ESPE2021 ePoster Category 2 Thyroid (46 abstracts)
Kinetics of FT4 serum concentrations in newborns and infants with congenital hypothyroidism during follow-up differ in the three severity groups
Britta Steffens 1 , Pascal Gächter 1 , Gilbert Koch 1 , Dagmar l'Allemand 2 , Marco Janner 3 , Daniel Konrad 4,4 , Tatjana Welzel 1 , Marc Pfister 1,6 & Gabor Szinnai 6,7
1Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, Switzerland; 2Pediatric Endocrinology and Diabetology, Children’s Hospital of Eastern Switzerland, St. Gallen, Switzerland; 3Pediatric Endocrinology, Diabetology and Metabolism, University Hospital Bern, University of Bern, Bern, Switzerland; 4Pediatric Endocrinology and Diabetology, University Children's Hospital Zürich, University of Zürich, Zürich, Switzerland; 5Children’s Research Center, University Children's Hospital Zürich, University of Zürich, Zürich, Switzerland; 6Department of Clinical Research, University of Basel, Basel, Switzerland; 7Pediatric Endocrinology and Diabetology, University Children’s Hospital Basel, University of Basel, Basel, Switzerland
Background: The goal of congenital hypothyroidism (CH) treatment is rapid normalization and maintenance of TSH and FT4 in the reference range. Recommended starting dose of levothyroxine (LT4) ranges from 10-15 mg/kg/d. Hyperthyroxinemia can be accepted in the context of normal TSH and LT4 should only be reduced in case of symptoms or repeatedly increased FT4. The aim of this study was to quantify duration and maximum peak of FT4 levels outside the reference range for each CH severity group.
Methods: Retrospective longitudinal multi-center study. For specifying periods of hyperthyroxinemia in each CH severity group, pharmacometric simulation of FT4 kinetics based on a recently developed mathematical pharmacokinetics (PK) model characterizing FT4 dynamics in infants with CH was performed. CH severity groups were based on FT4 at diagnosis (severe <5 nmol/l, moderate 5-10 nmol/l, mild >10 nmol/l). Data are median [IQR].
Results: Longitudinal data of 56 CH-patients (71% females, GA 40.9 weeks [38.6,41.4]) diagnosed at postnatal day 7 [6,9] with 236 FT4 and 232 TSH measurements were included. A normalization method was used to merge FT4 values since different assay- and age-specific reference ranges were used. Median starting doses for each severity group were lower than recommended by 2021 guidelines. Quantification of FT4 kinetics during follow-up by pharmacometric simulation of an average patient showed peak FT4 levels above target range at day 24, 24, and 27 for severe, moderate and mild CH, respectively. Time above age-specific FT4 target range for an average patient of the severity group was significantly shorter for severe vs. moderate (P 0.02) or mild CH (P 0.02) despite comparable number of consultations in the first 6 months (severe 4 [3,5], moderate 3.5 [2.5,4.5], mild CH 4 [2.5,5.5]) and no differences between severe and moderate CH in TSH at diagnosis nor starting dose.
| severe CH | moderate CH | mild CH | |
| Patients | 25 | 16 | 15 |
| LT4 starting dose (mcg/kg/d) | 10 [7.51,14.2] | 8.91 [7.15,13.12] | 7.06 [3.88,8.6] |
| Peak fold over FT4 reference range | 1.45 [1.3,1.75] | 1.55 [1.31,1.93] | 1.39 [0.98,1.54] |
| Days above FT4 reference range | 63 [47,89] | 135 [59.5,158.5] | 134 [82,152] |
Conclusions: While fold of peak FT4 levels above target range were similar for all three severity groups, moderate and mild CH patients were significantly longer hyperthyroxinemic. From a pharmacological point of view, severity-based dosing during follow-up might be helpful to reduce duration of FT4 levels above reference range. Prospective data are necessary to confirm these preliminary findings.
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