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Discrepant thyroid function test results in a 44-year-old man.


A 44-year-old Caucasian male was transferred to our hospital for increased concentrations of thyroid hormones and constitutional symptoms, including fatigue and muscle tenderness of 6 weeks' duration. Four weeks before admission, the patient's primary care physician found a diffuse goiter and ordered thyroid hormone testing (Table 1). Two weeks later, the patient developed generalized muscle pain and began a weight loss of 10 pounds until the day of admission. One day before admission, he had fever and diarrhea. The patient was then transferred with the suspicion of severe hyperthyroidism.

The patient's medical history included "hyperthyroidism" and goiter diagnosed at age 24 years. Since then, he has intermittently taken propylthiouracil several times for short periods. At age 34 years, the patient experienced anxiety, tachycardia, and spells of muscle pain. He underwent radioiodine therapy at that time but experienced no improvement in the symptoms or goiter. A few months later, the patient underwent a repeat radioactive iodine treatment with the same unsuccessful result. He has experienced anxiety and tachycardia spells, which were intermittently treated with propylthiouracil for short periods with no relief. He also experiences chronic cluster migraine headaches.

At admission, the patient's vital signs were as follows: temperature, 37 [degrees]C; pulse, 94/min; blood pressure, 140/70 mmHg. There was a diffuse goiter, with the thyroid gland approximately 4 times normal size. The patient had no eye bulging, eyelid lag, tremor, or brisk reflexes. His skin texture was normal. The following day, his pulse was 80/min, and his blood pressure was 120/70 mmHg. The patient's fever and diarrhea had resolved, and he remained afebrile.

An investigation of the discordant results in thyroid function tests was initiated.



The combination of goiter and increased concentrations of free thyroxine ([T.sub.4]) [3] and free triiodothyronine ([T.sub.3]) with unsuppressed thyroid-stimulating hormone (TSH) is suspicious for 4 conditions: (a) hyperthyroidism with a false increase in TSH due to antibody interference; (b) euthyroidism with a false increase in thyroid hormone due to antibody interference or abnormal binding to carrier proteins; (c) a TSH-secreting pituitary tumor; and (d) resistance to thyroid hormone.

False increases in TSH and free [T.sub.4] due to antibody interference have been discussed previously in this journal (1, 2). In patients with no clinical signs of hyperthyroidism, discordance between thyroid hormone concentrations and TSH is highly suspicious for antibody interference in either TSH or thyroid hormone measurement. Patients with underlying autoimmune disorders can develop antibodies against either thyroid hormone directly (i.e., thyroid hormone autoantibodies) or the animal antibodies (heterophile antibodies) used in immunoassays, which more commonly affect immunometric assays (such as those used for TSH measurement). Measurement of free thyroid hormones by equilibrium dialysis and measurement of TSH by another manufacturer's assay are approaches that can rule out immunoassay interference (1, 2). The presence of the symptoms and goiter in this patient, however, suggest another cause for the discrepant results.

Familial dysalbuminemic hyperthyroxinemia presents with an increased total [T.sub.4] concentration, owing to an increased binding of albumin to [T.sub.4]; however, these patients are usually asymptomatic and have a normal thyroid gland (3).

Patients with TSH-secreting pituitary tumors have clear features of hyperthyroidism and often have an enlarged thyroid. These very rare tumors are usually larger than 10 mm and cause dysfunction of other pituitary hormones due to tumor enlargement and compression of surrounding structures (4). An MRI evaluation of the pituitary is indicated to rule out this uncommon condition. This approach has one caveat, the presence of incidentalomas. Incidentalomas of the pituitary are detected in 10%-20% of patients undergoing MRI of the brain for unrelated reasons. The majority of them are smaller than 10 mm, and they do not cause symptoms of hyperthyroidism unless they are secreting TSH (4). If the suspicion of a TSH-secreting pituitary tumor is high, a measurement of the free a subunit of TSH would support this diagnosis. The concentration of serum sex hormone-binding globulin is increased in hyperthyroid states such as TSH-secreting pituitary tumors, whereas normal concentrations of this globulin are expected in patients with resistance to thyroid hormone (5).

Resistance to thyroid hormone lacks specific clinical manifestations. The manifestations are variable, and signs of hormone deficiency and excess often can coexist in the same patient. Relative common features of this syndrome include goiter (66%-95% of patients), tachycardia (33%-75%), hyperkinetic behavior (33%-68%), learning disabilities (30%), and short stature (18%-25%) (6). The disease has an autosomal dominant genetic basis, so the patient's medical history is helpful: 80% of patients have a parent with the same condition. Further questioning of our patient revealed that his mother, grandmother, and daughter all had goiter and were treated for hyperthyroidism. Unfortunately, we were unable to obtain their medical records.

The presence of goiter, increased thyroid hormones ([T.sub.4] and [T.sub.3]), and the absence of consistent clinical features of overt hyperthyroidism were important diagnostic clues for our patient. An MRI of the brain ruled out a TSH-secreting pituitary tumor. Evaluation for heterophile-blocking antibodies with the Scantibodies Heterophilic Blocking Tube in serum did not alter the TSH results, suggesting the absence of heterophile antibody interference. Quest Laboratories carried out a genetic analysis. Exons 3-10 of the THRB [4] (thyroid hormone receptor, beta) gene were amplified from genomic DNA by the PCR, and the amplified DNA was sequenced. Our patient was heterozygous for a mutation in the THRB gene, with an Ala residue replaced by Thr at position 317 in the protein, confirming the clinical diagnosis of resistance to thyroid hormone.

Measuring the biochemical response to the administration of 3 incremental doses of L-[T.sub.3] for 3 days is the best method to make the clinical diagnosis of resistance to thyroid hormone (6). Unfortunately, our patient did not show up in the endocrine clinic for follow-up.


The signaling of thyroid hormone is complex and highly regulated, owing to the expression of cell- and tissue-specific thyroid hormone transporters, thyroid hormone receptor isoforms, and interaction with co-repressors and coactivators. THRA (thyroid hormone receptor, alpha) and THRB encode thyroid hormone receptors THRA and THRB, and each has different patterns of gene expression and different splicing products. Many of the actions of thyroid hormone include potentiation of other signaling pathways, such as adrenergic signaling and metabolic-sensing nuclear receptors (7).

Mutations in the THRB protein explain 85%-90% of cases of resistance to thyroid hormone. The pathophysiology of the remaining 10%--15% of cases remains unknown, but it is plausible that mutations in cofactors that interact with the thyroid hormone receptor play a role (3). More than 1000 patients and more than 370 families with resistance to thyroid hormone have been described in the literature (8).

The mutant THRB molecules have either a reduced affinity for [T.sub.3] or an impaired interaction with one of the cofactors involved in the mediation of thyroid hormone action. Our patient had a mutation in amino acid residue 317, which is located in a region involved in binding [T.sub.3] and prevents appropriate binding. The replacement of Ala by Thr at position 317 has been reported in 29 families (8).

The THRA gene is expressed in cardiac and skeletal tissues, THRB splice variant 1 is expressed in brain, liver, and kidney, and THRB splice variant 2 is expressed in the hypothalamus and the pituitary. The tissue-specific expression of the genes encoding the different receptors sheds light on the conflicting hyperthyroid and hypothyroid symptoms. A defect in THRB leads to excess hormone, activating THRA and leading to cardiac and skeletal manifestations. Studies have shown that THRB knockout mice have tachycardia and THRA knockout mice have a decreased heart rate (9). These findings are not consistent with those in humans, and even affected members of the same family show different patterns of symptoms and signs (7, 8).

The reduced affinity of the thyroid hormone receptor leads to a reduced feedback action of thyroid hormones, and this situation is compensated for by higher TSH secretion. In the steady state, the thyroid hormones are increased, but TSH is unsuppressed. In patients with resistance to thyroid hormone, TSH has increased biological activity, which can explain the presence of goiter (10).


Goiter occurs as the thyroid attempts to produce more thyroid hormone to overcome the resistance. Tachycardia prompts 25% of adults with resistance to thyroid hormone to seek medical advice (6). From the laboratory point of view, increased [T.sub.4] and [T.sub.3] concentrations along with normal concentrations of TSH are typical, unless the patient had previous successful surgery or radioactive iodine therapy. In that case, symptoms of hypothyroidism will predominate, and the TSH concentration will be increased. Our patient had received 2 treatments with [sup.131]I several years earlier.

Surgery and radioactive iodine are ineffective. There is no specific treatment to correct the underlying defect; therapy is aimed at alleviating symptoms. The most common symptom is sinus tachycardia, which is present in 35%-75% of patients. If the disease is symptomatic, tachycardia can be treated with a [beta]-adrenergic blocking agent such as atenolol. Other symptoms, such as tremor, heat intolerance, and sweating, can also improve with atenolol treatment (6). Treatment with l-[T.sub.3] on alternating days has been effective in lowering TSH secretion and in reducing the size of the goiter.

The appropriate diagnosis of this condition prevents unnecessary therapy with radioactive ablation or surgery.


1. List some causes of goiter, increased free [T.sub.4] and free [T.sub.3] values, and a normal TSH result.

2. What laboratory tests could be done to help determine the cause of these laboratory values?

3. What is the role of clinical findings in confirming the diagnosis?

4. Is there a molecular test that can help to confirm the diagnosis?


* Resistance to thyroid hormone is a rare autosomal dominant disease caused mainly by mutations in the isoform of the thyroid hormone receptor.

* Diagnosis is based on increased thyroid hormone concentrations, a normal TSH concentration, and absent or mild symptoms of hyperthyroidism.

* Antibody interference needs to be considered after obtaining discordant results in thyroid function tests.

* A gene test is available and can identify up to 85% of patients with resistance to thyroid hormone.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, oranalysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form.

Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: P.E. Cryer, Novo Nordisk and Bristol-Myers Squibb/AstraZeneca.

Stock Ownership: None declared.

Honoraria: P.E. Cryer, Novo Nordisk and Bristol-Myers Squibb/ AstraZeneca.

Research Funding: None declared.

Expert Testimony: None declared.

Patents: None declared.


(1.) van der Watt G, Haarburger D, Berman P. Euthyroid patient with elevated serum free thyroxine. Clin Chem 2008;54:1239-41.

(2.) Kellogg MD, Law TC, Huang, RN. A girl with goiter and inappropriate thyroid-stimulating hormone secretion. Clin Chem 2008;54:1241-4.

(3.) Thyroid Disease Manager. Thyroid hormone resistance syndromes [by Refetoff S, Dumitrescu AM]. 2010. thyroid-hormone-resistance-syndromes/ (Accessed May 2013).

(4.) Beck-Peccoz P, Persani L, Mannavola D, Campi I. TSH-secreting adenomas. Best Pract Res Clin Endocrinol Metab 2009;23:597-606.

(5.) Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML. Pituitary incidentaloma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:894-904.

(6.) Weiss R, Refetoff S. Syndromes of resistance to thyroid hormone. In: Wondisford F, Radovic S, eds. Clinical management of thyroid disease. New York: Elsevier; 2009.

(7.) Brent GA. Mechanisms of thyroid hormone action. J Clin Invest 2012;122: 3035-43.

(8.) Weiss RE, Dumitrescu AM, Refetoff S. Syndromes of reduced sensitivity to thyroid hormone. In: Weiss RE, Refetoff S, eds. Genetic diagnosis of endocrine disorders. New York: Elsevier; 2010. p 105-16.

(9.) Olateju TO, Vanderpump MP. Thyroid hormone resistance. Ann Clin Biochem 2006;43:431-40.

(10.) Persani L, Asteria C, Tonacchera M, Vitti P, Krishna V, Chatterjee K, BeckPeccoz P. Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance. J Clin Endocrinol Metab 1994;78: 1034-9.

Julio Leey [1] * and Philip Cryer [2]

[1] Diabetes and Endocrine Care of Alton, BJC Medical Group, Alton, IL; (2) Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO.

* Address correspondence to this author at: Diabetes and Endocrine Care of Alton, BJC Medical Group, 2 Memorial Dr., Suite 203, Alton, IL 62002. Fax 618-433-6179; e-mail

Received December 27, 2012; accepted April 22, 2013.

DOI: 10.1373/clinchem.2012.202283

[3] Nonstandard abbreviations: [T.sub.4], thyroxine; [T.sub.3], triiodothyronine; TSH, thyroid-stimulating hormone.

[4] Human genes: THRB, thyroid hormone receptor, beta; THRA, thyroid hormone receptor, alpha.


Kenneth D. Burman *

Leey and Cryer (1) nicely discuss a patient with a heterozygous mutation in the THRB gene and review the differential diagnosis. A normal serum TSH value with increased total and free [T.sub.4] and [T.sub.3] concentrations should raise suspicion that the patient may not have typical thyrotoxicosis. Family members must be assessed for the mutation once the familial proband has been identified. It is important to identify patients with a [T.sub.3] receptor mutation so that inappropriate treatments can be avoided. Immunoassays for TSH measure serum TSH concentrations only and do not assess TSH biological activity. In unusual circumstances, immunoreactivity and bioactivity are discordant (2). For example, patients with pituitary or hypothalamic disorders may show a decreased ratio of TSH bioactivity to immunoreactivity. Patients with TSH-secreting pituitary tumors, conversely, may show enhanced TSH bioactivity (2). A mutation in the THRB protein is the most common form of thyroid hormone resistance; however, van Mullem et al. have recently described the syndrome of resistance associated with a THRA mutation (3). Furthermore, Visser (4) has described a different type of thyroid hormone resistance, in which the cellular membrane has a mutation in the monocarboxylate transporter 8 receptor, an important thyroid hormone transporter. Patients with mutations in this receptor may have severe neurologic and endocrine abnormalities. As Leey and Cryer (1) note, patients with TSH-secreting pituitary tumors have an increased molar ratio of [alpha] TSH to TSH (entire molecule). One caveat is that this ratio is a molar ratio and values for the a subunit (usually expressed in nanograms per milliliter) and TSH values (usually expressed in milliunits per liter) must be converted appropriately. A [T.sub.3] suppression test is rarely performed, because it may cause hyperthyroidism and the diagnosis of a [T.sub.3] receptor mutation can usually be made on a genetic basis.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, oranalysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Leey J, Cryer P. Discrepant thyroid function test results in a 44-year-old man. Clin Chem 2013;59:1703-6.

(2.) Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994;131:331-40.

(3.) van Mullem A, van Heerebeek R, Chrysis D, Visser E, Medici E, Andrikoula M, et al. Clinical phenotype and mutant TR[alpha]1. N Engl J Med 366: 1451-3.

(4.) Visser TJ. Thyroid hormone transporters and resistance. Endocr Dev 24:1-10.

Endocrine Section, Department of Medicine, Washington Hospital Center, Washington, DC.

* Address correspondence to the author at: Washington Hospital Center, 110 Irving St. NW, Washington, DC 20895. Fax 202-877-6588; e-mail kenneth.

Received June 13, 2013; accepted June 20, 2013.

DOI: 10.1373/clinchem.2013.209379


William E. Winter [1,2,3,4,5,6] *

Endocrine disorders can result from defects in hormone production, receptor binding, and postreceptor signaling. Concerning production, there can be an excess or a deficiency in a hormone, or a hormonopathy (e.g., an insulinopathy). In some hormonopathies, the defective hormone is not secreted but leads to apoptotic cell death and an absolute deficiency of the hormone (e.g., permanent neonatal diabetes caused by insulin gene mutations).

Autoantibodies that act like hormone agonists can produce states of hyperfunction or hypofunction when acting as receptor antagonists. Autoantibodies that bind to other cell surface receptors can also alter hormone secretion (e.g., agonist autoantibodies directed against the parathyroid's calcium-sensing receptor). An altered ability to sense the environment can produce hormone deficiency (e.g., glucokinase mutations producing maturity-onset diabetes of the young 2).

Defects in receptors or signaling typically lead to loss-of-function conditions (e.g., glucocorticoid, mineralocorticoid, or androgen resistance) although gain-of-function mutations do occur (e.g., testotoxicosis or the McCune-Albright syndrome). Receptor gain-of-function mutations allow an interface between the fields of endocrinology and oncology.

Endocrine disorders can be due to defective entry of hormones into target tissues (e.g., monocarboxylate transporter 8 mutations). Hormone metabolism can also be disrupted, allowing increased receptor interaction (e.g., apparent mineralocorticoid excess).

Defects in postreceptor signaling are extremely prevalent: The underlying disorder in most cases of type 2 diabetes is defective insulin signaling. The distribution of receptor subtypes among tissues can markedly affect the individual's phenotype (e.g., thyroid hormone [beta] receptor vs. [alpha] receptor mutations).

Lastly, mutations in genes controlling proteins regulated by hormones can produce clinical disease. Examples include nephrogenic diabetes insipidus from aquaporin 2 mutations, vitamin D-resistant rickets from SLC34A3 [7] [solute carrier family 34 (sodium phosphate), member 3] mutations, and mutations in SCNN1B (sodium channel, non-voltage-gated 1, [beta] subunit) or SCNN1G (sodium channel, non-voltage-gated 1, [gamma] subunit) in Liddle syndrome.

To maximally assist the clinician, the laboratorian must be aware of the huge variety of defects that can affect the endocrine system.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, oranalysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: W.E. Winter, LabCorp.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: None declared.

Expert Testimony: None declared.

Patents: None declared.

Departments of [1] Pathology, Immunology and Laboratory Medicine, [2] Pediatrics, and [3] Molecular Genetics and Microbiology, [4] Type 1 Diabetes TrialNet ICA Core Laboratory, [5] University of Florida Pathology Laboratories, and [6] Endocrine Autoantibody Laboratory, University of Florida, Gainesville, FL.

* Address correspondence to the author at: Department of Pathology, Immunology and Laboratory Medicine, Box 100275, Gainesville, FL 32610-0275. Fax 352-392-4495; e-mail

Received June 3, 2013; accepted June 14, 2013.

DOI: 10.1373/clinchem.2013.209387

[7] Human genes: SLC34A3, solute carrier family 34 (sodium phosphate), member 3; SCNN1B, sodium channel, non-voltage-gated 1, f subunit; SCNN1G, sodium channel, non-voltage-gated 1, y subunit.
Table 1. Thyroid hormone values. (a)

Analyte reference           Two years          Four weeks
interval, conventional        before             before
units (SI units)            admission          admission

Total [T.sub.4]
  5.6-13.6 [micro]g/dL   [up arrow] 17.0
  (72-176 nmol/L)             (220)
Total [T.sub.3]
  60-181 ng/dL           [up arrow] 282.4   [up arrow] 281.1
  (0.92-2.79 nmol/L)          (4.35)             (4.34)
Free [T.sub.4]
  0.8-1.91 ng/dL                             [up arrow] 3.3
  (10.3-24.7 pmol/L)                             (42.4)
Free [T.sub.3]
  227-420 pg/dL
  (3.5-6.47 pmol/L)
  0.5-5 mU/L

Analyte reference           Admission          Hospital
interval, conventional         day              day 2
units (SI units)

Total [T.sub.4]
  5.6-13.6 [micro]g/dL   [up arrow] 14.6
  (72-176 nmol/L)             (188)
Total [T.sub.3]
  60-181 ng/dL           [up arrow] 366.8
  (0.92-2.79 nmol/L)          (5.65)
Free [T.sub.4]
  0.8-1.91 ng/dL          [up arrow] 2.2    [up arrow] 2.0
  (10.3-24.7 pmol/L)          (29.6)            (25.7)
Free [T.sub.3]
  227-420 pg/dL          [up arrow] 733.7
  (3.5-6.47 pmol/L)           (11.3)
  0.5-5 mU/L                   1.6               1.2

(a) Analyte values above the upper reference limit
are indicated (1).
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Title Annotation:Clinical Case Study
Author:Leey, Julio; Cryer, Philip
Publication:Clinical Chemistry
Article Type:Case study
Date:Dec 1, 2013
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