Clinical Chemistry 45: 1377-1383, 1999;
(Clinical Chemistry. 1999;45:1377-1383.)
© 1999 American Association for Clinical Chemistry, Inc.
Clinical Perspectives in the Diagnosis of Thyroid Disease
Michael M. Kaplan
Associated Endocrinologists, 6900 Orchard Lake Road, Suite 203, West Bloomfield, MI 48322, and Departments of Medicine and Nuclear Medicine, William Beaumont Hospital, Royal Oak, MI 48073. Fax 248-855-5628; e-mail mmkallegro{at}aol.com
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Abstract
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Background: The wide array of available thyroid diagnostic tests
can help provide accurate diagnoses for most cases of thyroid disease
but can be confusing and costly when used inappropriately.
Methods: Published articles were reviewed and combined with the
author's clinical experience and data collected from patients.
Results: The discussions focus on confusing aspects of thyroid
diagnostic tests, the use and limitations of the thyrotropin test to
screen for thyroid dysfunction, biological factors that complicate the
interpretation of this and other thyroid diagnostic tests, and a
combined clinical and laboratory approach to (a) thyroid
diseases with only one important dimension ("simplex" conditions)
and (b) thyroid diseases with several important
dimensions ("multiplex" conditions).
Conclusion: The optimal use of thyroid diagnostic tests is
patient-specific and depends on the patient's specific thyroid
disease, the stage of disease, and coexisting medical
conditions.© 1999 American Association for Clinical Chemistry
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Introduction
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Several tests are available to evaluate a patient whose thyroid
gland is obviously abnormal or whose symptoms or physical signs raise
the possibility of thyroid disease. When used and interpreted
appropriately, these diagnostic tools can identify the abnormality in
nearly every case, but many factors contribute to suboptimal usage of
thyroid tests in clinical practice. At a trivial level, test
nomenclature can be confusing (Table 1
): some tests have similar names but measure different analytes,
and the same test may have different names (free thyroxine index =
"T7"; antithyroid microsomal antibody =
anti-thyroid peroxidase). However, most of the difficulty in thyroid
diagnosis stems from more substantive causes: complexities in the
biology of thyroid physiology and pathophysiology; limitations in
sensitivity, specificity, and diagnostic accuracy of the tests; or a
misunderstanding of the meaning of results. Clinical findings can and
must be integrated with thyroid diagnostic testing to yield accurate
and efficient answers to questions pertinent to the diagnosis and
treatment of thyroid patients. Three types of diagnostic tests will be
considered in this report: blood tests performed in the clinical
chemistry and immunology laboratories, imaging techniques, and
fine-needle biopsies.
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Screening for Thyroid Disease
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Because most clinical manifestations of thyroid dysfunction are
nonspecific (1), and some asymptomatic patients have thyroid
abnormalities that can cause adverse health effects (2)(3)(4)(5)(6)(7),
the high-sensitivity serum thyrotropin [thyroid-stimulating hormone
(TSH)1
] test is often performed on a screening basis when there is a
low pre-test probability of disease (2)(3)(4)(5). It is an
excellent screening test because its negative predictive value is very
high and the vast majority of results are negative (8).
However, screening is not the same as diagnosis, and abnormal TSH
values can occur in patients other than those with straightforward new
cases of hyperthyroidism and hypothyroidism (Table 2
) (9). In addition, because of the log-linear
relationship between serum TSH and free thyroxine
(T4) concentrations (10), interpatient
differences in the slope of the log[TSH] vs [free
T4] line (10) and the great
variability in analytical sensitivity of currently available TSH assay
methods in the range below normal, the severity of a thyroid hormone
excess or deficiency cannot be determined from the TSH value alone.
Therefore, when a patient with nonspecific symptoms and physical
findings has an abnormal serum TSH concentration, the most appropriate
response is further evaluation to verify that there is a thyroid
abnormality and, if so, determination of its cause and severity.
Particular caution is necessary in screening hospitalized and other
severely ill patients for thyroid disease. Severe nonthyroid illness,
whether physical or psychiatric, and drugs such as glucocorticoids or
dopamine can change the behavior of the pituitary-thyroid axis to cause
abnormally high or low serum TSH values in the absence of thyroid
disease, as judged by follow-up studies after patients have recovered
from their nonthyroid illnesses (11). In the absence of an
abnormal thyroid gland by careful physical examination, a hospital
inpatient with a mild or moderate (<20 mIU/L) increase in serum TSH
and an estimated free T4 (by either a
free-T4 test or a free-T4
index) within the health-related reference interval can usually
be followed without treatment and reevaluated later. The same holds
true for a patient with a subnormal serum TSH and estimated free
T4 and serum T3 values that
are not increased. In both cases, the great majority of patients do not
have clinically significant thyroid disease (11).
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Utility and Limitations of Thyroid Diagnostic Tests
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For patients with abnormal serum TSH concentrations, follow-up
consists of a focused history, physical examination with special
attention to the thyroid gland, a repeat TSH test for verification,
determination of serum thyroid hormone concentrations, and sometimes,
imaging studies. Unfortunately, it is not unheard of for patients to be
told that because they have high TSH concentrations, they need to take
thyroid medication lifelong and be sent a prescription for
T4 without further workup or explanation.
Moreover, because goitrous changes in the thyroid gland or the
development of thyroid nodules often do not alter thyroid function, a
TSH concentration within the reference interval in a patient with one
of these structural abnormalities provides only part of the necessary
information and does not mean that the patient's thyroid condition is
innocuous. Full evaluation of these cases requires some combination of
antithyroid antibody tests, imaging, and fine-needle biopsy.
Patients with abnormal TSH results should have serum thyroid hormone
determinations. Because >99% of T4 and
triiodothyronine (T3) in the blood are bound to
serum proteins, but only the free thyroid hormones are biologically
active, estimates of free thyroid hormone concentrations are
theoretically preferable to total-T4 and
total-T3 tests. A 1991 report from the American
Thyroid Association summarized the performance of different types of
free-T4 and free-T3 assays
(12), and there have been no major changes since then.
Free-T4 index methods can be used successfully if
their limitations and performance in various clinical settings are
understood, but they may be more subject to false-positive results than
other, more "direct", free-T4 assays
(12). Free-T3 assays are available,
but are not often used. Binding protein abnormalities can increase
total T3 in the absence of hyperthyroidism,
notably during estrogen treatment and pregnancy. If necessary, a
T-uptake test or thyroxine-binding globulin measurement can be used to
calculate a free-T3 index, or a
free-T3 test can be obtained to clarify an
ambiguous increased total-T3 result.
When hypothyroidism is suspected, a free-T4
estimate is appropriate because total-T3 and
free-T3 tests have inadequate sensitivity and
specificity in this setting. When hyperthyroidism is suspected, the
combination of a free-T4 estimate and a total- or
free-T3 estimate provides the most complete
assessment of the severity of hyperthyroidism and identifies cases of
"T3-toxicosis", i.e., a selective increase of
the serum T3 concentration. In some centers,
free-T4 and -T3 tests are
routinely used when the TSH is increased (8), but in others,
serum T3 measurements are obtained only when the
TSH is low and the free T4 is within the
reference interval. I prefer to monitor both serum free
T4 and T3 in patients with
low serum TSH (other than hypothyroid patients taking
T4), even after the thyroid diagnosis is known,
to establish patterns of increasing or decreasing values over time. In
patients with subclinical hyperthyroidism or those treated with
antithyroid drugs, identification of a temporal trend can be quite
valuable in deciding when to initiate or modify therapy, as illustrated
in the case report below.
Biological factors that can cause confusing thyroid diagnostic test
results are listed in Table 3
. Such results frequently generate patient referrals to my
associates and myself and can inappropriately raise patients' hopes or
fears. The first two blood test categories in Table 3
represent
non-disease. Children with learning disorders have been referred to me
because of serum T3 concentrations 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 thyroid hormone resistance
(13) is the problem and that I will solve the problem by
treating the thyroid. Instead, the children have serum
T3 concentrations within the age-appropriate
reference intervals (14), but the laboratory reports
a reference interval that actually applies only to nonpregnant adults
with no other medical problems. The parents of these children are
always disappointed, and sometimes are frustrated and angry. There are
also age- and pregnancy-related changes in the reference intervals for
serum total T4, free T4,
TSH, and thyroxine-binding globulin (14).
Imaging tests are also subject to misinterpretation (Table 3
). It is
common to receive a report describing a thyroid radioactive iodine
uptake value in the "hyperthyroid range" or "hypothyroid
range", although thyroid secretory function cannot accurately be
inferred from this test. Another problem is a thyroid ultrasound report
that describes the typical features of Hashimoto
thyroiditis—coarse texture of the parenchyma and multiple focal 1–6
mm hypoechoic areas (15)—with no mention of Hashimoto
disease as the most likely diagnosis, but with a summary stating only
that any one of the focal changes might be a cancer. The ultrasound
finding of one or two nonpalpable thyroid nodules <1 cm in diameter
with regular borders and no calcifications is another non-disease,
because an enormous number of people have them, and the chances of a
clinically significant cancer in such lesions are so small that
observation is considered appropriate management (16)(17)(18).
It is a disservice to the patient and the primary physician for the
ultrasound report to comment about this type of lesion only that
"cancer cannot be ruled out", but I encounter such reports often
and only rarely see a more appropriate comment such as, "this is a
nonspecific finding found in more than half of all individuals over age
60" (19).
In the evaluation of thyroid nodules by fine-needle biopsy, up to 20%
of cases have findings of a cellular follicular lesion for which
malignancy cannot be excluded (Table 3
) (20). Some
cytopathologists report these as follicular lesions without further
comment. Other experienced cytopathologists feel that they can
subdivide this type of lesion into risk categories with chances of
cancer ranging from 5–10% to >50% (20). Having a
specific degree of cancer risk may help in the decision between surgery
and observation for the patient who has an increased risk of surgical
complication because of age or coexisting illness. This information can
also help the surgeon decide on the extent of resection
(20).
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Simplex Thyroid Diseases
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Thyroid diseases with a single important dimension can be termed
"simplex" conditions. Examples are hypothyroidism with mild,
diffuse thyroid enlargement; hyperthyroid Graves disease without
ophthalmopathy; or a solitary thyroid nodule. Simplex does not,
however, necessarily imply that optimal clinical management is simple.
Table 4
presents the diagnoses of new patients in my practice, during a
1-year period, who had hyperthyroidism, hypothyroidism, or euthyroid
goiter. When the evaluation of hyperthyroidism included antithyroid
antibody tests and scintiscanning, Graves disease accounted for ~86%
of cases. The other 14% had diagnoses for which management differs
from that of Graves disease, e.g., in the appropriate dose of
radioactive iodine, the possibility of ethanol ablation for a single
toxic autonomous nodule, or the advisability of observation because of
the self-limited nature of the disease.
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Table 4. Causes of hyperthyroidism, hypothyroidism, and euthyroid
goiter in consecutive patients new to the author's practice in 1 year
(1991).
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Approximately 90% of the cases of hypothyroidism shown in Table 4
were
attributable to Hashimoto thyroiditis, but again, for the 10% with
other diagnoses the optimal management may differ. A patient who has
had radioiodine ablation for hyperthyroidism may require an unusually
low dose of T4 because of autonomous function in
the thyroid remnant. In patients taking T4 for
hypothyroidism caused by Hashimoto thyroiditis, many factors can alter
a patient's dose requirement (21)(22), and
patients with problems in T4 treatment are
referred to me with some regularity (Tables 2
and 4
).
In patients with diffuse euthyroid goiters (Table 4
), those with
negative antithyroid antibody tests (almost one-half) are more likely
to have autonomous function and a future risk of hyperthyroidism,
whereas those with positive antibody tests (~43%) have a greater
likelihood of future hypothyroidism (23). A recent study
suggested that levothyroxine treatment to shrink thyroid nodules is
more likely to succeed in patients with Hashimoto thyroiditis than in
patients with no evidence of autoimmunity (24).
If the prognosis and appropriate management of patients with Hashimoto
thyroiditis differ from those of patients with non-autoimmune
conditions, we should be able to detect thyroid autoimmunity reliably.
The diagnostic sensitivity of available antithyroid antibody test
methods may vary. One study (25) suggested that measurement
of only the anti-thyroid peroxidase (or "anti-microsomal") antibody
suffices because almost no patients have increased concentrations of
the anti-thyroglobulin antibody alone (Table 5
). However, using a different method to measure the
anti-thyroglobulin antibody and possibly testing a patient population
selected differently, I found substantially more patients with an
isolated increase of anti-thyroglobulin antibody than an isolated
increase of anti-microsomal antibody (Table 5
). Therefore, the
conclusion that performing both antithyroid antibody tests "increases
the cost without an offsetting diagnostic gain" (25) may
be limited to specific methods and/or patient populations. It would
seem premature to advise a universal abandonment of the
anti-thyroglobulin antibody test.
Another simplex condition is a solitary thyroid nodule. The diagnostic
evaluation is straightforward: check the TSH and do a needle biopsy
(16)(17). Management problems arise from the
5–20% of cases in which the biopsy specimens are insufficient for
diagnosis and the additional 20% for which the cytology is ambiguous
(20). In those cases, we must use other clinical risk
factors in deciding about surgery (26)(27)(28). Even for
nodules with benign cytology, controversy persists regarding the value
of suppressive treatment with T4 (29).
Thus, even in simplex thyroid diseases, many patients benefit from an
evaluation beyond the first-line tests. Welcome developments on the
laboratory front would be better standardization of tests such as
antithyroid antibodies, free T4, and free
T3 to allow results from different laboratories
to be interpreted similarly. In addition, the application of new
techniques, such as PCR amplification of tumor marker genes, to
fine-needle biopsy samples would help reduce the uncertainty about
cellular follicular lesions and further reduce the number of patients
operated on for benign thyroid nodules.
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Multiplex Thyroid Diseases
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More complicated problems, with two or more important dimensions,
can be designated "multiplex" thyroid conditions. Examples are
listed in Table 6
. The general categories include coexisting diseases, single
diseases that can cause several types of complications, and diseases
that evolve through several phases.
The identification of coexisting conditions requires a high index of
suspicion and sufficient experience to recognize atypical combinations
of test results and clinical findings, unusual patterns of test
results, per se, or unexpected responses of patients to usual
treatments. It is not rare for Graves disease and Hashimoto thyroiditis
to occur in the same patient, and some patients with this combination
spontaneously progress from hyperthyroidism to hypothyroidism. The
reverse sequence also occurs, but far less often. It is even rarer for
a patient to cycle up and down more than once. Lymphoma can arise
within the thyroid gland, usually against a background of Hashimoto
thyroiditis (30), presumably because of malignant
transformation of one or more of the inflammatory cells. Focal swelling
or a generalized increase in thyroid size despite adequate
levothyroxine replacement justifies cytological or surgical evaluation
for lymphoma, and consultation between the clinician and the
cytopathologist before a needle biopsy allows the pathologist to
arrange for the specimens to be specially processed for evaluation of
possible lymphoma.
In the thyroid diseases with several possible complications (Table 6
),
the investigation of one aspect of the disease can have implications
for other aspects. An example is a large multinodular goiter with
autonomous function. Potential problems are tracheal narrowing,
interference with swallowing, hyperthyroidism, and a disfiguring neck
mass. Computed tomography (CT) is sometimes necessary to evaluate the
possibility of tracheal or esophageal compression. However, if a CT
contrast agent is used, the thyroid is exposed to high concentrations
of stable iodine, which may cause iodine-induced thyrotoxicosis and
prevent ablative treatment with radioiodine. Once again, communication
between physicians is vital, in this case between the clinician and the
radiologist. Although contrast-enhanced CT images are sharper, it is
easy to identify the tracheal air column and obtain a satisfactory
assessment of thyroid size and geometry by a non-contrast CT scan. When
informed of thyroid abnormalities in patients, radiologists are happy
to arrange non-contrast studies.
Some thyroid diseases evolve through several phases (Table 6
).
Medically appropriate, cost-effective use of diagnostic tests differs
depending on whether the patient is at the stage of initial diagnosis,
in a disease phase in which future change is expected, or under
treatment requiring therapeutic monitoring. In addition, clinical and
laboratory findings from each check-up must be viewed in the context of
sequential test results over time.
Fig. 1
shows the progressive increase in secretory activity of an
autonomously functioning thyroid adenoma in a woman who was 45 years of
age at the time of initial evaluation. The serum TSH initially was
within the reference interval, and the contralateral lobe continued to
function. After 3 years, the TSH was suppressed, as was the function of
the extranodular thyroid tissue. However, the serum free
T4 was in the lower half of the reference range,
the patient felt fine, and the nodule was unobtrusive. By 1997, she was
menopausal and the serum free T4 had increased,
but she had no hyperthyroid symptoms and no cosmetic problems. The
serum free-T3 concentrations (not shown)
paralleled the serum free-T4 results. Radioiodine
ablative treatment was administered in 1997 because the progressive
increase in serum free T4, with concentrations
that predicted the development of overt hyperthyroidism within several
years, and because the persistently high-normal thyroid hormone
concentrations after 1994 could predispose her to postmenopausal
osteoporosis (7). This treatment decision was not based on
the last free-T4 result or any other single test
value. If sequential tests had been performed using a mixture of
free-T4 index and free-T4
concentration values or in different laboratories that used different
instruments or kits to measure serum free T4, it
would have been difficult, if not impossible, to discern the trend
toward hyperthyroidism. The imaging studies shown in Fig. 1
established
the diagnosis of an autonomous nodule rather than Graves disease, and
this information was used to select a relatively high therapeutic dose
of radioiodine because toxic nodular goiters are more radioresistant
than Graves disease thyroid glands (31).
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Figure 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.
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Another test in which the pattern of sequential test results can be
more important than single values is the serum thyroglobulin
concentration, used as a tumor marker in the long-term follow-up of
patients who have had thyroid cancer. However, currently available
serum thyroglobulin assays have wide intermethod variability in results
and analytical sensitivity, suboptimal interassay precision even when
only one method is used, and for some methods, susceptibility to
"hook" effects that greatly underestimate very high values
(32).
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Conclusion
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The appropriate use of thyroid diagnostic tests varies according
to the clinical setting: screening for thyroid dysfunction, initial
evaluation of an abnormal clinical or laboratory finding, management of
simplex thyroid diseases, elucidation of the components of multiplex
thyroid diseases, long-term follow-up of evolving abnormalities, or
monitoring of patients' responses to treatment. Reduction in needless
evaluation of thyroid non-disease can potentially be achieved by
improvements in test nomenclature, test standardization, and the
understanding of variations of healthy thyroid function and
structure. Communication among the clinician, the clinical pathologist,
and the radiologist greatly increases the value of diagnostic tests. In
all but the most straightforward cases of T4
treatment of hypothyroidism, the combination of clinical findings with
test results is vital in determining the best management plan for the
patient. Test results alone, however sophisticated and accurate, often
do not suffice.
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Footnotes
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1 Nonstandard abbreviations: TSH, thyrotropin (thyroid-stimulating hormone); T4, thyroxine; T3, triiodothyronine; and CT, computed tomography. 
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Abstract
Introduction
