MEDULLARY THYROID CANCER THAT STAINS NEGATIVE FOR CA 19-9 HAS DECREASED METASTATIC POTENTIAL.

OBJECTIVE: Presently, no clinical tools are available to diagnose the metastatic potential of medullary thyroid cancer (MTC) at disease presentation. Surveillance with calcitonin (Ct) and carcinoembryonic antigen (CEA) is currently recommended for the observation and diagnosis of metastatic disease after initial treatment of MTC. Recently, carbohydrate antigen (CA)19-9 staining has been associated with aggressive forms of MTC and metastatic spread. This pilot study explored whether positive CA19-9 staining of MTC tissue is associated with its metastatic potential. METHODS: Sixteen cases of MTC were identified, and tissue specimens were immunostained for CA 19-9 and other MTC tumor markers. Clinical information about patients' MTC was collected through a retrospective chart review. RESULTS: Overall, 63% of the specimens stained positive for CA19-9. The median size of positively staining specimens was 2.6 cm (interquartile range [IQR] 1.2-3.2) compared to 0.7 cm (0.5-1.2) in negatively staining MTC specimens (P = .04). All specimens from patients diagnosed with stage IV MTC stained positive for CA19-9, compared to only 40% of cases that were classified as stages I to III (P = .03). Furthermore, 100% of the primary specimens that were documented to have metastatic spread stained positive for CA19-9. The sensitivity for ruling out stage IV MTC based on negative staining for CA 19-9 was 100%. CONCLUSION: Based on these results, we conclude that negative staining of MTC for CA19-9 may be associated with its decreased metastatic potential.

Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice.

OBJECTIVE: The suitability of TSH reference limits derived from national databases to outpatient practices has not been established. We aimed to determine whether race and age influence the distribution of TSH and free T4 (fT4). DESIGN: A cross-sectional study of an urban outpatient medical practice. PARTICIPANTS: Patients (n = 22,116) without clinical evidence of thyroid disease or use of thyroid-specific medications. MEASUREMENTS: Comparison of TSH and fT4 distributions in specific racial and age groups including blacks, whites and Hispanics. RESULTS: TSH was distributed at higher concentrations, without skew, in whites compared to blacks (median, 1.54 mIU/l vs. 1.18 mIU/l, P < 0.001) and in old (>80 years old) compared to young (20-29 years old) (median, 1.61 mIU/l vs. 1.13 mIU/l, P < 0.001). In all patients, blacks and whites, 3%, 8% and 5%, respectively, of those aged > 80 years were misclassified as having high TSH compared to those aged 20-29 years (P < 0.001). Using TSH limits from national databases resulted in significant misclassification of patients with raised or lowered TSH. Mean fT4 was significantly lower in blacks than whites (17.5 +/- 4.38 pmol/l vs. 18.3 +/- 3.99 pmol/l, P < 0.001), did not differ between young and old, but decreased progressively (average 7%) as TSH increased to > 4.5 mIU/l. CONCLUSIONS: Reference limits for TSH differ between races and with age. Use of race- and age-specific reference limits decreases misclassification of patients with lowered or raised TSH in an urban practice. The unique fT4:TSH relationships of blacks and whites may be genetically determined. The implications of the small decrement in fT4 as TSH increases remain to be explored.

Virtual evaluation of selected cervical lymph nodes with three-dimensional ultrasound in thyroid cancer patients after thyroidectomy.

BACKGROUND: We evaluated the usefulness of three-dimensional (3D) ultrasound of cervical lymph nodes (LN), when two-dimensional (2D) ultrasound evaluation is not sufficient to clearly evaluate lymph node characteristics, in thyroid cancer patients being followed after thyroidectomy. METHODS: Two readers retrospectively analyzed 2D and 3D images of 147 LNs; LNs were categorized as normal, reactive, suspicious, or indeterminate, and confidence level was rated. Results were compared to cytological/clinical data. Inter-reader agreement was calculated. RESULTS: Addition of 3D ultrasound significantly increased specificity (0.787 with 2D ultrasound vs 0.905 with 2D + 3D ultrasound for reader 1, P = .009; 0.701 with 2D ultrasound vs 0.898 with 2D + 3D ultrasound for reader 2, P = .01). Addition of 3D ultrasound significantly increased confidence level of readers (P < .001). Inter-reader agreement in LN categorization was almost perfect with 2D + 3D ultrasound. CONCLUSION: 3D ultrasound of cervical LNs enables better demonstration of imaging features that are important in differentiating benign and malignant LNs. These improvements can potentially obviate the need for FNA in post thyroidectomy cancer patients.

Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians.

BACKGROUND: Subclinical thyroid disease is common; however, screening recommendations using serum thyrotropin (TSH) level determinations are controversial. METHODS: To study the use of serum TSH by primary care physicians and define populations at risk for having an abnormal TSH level at follow-up, based on initial TSH levels, we conducted an observational study of a large health care database in the setting of a health management organization. All outpatients without thyroid disease or pregnancy or taking medication that may alter thyroid function in whom the TSH level was measured in 2002 and during 5-year follow-up were included in this study. Repeated TSH level determinations were compared with the initial TSH level values. RESULTS: In 422 242 patients included, 95% of the initial serum TSH concentrations were within normal limits (0.35-5.5 mIU/L), 1.2% were decreased (<0.35 mIU/L), 3.0% were elevated (>5.5 to 10 mIU/L). In 346 549 patients without thyroid-specific medications, the TSH levels became normal in 27.2%, 62.1%, and 51.2%, whose initial serum TSH level was highly elevated, elevated, and decreased, respectively, and remain normal in 98% of the patients with normal initial TSH levels. When the initial serum TSH level was elevated, patients in the highest quintile of this group, who had a shorter interval between the first and second measurements, had a higher probability of a second highly elevated TSH concentration (P < .001). CONCLUSIONS: When the serum TSH level is normal, the likelihood of an abnormal level within 5 years is low (2%). More than 50% of patients with elevated or decreased serum TSH levels have normal levels in repeated measurements.

Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism.

CONTEXT: Measurements from all age groups defined the upper limit of the TSH reference range in National Health and Nutrition Examination Survey III. The TSH median, 97.5 centile and prevalence of subclinical hypothyroidism (SCH), normal serum T(4) and TSH greater than 4.5 mIU/liter, increased progressively with age. Age-adjusted reference ranges would include many people with TSH greater than 4.5 mIU/liter. OBJECTIVE: We determined whether increasing 50 and 97.5 centiles with age resulted from more patients with SCH in populations with normal TSH distribution or whether age-specific population shifts to higher serum TSH might account for these findings. DESIGN/SETTING/PATIENTS: We analyzed TSH, antithyroid antibodies, and TSH frequency distribution curves for specific age deciles in populations without thyroid disease, with or without antithyroid antibodies. RESULTS: Without thyroid disease, 10.6% of 20- to 29-yr-olds had TSH greater than 2.5 mIU/liter, increasing to 40% in the 80+ group, 14.5% of whom had TSH greater than 4.5 mIU/liter. When TSH was greater than 4.5 mIU/liter, the percentage with antibodies was 67.4% (age 40-49 yr) and progressively decreased to 40.5% in the 80+ group. TSH frequency distribution curves of the 80+ group with or without antibodies was displaced to higher TSH, including TSH at peak frequency. The 97.5 centiles for the 20-29 and 80+ groups were 3.56 and 7.49 mIU/liter, respectively. Seventy percent of older patients with TSH greater than 4.5 mIU/liter were within their age-specific reference range. CONCLUSION: TSH distribution progressively shifts toward higher concentrations with age. The prevalence of SCH may be significantly overestimated unless an age-specific range for TSH is used.

An Unusual Case of Metastatic Functional Thyroid Carcinoma With a Remarkable Treatment Response to Radioactive Iodine.

Functional thyroid carcinoma is an unusual cause of thyrotoxicosis. We describe the clinical presentation and treatment of a patient with thyrotoxicosis due to functional thyroid carcinoma and Graves disease, and discuss potential mechanisms causing the thyrotoxicosis. A 79-year-old woman with a remote history of hemithyroidectomy and current hyperthyroidism came to the hospital with upper and lower extremity weakness. Hospital evaluation revealed a suppressed thyroid-stimulating hormone (TSH) level, positive test for thyroid-stimulating immunoglobulins, as well as a thyroid nodule, lung masses, and a 4.4-cm gluteal mass. Fine-needle aspiration of the gluteal mass revealed metastatic differentiated thyroid carcinoma. Even after completion thyroidectomy and excision of her gluteal mass, her hyperthyroid status continued when she was not receiving levothyroxine. A radioactive iodine uptake and scan revealed unusually high lung uptake of 40%, and she was successfully treated with radioactive iodine (RAI) despite complete TSH suppression. The patient developed hypothyroidism 2 months after RAI administration; 6 months after RAI administration, her thyroglobulin (Tg) levels had fallen from a peak of 1976 ng/mL to 1.4 ng/mL. She had no anti-Tg antibodies. Repeated positron emission tomography-computed tomography nearly 1 year after RAI treatment shows substantial regression in the lung nodules, and Tg measured by mass spectroscopy is undetectable. This case demonstrates that thyrotoxicosis in the setting of metastatic thyroid carcinoma may be the result of functional thyroid carcinoma and may be successfully treated with selective surgery and RAI administration.

The thyrotropin reference range should remain unchanged.

CONTEXT: Recent recommendations to decrease the upper limit of the TSH reference range from 4.5 to 2.5 mIU/liter, based on the high proportion of normal people whose serum TSH is less than 2.5 mIU/liter and the observation that those with TSH between 2.5 and 4.5 mIU/liter [upper reference range (URR)] have increased risk of progression to overt hypothyroidism (Whickham, 20-yr data), have not been subjected to critical analysis. STUDY SUBJECTS: The study subjects were from the Reference Group of NHANES III, 14,333 people more than 12 yr old, without known thyroid disease or antithyroid antibodies; 85% had TSH levels below 2.5 mIU/liter, and 2.3% had subclinical hypothyroidism (SCH). An additional 9.7% had URR TSH, representing 20.6 million Americans, who would also be identified as SCH if the upper TSH limit were decreased. Many with URR TSH do not have thyroid disease. INTERVENTION: The time of phlebotomy is important, because the TSH level varies throughout the day, with early morning values greater than later ones, and is accentuated by sleep deprivation, strenuous exercise, or working during the night or evening shifts. Repeated measurements in the same individual vary considerably over months. RESULTS: About half of those with URR TSH probably have thyroid disease, but most with thyroid disease, antithyroid peroxidase antibodies, have TSH below 2.5 mIU/liter. Those with URR TSH with thyroid disease probably have minimal thyroid deficiency, without any reported adverse health consequences or benefit of treatments with levothyroxine. CONCLUSION: Because routine levothyroxine treatment is not recommended for SCH, it is certainly not warranted in individuals with URR TSH. For all patients with URR TSH, it is reasonable to determine serum TSH every 1-2 yr.

A model to determine workforce needs for endocrinologists in the United States until 2020.

The objective of this study was to define the workforce needs for the specialty of Endocrinology, Diabetes, and Metabolism in the United States between 1999 and 2020. An interactive model of factors likely to influence the balance between the supply and demand of endocrinologists during the next 20 years was constructed. The model used data from a wide range of sources and was developed under the guidance of a panel of experts derived from sponsoring organizations of endocrinologists. We determined current and projected numbers and demographics of endocrinologists in the U.S. workforce and the anticipated balance between supply and demand from 1999 to 2020. There were 3,623 adult endocrinologists in the workforce in 1999, of which 2,389 (66%) were in office-based practice. Their median age was 49 years. Both total office visits and services performed by endocrinologists (particularly for diabetes) increased substantially during the 1990s. Waiting time for an initial appointment is presently longer for endocrinologists than for other physicians. Compared with a balanced, largely closed-staff health maintenance organization, the current national supply of endocrinologists is estimated to be 12% lower than demand. The number of endocrinologists entering the market has continuously fallen over the previous 5 years, from 200 in 1995 to 171 in 1999. Even if this downward trend were abruptly stopped, the model predicts that demand will exceed supply from now until 2020. While this gap narrows from 2000 to 2008 due to projected growth of managed care, it widens thereafter due to the aging of both the population and the endocrine workforce. Inclusion of other factors such as projected real income growth and increased prevalence of age-related endocrine disorders (e.g., diabetes and osteoporosis) further accentuates the deficit. If the number of endocrinologists entering the workforce remains at 1999 levels, demand will continue to exceed supply from now through 2020 for adult endocrinologists, and the gap will widen progressively from 2010 onward. The present analysis indicates that the number of endocrinologists entering the workforce will not be sufficient to meet future demand. These data suggest that steps should be taken to stop the ongoing decline in the number of endocrinologists in training and consideration should be given to actions designed to increase the number of endocrinologists in practice in the years ahead.

Medullary thyroid cancer with undetectable serum calcitonin.

CONTEXT: Calcitonin is a sensitive biomarker that is used for diagnosis and follow-up in medullary thyroid cancer (MTC). In patients with tumors > 1 cm, it is uncommon for preoperative serum calcitonin to be in the normal laboratory reference range in patients with MTC, and even more unusual for serum calcitonin to be undetectable. THE CASE: A 39-year-old woman was found to have a left thyroid nodule on magnetic resonance imaging done for neck pain. Ultrasound and fine-needle aspiration biopsy were performed, and cytopathology was positive for malignant cells. The cells also had features suggestive of a neuroendocrine tumor, and the specimen was immune-stained with calcitonin. There was positive immunoreactivity for calcitonin in isolated cells of the cytospin, highly favoring a diagnosis of MTC. Serum calcitonin was < 2 pg/mL (<6 pg/mL), and serum carcinoembryonic antigen was 3.1 ng/mL (<5.2 ng/mL). Given the low calcitonin levels, procalcitonin was also tested and was elevated at 0.21 ng/mL (< 0.1 ng/mL). The patient subsequently underwent a total thyroidectomy and central and ipsilateral lateral lymph node dissection. Histopathology confirmed a 2.6 × 2.0 × 1.2-cm MTC, with strong, diffuse immunostaining for calcitonin. Postoperatively, serum calcitonin has remained undetectable, carcinoembryonic antigen has remained within the reference range, and procalcitonin has become undetectable. CONCLUSIONS: We present a rare case of a patient with MTC with undetectable preoperative serum calcitonin, whose tumor demonstrated strong, diffuse immunohistochemical staining for calcitonin. We discuss the possible pathogenesis of calcitonin-negative MTC and the challenges in following patients with this condition.

A model to determine workforce needs for endocrinologists in the United States until 2020.

The objective of this study was to define the workforce needs for the specialty of endocrinology, diabetes, and metabolism in the United States between 1999 and 2020. An interactive model of factors likely to influence the balance between the supply and demand of endocrinologists during the next 20 yr was constructed. The model used data from a wide range of sources and was developed under the guidance of a panel of experts derived from sponsoring organizations of endocrinologists. We determined current and projected numbers and demographics of endocrinologists in the United States workforce and the anticipated balance between supply and demand from 1999 to 2020. There were 3,623 adult endocrinologists in the workforce in 1999, of which 2,389 (66%) were in office-based practice. Their median age was 49 yr. Both total office visits and services performed by endocrinologists (particularly for diabetes) increased substantially during the 1990s. Waiting time for an initial appointment is presently longer for endocrinologists than for other physicians. Compared with a balanced, largely closed-staff health maintenance organization, the current national supply of endocrinologists is estimated to be 12% lower than demand. The number of endocrinologists entering the market has continuously fallen over the previous 5 yr, from 200 in 1995 to 171 in 1999. Even if this downward trend were abruptly stopped, the model predicts that demand will exceed supply from now until 2020. Whereas this gap narrows from 2000 to 2008 due to projected growth of managed care, it widens thereafter due to the aging of both the population and the endocrine workforce. Inclusion of other factors such as projected real income growth and increased prevalence of age-related endocrine disorders (e.g. diabetes and osteoporosis) further accentuates the deficit. If the number of endocrinologists entering the workforce remains at 1999 levels, demand will continue to exceed supply from now through 2020 for adult endocrinologists, and the gap will widen progressively from 2010 onward. The present analysis indicates that the number of endocrinologists entering the workforce will not be sufficient to meet future demand. These data suggest that steps should be taken to stop the ongoing decline in the number of endocrinologists in training and consideration should be given to actions designed to increase the number of endocrinologists in practice in the years ahead.

Sclerosing lymphocytic lobulitis of the breast in a patient with Graves' disease.

A 43-year-old woman presented to the endocrinologist with symptoms and signs of typical thyrotoxicosis caused by Graves' disease. Review of systems revealed that she had recently discovered a lump in her left breast. Evaluation of the left breast lesion led to a core biopsy that showed sclerosing lymphocytic lobulitis. This breast disease, well recognized in the pathology literature, occurs in various autoimmine disorders, particularly type 1 diabetes mellitus, and has occasionally been reported in Hashimoto's thyroiditis. The patient described here represents the first published association of sclerosing lymphocytic lobulitis of the breast with Graves' disease.

A model to determine workforce needs for endocrinologists in the United States until 2020.

The objective of this study was to define the workforce needs for the specialty of Endocrinology, Diabetes, and Metabolism in the United States between 1999 and 2020. An interactive model of factors likely to influence the balance between the supply and demand of endocrinologists during the next 20 years was constructed. The model used data from a wide range of sources and was developed under the guidance of a panel of experts derived from sponsoring organizations of endocrinologists. We determined current and projected numbers and demographics of endocrinologists in the U.S. workforce and the anticipated balance between supply and demand from 1999 to 2020. There were 3,623 adult endocrinologists in the workforce in 1999, of whom 2,389 (66%) were in office-based practice. Their median age was 49 years. Both total office visits and services performed by endocrinologists (particularly for diabetes) increased substantially during the 1990s. Waiting time for an initial appointment is presently longer for endocrinologists than for other physicians. Compared with a balanced, largely closed-staff health maintenance organization, the current national supply of endocrinologists is estimated to be 12% lower than demand. The number of endocrinologists entering the market has continuously fallen over the previous 5 years, from 200 in 1995 to 171 in 1999. Even if this downward trend were abruptly stopped, the model predicts that demand will exceed supply from now until 2020. While this gap narrows from 2000 to 2008 due to projected growth of managed care, it widens thereafter due to the aging of both the population and the endocrine workforce. Inclusion of other factors such as projected real income growth and increased prevalence of age-related endocrine disorders (e.g., diabetes and osteoporosis) further accentuates the deficit. If the number of endocrinologists entering the workforce remains at 1999 levels, demand will continue to exceed supply from now through 2020 for adult endocrinologists, and the gap will widen progressively from 2010 onward. The present analysis indicates that the number of endocrinologists entering the workforce will not be sufficient to meet future demand. These data suggest that steps should be taken to stop the ongoing decline in the number of endocrinologists in training and consideration should be given to actions designed to increase the number of endocrinologists in practice in the years ahead.

Subclinical thyroid disease: clinical applications.

Subclinical hypothyroidism and hyperthyroidism are diagnoses based on laboratory evaluation with few if any clinical signs or symptoms. Subclinical hypothyroidism is defined as an elevation in serum thyroid-stimulating hormone (TSH) above the upper limit of the reference range (0.45-4.5 mIU/L) with normal serum FT4 concentration; subclinical hyperthyroidism is defined as a decrease in serum TSH below the reference range with normal serum FT4 and T3 concentrations. Though these conditions represent the earliest stages of thyroid dysfunction, the benefits of detecting and treating subclinical thyroid disease are not well established. Most persons found to have subclinical thyroid disease will have TSH values between 0.1 and 0.45 mIU/L or between 4.5 and 10 mIU/L, for which the benefits of treatment are not clearly established; treatment may be beneficial in individuals with serum TSH lower than 0.1 mIU/L or higher than 10 mIU/L. This article illustrates approaches to managing patients with subclinical hypothyroidism and hyperthyroidism through 5 case scenarios that apply the principles of evidence-based medicine. Because of the substantial uncertainty concerning the consequences of untreated subclinical hypothyroidism and hyperthyroidism, as well as the benefit of initiating treatment, patient preferences are important in deciding on management of subclinical disease.

Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

CONTEXT: Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established. OBJECTIVES: To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted. DATA SOURCES: MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants. STUDY SELECTION AND DATA EXTRACTION: A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area. DATA SYNTHESIS: The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified. CONCLUSIONS: Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.

Ernie Mazzaferri.

NA.

The aging thyroid.

PURPOSE OF REVIEW: As life expectancy increases and population age advances, diagnosis and treatment of diseases common in the geriatric population assume an increasingly important role in modern medicine. In the last few years, the emergence of age-specific reference ranges for thyroid-stimulating hormone (TSH) has added to the complexity of diagnosis of thyroid dysfunction in this age group, especially in the 'subclinical' category. RECENT FINDINGS: The recent studies confirm an increase in population TSH distribution with age, both in cross-sectional and longitudinal studies. Conclusive evidence about adverse cardiovascular, metabolic, and cognitive consequences of subclinical hypothyroidism in the elderly remains elusive. The transient nature of subtle degrees of thyroid dysfunction in a significant proportion of elderly patients has also been reproduced in the recent publications. SUMMARY: A growing body of literature in the last few years, reviewed here, highlights the importance of employing additional caution before assigning diagnoses of hypothyroidism or hyperthyroidism to elderly patients and initiation of treatment modalities that can have long-lasting effects.

An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits.

BACKGROUND: The use of age- and ethnicity-specific thyrotropin (TSH) reference limits decreases misclassification of patients with thyroid dysfunction. Developing such limits requires TSH measurements in different subpopulations. METHODS: We determined, in the National Health and Nutrition Examination Survey III, the TSH median, 2.5th and 97.5th centiles as a function of age, and anti-thyroid antibodies (ABs) in specific racial/ethnic groups (REGs) designated as non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans, as classified by the U.S. Office of Management and Budget (OMB) Directive 15. We compared TSH limits of a thyroid disease-free population (n = 15,277) to a reference population (n = 13,344) formed by exclusion of AB+ subjects and TSH >10 mIU/L or <0.1 mIU/L. With quantile regression, we examined the effect of age, REG, gender, body weight, and urinary iodine concentration on TSH reference limits in the AB- population. RESULTS: AB status did not affect the 2.5th centile and median TSH in any REG or the 97.5th centile in Blacks. The average 97.5th centile of the disease-free Whites and Mexican Americans was 1.0 mIU/L higher than the reference population group. The TSH 2.5th, 50th, and 97.5th centiles increased with age and were lower in Blacks than in Whites or Mexican Americans. Women had lower 2.5th and 50th centiles than males. From these data, we developed equations to predict subpopulation-specific TSH reference limits. CONCLUSIONS: Our study provides a method to determine TSH limits in individual patients of different ages, gender, and REG criteria whose AB status is uncertain and it will enable clinicians to better classify patients within their subpopulation-specific TSH reference range.

Age- and race-based serum thyrotropin reference limits.

CONTEXT: TSH reference limits, particularly the upper limit, are controversial. The traditional and prevailing method for setting limits uses TSH distribution of thyroid disease-free individuals. The curve is not Gaussian, but skewed to higher concentrations, even after log-transformation; values in the skewed area are assumed to reflect mild hypothyroidism. The underlying assumption for this traditional approach, which has not previously been tested, is that the limits derived from this curve are applicable to all people. However, recent studies suggest that distinct subpopulations have unique TSH distribution and reference limits that are significantly different from limits established by the traditional approach. EVIDENCE ACQUISITION: A search was focused on articles that provide the basis for current recommendations for setting TSH reference limits as well as articles that suggest that the traditional method does not reflect accurately the TSH distribution and reference limits of distinct subpopulations within the United States. EVIDENCE SYNTHESIS: TSH distribution and reference limits shift to higher concentrations with age, even up to centenarians, and are unique for different racial/ethnic groups, being at higher concentrations in Caucasians than either Blacks or Hispanics originating from Puerto Rico or the Dominican Republic. The distribution curve derived by the traditional approach represents a composite of curves from specific subpopulations that do not provide appropriate reference limits for those unique groups. CONCLUSIONS: Age- and race-specific TSH distribution and reference limits, possibly influenced by genetic factors, should be employed to provide clinicians accurate limits for specific populations and guidance for further evaluation of thyroid dysfunction.