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Clinical Studies |
Division of Endocrinology, Department of Medicine, University Hospital of Basel, Basel, Switzerland
Address all correspondence and requests for reprints to: Jean-Jacques Staub, M.D., Division of Endocrinology, Department of Medicine, University Hospital of Basel, CH-4031 Basel, Switzerland.
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Abstract |
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Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 ± 2.7 vs. 4.4 ± 2.2 vs. 3.4 ± 2.0; P < 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 ± 1.6 vs. 2.1 ± 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P < 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = -0.52 (P < 0.0004), and that with T3 was r = -0.56 (P < 0.0001). In SCH, the best correlation was found between the new score and free T4 (r = -0.41; P < 0.0001) and TSH (r = 0.35; P < 0.0005).
Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In these cases, and especially in subclinical hypothyroidism, the decision to treat is often determined by the physician’s assessment of the clinical severity of the disease (2, 3). Therefore, it would be useful to have a symptom-rating scale to assess the clinical status and the potential effect of treatment. Three decades ago in 1969 Billewicz et al. (9) described a diagnostic index that scores the presence or absence of various signs and symptoms of hypothyroidism for the purpose of establishing a diagnosis. However, modern thyroid function tests were not available at the time of their studies.
The aim of our study was to reevaluate the signs and symptoms of hypothyroidism in the light of modern thyroid function tests and to develop a new convenient clinical score for individual assessment of the severity of thyroid failure. Additionally, we tested the ability of the clinical score to reflect tissue hypothyroidism by correlation analyses with TSH, thyroid hormones, and some tests reflecting thyroid hormone action at target tissues, such as ankle reflex time (ART) and total cholesterol (TC) levels (6).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 332 study subjects were selected from a cohort of patients and normal controls studied in a prospective manner in the Endocrine Outpatient Clinic of the University Hospital of Basel as a part of a project of the Swiss Research Foundation on hypothyroidism (6). The study was approved by the ethics committee for human studies of the University of Basel, and informed consent was given by each subject. Only females were included so as to exclude variations due to sex. All hypothyroid patients were ambulatory and in good general health. All euthyroid subjects were normal women; mainly staff members, their relatives, and friends. After an overnight fast, all the women underwent full medical assessment and laboratory examinations (hematology and blood chemistry and urine analysis) to exclude nonthyroidal illness.
Derivation sample
To define the new clinical score, we analyzed 50 patients (aged 55.2 ± 13.1 yr) with overt primary hypothyroidism characterized by elevated basal TSH (>20 mu/L) and decreased free T4 (fT4; <8 pmol/L) and 80 age-matched female euthyroid controls (aged 51.6 ± 9.9 yr). All controls underwent a euthyroid test with oral TRH (10). The underlying thyroid disorders were autoimmune thyroiditis (n = 30), treated Graves’ disease (n = 18), thyroidectomy for simple goiter (n = 1), and treated toxic adenoma (n = 1).
Definition of the new clinical score
Fourteen symptoms and signs of hypothyroidism (Fig. 1
) were evaluated by various physicians in our endocrine
clinic in all patients and controls as described by Billewicz et
al. (9). The physicians did not know the laboratory data of the
patients and control subjects, which were available after the clinical
examination only. The frequencies of symptoms and signs were calculated
as well as their sensitivity, specificity, and positive and negative
predictive values. They were quantified by a simple and convenient
system: 1 point = present, and 0 points = absent. The value
of the total score is given as the sum of the symptoms and signs
present (Tables 1 and 2).
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In a second phase of the study the new clinical score was assessed in 93 patients with subclinical hypothyroidism (SCH; aged 52.7 ± 12.7 yr) defined by elevated basal TSH (above 4 mU/L) and fT4 and T3 values within the respective reference ranges. The etiology of thyroid failure was treated Graves disease in 44 women, autoimmune thyroiditis in 35, thyroidectomy for simple goiter in 13 women, and treated toxic adenoma in 1 woman. In addition, we analyzed 109 euthyroid women with normal basal TSH and normal fT4 values (aged 43.4 ± 14.7 yr) as well as 67 of the 143 hypothyroid patients (aged 56.3 ± 13.3 yr; 28 with subclinical and 39 with overt hypothyroidism) when they were euthyroid after treatment with T4 for at least 3 months, as confirmed by a normal TSH response to oral TRH (10) on 2 separate occasions (mean T4 dose, 103 ± 27.5 µg/day).
Hormone measurements and tests of peripheral hormone action
TSH (normal, 0.1–4.0 mU/L; assay sensitivity, 0.10 mU/L) was determined by an immunoradiometric assay [h-TSH Behring (RIA-gnost), Frankfurt, Germany]. Before introduction of this second generation TSH assay, we used a conventional RIA for TSH determinations. The correlation analysis showed an excellent correlation between these two methods (n = 94; r = 0.926; P < 0.0001). fT4 (normal, 8.0–27 pmol/L) and T3 (0.9–3.0 nmol/L) were measured by RIA (10, 11). ART was assessed as a mean of six readings by photomotogram with an achillometer (Polymed A.G., Glattbrugg, Switzerland) recording three tracings on each side (normal range, 280–420 ms) (6). Creatine kinase (CK; normal range, 40–160 U/L), TC, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured by standard methods as described previously (6).
Statistical analysis
All data are expressed as the mean ± SD.
Differences between mean values of variables were tested by one-way
ANOVA, and differences between frequencies were determined by the
2 test. To assess the relationship between the new
clinical score and other parameters, a nonparametric regression model
(Spearman) was used. Receiver operating characteristic curves were
generated for direct comparison (independent of the chosen cut-off
points) of the new score with the Billewicz index (Fig. 2).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean values of TSH, fT4, and
T3 are summarized in Table 3.
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The frequencies of the 14 symptoms and signs in the derivation
sample are shown in Fig. 1
. Most frequent in the hypothyroid patients
were prolonged ART (77%) and complaints about dry skin (76%). Some
symptoms were also observed with a high frequency in euthyroid
controls. Pulse rate and cold intolerance had positive and negative
predictive values below 70% (Table 1) and were, therefore, excluded
from the new score.
In the control group, older women (
55 yr; n = 31) presented more
often with hypothyroid symptoms, especially constipation
(P < 0.005) and dry skin (P < 0.05),
compared with younger controls (<55 yr; n = 49). The new score
was considerably higher in older women (2.3 ± 1.5 vs.
1.2 ± 1.2; P < 0.001). The correlation analysis
revealed a significant correlation of the new score with age (r =
0.40; P < 0.0004). For the clinical judgment of
hypothyroidism, we, therefore, defined a simple age-correcting factor
by adding 1 point to the sum of symptoms and signs in women younger
than 55 yr.
The diagnostic ranges for the new score were set to achieve positive and negative predictive values of more than 90% for the clinical diagnosis or exclusion of hypothyroidism. This was obtained by choosing two cut-off points: hypothyroid range, more than 5 points (positive predictive value, 96.9%); euthyroid, 2 points or less (negative predictive value for exclusion of hypothyroidism, 94.2%); and intermediate range, 2–5 points. The values for sensitivity and specificity were 62% and 99% for the cut-off points 5% and 94%, respectively, and 61% for the cut-off point 2. According to this analysis, the following diagnostic ranges for the clinical judgment with the new (age corrected) score were defined: hypothyroid, more than 5 points; euthyroid, 0–2; and intermediate range, 3–5 points.
Using this definition, 62% of all overt hypothyroid patients
were classified as clinically hypothyroid by the new score [42% using
the definition of Billewicz et al. (9)]. In the subgroup of
patients with diminished T3, 84% were assessed
as clinically hypothyroid (Billewicz index, 76%), whereas 40% of the
patients with normal T3 reached the hypothyroid
range (Billewicz index, 8%). Surprisingly, we found two patients who
were clinically euthyroid with both scoring methods despite marked
biochemical hypothyroidism (basal TSH, 63.6 and 42.3 mU/L;
fT4, 3.2 and 3.9 pmol/L, respectively, with
normal T3 in one and low T3
in the other patient). 61% of the euthyroid controls were assessed as
clinically euthyroid by the new score (Billewicz index, 52%), and one
control subject was in the hypothyroid range (none with a Billewicz
index value). The remaining controls were classified into the
intermediate range (new score, 38%; Billewicz index, 48%; Fig. 3).
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Of the subclinically hypothyroid patients (n = 93), 24% (Billewicz index, 6%) were designated hypothyroid, 29% (Billewicz index, 29%) were designated euthyroid, and 47% (Billewicz index 65%) were scored in the intermediate range. The corresponding values for the second group of euthyroid subjects (n = 109) are (Billewicz index in parentheses): euthyroid, 66% (67%); hypothyroid, 6% (0%); and intermediate range, 28% (33%). Of the T4-treated patients (n = 67), 55% (52%) were in the euthyroid range, 2% (0%) were assessed as hypothyroid, and 43% (48%) were classified in the intermediate range.
Possible effect of smoking
Smoking has been shown recently to aggravate the clinical and metabolic expression of hypothyroidism (12). We, therefore, analyzed the new score in smokers and nonsmokers in all study subjects. The percentage of smokers in our study population was 19.5%. In euthyroid subjects, smoking did not affect the clinical evaluation. The new scores in all euthyroid women (n = 189) and T4-treated patients were: smokers vs. nonsmokers, 1.6 ± 1.7 vs. 1.6 ± 1.4 and 2.2 ± 1.5 vs. 2.1 ± 1.5 (P = NS for both comparisons). In SCH, the clinical score was slightly higher in smokers (3.8 ± 2.1 vs. 3.2 ± 1.9; P = NS). In overt hypothyroidism, however, smokers presented with a significantly higher clinical score than nonsmokers (7.6 ± 3.2 vs. 5.5 ± 2.7; P = 0.024).
Other tests of peripheral hormone action
The body mass index (BMI) was increased in overt hypothyroid
patients compared to that in controls (P < 0.01). The
BMI was clearly elevated in the subgroup of patients with severe
hypothyroidism (P < 0.001) and was moderately elevated
in patients with overt hypothyroidism but normal
T3 (Table 3). Interestingly, the patients with
SCH had a significantly higher BMI than the age-matched controls
(P < 0.01).
The TC and LDL-C values were elevated in the group of all overt
hypothyroid patients (P < 0.001) combined with a
decrease in HDL-C (P < 0.05). This was primarily due
to the marked changes in the subgroup of patients with decreased
T3 (P < 0.001), whereas in
patients with normal T3, these parameters were
only slightly altered compared with those in the controls
(P = NS; Table 3). In SCH, the TC and LDL-C values were
very similar to the control values. The HDL-C was slightly decreased
(P < 0.05).
The values for ART and CK were clearly elevated in overt hypothyroidism
in both subgroups with normal and decreased T3
(P < 0.001; Table 3). In SCH, the ART was also
increased (P < 0.001) compared with that in the
age-matched controls, whereas CK was not.
Correlation of the new clinical score with the laboratory findings
In the group of overt hypothyroid patients the new score showed an excellent correlation with tests of peripheral hormone action: for ART, r = 0.76; P < 0.0001; for TC, r = 0.60; P < 0.0001; and for CK, r = 0.55; P < 0.0003. However, no correlation was found with TSH (r = 0.01; P = NS). The correlation of the new score with thyroid hormones was similar or weaker compared with tests of peripheral hormone action: for fT4, r = -0.52; P < 0.0004; and for T3, r = -0.56; P < 0.0001. To avoid a possible bias due to comparison of measured ART with the clinical sign of delayed ankle reflex included in the score, we repeated the correlation analysis of the new score after removal of this clinical sign. Nevertheless, a similar result was obtained (r = 0.71; P < 0.0001). In contrast to overt hypothyroidism, in SCH the best correlation was found between the new score and fT4 (r = -0.41; P < 0.0001) and TSH (r = 0.35; P < 0.0005). The correlations of the new score with metabolic parameters of hypothyroidism were preserved in SCH: for ART, r = 0.33; P < 0.001; and for TC, r = 0.28; P < 0.01.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Some symptoms of hypothyroidism may also be common in euthyroid individuals. In our age-matched euthyroid controls these symptoms were more frequent in older females (55 yr), which resulted in higher values for the new clinical score than those in younger controls (2.3 1.5 vs. 1.2 1.2; P < 0.001). Therefore, we defined a convenient age-correcting factor (i.e. addition of 1 point to the sum of positive symptoms and signs in subjects younger than 55 yr) for clinical assessment.
Using this definition, 62% of all overt hypothyroid and 24% of
subclinical hypothyroid patients could be classified as clinically
hypothyroid by the new score, 42% and 6% using the definition of the
Billewicz index. This result may suggest a diagnostic superiority of
the new score compared to the Billewicz index. However, the
characteristics of the receiver operating curves reflecting the
relationship between sensitivity and specificity are very similar for
both scoring methods, as illustrated in Fig. 2. Compared with the
Billewicz index, the main advantage of the new score is its convenient
and simple scoring system.
In the age-matched control group (n = 80), 61% were classified as clinically euthyroid by the new score. A similar proportion of T4-treated patients and the second sample of euthyroid subjects were also assessed as euthyroid (55% and 66%), showing the good reproducibility of the clinical evaluation in euthyroid subjects with the new score.
Recently, smoking was described to aggravate clinical and metabolic manifestations of thyroid failure (12). In the present study we also found a tendency toward higher values for the new score in smokers compared to nonsmokers with SCH (3.8 ± 2.1 vs. 3.2 ± 1.9; P = NS) and significantly elevated values in smokers with overt hypothyroidism (7.6 ± 3.2 vs. 5.5 ± 2.7; P = 0.024) in contrast to no effect of smoking on the clinical score in euthyroid women or T4-treated patients.
It is of special interest that some patients with severe biochemical hypothyroidism had only mild clinical signs, whereas other patients with minor biochemical changes had quite severe clinical manifestations. Thus, we assume that tissue hypothyroidism at the peripheral target organs must be different in the individual patient. Therefore, the clinical score can give a valuable estimate of the individual severity of metabolic hypothyroidism. In overt hypothyroidism we could demonstrate that the new score correlates as well as or even better with parameters reflecting tissue hypothyroidism, such as ART and TC, than with circulating thyroid hormones or TSH. Using the nonparametric regression model, we found a very good correlation for ART but no correlation for TSH, despite the fact that the pituitary is also a target organ for thyroid hormones. In SCH, the early stage of thyroid failure, however, the best correlation was present between the new score and fT4 and basal TSH. There is no doubt that basal TSH is the best parameter for early detection of thyroid dysfunction. In overt hypothyroidism, however, the pituitary TSH stimulation is probably at the top of the dose-response curve with maximal TSH secretion, and therefore, basal TSH becomes a poor indicator of tissue hypothyroidism in advanced thyroid failure. Discordant responses between the pituitary and peripheral target tissues have been described in patients with primary hypothyroidism treated with L-T3 (14).
Faced with the variability of the clinical findings in overt and subclinical hypothyroidism, we cannot recommend the use of the new clinical score for the purpose of establishing the diagnosis of hypothyroidism. Routine thyroid function testing is the best and most reliable way to identify patients with thyroid failure. The purpose of this score is to assess the severity of tissue hypothyroidism, to evaluate patients with discordant laboratory results, and to monitor the effect of treatment, especially in subclinical hypothyroidism. As in our T4-treated group of patients, one of the major findings of Cooper and colleagues (15) and Nystrom and colleagues (16) in assessing patients with SCH treated with T4 was that their patients felt better when treated, even if they did not feel badly initially. Therefore, clinical evaluation using a standardized score can give valuable information about the individual severity of impaired thyroid function and the effect of treatment. According to a recent statement: "The ultimate test of whether a patient is experiencing the effects of too much or to little thyroid hormone is not the measurement of hormone concentration in the blood but the effect of thyroid hormones on the peripheral tissues" (17).
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Acknowledgments |
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Footnotes |
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Received August 13, 1996.
Revised October 28, 1996.
Accepted November 20, 1996.
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References |
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G. J. Canaris, N. R. Manowitz, G. Mayor, and E. C. Ridgway The Colorado Thyroid Disease Prevalence Study Arch Intern Med, February 28, 2000; 160(4): 526 - 534. [Abstract] [Full Text] [PDF]
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