LETTER TO THE EDITOR

Lack of standardized description of TRAb assays

Karen Tan • Tze Ping Loh • Sunil Sethi

Received: 11 October 2012 / Accepted: 1 November 2012 / Published online: 20 November 2012

� Springer Science+Business Media New York 2012

Abstract Anti-thyroid stimulating hormone (TSH)

receptor antibodies (TRAb) exist as both stimulating and

blocking antibodies. The current TRAb assays widely

available to clinicians are receptor-binding assays. Bioas-

says that differentiate between stimulating and blocking

TRAb are technically challenging and expensive. The ter-

minology used to describe the different assays is confusing

and a potential source of misinterpretation of TRAb results.

In this article, we point out a typographical error in the

2011 American Thyroid Association and American Asso-

ciation of Clinical Endocrinologists’ Guidelines on

Hyperthyroidism where the term thyroid stimulating

immunoglobulin (TSI) instead of thyroid binding inhibition

immunoglobulin (TBII) was used in the description of

TRAb results, to highlight the need to harmonize the ter-

minology of TRAb assays to improve patient care.

Keywords Anti-TSH receptor antibody (TRAb) �Thyroid binding inhibitor immunoglobulin (TBII) �Thyroid stimulating immunoglobulin (TSI) � Thyroid

blocking immunoglobulin (TBI)

The terminology used to describe the different assays

measuring different forms of TRAb is confusing and a

potential source for misinterpretation of TRAb results.

In the 2011 American Thyroid Association (ATA) and

American Association of Clinical Endocrinologists’

(AACE) Guidelines on Hyperthyroidism and Other Causes

of Thyrotoxicosis published in Thyroid [1], the sentence on

the identified risk factors for Graves’ ophthalmopathy (GO)

‘‘…high serum pretreatment TRAb levels ([50 % TBII

inhibition or TSI [8.8 IU/L) (320)…’’ contains a typo-

graphical error. It should read ‘‘… high serum pretreatment

TRAb levels (TBII inhibition of [50 % or TRAb of

[8.8 IU/L) (320)…’’

In reference 320 [2], the authors wrote ‘‘… with TBII

values above 8.8 IU/L has a 18.4-fold higher risk of a

severe course of GO…’’ In this article, anti-TSH receptor

antibody (TRAb) was measured using a thyroid binding

inhibition immunoglobulin (TBII) assay based on the

human recombinant TSH receptor (TRAK human LIA;

B.R.A.H.M.S AG). In this assay, detection is based on the

ability of TRAb in the patient’s serum to prevent the

binding of labeled TSH to the TSH receptor. First, the

patient sample and standard samples with a known TRAb

concentration are incubated with the human TSH receptor.

After an initial wash, labeled bovine TSH is added. In a

second wash, unbound labeled TSH is removed and the

remaining bound TSH is measured. The level of the mea-

sured signal is inversely proportional to the quantity of

TRAb in the patient sample. The TRAb concentration in

the patients’ sample is calculated from a standard curve of

samples with a known TRAb concentration. The initial

output of the assay is the percentage competitive inhibition

of the TRAb on the labeled bovine TSH. A 50 % inhibition

in this assay roughly corresponds to 8.8 IU/L of TRAb.

TRAb is an autoantibody to the TSH receptor and is

further divided into stimulatory and inhibitory subtypes.

The TBII assay measures total TRAb concentrations and

does not distinguish between their functional subtypes.

TBII, in our opinion, is a poor term since the ‘‘inhibition’’

refers to the assay principle and not the functional status of

K. Tan (&) � T. P. Loh � S. Sethi

Department of Laboratory Medicine, National University Health

Systems, 5 Lower Kent Ridge Road National University

Hospital Main Building Level 3, Singapore 119074, Republic of

Singapore

e-mail: karen.tan@mohh.com.sg

123

Endocrine (2013) 43:732–733

DOI 10.1007/s12020-012-9834-5

TRAb. The origin of this term may stem from the historical

development of TRAb assays [3], and should best be

avoided. Although these assays have been calibrated to the

WHO reference standard 90/672, clinically significant

inter-method variability is still observed [4].

Thyroid stimulating immunoglobulin (TSI) or thyroid

stimulating antibody (TSAb) is the measure of the bioac-

tivity of the TRAb, as assessed by bioassays. This is per-

formed by incubating the patient’s serum with TSH

receptor expressing cell lines and measuring the cAMP

produced [5]. Results are expressed as specimen-to-refer-

ence ratio percentages (%SRR) [5]. Thyroid blocking

immunoglobulin (TBI) or thyroid blocking autoantibody

(TBAb) is the measure of the biological inhibitory effect of

the TRAb on TSH receptor. TBI is measured using bio-

assay, where a known amount of TSH is added and the

percentage inhibition of TSH bioactivity, compared to a

control without the patient’s serum, is quantified [5].

Currently, these bioassays are not harmonized and display

marked inter-method variability.

The current TRAb assays widely available to clinicians

are receptor binding assays. Bioassays that differentiate

between stimulating and blocking TRAb are more expen-

sive and technically challenging. TSI and TRAb measured

by receptor binding assays are not inter-changeable and it

is important for clinicians to clearly distinguish between

them. More efforts should be made to harmonize the ter-

minology of TRAb assays to improve patient care. We

propose that the term TBII be avoided in describing TRAb

assays and the term TRAb be used to describe the com-

monly used receptor binding assays. The term TSI may be

used to describe bioassays measuring thyroid stimulating

antibodies, and the term TBI to describe bioassays mea-

suring thyroid blocking antibodies.

Conflict of interest To the best of our knowledge, no conflict of

interest, financial or other, exists.

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