Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Division of EndocrinologyUNIFESP, EPM, Division of EndocrinologySciEL

Vieira, José Gilberto Henriques

Arquivos Brasileiros de Endocrinologia & Metabologia

José Gilberto Henriques Vieira

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Defining reference values for TSH: nearing perfection in a imperfect world

Vieira, José Gilberto Henriques [UNIFESP]

Repositório Institucional UNIFESP

Copyright© ABE&M todos os direitos reservados.589Arq Bras Endocrinol Metab. 2010;54/7editorialDefining reference values for TSH: nearing perfection in a imperfect worldDefinição de valores de referência para TSH: chegando à perfeição num mundo imperfeitoJosé Gilberto Henriques Vieira1The use of diagnostic laboratory tests usually includes a comparison of the result obtained in a given patient to a reference range. The definition of this reference or “normal” range is a priori simple: one has to measure the analyte in a “normal” population using a reference method, and there you are! Unfortunately life is not that easy. Routine methods frequently provide results that are not exactly comparable to the reference methods and, worst of nightmares, we don’t really know what a “nor-mal” population is.Let’s take the example of TSH measurement. Thyroid Stimulating Hormone (TSH) is a complex glycoprotein that contains two different subunits (alpha and beta) that organize as a heterodimeric complex. Being a glycosylated protein, the amount of sugar can vary substantially with implications on the antibody recognition as well as on the biological action. As a consequence, several forms are found in circulation. The seminal work of Utiger (1) describing the first practical TSH radioimmunoassay, introduced the possibility of routine measurement of TSH and its use as a diagnostic tool for the diagnosis of thyroid diseases. Since that time (1965) measuring TSH has become an extremely useful tool in the study of thyroid diseases. The first radioimmu-noassay methods for the measurement of TSH had limitations in sensitivity, and at that time TRH stimulation tests were used to define hyperthyroidism and borderline cases of hypothyroidism (2). With methodological evolution provided by the availability of monoclonal antibodies and the introduction of the non-competitive immunometric design, sensitivity no longer poses a problem (3). Automatic, extremely sensitive and reproducible methods are provided by all the major diagnostic companies, and are widely available for clinical use. Assay specificity and comparability is a pending issue, but efforts in standardization and harmonization of the most used assays are strongly being pursued (4).Thyroid diseases are quite common and sometimes oligo or asymptomatic. As a consequence TSH measurement became one of the most requested laboratory tests. The fact that the TSH results do not follow a Gaussian distribution poses an extra challenge, mainly in the definition of the upper limit of the normal range. Additionally, TSH levels in the normal population present a higher inter than intra individual varia-tion, in other words, one should interpret a given TSH value bearing in mind that each person has his own range of variation of thyroid hormone levels, a phenomenon very well described by the Danish group of Andersen and cols. (5). Genetic reasons may be behind this characteristic (6).1 Associate professor, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo (Unifesp/EPM); medical advisor, Grupo Fleury, São Paulo, SP, BrazilCorrespondência para:José Gilberto Henriques VieiraAv. General Valdomiro de Lima, 50804344-903 − São Paulo, SP, Braziljose.vieira@fleury.com.brCopyright© ABE&M todos os direitos reservados.590 Arq Bras Endocrinol Metab. 2010;54/7In an effort to define a reliable normal range for TSH, the National Academy of Clinical Biochemistry (NACB, Washington, DC, USA) proposed very com-plex selection criteria, including absence of family his-tory, negativity for thyroid antibodies and no visible or palpable goiter (7). The inclusion of a normal ultraso-nographic examination of the cervical region was later proposed by a German group and the result was that from a blood donor population (adult and otherwise healthy), only 52% were considered for the definition of normal range of TSH (8).In this ABE&M issue, Rosario and cols. (9) publish a carefully designed paper defining the TSH normal values found in an adult Brazilian population. They used the same NACB criteria, without cervical ultraso-nographic examination. From an initial population of 1,611 volunteers, 40% were excluded for not fulfilling the inclusion criteria, and the TSH assay used in the study is one of the most employed in our country. In the final adult population studied (n = 960) the 2.5th and the 97.5th percentiles were 0.43 and 3.24 mUI/L, respectively. The stringency of the selection criteria can be evaluated by the observation that the minimum and maximum values were 0.35 and 4.8 mUI/L, respecti-vely. These values are in concordance with most of the similar studies performed in different populations (8).To have solid information about reference ranges is, by any perspective, extremely important. The availa-bility of robust, sensitive and harmonized methods, as is the case nowadays for TSH, should prompt a more confident use of the assay results. However, one word of caution should be introduced with this new condi-tion: to classify a patient as outside a normal range can have important implications. The diagnosis and treat-ment of subclinical thyroid dysfunction, in special pa-tients with slightly high TSH levels, is a still debatable issue (10). To have better laboratory methods, and to define strict normal ranges, amplifies our diagnostic ar-mamentarium as well as our responsibility of properly using the information.RefeRences1.	 Utiger	 RD.	 Radioimmunoassay	 of	 human	 plasma	 thyrotropin.	JCI.	1965;	44:1277-86.2.	 Maciel	RMB,	Vieira	JGH,	Russo	EMK,	Kater	CE,	Juliano-Neto	L,	Chacra	AR.	Secreção	de	 tirotrofina	 (TSH),	 triiodotironina	 (T3)	e	prolactina	após	a	administração	de	hormônio	liberador	de	tiro-trofina	(TRH)	obtido	por	síntese	em	fase	sólida.	Rev	Ass	Med	Bra-sil.	1979;25:135-40.3.	 Vieira	 JGH,	 Kunii	 IS,	 Nishida	 SK,	 Matsumura	 LK,	 Russo	 EMK,	Maciel	 RMB.	 Desenvolvimento	 e	 aplicação	 de	 um	 método	imunofluo	rométrico	 para	 a	 dosagem	 de	 tirotrofina	 humana	(TSH)	no	soro	e	em	sangue	total	colhido	em	papel	de	filtro.	Arq	Bras	Endocrinol	Metab.	1992;36:7-12.4.	 Thienpont	LM,	Van	Uytfanghe	K,	Beastall	G,	Faix	JD,	Ieiri	T,	Miller	WG,	et	al.	Report	of	the	IFCC	Working	Group	for	Standardization	of	Thyroid	 Function	Tests;	 part	 1:	 thyroid-stimulating	 hormone.	Clin	Chem.	2010;	56:902-11.5.	 Andersen	S,	Pedersen	KM,	Bruun	NH,	Laurberg	P.	Narrow	indivi-dual	variations	in	serum	T4	and	T3	in	normal	subjects:	a	clue	to	the	understanding	of	subclinical	thyroid	disease.	J	Clin	Endocri-nol	Metab.	2002;87:1068-72.6.	 Peters	RP,	van	Toor	H,	Klootwijk	W,	de	Rijke	YB,	Kuiper	GGJM,	Uit-terlinden	AG,	et	al.	Polymorphisms	in	thyroid	hormone	pathway	gene	are	associated	with	plasma	TSH	and	iodothyronine	levels	in	healthy	subjects.	J	Clin	Endocrinol	Metab.	2003;88:2880-8.7.	 Baloch	Z,	Carayon	P,	Conte-Devolx	B,	Demers	LM,	Felt-Rasmus-sen	U,	Henry	J-F,	et	al.	Laboratory	Medicine	Guidelines.	Labora-tory	support	for	the	diagnosis	and	monitoring	of	thyroid	disease.	Thyroid.	2003;13:3-126.8.	 Kratzsch	 J,	 Fiedler	 GM,	 Leichtle	 A,	 Brügel	 M,	 Buchbinder	 S,	Otto	L,	et	al.	New	reference	intervals	for	thyrotropin	and	thyroid	hormones	based	on	National	Academy	of	Clinical	Biochemistry	criteria	and	 regular	ultrasonography	of	 the	 thyroid.	Clin	Chem.	2005;51:1480-6.9.	 Rosario	 PW,	 Xavier	 ACM,	 Calsolari	 MR.	TSH	 reference	 values	for	 adult	 Brazilian	 population.	 Arq	 Bras	 Endocrinol	 Metab.	2010;54:603-6.10.	 Biondi	 B,	 Cooper	 DS.	 The	 clinical	 significance	 of	 subclinical	thyroid	dysfunction.	Endocrine	Reviews	2008;29:76-131.Defining reference values for TSH

Definição de valores de referência para TSH: chegando à perfeição num mundo imperfeito

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Definição de valores de referência para TSH: chegando à perfeição num mundo imperfeito

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