1378 Kaplan: Diagnosis of Thyroid Disease
majority of patients do not have clinically significant
Table 1. Confusing thyroid test nomenclature.
thyroid disease (11 ).
Possible intended meanings [incorrect meanings
Test name sometimes encountered]
Free T4 Free-T4 index (or “T7”) Utility and Limitations of Thyroid Diagnostic Tests
Free T4 concentration For patients with abnormal serum TSH concentrations,
T3 Serum total T3 concentration, serum free T3 follow-up consists of a focused history, physical exami-
concentration, T3-uptake test to assess T4 nation with special attention to the thyroid gland, a repeat
binding to serum proteins
TSH test for verification, determination of serum thyroid
Thyroglobulin Serum thyroglobulin concentration,
[anti-thyroglobulin antibody test], hormone concentrations, and sometimes, imaging studies.
[thyroxine-binding globulin] Unfortunately, it is not unheard of for patients to be told
Uptake test T3- (or T4-) uptake test to assess T4 binding to that because they have high TSH concentrations, they
serum proteins, radioiodine uptake by the thyroid need to take thyroid medication lifelong and be sent a
gland, “uptake scan”, i.e., thyroid scintiscan
combined with thyroid radioiodine uptake prescription for T4 without further workup or explana-
measurement tion. Moreover, because goitrous changes in the thyroid
Anti-thyroid Anti-thyroglobulin antibody, anti-thyroperoxidase (or gland or the development of thyroid nodules often do not
antibody anti-microsomal) antibody, anti-TSH-receptor alter thyroid function, a TSH concentration within the
antibody, antibody against the thyrocyte Na/I
symporter, [anti-mitochondrial antibody]
reference interval in a patient with one of these structural
abnormalities provides only part of the necessary infor-
mation and does not mean that the patient’s thyroid
ized and other severely ill patients for thyroid disease. condition is innocuous. Full evaluation of these cases
Severe nonthyroid illness, whether physical or psychiat- requires some combination of antithyroid antibody tests,
ric, and drugs such as glucocorticoids or dopamine can imaging, and fine-needle biopsy.
change the behavior of the pituitary-thyroid axis to cause Patients with abnormal TSH results should have serum
abnormally high or low serum TSH values in the absence thyroid hormone determinations. Because 99% of T4
of thyroid disease, as judged by follow-up studies after and triiodothyronine (T3) in the blood are bound to serum
patients have recovered from their nonthyroid illnesses proteins, but only the free thyroid hormones are biologi-
(11 ). In the absence of an abnormal thyroid gland by cally active, estimates of free thyroid hormone concentra-
careful physical examination, a hospital inpatient with a tions are theoretically preferable to total-T4 and total-T3
mild or moderate ( 20 mIU/L) increase in serum TSH tests. A 1991 report from the American Thyroid Associa-
and an estimated free T4 (by either a free-T4 test or a tion summarized the performance of different types of
free-T4 index) within the health-related reference interval free-T4 and free-T3 assays (12 ), and there have been no
can usually be followed without treatment and reevalu- major changes since then. Free-T4 index methods can be
ated later. The same holds true for a patient with a used successfully if their limitations and performance in
subnormal serum TSH and estimated free T4 and serum various clinical settings are understood, but they may be
T3 values that are not increased. In both cases, the great more subject to false-positive results than other, more
Table 2. Some causes of abnormal serum TSH concentrations.
TSH below normal TSH above normal
Primary hyperthyroidism Primary hypothyroidism
Pituitary/hypothalamic disease with central hypothyroidism Pituitary thyrotroph adenoma
Pituitary resistance to thyroid hormone (central hyperthyroidism)
Generalized thyroid hormone resistance
Prolonged thyrotroph cell suppression after recent hyperthyroidism Thyrotoxicosis from overly rapid correction of severe hypothyroidism with
in euthyroid or hypothyroid patient parenteral T4
Old age Old age
Drugs, e.g., glucocorticoids, dopamine Drugs, e.g., amiodarone
Problems with T4 treatment Problems with T4 treatment
Overdosage in treatment for fatigue or overweight Underdosage based on misleadingly high total T4
Altered gastrointestinal absorption because of drugs or disease Altered gastrointestinal absorption because of drugs or disease
Altered T4 clearance because of drugs Altered T4 clearance because of drugs
Patient compliance problems Patient compliance problems
Prescription error Prescription error
Testing too soon after T4 dose decrease Testing too soon after T4 dose increase
Many severe systemic illnesses Recovery phase after severe systemic illness
Combination of pulsatile TSH secretion and analytical precision Combination of pulsatile TSH secretion and analytical precision limits
limits Antibody in patient serum against antibody in TSH assay, causing
Clinical Chemistry 45, No. 8(B), 1999 1379
“direct”, free-T4 assays (12 ). Free-T3 assays are available,
Table 3. Biological pitfalls in thyroid test interpretation.
but are not often used. Binding protein abnormalities can
increase total T3 in the absence of hyperthyroidism, nota-
Anomalous binding of T4 or T3 to serum proteins
bly during estrogen treatment and pregnancy. If neces-
sary, a T-uptake test or thyroxine-binding globulin mea-
surement can be used to calculate a free-T3 index, or a Disease induced
free-T3 test can be obtained to clarify an ambiguous Pregnancy
increased total-T3 result. Altered reference intervals for thyroid hormones or TSH
When hypothyroidism is suspected, a free-T4 estimate Childhood
is appropriate because total-T3 and free-T3 tests have Pregnancy
inadequate sensitivity and specificity in this setting. When Old age
hyperthyroidism is suspected, the combination of a Disrupted set point of the hypothalamic-pituitary-thyroid axis
free-T4 estimate and a total- or free-T3 estimate provides Nonthyroid illness
the most complete assessment of the severity of hyperthy- Drugs
roidism and identifies cases of “T3-toxicosis”, i.e., a selec- Thyroid hormone resistance
tive increase of the serum T3 concentration. In some Acute psychiatric illness
centers, free-T4 and -T3 tests are routinely used when the Imaging tests
TSH is increased (8 ), but in others, serum T3 measure- High radioiodine uptake by the thyroid gland without
ments are obtained only when the TSH is low and the free hyperthyroidism (“hypertrapping”)
Hashimoto thyroiditis with normal or low thyroid function
T4 is within the reference interval. I prefer to monitor both
Congenital thyroperoxidase deficiency
serum free T4 and T3 in patients with low serum TSH
(other than hypothyroid patients taking T4), even after the
Low radioiodine uptake by the thyroid gland without
thyroid diagnosis is known, to establish patterns of in- hypothyroidism
creasing or decreasing values over time. In patients with Hyperthyroid phase of subacute and postpartum thyroiditis
subclinical hyperthyroidism or those treated with antithy- Exposure to high concentrations of nonradioactive iodine
roid drugs, identification of a temporal trend can be quite Altered thyroid parenchymal sonographic texture in Hashimoto
valuable in deciding when to initiate or modify therapy, thyroiditis
as illustrated in the case report below. Multiple focal changes difficult to distinguish from colloid
Biological factors that can cause confusing thyroid nodules or neoplasms
Very high prevalence of nonpalpable nodules 1 cm in middle-
diagnostic test results are listed in Table 3. Such results aged and elderly individuals when ultrasound thyroid imaging
frequently generate patient referrals to my associates and is performed
myself and can inappropriately raise patients’ hopes or Cytology
fears. The first two blood test categories in Table 3 Continuum of cytologic features in benign and well-differentiated
represent non-disease. Children with learning disorders follicular neoplasms
have been referred to me because of serum T3 concentra- Inconclusive or suspicious thyroid fine-needle biopsy cytology
tions above a laboratory’s stated reference interval, with a
serum TSH concentration within the reference interval.
The parents have been told that either hyperthyroidism or mm hypoechoic areas (15 )—with no mention of Hashi-
thyroid hormone resistance (13 ) is the problem and that I moto disease as the most likely diagnosis, but with a
will solve the problem by treating the thyroid. Instead, the summary stating only that any one of the focal changes
children have serum T3 concentrations within the age- might be a cancer. The ultrasound finding of one or two
appropriate reference intervals (14 ), but the laboratory nonpalpable thyroid nodules 1 cm in diameter with
reports a reference interval that actually applies only to regular borders and no calcifications is another non-
nonpregnant adults with no other medical problems. The disease, because an enormous number of people have
parents of these children are always disappointed, and them, and the chances of a clinically significant cancer in
sometimes are frustrated and angry. There are also age- such lesions are so small that observation is considered
and pregnancy-related changes in the reference intervals appropriate management (16 –18 ). It is a disservice to the
for serum total T4, free T4, TSH, and thyroxine-binding patient and the primary physician for the ultrasound
globulin (14 ). report to comment about this type of lesion only that
Imaging tests are also subject to misinterpretation “cancer cannot be ruled out”, but I encounter such reports
(Table 3). It is common to receive a report describing a often and only rarely see a more appropriate comment
thyroid radioactive iodine uptake value in the “hyperthy- such as, “this is a nonspecific finding found in more than
roid range” or “hypothyroid range”, although thyroid half of all individuals over age 60” (19 ).
secretory function cannot accurately be inferred from this In the evaluation of thyroid nodules by fine-needle
test. Another problem is a thyroid ultrasound report that biopsy, up to 20% of cases have findings of a cellular
describes the typical features of Hashimoto thyroiditis— follicular lesion for which malignancy cannot be excluded
coarse texture of the parenchyma and multiple focal 1– 6 (Table 3) (20 ). Some cytopathologists report these as
1380 Kaplan: Diagnosis of Thyroid Disease
follicular lesions without further comment. Other experi- Approximately 90% of the cases of hypothyroidism
enced cytopathologists feel that they can subdivide this shown in Table 4 were attributable to Hashimoto thyroid-
type of lesion into risk categories with chances of cancer itis, but again, for the 10% with other diagnoses the
ranging from 5–10% to 50% (20 ). Having a specific optimal management may differ. A patient who has had
degree of cancer risk may help in the decision between radioiodine ablation for hyperthyroidism may require an
surgery and observation for the patient who has an unusually low dose of T4 because of autonomous function
increased risk of surgical complication because of age or in the thyroid remnant. In patients taking T4 for hypothy-
coexisting illness. This information can also help the roidism caused by Hashimoto thyroiditis, many factors
surgeon decide on the extent of resection (20 ). can alter a patient’s dose requirement (21, 22 ), and pa-
tients with problems in T4 treatment are referred to me
Simplex Thyroid Diseases with some regularity (Tables 2 and 4).
Thyroid diseases with a single important dimension can In patients with diffuse euthyroid goiters (Table 4),
be termed “simplex” conditions. Examples are hypothy- those with negative antithyroid antibody tests (almost
roidism with mild, diffuse thyroid enlargement; hyper- one-half) are more likely to have autonomous function
thyroid Graves disease without ophthalmopathy; or a and a future risk of hyperthyroidism, whereas those with
solitary thyroid nodule. Simplex does not, however, nec- positive antibody tests ( 43%) have a greater likelihood
essarily imply that optimal clinical management is simple. of future hypothyroidism (23 ). A recent study suggested
Table 4 presents the diagnoses of new patients in my that levothyroxine treatment to shrink thyroid nodules is
practice, during a 1-year period, who had hyperthyroid- more likely to succeed in patients with Hashimoto thy-
ism, hypothyroidism, or euthyroid goiter. When the eval- roiditis than in patients with no evidence of autoimmu-
uation of hyperthyroidism included antithyroid antibody nity (24 ).
tests and scintiscanning, Graves disease accounted for If the prognosis and appropriate management of pa-
86% of cases. The other 14% had diagnoses for which tients with Hashimoto thyroiditis differ from those of
management differs from that of Graves disease, e.g., in patients with non-autoimmune conditions, we should be
the appropriate dose of radioactive iodine, the possibility able to detect thyroid autoimmunity reliably. The diag-
of ethanol ablation for a single toxic autonomous nodule, nostic sensitivity of available antithyroid antibody test
or the advisability of observation because of the self- methods may vary. One study (25 ) suggested that mea-
limited nature of the disease. surement of only the anti-thyroid peroxidase (or “anti-
microsomal”) antibody suffices because almost no pa-
tients have increased concentrations of the anti-
Table 4. Causes of hyperthyroidism, hypothyroidism, and
thyroglobulin antibody alone (Table 5). However, using a
euthyroid goiter in consecutive patients new to the
different method to measure the anti-thyroglobulin anti-
author’s practice in 1 year (1991).
body and possibly testing a patient population selected
Diagnosis n %
differently, I found substantially more patients with an
Hyperthyroidism 120 100
isolated increase of anti-thyroglobulin antibody than an
Graves disease 103 85.8
isolated increase of anti-microsomal antibody (Table 5).
Toxic multinodular goiter 7 5.8
Therefore, the conclusion that performing both antithy-
Single toxic adenoma 4 3.3
Subacute or postpartum thyroiditis 4 3.3
roid antibody tests “increases the cost without an offset-
Pituitary resistance to thyroid hormone 1 0.8
ting diagnostic gain” (25 ) may be limited to specific
Hyperemesis gravidarum 1 0.8 methods and/or patient populations. It would seem pre-
Hypothyroidism 260 100 mature to advise a universal abandonment of the anti-
Hashimoto thyroiditis, new 123 47.3 thyroglobulin antibody test.
Hashimoto thyroiditis, treated Another simplex condition is a solitary thyroid nodule.
Euthyroid 58 22.3 The diagnostic evaluation is straightforward: check the
Undertreated 28 10.8 TSH and do a needle biopsy (16, 17 ). Management prob-
Overtreated 25 9.6 lems arise from the 5–20% of cases in which the biopsy
Spontaneous, antibody-negative 10 3.8 specimens are insufficient for diagnosis and the addi-
Post radioiodine, untreated 9 3.5 tional 20% for which the cytology is ambiguous (20 ). In
Antithyroid drug overdose 1 0.4 those cases, we must use other clinical risk factors in
Iodine overload or lithium therapy 3 1.2 deciding about surgery (26 –28 ). Even for nodules with
Generalized thyroid hormone resistance 3 1.2 benign cytology, controversy persists regarding the value
Euthyroid goiter 255 100 of suppressive treatment with T4 (29 ).
Diffuse, antibody-negative 122 47.8 Thus, even in simplex thyroid diseases, many patients
Diffuse, Hashimoto thyroiditis 110 43.1 benefit from an evaluation beyond the first-line tests.
Multinodular 16 6.3 Welcome developments on the laboratory front would be
Compensatory, post surgery 5 2.0
better standardization of tests such as antithyroid anti-
Lithium therapy 2 0.8
bodies, free T4, and free T3 to allow results from different
Clinical Chemistry 45, No. 8(B), 1999 1381
Table 5. Comparative utility of anti-thyroid antibody tests in relation to patient population and test methods.
Agglutination method for anti-
thyroglobulina RIA method for anti-thyroglobulinb
microsomal Anti-thyroglobulin % of 700 % of 139
antibody antibody n positives n positives
Negative Negative 1330 161
Positive Positive 185 26 87 63
Positive Negative 507 72 9 6
Negative Positive 8 1 43 31
Total 2030 300
Data for the agglutination anti-thyroglobulin method are those of Nordyke et al. (25) on consecutive patients referred to a clinic and hospital laboratory, most “on
suspicion or presence of Hashimoto’s thyroiditis, a goiter, hypothyroidism, or Graves’ disease”, using the Ames Sera-Tek kit (Ames Division, Miles Inc., Diagnostics
Data for the RIA anti-thyroglobulin method are from consecutive patients, referred to my office, who had findings suggesting the same conditions or other causes
of hyperthyroidism and for whom the anti-thyroglobulin antibody was measured by RIA (33), using a kit from Kronus. In both sets of data, the anti-thyroid microsomal
antibody was assayed by the Ames Sera-Tek agglutination kit.
laboratories to be interpreted similarly. In addition, the high index of suspicion and sufficient experience to
application of new techniques, such as PCR amplification recognize atypical combinations of test results and clinical
of tumor marker genes, to fine-needle biopsy samples findings, unusual patterns of test results, per se, or
would help reduce the uncertainty about cellular follicu- unexpected responses of patients to usual treatments. It is
lar lesions and further reduce the number of patients not rare for Graves disease and Hashimoto thyroiditis to
operated on for benign thyroid nodules. occur in the same patient, and some patients with this
combination spontaneously progress from hyperthyroid-
Multiplex Thyroid Diseases ism to hypothyroidism. The reverse sequence also occurs,
More complicated problems, with two or more important but far less often. It is even rarer for a patient to cycle up
dimensions, can be designated “multiplex” thyroid con- and down more than once. Lymphoma can arise within
ditions. Examples are listed in Table 6. The general the thyroid gland, usually against a background of Hashi-
categories include coexisting diseases, single diseases that moto thyroiditis (30 ), presumably because of malignant
can cause several types of complications, and diseases transformation of one or more of the inflammatory cells.
that evolve through several phases. Focal swelling or a generalized increase in thyroid size
The identification of coexisting conditions requires a despite adequate levothyroxine replacement justifies cy-
tological or surgical evaluation for lymphoma, and con-
sultation between the clinician and the cytopathologist
Table 6. Examples of multiplex thyroid diseases.
before a needle biopsy allows the pathologist to arrange
Coexisting unrelated conditions
for the specimens to be specially processed for evaluation
Hashimoto thyroiditis follicular cell neoplasm
of possible lymphoma.
Serum T4 and T3 protein-binding anomalies true thyroid
dysfunction In the thyroid diseases with several possible complica-
Coexisting related diseases tions (Table 6), the investigation of one aspect of the
Hashimoto thyroiditis Graves disease disease can have implications for other aspects. An ex-
Hashimoto thyroiditis and lymphoma ample is a large multinodular goiter with autonomous
Diseases with several possible complications function. Potential problems are tracheal narrowing, in-
Goiter: tracheal or esophageal compression, thyroid dysfunction, terference with swallowing, hyperthyroidism, and a dis-
unacceptable appearance figuring neck mass. Computed tomography (CT) is some-
Nodule: cancer risk, unacceptable appearance times necessary to evaluate the possibility of tracheal or
Graves disease: hyperthyroidism, eye abnormalities esophageal compression. However, if a CT contrast agent
Diseases that evolve over weeks to months is used, the thyroid is exposed to high concentrations of
Subacute or postpartum thyroiditis: thyroid function, size, and stable iodine, which may cause iodine-induced thyrotox-
discomfort all change
icosis and prevent ablative treatment with radioiodine.
Hemorrhage into a nodule: pain and swelling can vary
Diseases that evolve over years
Once again, communication between physicians is vital,
Autonomously functioning adenoma: regression, infarction,
in this case between the clinician and the radiologist.
increase in size function Although contrast-enhanced CT images are sharper, it is
Simple goiter: increase in size, function, nodularity easy to identify the tracheal air column and obtain a
Graves disease in remission: many patients ultimately become satisfactory assessment of thyroid size and geometry by a
hypothyroid non-contrast CT scan. When informed of thyroid abnor-
Thyroid cancer: slow progression of residual disease or late malities in patients, radiologists are happy to arrange
1382 Kaplan: Diagnosis of Thyroid Disease
Some thyroid diseases evolve through several phases laboratories that used different instruments or kits to
(Table 6). Medically appropriate, cost-effective use of measure serum free T4, it would have been difficult, if not
diagnostic tests differs depending on whether the patient impossible, to discern the trend toward hyperthyroidism.
is at the stage of initial diagnosis, in a disease phase in The imaging studies shown in Fig. 1 established the
which future change is expected, or under treatment diagnosis of an autonomous nodule rather than Graves
requiring therapeutic monitoring. In addition, clinical and disease, and this information was used to select a rela-
laboratory findings from each check-up must be viewed tively high therapeutic dose of radioiodine because toxic
in the context of sequential test results over time. nodular goiters are more radioresistant than Graves dis-
Fig. 1 shows the progressive increase in secretory ease thyroid glands (31 ).
activity of an autonomously functioning thyroid adenoma Another test in which the pattern of sequential test
in a woman who was 45 years of age at the time of initial results can be more important than single values is the
evaluation. The serum TSH initially was within the refer- serum thyroglobulin concentration, used as a tumor
ence interval, and the contralateral lobe continued to marker in the long-term follow-up of patients who have
function. After 3 years, the TSH was suppressed, as was had thyroid cancer. However, currently available serum
the function of the extranodular thyroid tissue. However, thyroglobulin assays have wide intermethod variability in
the serum free T4 was in the lower half of the reference results and analytical sensitivity, suboptimal interassay
range, the patient felt fine, and the nodule was unobtru- precision even when only one method is used, and for
sive. By 1997, she was menopausal and the serum free T4 some methods, susceptibility to “hook” effects that
had increased, but she had no hyperthyroid symptoms greatly underestimate very high values (32 ).
and no cosmetic problems. The serum free-T3 concentra-
tions (not shown) paralleled the serum free-T4 results. Conclusion
Radioiodine ablative treatment was administered in 1997 The appropriate use of thyroid diagnostic tests varies
because the progressive increase in serum free T4, with according to the clinical setting: screening for thyroid
concentrations that predicted the development of overt dysfunction, initial evaluation of an abnormal clinical or
hyperthyroidism within several years, and because the laboratory finding, management of simplex thyroid dis-
persistently high-normal thyroid hormone concentrations eases, elucidation of the components of multiplex thyroid
after 1994 could predispose her to postmenopausal osteo- diseases, long-term follow-up of evolving abnormalities,
porosis (7 ). This treatment decision was not based on the or monitoring of patients’ responses to treatment. Reduc-
last free-T4 result or any other single test value. If sequen- tion in needless evaluation of thyroid non-disease can
tial tests had been performed using a mixture of free-T4 potentially be achieved by improvements in test nomen-
index and free-T4 concentration values or in different clature, test standardization, and the understanding of
Fig. 1. Evolution of an autonomously functioning thyroid adenoma.
The graph shows serum free-T4 concentrations between 1989 and 1997. The thickened portion of the y-axis is the reference interval. The arrow denotes the time of
administration of radioactive iodine ablative therapy. The upper image is a pertechnetate thyroid scintigram from 1989, showing persistent function in the left lobe;
the lower image is a pertechnetate scintigram from 1992, when the serum TSH was first suppressed, showing negligible tracer uptake in the left lobe. The TSH
concentration remained suppressed thereafter.
Clinical Chemistry 45, No. 8(B), 1999 1383
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tic tests. In all but the most straightforward cases of T4
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