often on the particular method. Dual assessment clearly is necessary to identify the serum free T4-TSH combinations that indicate true thyroid dysfunction. When a patient

 That is, they have no clinical

manifestations of thyroid dysfunction and normal serum

free T4 and T3 concentrations.

Regardless of which initial test is used, assessment of

thyroid status has a high priority in patients at increased

risk of having thyroid dysfunction, as for example in those

with goiter, those treated previously for thyrotoxicosis

or receiving lithium or amiodarone, and patients with

associated autoimmune disease or connective tissue

diseases or a history of neck or whole body irradiation.

Untreated Patients

In untreated ambulatory patients, a normal serum TSH

concentration has high negative predictive value in ruling

out thyroid disease. If serum TSH is abnormal, serum free

T4 is done. Diagnostic strategies have been evaluated in

which serum T4 measurements are done routinely only

if the serum TSH is abnormal, unless pituitary disease is

suspected. Long-term assessment of this approach will

need to balance cost savings against potentially serious

adverse outcomes; for example, if thyrotoxicosis is

missed because of normal serum TSH values, or central

hypothyroidism is missed on the basis of normal serum

TSH values.

The following groups of patients will be incompletely or

incorrectly assessed if either serum TSH or free TSH or free

T4 alone is measured.

¾ Patients with subclinical hypothyroidism (high serum

TSH, normal free T4) in whom replacement therapy

may be beneficial.

¾ Those with subclinical thyrotoxicosis (low serum TSH,

normal free T4) in whom treatment with an antithyroid

drug or thyroid ablation may be beneficial.

752 Concise Book of Medical Laboratory Technology: Methods and Interpretations ¾ Those being treated for thyrotoxicosis, in whom

suppression of TSH secretion may persist for weeks

or months after normalization of serum T4 and T3 on

drug.

¾ Those with central (secondary or hypothyrotropic)

hypothyroidism (low serum free T4 low or normal TSH),

who should be evaluated for adrenal insufficiency

before T4 therapy is initiated.

¾ Those with binding abnormalities such as familial

dysalbuminemic hyperthyroxinemia (FDH) or T4 or T4

binding autoantibodies in whom some serum free T4

estimates are invalid.

¾ Those with thyroid hormone resistance with high serum

T4 and T3 concentrations and normal or high serum

TSH concentrations, who are often not recognized until

after inappropriate treatment has been given.

¾ Those with thyrotoxicosis caused by excess TSH

secretion caused by a pituitary tumor or selective

pituitary resistance to thyroid hormone.

Not withstanding the widespread acceptance of serum

TSH as a single initial test, some still advocate an estimate

of free T4 as the best initial test for suspected thyrotoxicosis.

Assessment of the Response to Treatment

In the testing of ambulatory patients with known thyroid

disease, the use of serum TSH alone can also be considered.

In a study of ambulatory patients attending a thyroid clinic,

hyperthyroid patients taking T4 for either replacement or

suppression, seldom needed a serum free T4 measurement

of the serum TSH was greater than 0.05 mU/L; although

at lower values, the magnitude of hyperthyroxinemia

did influence management. In contrast, in patients with

newly diagnosed thyrotoxicosis, measurements of serum

free T4 or free T3, or both, were necessary in addition to

serum TSH not only to establish the degree of hormone

excess but also to evaluate the response to treatment.

This study included a few new cases of hypothyroidism,

in whom serum T4 measurement also would be required

to establish the degree of hormone deficiency. In patients

with thyroiditis and pituitary-hypothalamic disease,

combined assessment was required.

In evaluating patients receiving T4 therapy, some

have suggested that hormone measurements add little

to a clinical assessment made by experts, but there

is justification for periodic serum TSH assessment to

avoid subtle tissue effects of thyroid hormone excess of

deficiency. A serum TSH value in the low-normal range

is, probably, the best single indicator of appropriate

dosage and is certainly of more use than a serum free T4

value alone, which may be increased slightly depending

on the time interval between dose and sampling. In some

situations (e.g. patients with ischemic heart disease and

hypothyroidism), the appropriate dose of T4 should be

based on clinical judgement rather than laboratory findings.

Difficult Diagnostic Situations

The prevalence of abnormal serum T4 or TSH values

in patients with acute medical or psychiatric illness is

high, but there is controversy as to the value of thyroid

function testing in these situations, because most

of the abnormalities do not indicate the presence of

thyroid disease in acutely ill patients because of the

potential importance of intercurrent thyroid disease

and the difficulty in assessing clinical features of thyroid

dysfunction, others suggest that testing should not be

done without some clinical indication.

In patients hospitalized for acute illness one or more of

the assumptions outlined above may not be justified; for

example, when there are wide fluctuations from the steady

state. Serum TSH values frequently are subnormal in the

absence of thyrotoxicosis and serum free T4 estimates

are subject to multiple interfering influences, depending

often on the particular method. Dual assessment clearly is

necessary to identify the serum free T4-TSH combinations

that indicate true thyroid dysfunction. When a patient

has both thyroid dysfunction and a severe nonthyroidal

illness, assessment becomes especially difficult because

the effects of the illness, medications, or changes in

nutrition can alter the expected changes in serum free T4

or TSH. Only clinical re-evaluation and repeated sampling

may resolve the dilemma.

Thyroid Diagnosis and Treatment

There are three general principles upon which the

physician should focus when evaluating thyroid function

in a patient. These principles are:

¾ The thyroid gland is the principal site of thyroid

dysfunction

¾ Autoimmune thyroid disease is the most common

etiology producing the dysfunction

¾ Thyroid status is best determined by a combined

measurement employing a serum free thyroxine (FT4)

estimate and thyrotropin (TSH).

For both hypothyroidism and hyperthyroidism, TSH

and an estimate of free T4 (FT4) are recommended.

T3 or free T3 may be needed to confirm hyperthyroidism if free T4 is within limits. Anti-thyroid

antibodies, preferably antithyroid peroxidase (anti-TPO),

may establish an autoimmune mechanism.

The Endocrine System 753

Recommendations for Thyroid Testing

¾ Hyperthyroid

• Symptomatic Free T4, TSH

• Post-therapy Free T4 (Free T3)

¾ Hypothyroid

• Symptomatic TSH, free T4 (anti-TPO)

• Subclinical TSH-first (T4, anti-TPO)

¾ Monitor replacement TSH

¾ Hypopituitary TSH and free T4

¾ Acutely Ill None without suspicion

¾ Pregnant

¾ Diagnosis TSH, free T4

¾ Hypo, treated TSH

¾ Elderly

• Healthy None

• Ill None

¾ Women > 60 years TSH

¾ High risk* TSH

¾ Healthy adults None without suspicion

*Ambigious symptoms, concurrent illness associated with

thyroid disease, drugs associated with thyroid dysfunction.

Diagnostic Approach to Anomalous

Serum T3, T4, and TSH Values

¾ Clinical re-evaluation, with particular attention to

long-term features suggestive of thyroid disease and to

the medication history.

¾ Measurement of serum TSH by a third-generation

method to identify conclusively the degree of TSH

suppression.

¾ Measurement of the serum T3 concentration with

appropriate binding correction (free T3)

¾ An authentic estimate of serum free T4 (particularly in

euthyroid hyperthyroxinemia).

¾ Follow-up to establish whether the abnormality is

transient or persistent.

¾ Search for evidence of unusual binding abnormalities

or hormone resistance in the propositus and family

members.

Typical Reference Ranges for Serum

Thyroid Hormones and TSH in Humans*

CALCITONIN

Calcitonin is produced by the parafollicular cells of the

thyroid. The main effect in man is to inhibit bone resorption,

it lowers serum calcium and phosphorus. Hypocalcemia

decreases calcitonin secretion; hypercalcemia increases

calcitonin secretion. A syndrome of calcitonin excess—

medullary carcinoma of the thyroid—is recognized in

man. Little effect on calcium homeostasis is observed.

However, the finding of elevated levels of the hormone is

useful in the early detection of tumors.

Clinical Relevance

a. Increased levels are associated with:

1. Medullary thyroid cancers

2. C cell hyperplasia

3. Chronic renal failure

4. Pernicious anemia

5. Zollinger-Ellison syndrome

6. Cancers of lung, breast and pancreas.

b. In a small proportion of patients who do have

medullary cancer, the fasting level of calcitonin is

normal. In these instances, a provocative test using

calcium or pentagastrin should be followed by an

abnormally large increase in calcitonin levels.

Procedure

1. A pentagastin injection is administered. Blood samples

are drawn before the injection and 1½ and 5 minutes

after injection.

2. Another method is to infuse calcium (15 mg/kg) over

a 4 hours period and collect blood samples before

infusion and again at 3 to 4 hours.

Interfering Factors

Levels are normally increased in

¾ Pregnancy at term

¾ Newborns.