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CASE REPORT
Year : 2020  |  Volume : 17  |  Issue : 3  |  Page : 152-154

Multiple myeloma masquerading as T3 toxicosis


Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Submission18-Jun-2020
Date of Acceptance20-Oct-2020
Date of Web Publication20-Jan-2021

Correspondence Address:
Dr. S Chitra
Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_46_20

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  Abstract 


We report a case of a 52-year-old man who was referred by his primary care physician to rule out thyroid illness. His thyroid function tests (TFTs) revealed isolated elevation of total T3 (TT3) with normal total T4 (TT4), free T3 (FT3), free T4 (FT4), and unsuppressed thyroid stimulating hormone (TSH) raising the suspicion of antibody interference or abnormal thyroid hormone-binding proteins. To identify antibody interference, we repeated the immunoassay using varied platforms and assay methods. The total T3 levels which were high in one-step immunoassay normalized in two-step immunoassay. On further evaluation, the patient was diagnosed with multiple myeloma and the antibody interference was secondary to IgG monoclonal antibody binding specifically to analog T3 leading to spurious results. Ours is the first report from India and the fourth case in literature to report a multiple myeloma antibody interfering with TFTs.

Keywords: Antibody interference, familial dysalbuminemic hypertriiodothyroninemia - T3, multiple myeloma, one-step immunoassay, T3 toxicosis, thyroid function test, two-step immunoassay


How to cite this article:
Veechika P, Chitra S. Multiple myeloma masquerading as T3 toxicosis. Thyroid Res Pract 2020;17:152-4

How to cite this URL:
Veechika P, Chitra S. Multiple myeloma masquerading as T3 toxicosis. Thyroid Res Pract [serial online] 2020 [cited 2021 Mar 5];17:152-4. Available from: https://www.thetrp.net/text.asp?2020/17/3/152/307557




  Introduction Top


Highly sensitive immunoassays are the most commonly employed tests for the biochemical diagnosis of thyroid disorders. Two types of immunoassays are used in thyroid function tests (TFTs), competitive assays for smaller analytes (TT4, TT3, FT4, and FT3), and non-competitive or sandwich assays for larger analytes (TSH).[1] Although the sensitivity is high, the specificity is affected by various assay antibody interferences[2] leading to false-positive test results and unnecessary treatment. Rarely, these interferences may be due to sinister causes such as multiple myeloma.


  Case Report Top


A 52-year-old male was referred from his primary care physician with an abnormal TFT report with presenting complaints of weight loss, sweating, generalized fatigue, and breathlessness on exertion. There were no other symptoms. The patient owns a stationary shop and there was no personal or family history of any autoimmune disorder, exposure to pets, or use of prescription or over-the-counter medication.

On physical examination, the patient had pallor and tachycardia. There were no other signs of thyrotoxicosis, ophthalmopathy, or goiter. The systemic examination was normal. Investigations by his primary care physician revealed a TSH: 4.06 uIU/mL (reference range: 0.45–4.9), TT4: 5.42 ug/dL (4.5–12.5, one-step immunoassay), TT3: >456 ng/dL (62–154, one-step immunoassay), FT3: 2.93 pg/mL (2.7–5.2, two-step immunoassay), and FT4: 1.01 ng/dL (0.8–1.8, two-step immunoassay). This profile was suggestive of two conditions, immunoassay antibody interference or euthyroid hypertriiodothyroninemia secondary to familial dysalbuminemic hypertriiodothyroninemia – T3[3] (FDH-T3).

Since immunoassay antibody interference is more common than FDH-T3, we proceeded to investigate antibody interference by repeating the tests on different platforms and assay methods. The Abbott architect two-step immunoassay revealed a TT4: 3.82 ug/dL (4.87–11.5), TT3: 41.91 ng/dL (64–152), FT4: 0.76ng/dL (0.8–1.8), FT3:1.68pg/mL (2.8–5.42), and TSH: 1.28 uIU/mL (0.45–4.9). With two-step immunoassay, we found low levels of both total and free hormones. We repeated the test on yet another platform, the Beckman Access one-step assay for total hormones and two-step assay for free hormones. The one-step assay on a different platform again showed an elevated TT3 but low TT4 [Table 1]. In FDH-T3, TT3 levels would remain higher even on a two-step assay which confirms the presence of an interfering antibody specific to T3.
Table 1: Thyroid function tests performed on different platforms and assay methods

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Further investigation for a significant weight loss revealed Hb: 8.3 g/dL, ESR: 120 mm at 2 h, serum albumin: 2.9 g/dL, serum globulin: 10.3g/dL, and an albumin globulin ratio of 0.2 which raised suspicion of a paraproteinemia. His serum protein electrophoresis showed IgG kappa monoclonal gammopathy. A bone marrow biopsy confirmed the diagnosis of multiple myeloma.


  Discussion Top


The prevalence of interferences with thyroid function immunoassays has been reported to be about 1%.[4] The main types of interferences include macro-TSH, biotin, anti-streptavidin antibodies, anti-ruthenium (-Ru) antibodies, TH autoantibodies (THAAbs), and heterophilic antibodies.[4] Other conditions which present with abnormal TFTs include physiological states like pregnancy, inter-current illness (nonthyroidal illness [NTI]), acute psychosis and drug therapy (e.g., amiodarone, iodine, dopamine, glucocorticoids, lithium, estrogens [increases thyroid binding globulin levels], androgens [decreases TBG], tyrosine kinase inhibitors, immunomodulators, somatostatin analogs, retinoids, biotin, and heparin).[5] The rare causes include inherited abnormal thyroid hormone-binding proteins (FDH-T4 and FDH-T3), abnormal TH transport (MCT8 mutations), metabolism (functional deiodinase deficiency), action (resistance to thyroid hormone), and TSH-secreting pituitary adenomas.[5]

Methods to investigate immunoassay antibody interference include repeat analysis with different methods (single- vs. double-antibody procedure, one- vs. two-step assay, and analog vs. nonanalog tracer), demonstration of nonlinear response to sample dilution or iodothyronine binding to the patient's IgG by electrophoresis, polyethylene glycol precipitation, block heterophile antibody with nonimmune serum or using blocking tubes, and suppression of patient antibodies with immunosuppressive therapy.[6]

In this case, we identified interference by repeating the test using one-step and two-step immunoassay methods. The TT3 levels were spuriously elevated on one-step immunoassay. The access (Beckman coulter) TT3 assay is a competitive one-step immunoassay, in which the patient serum, T3 analog, and anti-T3 alkaline phosphatase conjugate all react in one step. T3 in the sample competes with the T3 analog coupled to biotin for anti-T3 alkaline phosphatase conjugate. The T3 analogue: antibody complexes are bound to streptavidin coated solid phase while the sample T3: antibody complex is unbound. Thus, washing removes only the unbound sample T3: antibody complexes. Then, the chemiluminescent substrate Lumi-Phos* 530 (an alkaline phosphatase substrate) is added to the vessel and light generated by the reaction is measured. The light production is inversely proportional to the concentration of TT3 in the sample.[7]

In our patient, IgG monoclonal antibody present in high concentration was binding specifically to analog T3 preventing its binding to anti-T3 alkaline phosphatase, allowing T3 in the sample to bind to anti-T3 alkaline phosphatase noncompetitively. After the wash step, all of the sample T3: anti-T3 alkaline phosphatase not bound to the solid phase was eliminated leaving behind only analog T3: IgG monoclonal antibody complexes. On adding the Lumi-Phos* 530, because there is no alkaline phosphatase for the reaction to occur, no light is produced leading to spuriously high levels of TT3.

In a two-step immunoassay, the sample thyroid hormone is extracted from serum by antibody-coated tubes, and the extraction is followed by a wash step which removes any interfering antibodies.[2] The T3 analog is then added which binds to the unbound sites on the capture antibody giving reliable estimates of the serum hormone.

The low levels of thyroid hormones (TT4, TT3, FT4, and FT3) on two-step immunoassay with unsuppressed TSH levels in our case are suggestive of NTI[8] which has been reported in multiple myeloma.

Cissewski et al.[9] first described a case of factitious hyperthyroxinemia in multiple myeloma where IgA monoclonal antibody was bound to T4 and T3 producing an apparent euthyroid hyperthyroxinemia. Antonopoulou and Silverberg[10] and Ram et al.[11] described IgA and IgG monoclonal antibodies, respectively, causing elevated levels of only T3.


  Conclusion Top


When thyroid function tests are not concordant with clinical scenario, always suspect antibody interference in the assay. Such antibody interferences are mostly benign, very rarely it could be multiple myeloma. Repeating the test on different platforms and assay methods as an initial step will aid in the diagnosis.

Acknowledgement

We thank Dr. Ashwin Kumar A S, MD Biochemistry for his support.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ceccarini G, Santini F, Vitti P. Tests of Thyroid Function. In: Vitti P, Hegedus L, editors. Thyroid Diseases. Endocrinology. Cham: Springer; 2017.  Back to cited text no. 1
    
2.
Després N, Grant AM. Antibody interference in thyroid assays: A potential for clinical misinformation Clin Chem 1998;44:440-54.  Back to cited text no. 2
    
3.
Sunthornthepvarakul T, Likitmaskul S, Ngowngarmratana S, Angsusingha K, Kitvitayasak S, Scherberg NH, et al. Familial dysalbuminemic hypertriiodothyroninemia: a new, dominantly inherited albumin defect. J Clin Endocrinol Metab 1998;83:1448-54.  Back to cited text no. 3
    
4.
Favresse J, Burlacu MC, Maiter D, Gruson D. Interferences with thyroid function immunoassays: Clinical implications and detection algorithm. Endocr Rev 2018;39:830-50.  Back to cited text no. 4
    
5.
Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 2013;27:745-62.  Back to cited text no. 5
    
6.
Srichomkwun P, Scherberg NH, Jakšić J, Refetoff S. Diagnostic dilemma in discordant thyroid function tests due to thyroid hormone autoantibodies. AACE Clin Case Rep 2017;3:e22-5.  Back to cited text no. 6
    
7.
2009-2010 NHAHES Lab Method: Total Triiodothyronine, Total T3. Available from: https://www.cdc.gov/NCHS/.data/nhanes/nhanes_09_10/THROD_F_met_TT3_CLS.pdf. [Last accessed on 2020 Sep 23].  Back to cited text no. 7
    
8.
Hrycek A, Gruszka A. Thyroid hormone and insulin-like growth factor-I in patients with multiple myeloma treated with melphalan and prednisone. Arch Med Res 2006;37:74-8.  Back to cited text no. 8
    
9.
Cissewski K, Faix JD, Reinwein D, Moses AC. Factitious hyperthyroxinemia due to a monoclonal IgA in a case of multiple myeloma. Clin Chem 1993;39:1739-42.  Back to cited text no. 9
    
10.
Antonopoulou M, Silverberg A. Spurious T3 thyrotoxicosis unmasking multiple myeloma. Case Rep Endocrinol 2013;2013:739302.  Back to cited text no. 10
    
11.
Ram N, Furqan S, Ahmed S. Is it T3 thyrotoxicosis? A case of falsely elevated tri-iodothyronine (T3) levels leading to a diagnosis of multiple myeloma. Case Rep Endocrinol 2019;2019:5028534.  Back to cited text no. 11
    



 
 
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