With Mirjana Barjaktarovic, MD, MSc
Researchers from Erasmus Medical Center in Rotterdam and at University Medical Center in Utrecht in the Netherlands discovered large variations in reported reference ranges for pediatric thyroid-stimulating hormone (TSH) and free T4 (FT4) both within and across age ranges,1 according to findings published in Thyroid.
“We found a minimal association between TSH and FT4 occurred in a population-based, prospective, pediatric cohort, suggesting that the hypothalamus-pituitary-thyroid axis may be unaffected by factors that interfere with thyroid function,” said Mirjana Barjaktarovic, MD, MSc, the lead author, who is a PhD candidate at the University Medical Center in Utrecht. Factors that correlated with differences in TSH and FT4 in this population were weight, sex, and ethnicity, while height and time at venipuncture only correlated with variability of TSH.1
“Our study provides an overview of all the available published studies on childhood TSH and FT4 reference ranges, which can help clinicians in assessing the generalizability of a reference range to his/her own clinical population,” Dr. Barjaktarovic told EndocrineWeb.
Pediatric hypothyroidism is correlated with decreased growth, postponed maturation of the skeleton, cognitive deficits, and delayed puberty, and pediatric hyperthyroidism is correlated with increased growth, advanced aging of the skeleton, mood disorders, and tachychardia.2, 3 Additionally, mild dysfunction of the thyroid in a child can result in impaired health outcomes, underscoring the importance of establishing satisfactory reference ranges for TSH and FT4.
Cutoff points for pediatric reference ranges of thyroid-stimulating hormone (TSH) and free T4 (FT4) reflect no consistent levels or endpoints.1 Additionally, any possible influencing factors for pediatric thyroid function are not well understood. Therefore, this study offered a first analysis of existing research on selection of reference ranges for thyroid function levels in children and assessed the factors affecting TSH and FT4 in a population-based, prospective, pediatric cohort.1
“Our results show substantial variation in thyroid function reference ranges across different age categories, different assays, and also between studies using a similar assay, indicating study methodological differences,” said Dr. Barjaktarovic,
“When trying to interpret lab levels, it is important to realize that considerable differences can occur based on these factors, and this might prompt clinicians to reconsider the origin of their own reference ranges,” she said.
The Netherlands researchers systematically searched Embase, Web of Science, Ovid Medline, Google Scholar, and the National Library of Medicine’s Pubmed databases to identify relevant studies on pediatric thyroid reference ranges. Published reference ranges for both TSH and FT4 varied across and within age ranges. Endpoints for low TSH ranged from 0.13 to more than 1 mU/L, and cutoffs for high TSH ranged from 2.36 to more than 10 mU/L. Low FT4 ranged from 7.0 to over 10 pmol/L, and high FT4 ranged from 15.5 to over 30 pmol/L.
This study examined a non-selected sample of 4,273 children from a cohort. Median age was 6.0 years (range: 4.9-9.1).1 The researchers assessed age, sex, anthropomorphic characteristics (e.g. height), maternal education, ethnicity, time and season at venipuncture for potential associations with levels of TSH and FT4. The study was embedded within the Generation R Study, which is a population-based prospective cohort spanning from early fetal life onward, in Rotterdam.
Weight, sex, and ethnicity correlated with TSH (P ≤.03) and with FT4 (P ≤0.01), while height and time at venipuncture only correlated with TSH (P <0.0001).
Dr. Barjaktarovic and colleagues also assessed the extent to which between-individual variation in the factors affecting TSH and FT4 could impact the calculation of reference ranges.1 The lower limit of between-individual variation for factors affecting TSH ranged from 0.64 to 0.96 mU/L (total population 0.87 mU/L), and the range for the upper limit was 4.30 to 5.62 mU/L (total population 5.20 mU/L). For FT4, the lower limit ranged from 13.6 to 14.2 pmol/L (total population 13.8 pmol/L), and the upper limit ranged from 20.2 to 23.0 pmol/L (total population 20.8 pmol/L).1
Need for Consistent Thyroid Ranges in Children to Improve Treatment
At present, there is no consensus on the definition of abnormal thyroid function levels or of reference ranges in the pediatric population. This lack of uniformity in reporting research may impact the ability of clinicians to ascertain whether a child has subtle thyroid disease with hormone levels near various cutoff ranges, or simply does not receive an accurate diagnosis,1 according to the authors.
“Although the diagnosis of thyroid disorders may not be problematic in cases of overt disease, our results may prove especially useful in cases of subclinical disorders,” said Dr. Barjaktarovic told Practical Pain Management.
Results from both the literature review and from an assessment of factors affecting between-individual variation emphasize the critical need for defining and understanding reference ranges for pediatric thyroid function, said Dr. Barjaktarovic. Evidence-based recommendations defining abnormal pediatric thyroid function are needed, particularly to address the wide variability in current research.
“Our literature overview is limited by the lack of consistency across studies, which makes it practically impossible to combine all published study results. A potential limitation of our study is that our study population comprised a relatively narrow age range (95% range 5.7-8.0 years), which makes the extrapolation of our results to other age categories not possible,” Dr. Barjaktarovic said.
This research was supported by ZonMW, which is the Netherlands Organization for Health Research and Development, and by a fellowship from ERAWEB, a program offered by six Western Balkan universities and five universities in the E.U. to foster inter-university collaborations and research.
The authors stated no competing interests.
1. Onsesveren I, Barjaktarovic M, Chaker L, de Rijke YB, et al. Childhood Thyroid Function Reference Ranges and Determinants: a Literature Overview and a Prospective Cohort Study. Thyroid. 2017 Sep 23.
2. Hanley P, Lord K, Bauer AJ. Thyroid Disorders in Children and Adolescents: A Review. JAMA Pediatr. 2016.
3. Brown RS. Disorders of the Thyroid Gland in Infancy, Childhood and Adolescence. 2000.
4. Lazarus J, Brown RS, Daumerie C, Hubalewska‐Dydejczyk A, Negro R, Vaidya B. European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 3:76‐94. 2014.