Monitoring Therapy

CASE 52-5, QUESTION 4: Ten days after starting L-thyroxine therapy, M.W. continues to complain of

tiredness, fatigue, and difficulty singing despite excellent adherence. Thyroid function tests show a TT4

of 4

mcg/dL (normal, 4.8–10.4), an FT4

of 0.5 ng/dL (normal, 0.8–1.4), and a TSH of 40 microunits/mL (normal,

0.45–4.1). What therapeutic options are available? How should M.W.’s thyroid function tests be interpreted?

Clinical improvement in the signs and symptoms of hypothyroidism and

normalization of laboratory parameters are appropriate therapeutic end points. If the

replacement dose is sufficient, some correction of her symptoms should occur after 2

to 3 weeks, but maximal effects will not be evident for 4 to 6 weeks. Typically,

improvement of anemia and hair and skin changes is delayed and requires several

months of treatment before resolution.

60,66

In patients with severe myxedema, a transiently elevated T4

level might occur at 6

weeks because the metabolic clearance of T4

is decreased by the hypometabolic state

associated with hypothyroidism.

FT4 or FT4

I and TSH should be checked about 6 to 8 weeks after the initiation of

therapy because T4 has a half-life of 7 days, and three to four half-lives are needed to

reach steady-state levels. Levels obtained before this time (as in M.W.) may be

misleading and should be interpreted cautiously. No change in her L-thyroxine dosage

should be attempted at this time.

CASE 52-5, QUESTION 5: Eight weeks later, on a routine follow-up visit, M.W. still feels tired and not back

to her normal self. She denies any symptoms of hyperthyroidism. Her thyroid function tests show a TT4

of 14

mcg/dL (normal, 4.8–10.4), a TT3

of 100 ng/dL (normal, 58–201), FT4

of 1.9 ng/dL (normal, 0.7–1.9), and a

TSH of 3.5 microunits/mL (normal, 0.45–4.1). How should M.W.’s thyroid function tests be interpreted? What

changes, if any, should be recommended in her therapeutic regimen?

Patients treated with L-thyroxine may develop an elevated TT4 concentration and

FT4 without overt clinical signs of hyperthyroidism.

83,91 Despite these elevated

levels, patients are euthyroid, as evidenced by a normal TSH. Because T3

is not

being released from the nonfunctioning thyroid gland, a higher concentration of T4

is

necessary to increase the amount of T3 obtained from peripheral conversion. Jonklaas

et al. reported that the mean FT4 was significantly higher (1.34 ng/dL) in patients

receiving L-thyroxine postoperatively compared to their euthyroid levels before

thyroidectomy (FT4

, 1.06 ng/dL).

83 T3

levels on L-thyroxine replacement were also

comparable after surgery to presurgery levels. However, lower T3

levels were noted

only in those in whom TSH levels were greater than 4.5 microunits/mL, indicating

that low T3

levels are likely a result of suboptimal L-thyroxine replacement. Thus, the

TSH appears to be the best indicator of euthyroidism in patients treated with Lthyroxine.

Another possibility is that the elevated thyroid levels may only be an artifact of the

laboratory collection time. Before any changes in her dosing regimen are made,

M.W. should be asked about the time she takes the drug and its relationship to the

time of her blood draw. Random sampling of FT4 and TSH levels can be

significantly different when compared with trough levels.

92,93

In one study, the FT4

level was 12% higher and the TSH level 19% lower when obtained from random

samples compared with trough samples.

93 Transient elevations in FT4

levels were

detected for 9 hours after ingestion of the oral L-thyroxine.

The symptoms of fatigue that M.W. is experiencing are likely not because of her

hypothyroidism. Patients may continue to have symptoms of hypothyroidism despite

normalization of the TSH value. Although some have suggested that the goal TSH be

titrated to 1 to 2 microunits/mL or lower for replacement therapy to improve wellbeing, this is controversial. One study found that changes in T4 dosing to achieve

TSH concentrations of 2 to 4.8 microunits/mL, 0.3 to 1.9 microunits/mL, or <0.3

microunits/mL in hypothyroid patients did not result in improvements in well-being,

psychologic, or hypothyroid symptoms, or quality of life.

94 Data justifying the safety

of higher T4 replacement doses found that achievement of a low but detectable TSH

level (0.04–0.4 microunits/mL) was not associated with an increased risk of

cardiovascular disease or fractures compared to those with suppressed (<0.03

microunits/mL) or elevated (>4 microunits/mL) TSH levels.

95

In conclusion, if an elevated TT4 and FT4 are noted without any symptoms of

thyrotoxicosis (as in M.W.), the dosage should not be decreased; rather, a trough FT4

and TSH level should be obtained to eliminate excessive dosing or any laboratory

artifacts. Alternatively, obtaining a level at least 9 hours after levothyroxine

administration also seems appropriate. Repeat values should be in the normal range

if the dosing is correct. An excessively suppressed TSH confirms a dosage that is too

high. In M.W., the lack of hyperthyroid symptoms suggests euthyroidism, and no

changes in her therapeutic regimen should be attempted until trough levels are

available. Evaluation for other causes of fatigue should be explored.

TRIIODOTHYRONINE

CASE 52-6

QUESTION 1: C.B., a 65-year-old woman, complains of fatigue and vague muscle aches and pains, which

she attributes to insufficient thyroid medication. On physical examination, the thyroid gland is palpable but not

enlarged, and DTRs are 2 plus and brisk. Her dose of T3 was increased from 25 mcg TID to 50 mcg TID

about 2 weeks ago based on the results of a recent FT4

of 0.5 ng/dL (normal, 0.8–1.4). She denies taking any

other medications. Is C.B.’s thyroid hormone replacement appropriate?

As noted previously, T3

is not the drug of choice for thyroid replacement. The use

of L-thyroxine would simplify her dosing regimen and facilitate monitoring.

The low FT4 did not justify increasing C.B.’s T3 dose. Because she is receiving

T3

, the FT4

, which is a measure of free T4

, will always be low and will never reach

normal levels. In fact, her vague complaints may be related to hyperthyroidism

because she is receiving the equivalent of 0.2 to 0.3 mg of L-thyroxine daily. TSH

and FT3

levels are most useful in monitoring patients receiving T3

therapy. A TSH

level should be obtained to evaluate her thyroid function. A suppressed TSH and an

elevated FT3 would indicate hyperthyroidism. It is important to remember that in an

older patient, hyperthyroidism might not always produce symptoms because of an

“apathetic” sympathetic system.

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L-Thyroxine should be initiated cautiously in older patients to avoid exacerbating

any preexisting arteriosclerotic heart disease that might be masked by the

hypothyroidism (see Case 52-11, Questions 2 and 3). In general, older patients

require smaller replacement dosages (approximately ≤1.6 mcg/kg/day of T4

) than

their younger counterparts.

96–98 Dosages of <50 mcg/day of T4 are common in patients

older than 60 years. However, this lower T4 dosage is not universal for all older

subjects.

98 The reason that older patients need lower dosages is unclear, but it has

been suggested that the lower requirements result from an age-related decrease in T4

degradation rates. Because dosage requirements change with age, patients should be

reassessed annually to determine whether the original dosage prescribed is still

appropriate.

In C.B., who had been on T3 without any evidence of cardiac toxicity, a less

cautious approach in changing to T4 can be attempted. An empiric L-thyroxine dosage

of 68 mcg/day (40 kg × 1.6 mcg/kg/day) is an approximate dosing end point for C.B.

The T3 should be discontinued and T4

initiated in a dose of 50 mcg/day; this dosage

can be adjusted as needed based on C.B.’s symptoms and thyroid function tests. After

T3

therapy is discontinued, its effects will disappear over 3 to 5 days. In contrast, T4

levels rise slowly over 4 to 5 days, so no overlap in T3 administration is necessary

to prevent hypothyroidism.

Parenteral Dosing

CASE 52-7

QUESTION 1: G.F., a 70-year-old man with long-standing hypothyroidism, has been receiving L-thyroxine 0.1

mg/day. Currently, he is in the hospital with a stroke and paralysis that prohibits him from swallowing oral

medications. His last thyroid function tests were normal. What is a reasonable method of administering thyroid

hormone to G.F.?

Because L-thyroxine has a half-life of 7 days, administration can be delayed for up

to 1 week, assuming G.F. can resume oral intake at that time. However, if parenteral

administration is required, L-thyroxine is available as an intramuscular (IM) or IV

injection. The IV route is preferred because IM absorption may be slow and

unpredictable, particularly if the circulation is compromised. Because the oral

absorption of T4

is approximately 80%,

72 parenteral doses should be decreased.

Once IV L-thyroxine replacement is successful, maintenance with a once-weekly IM

injection can be continued if oral ingestion is not feasible.

99

Hypothyroidism in Pregnancy

CASE 52-8

QUESTION 1: P.K. is a 35-year-old woman with Hashimoto’s thyroiditis, who is 6 weeks pregnant.

Laboratory test results showed TT4

, 5 mcg/dL (normal, 4.8–10.4) and FT4

, 0.7 ng/dL (normal, 0.8–1.4). She

takes her medications in the morning, which include L-thyroxine 0.1 mg/day and a prenatal vitamin enriched

with iron and calcium. What dosing adjustments are required because of P.K.’s pregnancy?

Inadequately treated or undiagnosed maternal hypothyroidism can be detrimental to

the mother and the developing fetus.

100,101 Miscarriage, spontaneous abortion,

hypertension, preeclampsia, and higher rates of cesarean sections and stillbirths have

been reported with maternal hypothyroidism. Congenital defects, congenital

hypothyroidism (see Case 52-8, Question 2), abnormal fetal development, and

impaired cognitive development in the newborn have been attributed to maternal

hypothyroidism. The IQ scores of children born to mothers with undiagnosed

hypothyroidism during pregnancy averaged 7 points lower than children born to

euthyroid mothers.

100 A delay in both mental and motor development was observed in

children aged 1 to 2 years old who were born to mothers with hypothyroxinemia but

normal TSH levels during the first trimester of pregnancy.

101 Normal maternal thyroid

function is essential during early fetal development. Fetal thyroid hormone

production begins by the end of the first trimester, with the fetus relying on maternal

thyroid hormones until that time. Transfer of maternal thyroid hormones is under the

control of the placenta.

102 The risk of congenital hypothyroidism is small if maternal

antibodies from Hashimoto’s thyroiditis cross the fetal circulation. The infant’s cord

blood should be assayed at birth to ensure that TSH is normal and that the child is

euthyroid.

The majority of women with primary hypothyroidism will require a 30% to 50%

increase in the prepregnancy T4 dosage to maintain euthyroidism during the first

trimester of pregnancy.

102–105 The only evidence of increased T4 demands is an

elevated TSH level (e.g., subclinical hypothyroidism) that occurs between weeks 5

(but can be as early as 3) and 16 of gestation. Often, no clinical symptoms of

hypothyroidism are evident, and the FT4 and the index are normal. Because of the

adverse consequences associated with maternal hypothyroidism, some have

advocated universal TSH screening of all pregnant women

106 as well as empirically

increasing the prepregnancy T4 dosage by 30% (extra 2 pills/week) as soon as

pregnancy is confirmed.

104 Because there is a physiologic decrease in TSH during

pregnancy caused by the TSH-like activity of human chorionic gonadotropin, the

upper limit of the normal TSH range should be adjusted for pregnancy.

102 TSH should

be no higher than 2.5 microunits/mL during the first trimester and 3.0 microunits/mL

in the second and third trimesters.

105

Physiologic explanations for the increase in thyroid hormone requirements include

the twofold increase in TBPA caused by high estrogen levels, increased volume of

distribution of thyroid hormones, as well as maternal transport of T4

.

102,105 Rising

HCG concentrations result in increased production of thyroid hormones.

102 Changes

in serum proteins cause direct immunoassay of FT4

to yield incorrect results. A

newer assay, measurement of T4

in the dialysate or ultrafiltrate of serum samples

using liquid chromatography or tandem mass spectrometry, has been shown to

produce reliable trimester-specific reference ranges for FT4

; however, these assays

are not universally available.

107

In the absence of trimester-specific reference ranges

for dialysate or ultrafiltrate measured FT4

, the FT4

index or TT4 should be used to

evaluate thyroxine production.

35

It is important to recognize that coadministration of

iron- and calcium-containing prenatal vitamins reduced T4 absorption (see Case 52-

9, Question 1) and that these drug interactions may affect dosage requirements. When

prenatal vitamins with iron and calcium were separated by 4 hours from T4

administration, only 31% of women required an increase in T4 dose.

108 The increase

in thyroid hormone requirements are likely because of a combination of physiologic

and drug interaction causes. Women should be followed closely during pregnancy

with monthly monitoring during the first half of pregnancy and at least once between

gestation weeks 26 and 32. If necessary, the T4 dosage should be adjusted to maintain

a TSH in pregnancy-adjusted ranges and an ultrafiltrate-measured FT4

, FT4

I, or TT4

in the upper limits of normal based on adjusted normal ranges. When the TT4

is used,

reference ranges should be increased by 50%.

35,107

P.K.’s low TT4 and FT4 are concerning. The TT4 should be much higher because

of pregnancy-associated increases in TBG. The TSH level should be obtained, and

the daily dosage of T4 should be increased to 125 mcg after eliminating the

possibility of patient non-adherence and drug interactions. Ingestion of the prenatal

vitamins with iron and calcium should be separated by at

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least 4 hours from T4

. PK could also be instructed to take the T4 at night for better

absorption.

73 The TSH should be repeated in 6 weeks, and the dosage should be

adjusted as needed to keep the TSH in the range as above. After delivery, the dosage

should be reduced to prepregnancy levels and the FT4 and TSH rechecked to ensure

euthyroidism.

CONGENITAL HYPOTHYROIDISM

CASE 52-8, QUESTION 2: P.K. delivered a healthy baby, T.K., at term without difficulty. T.K.’s

postpartum screening serum T4

level was 5 mcg/dL (normal, 4.8–10.4), and TSH was 35 microunits/mL

(normal, 0.45–4.1). At home, T.K. became lethargic, had a weak cry, sucked poorly, and failed to thrive.

Assess the situation (including a treatment plan and prognosis). How is mental development affected?

T.K.’s symptoms are suggestive of congenital hypothyroidism, although in most

infants the clinical signs and symptoms are so subtle and nonspecific that they are

easily missed until the child is several months old. The early clinical findings include

prolonged jaundice, skin mottling (cutis marmorata), lethargy, poor feeding,

constipation, hypothermia, hoarse cry, large fontanels, distended abdomen,

hypotonia, slow reflexes, and piglike facies. Respiratory difficulties, delayed

skeletal maturation, and choking (but not palpable goiter) may be present. These

infants are also at risk for additional congenital defects or complications.

109 Mass

neonatal screening programs have been successful in detecting congenital

hypothyroidism within the first few weeks of life before clinical manifestations are

apparent and before irreversible changes occur.

The postpartum low serum T4 concentration and elevated TSH level (>20

microunits/mL) in T.K. are of concern and should be verified. Transient

hypothyroidism can result from intrauterine exposure to thioamides or excess

iodides, or from transplacental passage of TRAb from the mother. Thyroid function

tests often normalize without treatment in 3 to 6 months as the TRAb is cleared by the

infant.

109 The diagnosis of hypothyroidism should be confirmed by a low serum T4

, a

low FT4

, and an elevated TSH concentration during the next few weeks. Serum T3

concentrations are often in the normal range and are not helpful. Normal serum T4

concentrations are higher in the first few weeks of life and gradually return to normal

by 2 to 4 months of life. The FT4

I may also be elevated. Because of these confusing

changes, thyroid serum levels should be compared with the normal range for the

approximate postnatal age.

Thyroid hormones play a critical role in normal growth and development,

particularly of the CNS, during the first 3 years of life. If untreated, dwarfism and

irreversible mental retardation occur. T.K.’s normal mental (IQ) and physical

development will be determined by the age at which treatment is started, the initial

dosage of T4

, the serum T4

level attained during therapy, the adequacy with which

treatment is maintained, and the cause and severity of the initial deficiency.

110–116

There is an inverse relationship between the amount of time to reach a euthyroid state

and the likelihood of impaired neurologic development.

109

Sodium L-thyroxine is the preparation of choice for replacement. T4

tablets can be

crushed and mixed with breast milk or formula; suspensions are not stable and should

not be used. T4

tablets should not be mixed with soy-based formulas because

decreased absorption and longer time to reach a TSH <10 microunits/mL may occur.

If a soy-based formula is required, the dosage of T4 should be administered halfway

between feeds.

109 T3

is less desirable because its short half-life causes a greater

fluctuation in plasma levels (Table 52-8). The initial replacement dose of T4 should

raise the serum T4 as rapidly as possible to minimize the consequences of

hypothyroidism on cognitive function. A delay in starting therapy of even a few days

has resulted in a poorer IQ outcome.

111,112,116 A minimum T4 dosage of 10 to 15

mcg/kg/day is recommended to raise the serum T4

to >10 mcg/dL (129 nmol/L) by 7

days.

110 However, some suggest that higher than previously recommended dosages of

12 to 17 mcg/kg/day might be more effective, but concern about negative neurologic

outcomes exists.

109,111,112

In the full-term healthy infant, full initial replacement T4

doses are appropriate unless the infant has underlying heart disease or is extremely

sensitive to the effects of thyroid hormones. In these infants, reduced doses of T4

(approximately 25%–33% of the recommended dose) can be started and increased

gradually by similar increments until the therapeutic dose is achieved. The

recommended replacement dose decreases with age and is shown in Tables 52-4 and

52-9.

Table 52-9

T4 Recommended Replacement Dose

Age Daily mcg/kg T4

3–6 months 10–15

6–12 months 5–7

1–10 years 3–6

>10 years 2–4

T4

, thyroxine.

Mental development and attainment of normal growth are not severely impaired if

adequate T4

treatment is initiated before 3 months of age to achieve a T4

level >10

mcg/dL (129 nmol/L).

109–112

,

114 Children with the most severe congenital

hypothyroidism had IQs lower than their siblings.

113 Young adults 20 years after

congenital hypothyroidism showed impaired motor and intellectual outcomes after

suboptimal T4

(<7.8 mcg/kg/day) therapy compared to sibling controls.

114 However,

those receiving optimal therapy still had some memory, attention, and behavior

deficits.

117 Newborns starting L-thyroxine during the first 4 to 6 weeks of life have

mean IQs similar to controls. The IQ drops if treatment is delayed until 6 weeks and

3 months (mean IQ, 95), or until 3 and 6 months (mean IQ, 75). When treatment is

delayed until 6 months to 1 year of age, normal mental development is impaired

despite subsequent treatment. Higher IQs also were found in children who received

T4 dosages >10 mcg/kg/day and achieved a mean T4

level >14 mcg/dL (181 nmol/L)

in the first month of therapy.

109,111,112,116,118 Neurologic deficits were also more likely

to occur in infants whose thyroid replacement was delayed or inadequate (T4 <8

mcg/dL [103 nmol/L] within 30 days of therapy and/or had delayed TSH

normalization [18–24 months]). Additional risk factors for low IQs and poor motor

and speech skills despite adequate therapy include clinical signs of hypothyroidism

during fetal life, T4 <2 mcg/dL at birth, thyroid aplasia, and retarded bone

age.

109,110,112

The goal of therapy is a T4

in the upper normal range (e.g., 10–18 mcg/dL and/or

an FT4 of 2 to 5 ng/dL) during the first 2 weeks of therapy, and then a lower target

thereafter: a T4 of 10 to 16 mcg/dL (and/or an FT4 of 1.6–2.2 ng/dL). IQs are

improved if TSH levels are normalized within the first month of therapy but no later

than 3 months.

111,112,116,118 Thyroid function tests should be routinely monitored 2 to 4

weeks after starting therapy, then every 1 to 2 months during the first 6 months of life,

every 3 to 4 months until age 3, and finally, every 6 to 12 months until growth is

complete.

109 Although TSH suppression is the most reliable index of adequate

replacement in older children, normalization of the TSH should not be used as the

sole monitoring parameter in infants because the TSH may lag behind correction of

the T4 and/or FT4

levels. Overtreatment should be avoided to prevent

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brain dysfunction, acceleration of bone age, and craniosynostosis (premature

closure of the cranial sutures). Normal growth and development should also be a

treatment goal. Other clinical end points include an improvement in activity level,

skin color, temperature, facial appearance, and reversal of other symptoms and signs

of hypothyroidism. The child will require lifelong replacement therapy.

UNRESPONSIVENESS TO LEVOTHYROXINE AND DRUG–DRUG

INTERACTIONS

CASE 52-9

QUESTION 1: R.T., a 45-year-old woman, complains of weight gain, heavy menses, sluggishness, and cold

intolerance. Her present medical problems include Hashimoto’s thyroiditis, treated with L-thyroxine 150 mcg

daily; hypercholesterolemia treated with cholestyramine 4 g 4 times a day (QID); anemia, treated with FeSO4

325 mg twice a day (BID); dysmenorrhea treated with estrogen-containing birth control pills daily; and a history

of peptic ulcer disease, treated with antacids and sucralfate 1 g BID. She was recently started on calcium

carbonate 1 g BID and raloxifene 60 mg daily to protect her bones. Her laboratory data include the following

findings:

Cholesterolserum concentration, 280 mg/dL

TSH, 21 microunits/mL (normal, 0.45–4.1)

FT4

, 0.6 ng/dL (normal, 0.8–1.4)

Positive TgAb and TPOAb

R.T. admits that she self-increased her L-thyroxine dose because she feels better on the higher dose. Why is

R.T. apparently unresponsive to thyroid therapy?

R.T.’s complaints and laboratory values confirm inadequate treatment of

hypothyroidism despite thyroid therapy. Possible causes of therapeutic failure

include non-adherence, error in diagnosis, poor absorption, subpotent medication,

rapid metabolism, and tissue resistance.

71,119,120 Thyroid resistance is rare, and nonadherence, error in diagnosis, and rapid metabolism do not appear to be reasonable

explanations in R.T.

The most likely explanations are poor bioavailability and/or a subpotent

preparation. The timing of T4 administration with her meals should be ascertained

because its bioavailability is improved when it is taken on an empty stomach and at

night.

71,73,121,122 Significantly lower TSH levels are achieved when levothyroxine is

taken on an empty stomach than with food or at night.

122 Simultaneous

coadministration of T4 with soy proteins, coffee, or high-f iber diets (e.g., oat bran,

soybean) should also be avoided because T4s absorption can be impaired.

123–125

R.T.’s history does not include surgical bowel resection or GI disorders (e.g.,

steatorrhea, malabsorption). Evidence for incomplete absorption of the hormone can

be obtained by comparing R.T.’s response to oral and parenteral T4

.

119