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A girl with goiter and inappropriate thyroid-stimulating hormone secretion.

CASE

A 15-year-old white girl presented with neck tenderness. On examination, a nodule nodule: see concretion.
nodule

In geology, a rounded mineral concretion that is distinct from, and may be separated from, the formation in which it occurs.
 was palpated in the right thyroid lobe. The neck was supple without abnormal lymphadenopathy lymphadenopathy /lym·phad·e·nop·a·thy/ (-op´ah-the) disease of the lymph nodes.

angioimmunoblastic lymphadenopathy , angioimmunoblastic lymphadenopathy with dysproteinemia
. Eye findings related to Graves orbitopathy were absent. Weight, height, and blood pressure were unremarkable, but the heart rate was high at 104-114 bpm. The patient had a history of attention deficit hyperactivity disorder attention deficit hyperactivity disorder (ADHD), formerly called hyperkinesis or minimal brain dysfunction, a chronic, neurologically based syndrome characterized by any or all of three types of behavior: hyperactivity, distractibility, and impulsivity.  and was taking atomoxetine and fluoxetine fluoxetine /flu·ox·e·tine/ (floo-ok´se-ten) a selective serotonin reuptake inhibitor used as the hydrochloride salt in the treatment of depression, obsessive-compulsive disorder, bulimia nervosa, and premenstrual dysphoric disorder. . There was no history of childhood neck irradiation or family history of thyroid cancer. Several maternal relatives have acquired thyroid dysfunction.

Sonography sonography: see ultrasound  showed a 2-cm nodule in the right thyroid lobe. Fine-needle aspiration showed benign cytology, but the family requested right thyroid lobectomy lobectomy /lo·bec·to·my/ (lo-bek´tah-me) excision of a lobe, as of the lung, brain, or liver.

lo·bec·to·my
n.
Excision of a lobe of an organ or a gland.
 for persistent neck tenderness. Preoperative pre·op·er·a·tive
adj.
Preceding a surgical operation.



preoperative

preceding an operation.


preoperative care
the preparation of a patient before operation.
 laboratory data revealed a total thyroxine ([T.sub.4]) (3) concentration of 170 nmol/L [reference interval (RI) 67-138 nmol/L] (13.2 [micro],g/dL, RI 5.2-10.7), total truodothyronine ([T.sub.3]) concentration of 3.2 nmol/L (RI 1.32.4 nmol/L) (206 ng/dL, RI 86-153), a thyroid-stimulating hormone (TSH TSH thyroid-stimulating hormone; see thyrotropin.

TSH
abbr.
thyroid-stimulating hormone


Thyroid-stimulating hormone (TSH) 
) concentration of 0.5 mIU/L (RI 0.3-5.0 mIU/L), and a thyroid hormone binding ratio (1/T-uptake) of 1.72 (RI 0.77-1.16) (Table 1). Analyses were conducted by chemiluminescent chem·i·lu·mi·nes·cence  
n.
Emission of light as a result of a chemical reaction at environmental temperatures.



chem
 immunoassay Immunoassay

An assay that quantifies antigen or antibody by immunochemical means. The antigen can be a relatively simple substance such as a drug, or a complex one such as a protein or a virus.
 on the Roche Elecsys 2010 platform. Free [T.sub.3] and free [T.sub.4] indices as calculated by the clinicians were 5.5 nmol/L (RI 1.3-2.4 nmol/L) and 292 nmol/L (RI 67-138 nmol/L), respectively, and, in the context of the patient's normal TSH concentration, suggested the possibility of inappropriate TSH secretion due to resistance to thyroid hormone or a TSH-secreting pituitary adenoma. Analyses for serum free [T.sub.4] measured by direct dialysis and RIA were conducted at Mayo Medical Laboratories and revealed a normal free [T.sub.4] of 16.8 pmol/L (RI 10.3-25.8 pmol/L) (1.3 ng/dL, RI 1-2 ng/ dL). Although certain of the patient's features, including her tachycardia tachycardia: see arrhythmia.
tachycardia

Heart rate over 100 (as high as 240) beats per minute. When it is a normal response to exercise or stress, it is no danger to healthy people, but when it originates elsewhere, it is an arrhythmia.
 (1, 2), were consistent with the syndrome of inappropriate TSH secretion, this syndrome is extremely rare and the recommended standard of care is to repeat thyroid function tests after [greater than or equal to] 1 week (2) to exclude the effects of nonthyroidal illness and to assess the possibility of laboratory artifact (3). Accordingly, the patient's scheduled surgery was postponed to accurately assess her thyroid function status.

DISCUSSION

This case presents an interesting combination of thyroid function testing results with increased thyroid hormone concentrations and normal TSH concentrations in a clinically euthyroid Euthyroid
Having the right amount of thyroxin stimulation.

Mentioned in: Goiter


euthyroid

having a normally functioning thyroid gland.
 patient. An evaluation for laboratory artifact is recommended whenever initial results suggest the diagnosis of inappropriate TSH secretion, because of the extreme rarity of this condition and the risk of iatrogenesis Iatrogenesis literally means "brought forth by a healer" (iatros means healer in Greek); as such, it can refer to good or bad effects, but it is almost exclusively used to refer to a state of ill health or adverse effect or complication caused by or resulting from medical  in patients with falsely abnormal thyroid function tests (3).

Data from a repeat analysis of thyroid function tests are presented in Table 1. Results were similar to previous analyses (Table 1). To investigate possible antibody interference, thyroid testing using an alternative chemiluminescent immunoassay was conducted at 2 laboratories using the Advia Centaur centaur (sĕn`tôr), in Greek mythology, creature, half man and half horse. The centaurs were fathered by Ixion or by Centaurus, who was Ixion's son.  platform (Siemens Healthcare Diagnostics) (Table 1). Samples treated using the Heterophilic Blocking Tube (Scantibodies Laboratory) confirmed that Roche Elecsys methods were affected by antibody interference (Table 1).

Total [T.sub.4] and [T.sub.3] assays on the Roche Elecsys platform use sheep-derived antibodies and are based on competitive test principles. The T-uptake assay also uses sheep antibodies and follows a modified competitive principle. In contrast, the Siemens Advia Centaur platform uses mouse antibodies. The Roche TSH assay uses mouse antibody and a human/mouse chimera antibody and is noncompetitive in principle.

The Scantibodies Heterophilic Blocking Tube data strongly suggested interference by heterophile antibodies (HABs), which are endogenous antibodies that bind to immunoglobulins of other species (4). Typically, HABs bind to the constant portion of assay antibodies and in noncompetitive assay formats create a bridge between capture and detection antibodiess leading to falsely increased results (5). In competitive assay formats, this Fc binding can prevent or interfere with antigen binding, leading to a false increase (5). Our observation that the heterophile blocking tube caused an increase (not decrease) in the noncompetitive assay (TSH) did not support typical HAB interference via binding the Fc portion. A false-negative value can be seen, however, when the interfering antibodybinds to 1 of the 2 antibodies in a noncompetitive assay (6), as in the Roche Elecsys TSH assay.

Heterophile antibody binding to the variable region of the assay antibody (idiotypic interaction) is less common (5). Idiotypic interactions occur mainly in patients who have received treatment with animal immunoglobulins (5). In light of the rarity of idiotypic interactions, the interferences observed in samples from this patient with assay antibodies against 3 differing antigens, coupled with no known history of treatment of the patient with animal immunoglobulins, practically excluded the possibility of an idiotypic interaction from a human antianimal antibody.

Rheumatoid factor (RF) can also exhibit nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.

2. not directed against a particular agent, but rather having a general effect.


nonspecific

1.
 binding and typically binds to the Fc portion of assay antibodies, inhibiting or preventing antigen binding (5). In the noncompetitive format of the Roche total TSH assay, this would typically result in a signal increase, opposite of our findings.

As such, we began to look for a common factor in all the assays. According to the manufacturer, all the assays used a streptavidin-labeled magnetic particle to which biotin biotin: see vitamin; coenzyme.
biotin

Organic compound, part of the vitamin B complex, essential for growth and well-being in animals and some microorganisms.
 (attached to exogenous hormone or a TSH-specific antibody) would bind. Additionally, all had a ruthenium ruthenium (rthē`nēəm), metallic chemical element; symbol Ru; at. no. 44; at. wt. 101.07; m.p. about 2,310°C;; b.p. about 3,900°C;; sp. gr. 12.  complex linked to the detection antibody. Therefore, antibodies against streptavidin, biotin, and the ruthenium-complex label were considered (7).

An aliquot aliquot (al-ee-kwoh) adj. a definite fractional share, usually applied when dividing and distributing a dead person's estate or trust assets. (See: share)  sent to Roche Diagnostics was tested with the addition of "Ru-interference blocking agent" above that normally found in the assay. Results were not suggestive of interference against the ruthenium complex [free [T.sub.4] without Mocker 14.7 pmol/L (1.1 ng/dL) and with Mocker 14.6 pmol/L (1.1 ng/dL)]. However, because free [T.sub.4] by the Roche method did not appear to exhibit interference as seen with the other Roche methods, the workup work·up
n. Abbr. w/u
A thorough medical examination for diagnostic purposes.
 conducted by Roche Diagnostics to investigate possible Ru-interference by measuring free [T.sub.4] may not be sufficient to address the question. A more appropriate investigation would have used total [T.sub.4] (with demonstrated interference) and addition of the specific Mocker to see if the interference is removed.

To investigate streptavidin and biotin interference, patient sample was applied to a streptavidin agarose column (Pierce Biotechnology). Untreated sample results were 0.51 mIU/L, 165 nmol/L (13 [micro]g/dL) and 1.72 for TSH, total [T.sub.4], and T-uptake, respectively. After treatment, the values were 0.48 mIU/L,154 nmol/L (12 [micro]g/dL), and 1.77. The results indicate that interference due to endogenous biotin, or to antibodies against streptavidin or other molecules interacting with streptavidin, was unlikely. To date, the exact nature of the antibody interference is unknown.

Like all immunoassays, methods for thyroid hormones can be affected by unpredictable and sometimes transient antibody interferences (5, 8). Because these cases are rare and patient specific, it is not possible to detect them using routine quality control practices. Assay reagents typically contain blocking agents (nonimmune sera, antibody fragments, immobilized IgG) to reduce the incidence of antibody-based interference, but it has been estimated that 0.1% of samples have titers high enough to overcome these Mockers (8). Estimates of the rate of interference are typically <1% but range from approximately 0.4% to 4% (5, 9).

It is generally accepted that interference investigations should include: (a) repeat analysis; (b) dilutional analysis; (c) addition of immunoglobulins to block interfering antibodies; and (d) use of an alternative immunoassay (5, 10). Several studies have shown that the investigation must use multiple approaches (8, 10). It is important to keep in mind that negative results do not exclude the presence of an interfering substance. Detailed studies, typically beyond the scope of most clinical laboratories, are required to specifically confirm and identify the presence of an interfering antibody.

A nonlinear response to dilution is suggestive of antibody interference but can also result from hook effect or cross-reactivity. Commonly, the assessment of linearity is subjective, based on rules of thumb such as that linear results should agree within 10% of the original undiluted sample result. However, as Ismail and colleagues point out (8, 9), this is not appropriate and will provide poor detection of interference. Additionally, laboratories should use only diluents validated by the manufacturer, and be aware that some immunoassays do not support sample dilution.

Although immunoglobulins from the animal species used to generate assay antibodies are added to bind with potential interferents, and mitigate their impact, it has also been recommended to add immunoglobulin from a second species (11). This makes for a complex investigation if multiple species are involved. A commercially available product (Heterophilic Blocking Tube; Scantibodies Laboratories) adds proprietary binders to the sample and simplifies the conduct of blocking studies.

Removal of interfering antibodies can be accomplished with commercially available protein G, protein A affinity columns, or polyethylene glycol (PEG). It is important to control for the effect of the treatment by measuring another analyte and correct for recovery. Results obtained from antibodyremoval studies are not reportable, and indicate only that the original values are questionable.

The requirements for proper assessment of dilution and blocking studies are time consuming and costly. Thus, retesting with an alternative method is the easiest and quickest means to assess interference. It is important to select methods that use antibodies from different animal species than those in the original assay. Laboratory scientists should keep in mind that using alternative method evaluation does not indicate which method is correct.

In the case of this specific patient, the incorrect diagnosis of inappropriate TSH secretion would have obligated expensive tests such as brain MRI 1. (application) MRI - Magnetic Resonance Imaging.
2. MRI - Measurement Requirements and Interface.
 and, if a pituitary pituitary /pi·tu·i·tary/ (pi-too´i-tar?e)
1. hypophysial.

2. pituitary gland; see under gland.


anterior pituitary  adenohypophysis.
 incidentaloma was present, could have led to inappropriate treatment with medications or even surgery. Clinicians must recognize that symptoms of thyroid dysfunction can be variable and nonspecific and consider the possibility of laboratory artifact. In summary, antibody interference in immunoassays remains a problem that requires constant vigilance and good communication between laboratory scientists and clinicians. Both need to maintain awareness of the problem and review data against clinical findings before initiating interventions that may be unnecessary.

POINTS TO REMEMBER

* Investigation of immunoassay interference should include repeat analysis, determination of nonlinearity with dilution, testing by alternative method, and removal of interfering antibodies or blocking studies.

* Changes in measured concentration after removal of immunoglobulins or addition of blocking agents are indicative of antibody interference, but no effect does not rule out interference.

* Results obtained after dilution, immunoglobulin removal, or blocking studies should not be reported, as they may not reflect true concentrations.

* Clear communications between clinicians and the laboratory are required to minimize the impact of assay interference on clinical decision making.

Grant/Funding Support: None declared.

Financial Disclosures: None declared.

References

(1.) Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA, Mixson AJ, Weintraub BD. Attention deficit-hyperactivity disorder attention deficit-hyperactivity disorder Attention deficit disorder Psychiatry An inability to control behavior due to difficulty in processing neural stimuli, resulting in ↑ motor activity, ↓ attention span Epidemiology ADHD is the most common  in people with generalized resistance to thyroid hormone. N Engl J Med 1993;328:997-1001.

(2.) Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14:348-99.

(3.) Davies TF, Larsen PR. Thyrotoxicosis thyrotoxicosis /thy·ro·tox·i·co·sis/ (thi?ro-tok?si-ko´sis) a morbid condition due to overactivity of the thyroid gland; see Graves' disease.

thy·ro·tox·i·co·sis
n.
. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia, PA: Saunders Elsevier, 2008;333-76.

(4.) Kaplan IV, Levinson SS. When is a heterophile antibody not a heterophile antibody? When it is an antibody against a specific immunogen. Clin Chem 1999;45:616-8.

(5.) Despres N, Grant AM. Antibody interference in thyroid assays: a potential for clinical misinformation mis·in·form  
tr.v. mis·in·formed, mis·in·form·ing, mis·in·forms
To provide with incorrect information.



mis
. Clin Chem 1998;44:440-54.

(6.) Kricka U. Human anti-animal antibody interferentes in immunological assays. Clin Chem 1999;45:942-56.

(7.) Sapin R, Agin a·gin   Chiefly Upper Southern U.S.
prep.
1. Against.

2. Opposed to: I'm agin him.

3. Next to; beside; near.

4. By or before (a specified time).
 A, Gasser F. Efficacy of a new blocker against anti-ruthenium antibody interference in the Elecsys free truodothyronine assay. Clin Chem Lab Med 2007;45:416-8.

(8.) Ismail AA, Walker PL, Cawood ML, Barth JH. Interference in immunoassay is an underestimated problem. Ann Clin Biochem 2002;39:366-73.

(9.) Ismail AA. On detecting interference from endogenous antibodies in immunoassays by doubling dilutions test. Clin Chem Lab Med 2007;45:851-4.

(10.) Immunoassay Interference by Endogenous Antibodies; Proposed Guideline. CLSI CLSI Clinical and Laboratory Standards Institute (Wayne, PA)
CLSI Cisco Link Services Interface
 document I/LA30-P: Clinical and Laboratory Standards Institute, 2007.

(11.) Levinson SS, Miller JJ. Towards a better understanding of heterophile (and the like) antibody interference with modern immunoassays. Clin Chim Acta 2002;325:1-15.

Mark D. Kellogg, [1] * Terence C. Law, [1] Stephen Huang, [2] and Nader Rifai [2]

[1] Department of Laboratory Medicine, Children's Hospital Boston Children's Hospital Boston is a children's hospital located in the Longwood Medical and Academic Area of Boston, Massachusetts. Located at 300 Longwood Avenue, Children's is adjacent both to its teaching affiliate, Harvard Medical School, and to Dana-Farber Cancer Institute. , and Department of Pathology, Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. , Boston, MA; [2] Division of Endocrinology, Children's Hospital Boston, and Department of Medicine, Harvard Medical School, Boston, MA.

[3] Nonstandard non·stan·dard  
adj.
1. Varying from or not adhering to the standard: nonstandard lengths of board.

2.
 abbreviations: [T.sub.4], thyroxine; RI, reference interval; [T.sub.3], truodothyronine; TSH, thyroid-stimulating hormone; HAB, heterophile antibody.

* Address correspondence to this author at: Department of Laboratory Medicine, Children's Hospital Boston, Farley 720, 300 Longwood Ave., Boston, MA 02115. E-mail mark.kelloggQchildrens.harvard.edu.

Received December 13, 2007; accepted April 4, 2008.

Previously published online at D01: 10.1373/clinchem.2007.102087
Table 1. Laboratory data. (a)

                                      Total            Total
                                    [T.sub.4],      [T.sub.3],
                                      nmol/L          nmol/L
                                  ([micro]g/dL)       (ng/dL)

March 1, 2007
  Roche Elecsys                   170 (13.2)      3.2 (208)
March 12, 2007
  Roche Elecsys                   173 (13.4)      3.7 (240)
May 11, 2007
  Roche Elecsys                   147 (11.4)      2.8 (182)
July 11, 2007
  Roche Elecsys                   161 (12.5)      2.7 (175)
  Siemens Centaur, laboratory 1    92 (7.1) (b)   2.0 (130) (c)
  Siemens Centaur, laboratory 2    88 (6.8) (b)   2.1 (136) (c)
August 10, 2007
  Roche Elecsys pre-HBT           154 (11.9)      2.8 (182)
  Roche Elecsys post-HBT           88 (h.8)       2.1 (136)

                                            Thyroid
                                            hormone
                                   TSH,     binding
                                   mIU/L     ratio

March 1, 2007
  Roche Elecsys                   0.5       1.72
March 12, 2007
  Roche Elecsys                   0.5       1.54
May 11, 2007
  Roche Elecsys                   0.6       1.47
July 11, 2007
  Roche Elecsys                   0.5       1.43
  Siemens Centaur, laboratory 1   1.0 (d)   1.13 (e)
  Siemens Centaur, laboratory 2   1.1 (d)   1.01 (e)
August 10, 2007
  Roche Elecsys pre-HBT           0.5       1.38
  Roche Elecsys post-HBT          1.1       0.98

(a) Unless noted otherwise, reference intervals for total [T.sub.4],
67-138 nmol/L (5.2-10.7 [micro]g/dL); total [T.sub.3], 1.3-2.4 nmol/L
(86-154 ng/dL); TSH, 0.3-5.0 mIU/L; and thyroid hormone binding
ratio (1/T-uptake), 0.77-1.16. HBT, Heterophilic Blocking Tube
(Scantibodies Laboratory).

(b) Reference interval 64-126 nmol/L (5.0-9.8 Fig/dL).

(c) Reference interval 1.5-2.8 nmol/L (97-186 [micro]g/dL).

(d) Reference interval 0.7-6.4 mIU/L.

(e) Reference interval 0.79-1.16.


Commentary

Kenneth D. Burman

Interferences in laboratory tests, immunoassays in particular, continue to be a significant challenge in clinical laboratory practice [1]. A raised awareness to this type of analytical problem is important if laboratories are to avoid reporting incorrect test results. In spite of all efforts by the diagnostic community, interferences still occur, sometimes with disastrous consequences for the patient.

These 2 cases illustrate 2 different circumstances that led to the suspicion of assay interference. In the case reported by van der Watt et al., it was discordance discordance /dis·cor·dance/ (dis-kord´ans) the occurrence of a given trait in only one member of a twin pair.discor´dant

dis·cor·dance
n.
 in thyroid test results that alerted the laboratory, and in the case reported by Kellogg et al., investigation of a possible laboratory artifact was a component in the standard of care for the suspected rare syndrome of inappropriate thyroid-stimulating hormone (TSH) secretion.

Both cases illustrate the investigations that are required to establish the presence of an interference. These investigations include repeat analysis, reanalysis using another method, dilution, blocking, fractionation fractionation /frac·tion·a·tion/ (frak?shun-a´shun)
1. in radiology, division of the total dose of radiation into small doses administered at intervals.

2.
 of the sample by (for example) precipitation, and investigating possible exposure of the patient to animals or animal products (e.g., monoclonal antibody preparations for therapy or imaging). The manufacturer of a test kit can also be an ally in such investigations. Kellogg et al. collaborated with the test kit manufacturer in some of the blocking studies that used a Ru-interference blocking agent designed to reveal an interference with the ruthenium complex used in the free thyroxine ([T.sub.4]) assay.

In its own way, each case is notable. The case reported by Kellogg et al. is of special interest, as it is one of the relatively few reported cases of a negative interference in a sandwich immunoassay caused by a circulating antibody (2, 3). The more common finding is a false-positive result due to an interfering antibody [e.g., human antimouse antibody (HAMA)]. This case also illustrates that often it is not possible to verify the exact identity of an interferent. These types of studies are also frustrated by the limited amount of specimen available and patients who are lost to follow-up, thus precluding extensive and exhaustive studies. The van der Watt et al. case represents an example of false-positive interference in a competitive assay (due to binding of a putative antithyroxine antibody to the conjugate conjugate /con·ju·gate/ (kon´jdbobr-gat)
1. paired, or equally coupled; working in unison.

2. a conjugate diameter of the pelvic inlet; used alone usually to denote the true conjugate diameter; see
) and illustrates the differing effects of the interferent in a 1-step vs a 2-step analog-based free hormone assay.

In light of the continuing problems with interferences, the question remains whether the Holy Grail of immunoassays, the interference-free immunoassay, will ever be within reach. Incremental improvements to the efficacy of blocking agents have not eradicated the problem. Alternative strategies, such as incubating all samples in the Scantibody-type blocking tubes, are prohibitive owing to cost and adverse impact on operational efficiency of the laboratory. Some believe that the answer lies with chickens (4)! Chicken antibodies are not susceptible to common interferences such as rheumatoid factors and HAMA. Despite this beneficial feature, chicken antibodies have not made serious inroads into the dominant position held by mouse monoclonal and other animal antibodies as immunoassay reagents. A more ambitious notion is that the immunoassay, and its attendant problems, will be replaced by some superior non-antibody-based analytical technique. It is not clear what technology might sweep away a firmly entrenched method such as immunoassay with its >50-year history of development and application. In 2008, in what seems the heyday of the immunoassay, it is difficult to predict such a sea change. However, we should not forget that massive disturbances to the status quo are rarely predicted with any accuracy, and hence immunoassay is not necessarily guaranteed a role as the method of choice for its current range of analytes.

Grant/Funding Support: None declared.

Financial Disclosures: None declared.

References

(1.) Kricka U. Interferences in immunoassay: still a threat. Clin Chem 2000;46: 1037-8.

(2.) Bohner J, von Pape KW, Hannes W, Stegmann T. False-negative immunoassay results for cardiac troponin I probably due to circulating troponin I autoantibodies. Clin Chem 1996;42:2046.

(3.) Giovanella L, Ghelfo A. Undetectable serum thyroglobulin thyroglobulin /thy·ro·glob·u·lin/ (thi?ro-glob´u-lin) an iodine-containing glycoprotein of high molecular weight, occurring in the colloid of the follicles of the thyroid gland; the iodinated tyrosine moieties of thyroglobulin form the  due to negative interference of heterophile antibodies in relapsing thyroid carcinoma. Clin Chem 2007;53:1871-2.

(4.) Carlander D, Stalberg J, Larsson A. Chicken antibodies: a clinical chemistry perspective. Upsala J Med Sci 1999;104:179-89.

Department of Pathology & Laboratory Medicine, University of Pennsylvania (body, education) University of Pennsylvania - The home of ENIAC and Machiavelli.

http://upenn.edu/.

Address: Philadelphia, PA, USA.
 Medical Center, Philadelphia, PA.

Address correspondence to the author at: Department of Pathology & Laboratory Medicine, 7.103 Founders Pavilion, University of Pennsylvania Medical Center, 3400 Spruce St., Philadelphia, PA 19104. E-mail kricka@mail.med.upenn.edu.

Received April 14, 2008; accepted April 23, 2008.

Previously published online at D01: 10.1373/clinchem.2008.108282

Commentary

Kenneth D. Burman

Discordant measurements of serum truodothyronine ([T.sub.4]), [1] thyroxine ([T.sub.3]), and thyroid-stimulating hormone (TSH) should always raise suspicions for unusual conditions. The clinical condition of the patient is especially relevant and should help guide further laboratory investigation. In the vast majority of instances, when a patient has authentic clinical hyperthyroidism hyperthyroidism: see thyroid gland.  with an increased [T.sub.4] or [T.sub.3], serum TSH should be low or undetectable (i.e., <0.01 mIU/L). Van Der Watt et al. nicely describe the possible causes of an increased serum free [T.sub.4] ([FT.sub.4]) with a normal [FT.sub.3] and TSH. I would like to emphasize several specific circumstances. A TSH-secreting pituitary tumor can mediate hyperthyroidism although serum TSH is low or normal (1). TSH bioactivity depends on proper glycosylation of the TSH molecule, and this may be altered in patients with a TSH-secreting pituitary tumor or a nonfunctional pituitary tumor (1). In these circumstances, measured TSH may be discordant from TSH bioactivity. TSH-secreting pituitary tumors may also disproportionately secrete a subunit of TSH compared with the entire TSH molecule (1).

If discordant [FT.sub.4], [FT.sub.3], or TSH values are obtained, it is appropriate to repeat the measurements in several different assays. Measurement of total [T.sub.4] and [T.sub.3] may also be helpful. The degree of laboratory abnormality suggests assay interference. In the case described by van der Watt et al., [FT.sub.4] was markedly increased in the context of normal [FT.sub.3] and TSH. The coexistence of another autoimmune disorder, subacute cutaneous cutaneous /cu·ta·ne·ous/ (ku-ta´ne-us) pertaining to the skin.

cu·ta·ne·ous
adj.
Of, relating to, or affecting the skin.


Cutaneous
Pertaining to the skin.
 lupus erythematosus (as well as Hashimoto's thyroiditis) also suggests there may be specific [T.sub.3] or [T.sub.4] antibodies formed. Finally, the performance of additional biologic testing such as a radioactive iodine uptake may be helpful.

In the case report of Kellogg et al., a young woman with attention deficit hyperactivity disorder (ADHD Attention-Deficit/Hyperactivity Disorder (ADHD) Definition

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by distractibility, hyperactivity, impulsive behaviors, and the inability to remain focused on tasks or
) had increased serum total [T.sub.4] and total [T.sub.3], with low normal TSH. [FT.sub.4] determined by direct dialysis and RIA were normal. They investigated the patient's serum sample and determined there was antibody interference, although the precise nature of the antibody could not be identified. Several issues should be further emphasized.

Discordant thyroid function tests can occur due to antibody interference as described. The occurrence of discordant thyroid function tests in a young woman with a history of ADHD does raise the possibility of thyroid hormone resistance Thyroid hormone resistance describes a rare syndrome where the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, or not completely suppressed as would be expected.  (2).

Thyroid hormone resistance (which is relevant to the patients in both the van der Watt et al. and Kellogg et al. case reports) usually occurs as a result of a molecular defect in the [T.sub.3] receptor that decreases the ability of the receptor to bind [T.sub.3], resulting in impaired [T.sub.3] action in the periphery as well as the pituitary level (3). These patients may be clinically euthyroid despite having increased [T.sub.4] and/or [T.sub.3] and detectable TSH (3). Family members may have similar findings, helping to confirm the diagnosis; clinically it is difficult to sequence the [T.sub.3] receptor, as the test is not readily available commercially.

Although the vast majority of cases of thyroid hormone resistance are due to nuclear [T.sub.3] perturbations, recently Friesema et al. (4) have described patients with altered membrane thyroid hormone transport proteins. They identified inactivating mutations of the monocarboxylate transporter 8 and associated severe clinical abnormalities of psychomotor retardation and discordant thyroid hormone concentrations.

Kellogg et al. also discuss the ability of heterophilic antibodies to interfere in thyroid hormone and TSH assays. These antibodies can interfere with total as well as free thyroid hormone measurements and are found most commonly in individuals with autoimmune disorders or who have worked with animals.

It has been thought that the quickest method to help determine whether there are interfering substances in a thyroid hormone assay is to dilute the sample and determine if the measured concentrations in the diluted sample are linear and parallel with those for a standard or another serum sample. Kellogg et al. point out that this technique may be insensitive and may not be applicable to all assays. More efficient and direct laboratory measures (e.g., addition of blocking immunoglobulins and alternate assay measurements) should be used when discordant results are obtained.

The case reports of van der Watt et al. and Kellogg et al. nicely emphasize the clinical importance of recognizing and evaluating circumstances that can result in discordant values of [T.sub.4], [T.sub.3], and TSH.

Grant/Funding Support: Supported by a thyroid cancer study, Pfizer Inc.

Financial Disclosures: None declared.

References

(1.) Beck-Peccoz P, Piscitelli G, Amr S, Ballabio M, Bassetti M, Giannattasio G, et al. Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin thyrotropin (thī'rätrō`pĭn) or thyroid-stimulating hormone (TSH), hormone released by the anterior pituitary gland that stimulates the thyroid gland to release thyroxine.  (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity. J Clin Endocrinol Metab 1986;62:704-11.

(2.) Weiss RE, Stein MA, Trommer B, Refetoff S. Attention-deficit hyperactivity disorder Attention-deficit hyperactivity disorder (ADHD)
A condition in which a person (usually a child) has an unusually high activity level and a short attention span. People with the disorder may act impulsively and may have learning and behavioral problems.
 and thyroid function. J Pediatr 1993;123:539-45.

(3.) Weiss RE, Refetoff S. Resistance to thyroid hormone. Rev Endocr Metab Disord 2000;1:97-108.

(4.) Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 2003;278:40128-35.

Kenneth D. Burman

Endocrine Section, Washington Hospital Center, and Department of Medicine, Georgetown University, Washington, DC.

Address correspondence to the author at: Section of Endocrine, Washington

Hospital Center, 110 Irving Street, NW, Room 2A-72, Washington, DC 200102975. Fax 202-877-6588; e-mail kenneth.d.burman@medstar.net.

Received April 29, 2008; accepted April 29, 2008.

Previously published online at DOI (Digital Object Identifier) A method of applying a persistent name to documents, publications and other resources on the Internet rather than using a URL, which can change over time. : 10.1373/clinchem.2008.108290

[1] Nonstandard abbreviations: [T.sub.4], truodothyronine; [T.sub.3], thyroxine; TSH, thyroidstimulating hormone.
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Title Annotation:Clinical Case Studies
Author:Kellogg, Mark D.; Law, Terence C.; Huang, Stephen; Rifai, Nader
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Jul 1, 2008
Words:4202
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