Low FT4 Concentrations around the Start of Recombinant Human Growth Hormone Treatment: Predictor of Congenital Structural Hypothalamic-Pituitary Abnormalities?

Iersel, Laura van; Santen, Hanneke M van; Zandwijken, Gladys R J; Zwaveling-Soonawala, Nitash; Hokken-Koelega, Anita; Trotsenburg, A S Paul van

doi:10.1159/000486033

Cited by 19 publications

(21 citation statements)

References 24 publications

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“…This development implies either a genetically determined vulnerability or masked insufficiency of pituitary or hypothalamic cells or an acquired damage of the hypothalamic-pituitary axis with progressive dysfunction. Treatment with recombinant human GH (rhGH) may unmask TSH deficiency in some patients with GHD [ 2 ]. Additional pituitary deficits also arise over time in monogenic hypopituitarism caused by mutations in PROP1 , POU1F1 , HESX1 , and other developmental genes [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts’ consensus

et al. 2020

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Isolated growth hormone deficiency (GHD) is defined by growth failure in combination with retarded bone age, low serum insulin-like growth factor-1, and insufficient GH peaks in two independent GH stimulation tests. Congenital GHD can present at any age and can be associated with significant malformations of the pituitary-hypothalamic region or the midline of the brain. In rare instances, genetic analysis reveals germline mutations of transcription factors involved in embryogenesis of the pituitary gland and the hypothalamus. Acquired GHD is caused by radiation, inflammation, or tumor growth. In contrast to organic GHD, idiopathic forms are more frequent and remain unexplained. There is a risk of progression from isolated GHD to combined pituitary hormone deficiency (> 5% for the total group), which is clearly increased in children with organic GHD, especially with significant malformation of the pituitary gland. Therefore, it is prudent to exclude additional pituitary hormone deficiencies in the follow-up of children with isolated GHD by clinical and radiological observations and endocrine baseline tests. In contrast to primary disorders of endocrine glands, secondary deficiency is frequently milder in its clinical manifestation. The pituitary hormone deficiencies can develop over time from mild insufficiency to severe deficiency. This review summarizes the current knowledge on diagnostics and therapy of additional pituitary hormone deficits occurring during rhGH treatment in children initially diagnosed with isolated GHD. Although risk factors are known, there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency. Lifelong monitoring of the endocrine function of the pituitary gland is recommended in humans with organic GHD. This paper is the essence of a workshop of pediatric endocrinologists who screened the literature for evidence with respect to evolving pituitary deficits in initially isolated GHD, their diagnosis and treatment.

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Section: Introductionmentioning

confidence: 99%

“…Thyroid-stimulating hormone (TSH) deficiency is the most frequent secondary pituitary hormone deficiency in children initially diagnosed with GHD, with a reported prevalence of 6.3% during the first 2 years of treatment [ 2 ]. The clinical characteristics of TSH deficiency are milder than in primary hypothyroidism.…”

Section: Introductionmentioning

confidence: 99%

Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts’ consensus

et al. 2020

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“…With the current study, we visualized the FP that was referred due to a T4/TBG ratio ≤17 (n = 1,196 Although the large number of false-positive referrals (low specificity) forms the major drawback of the current NBS algorithm to detect also CH-C patients, it should be noted that between 1995 and 2015 per year on average 0.8 patients with CH-C were missed by NBS (unpublished data from a national voluntary registration for pediatric disorders). In addition, in a recent study, we showed that this number may be even higher (2-3 missed CH-C patients per year) [11]. Hence, the sensitivity of the Dutch screening algorithm to detect CH-C patients is not 100%.…”

Section: Discussionmentioning

confidence: 80%

Improving the Dutch Newborn Screening for Central Congenital Hypothyroidism by Using 95% Reference Intervals for Thyroxine-Binding Globulin

et al. 2021

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Introduction: Newborn screening (NBS) for congenital hypothyroidism (CH) in the Netherlands consists of thyroxine (T4), thyroid-stimulating hormone (TSH), and T4-binding globulin (TBG) measurements to detect thyroidal CH and central CH (CH-C). CH-C is detected by T4 or a calculated T4/TBG ratio, which serves as an indirect measure of free T4. TSH and TBG are only measured in the lowest 20 and 5% of daily T4 values, respectively. A recent evaluation of the Dutch NBS for CH showed that the T4 and T4/TBG ratio contribute to the detection of CH-C but also lead to a low positive predictive value (PPV). Dried blood spot (DBS) reference intervals (RIs) are currently unknown and may contribute to improvement of our NBS algorithm. Materials and Methods: RIs of T4, TSH, TBG, and the T4/TBG ratio were determined according to Clinical & Laboratory Standards Institute guidelines in heel puncture cards from routine NBS in both sexes and at the common NBS sampling ages. Scatter plots were used to compare the healthy reference population to previously published data of CH-C patients and false positives. Results: Analyses of 1,670 heel puncture cards showed small differences between subgroups and led to the formulation of total sample DBS RIs for T4 (56–118 nmol/L), TSH (<2.6 mIU/L), TBG (116–271 nmol/L), and the T4/TBG ratio (>20). 46% of false-positive referrals based on T4 alone had a TBG below the RI, indicating preventable referral due to partial TBG deficiency. One case of CH-C also had partial TBG deficiency (TBG 59 and T4 12 nmol/L blood). Discussion/Conclusion: Established DBS RIs provided possibilities to improve the PPV of the Dutch CH NBS algorithm. We conclude that by taking partial TBG deficiency into account, approximately half of T4 false-positive referrals may be prevented while maintaining NBS sensitivity at the current level.

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“…The actual false-negative count is likely to be higher, as also CH-C, central congenital hypothyroidism; CH-T, thyroidal congenital hypothyroidism; ELISA, enzyme-linked immuno sorbent assay; PPV, positive predictive value; RIA, radio-immunoassay; T4, total thyroxine; TBG, thyroxine-binding globulin. suggested in a study showing the occurrence of (probable) CH-C after initiation of growth hormone treatment in children with congenital growth hormone deficiency (15). Our unique stepwise T4-TSH-TBG NBS algorithm resulted in a PPV of 21.0%.…”

Section: Discussionmentioning

confidence: 82%

Critical evaluation of the newborn screening for congenital hypothyroidism in the Netherlands

Stroek

Heijboer

Bouva

et al. 2020

European Journal of Endocrinology

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Objective: Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pituitary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤17 in a second heel puncture is suggestive of CH-C. Design and methods: In the present study, we evaluated eleven years of Dutch CH NBS using a database of referred cases by assessing the contribution of each criterion in the unique stepwise T4-TSH-TBG NBS algorithm. Results: Between 2007 and the end of 2017, 1,963,465 newborns were screened in the Netherlands. Use of the stepwise algorithm led to 3,044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. 62.8% of CH-C cases were detected by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T4-TSH-TBG NBS algorithm was 21.0%. Conclusion: This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS algorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the Netherlands, at the cost of a lower PPV compared to TSH-based NBS strategies.

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Low FT4 Concentrations around the Start of Recombinant Human Growth Hormone Treatment: Predictor of Congenital Structural Hypothalamic-Pituitary Abnormalities?

Cited by 19 publications

References 24 publications

Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts’ consensus

Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts’ consensus

Improving the Dutch Newborn Screening for Central Congenital Hypothyroidism by Using 95% Reference Intervals for Thyroxine-Binding Globulin

Critical evaluation of the newborn screening for congenital hypothyroidism in the Netherlands

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