confusing picture; however, the presence of a TSH

within the normal range indicates euthyroidism. J.P. should be continued on her

current regimen with follow-up monitoring of thyroid tests.

HYPOTHYROIDISM

Clinical Presentation

CASE 52-5

QUESTION 1: M.W., a 70-kg, 23-year-old voice student, thinks that her neck has become “fatter” over the

past 3 to 4 months. She has gained 10 kg, feels mentally sluggish, tires easily, and finds that she can no longer

hit high notes. Physical examination reveals puffy facies, yellowish skin, delayed DTRs, and a firm, enlarged

thyroid gland. Laboratory data include the following results:

FT4

, 0.6 ng/dL (normal, 0.8–1.4)

TSH, 60 microunits/mL (normal, 0.45–4.1)

TPOAb, 136 WHO units (normal, <100)

Assess M.W.’s thyroid status based on her clinical and laboratory findings.

M.W. presents with many of the clinical features of hypothyroidism as presented in

Table 52-3. These include weight gain, mental sluggishness, easy fatigability,

lowering of the voice pitch, puffy facies, yellowish tint of the skin, delayed DTRs,

and enlarged thyroid.

62 The diagnosis of hypothyroidism is confirmed by her

laboratory findings of a low FT4

, an elevated TSH value, and positive TPOAb.

A firm goiter, thyroid antibodies, and clinical symptoms of hypothyroidism

strongly suggest Hashimoto’s thyroiditis. She has no history of prior antithyroid drug

use, surgery, or RAI treatment, which are common causes of iatrogenic

hypothyroidism. She is also not taking any goitrogens or drugs known to cause

hypothyroidism (Table 52-2).

Treatment with Thyroid Hormones

THYROID HORMONE PRODUCTS

CASE 52-5, QUESTION 2: What thyroid preparation should be used to treat M.W.’s hypothyroidism? Are

differences, advantages, or disadvantages significant among the various generic and brand name formulations of

thyroid hormones?

The principal goals of thyroid hormone therapy are to attain and maintain a

euthyroid state. Thyroid preparations (Table 52-8

63–66

) are synthetic ( L-thyroxine, Ltriiodothyronine, liotrix) or natural (desiccated thyroid). The latter come from animal

tissues.

Desiccated Thyroid

Desiccated thyroid is derived from pork thyroid glands, although beef and sheep are

also used. Today, starting patients on desiccated thyroid is not justified. The USP

requires only that desiccated thyroid contain 0.17% to 0.23% organic iodine by

weight. These requirements do not seem stringent enough because potency may vary

with changes in the proportion of the two active hormones (T3 and T4

) or with

changes in the amount of organic iodine present.

67,68 This variable potency seems to

be particularly true of generic formulations compared with the biologically

standardized Armour brand of desiccated thyroid. Inactive desiccated thyroid

preparations that contain negligible amounts of T3 and T4 or even iodinated casein

instead of active hormone have been identified in various brands sold in retail

pharmacies and in over-the-counter products found in health food stores.

68–70

Likewise, preparations with greater-than-expected activity caused by an abnormally

high T3 content have resulted in thyrotoxicosis.

Table 52-8

Thyroid Preparations

Drug/Dosage Forms Composition

Dosage

Equivalent Comments

Thyroid USP (Armour)

Tab: 0.25, 0.5, 1, 1.5, 2, 3,

4, and 5 gr

Desiccated hog,

beef, or sheep

thyroid gland

Standardized iodine

content

1–1.67 gr

a Unpredictable T4

:T3

ratio;

supraphysiologic elevations in T3

levels might produce toxic symptoms;

Armour brand preferred

L-Thyroxine (Levoxyl,

Levothroid, Synthroid,

Unithroid, various)

Tab: 0.013, 0.025, 0.050,

0.075, 0.088, 0.112, 0.125,

0.137, 0.15, 0.175, 0.2, and

0.3 mg

Inj: 200 and 500 mcg

Synthetic T4 60 mcg

a Stable, predictable potency; well

absorbed; more potent than

desiccated thyroid. When changing

from >2 gr desiccated thyroid to

L-T4

, a lower dosage of L-T4 might

be needed to avoid toxicity. Weight

should be considered in dosing (1.6–

1.7 mcg/kg/day). L-T4

absorption can

be impaired by iron, aluminumcontaining products (e.g., antacids,

sucralfate), Kayexalate, calcium

preparations, proton pump inhibitors,

cholesterol resin and phosphate

binders, raloxifene, soy, bran, coffee,

fiber enriched foods. L-T4

metabolism increased by

anticonvulsants, rifampin, imatinib,

bexarotene, and pregnancy

L-Triiodothyronine

(Cytomel)

Tab: 5, 25, and 50 mcg

Inj: 10 mcg/mL (Triostat)

Synthetic T3

25–37.5 mcg Complete absorption; requires multiple

daily dosing; toxicity similar to all T3

-

containing products; see desiccated

thyroid comments

Liotrix (Thyrolar)

Tab: 0.25, 0.5, 1, 2, and 3

gr

60 mcg T4

:15 mcg

T3

50 mcg T4

:12.5 mcg

T3

Thyrolar-1 No need for liotrix because T4

is

converted to T3

peripherally;

expensive, stable, and predictable

content

aHistorically, 60 mg (1 gr) of desiccated thyroid = 60 mcg of T4

.

66 This conversion was determined with older

TSH assays, without direct measurement of FT4

and has been challenged. The conversion is now typically

reported as 80 mcg

63

, 88 mcg,

64 or 100 mcg

65 of T4

per 60 mg of desiccated thyroid. The T3

component of

desiccated thyroid is an additional factor to consider when converting from one to the other and an exact equivalent

dose has not been determined.

gr, grain; Inj, injection; L-T4

, levothyroxine; T3

, triiodothyronine; T4

, thyroxine; Tab, tablet; USP, United States

Pharmacopeia.

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Allergic reactions to the animal protein are another concern. In addition,

desiccated thyroid suffers from two problems inherent to all T3

-containing

preparations. Because T3

is absorbed more rapidly than T4

, supraphysiologic

elevations in plasma T3

levels occur after oral ingestion, which can produce mild

thyrotoxic symptoms in some patients. FT4

levels are low during T3 administration

and, if misinterpreted, can result in the erroneous administration of more hormone.

These problems with T3 are easily missed unless T3

levels are routinely monitored.

Because significant amounts of T4 are converted to T3 peripherally, oral

administration of T3 offers no advantage and is not usually needed (see

Triiodothyronine section).

Loss of tablet potency can occur from prolonged storage of desiccated thyroid

preparations, but this instability is not as important as once believed. Because the

only apparent advantage of desiccated thyroid is its low cost, it should not be

considered the drug of choice for replacement therapy. Patients maintained on

desiccated thyroid should be encouraged to change to L-thyroxine (T4

). Although 60

mg (1 g) of desiccated thyroid is theoretically equal in potency to 75 to 100 mcg of

T4

,

66

this equivalency may not hold true if the desiccated thyroid preparation is less

active than its labeled content. The patient’s weight should also be considered when

switching therapy (see Case 52-5, Question 3).

The synthetic thyroid preparations differ from one another in their relative potency,

onset of action, and biological half-life.

Levothyroxine or L-Thyroxine

L-Thyroxine is the thyroid replacement of choice.

35,65,71

Its advantages include

stability, uniform potency, relatively low cost, and lack of allergenic foreign protein

content. The long half-life of 7 days permits once-a-day dosing and, if necessary, the

creation of special convenience schedules, such as the omission of medication on

weekends. The mean absorption of a commonly used branded preparation is 81%.

72

Absorption is optimal on an empty stomach.

73 Current guidelines recommend taking

L-thyroxine either 60 minutes before breakfast or 3 to 4 hours after the evening meal

for consistent absorption.

35,65 Several medications can also impair L-thyroxine

absorption (see Case 52-9, Question 1).

Concerns about generic and branded L-thyroxine tablet stability and potency,

bioavailability, and product interchangeability existed because L-thyroxine

preparations were grandfathered in by the 1938 Food, Drug, and Cosmetic Act. To

address these concerns, the U.S. Food and Drug Administration (FDA) required that

all manufacturers of L-thyroxine products submit a New Drug Application (NDA) by

August 2001 or cease production by 2003 if the NDA was not filed.

74 Several FDAapproved brand and generic (formulations approved under the NDA received AB or

BX ratings, indicating interchangeability for some generic and brand preparations.

Raising concerns about the methodology the FDA used to determine bioequivalence,

the American Thyroid Association, The Endocrine Society, and the American

Association of Clinical Endocrinologists issued joint position statements expressing

their displeasure with the FDA’s conclusions of interchangeability.

75 Abbot

Laboratories, the manufacturer of Synthroid, and others also disagreed with the

FDA’s findings.

76 Although this issue remains controversial, the preponderance of the

evidence supports the FDA ratings and suggests that these preparations are likely to

be interchangeable in the majority of patients.

35,65,77–80

Triiodothyronine

T3

(Cytomel) is not recommended for routine thyroid hormone replacement because

of the problems identified earlier with T3 administration (see Desiccated Thyroid

section).

71 Numerous randomized studies now conclude that replacement with

combination T4 and small dosages of T3 offer no advantage to T4 alone, despite an

initial study showing improved cognitive performance and mood changes

81,82

Furthermore, a prospective study found that T3

levels post-thyroidectomy in 50

patients receiving only levothyroxine were similar to T3

levels in these euthyroid

patients before surgery confirming that levothyroxine alone is sufficient for

replacement.

83

Its use to enhance contractility in coronary bypass surgery is

controversial.

84

Although T3

is well absorbed, it has a relatively short half-life (1.5 days),

necessitating multiple daily dosing to ensure a uniform response. Other disadvantages

include higher expense and a greater potential for cardiotoxicity. Its primary use is

for patients who require short-term hormone replacement therapy and rarely in those

in whom T4 conversion to T3 might be impaired. Proponents favoring thyroid

treatment of the “euthyroid sick” syndrome identify T3 as the hormone replacement of

choice. T3

therapy should be monitored using the TSH and TT3 or FT3

levels.

Liotrix

Liotrix is a combination of synthetic T4 and T3

in a physiologic ratio of 4:1. This

preparation is subject to the same disadvantages common to all T3

-containing

preparations. It is also stable and potent, but it is more expensive than other thyroid

preparations. Because oral administration of T3

is not needed and there is no

advantage of adding T3

to T4

therapy, this expensive preparation is not

recommended.

81,82 Patients should be changed to an equivalent dosage of L-thyroxine.

THYROXINE

Dosage

CASE 52-5, QUESTION 3: What would you recommend as appropriate starting and maintenance dosages of

T4

for M.W.?

The maintenance dosage for M.W. can be estimated from her weight. Average

replacement doses of 1.6 to 1.7 mcg/kg/day (e.g., 100–125 mcg) are sufficient in

most patients to normalize the TSH.

62,71 L-Thyroxine dosages that suppress TSH

levels to below normal or undetectable levels (subclinical hyperthyroidism) should

be avoided to prevent osteoporosis and cardiac toxicity.

71,85–89 Excessive L-thyroxine

can cause tachycardia, atrial arrhythmias, impaired ventricular relaxation, reduced

exercise performance, and increased risk of cardiac mortality.

85 These considerations

are especially important in older patients, who might require less T4

than their

younger counterparts and who are particularly sensitive to minute changes in T4

doses (see Case 52-6). As patients age, the dosage should be evaluated yearly and

decreased if necessary to maintain a normal TSH level.

How rapidly T4

replacement can proceed depends on the likelihood of invoking

cardiac toxicity in susceptible patients. Minute doses of T4

(e.g., <75 mcg) can

increase heart rate, stroke volume, oxygen consumption, and cardiac workload before

euthyroidism occurs. One double-blind study compared the clinical outcome between

starting full replacement doses versus gradual 25-mcg incremental doses in relatively

young hypothyroid subjects with asymptomatic cardiac disease and concluded that

those receiving full doses normalized thyroid function tests more rapidly (4 weeks)

and without any toxicity.

90 Because M.W. has no identifiable risk factors (see Case

52-11, Question 3) for cardiotoxicity that require careful dosage titration (e.g., old

age, cardiac disease, long duration of hypothyroidism), she can be started on an

estimated full

p. 1049

p. 1050

replacement dose of 125 mcg daily of L-thyroxine (70 kg × 1.7 mcg/kg/day = 120

mcg).

35 An alternative conservative approach would be to start with 100 or 112

mcg/day, check the FT4 or FT4

I and TSH tests after 6 to 8 weeks of therapy, and if

the TSH is still elevated without any symptoms of toxicity, increase the dosage to

125 mcg/day. The appropriate replacement dose will produce a TSH of 1 to 2

microunits/mL, normalize FT4 or FT4

I levels, and reverse clinical symptoms of

hypothyroidism. Generally, dosing adjustments should not exceed monthly increments

of 12.5 to 25 mcg/day. Even in the absence of overt coronary disease, patients over

age 50 to 60 should be started on a lower dose of L-thyroxine (50 mcg/day) and

titrated.

35