Clinical evidence-based cutoff limits for GH stimulation tests in children with a backup of results with reference to mass spectrometry

Abstract

Context: Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations. Objective: We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method. Design and setting: In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD. Patients: We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation. Results: Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 mg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 mg/l. For ID-MS, cutoffs of 5.48 mg/l (22k GH) and 7.43 mg/l (total GH) were ascertained. Conclusion: The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future.

Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD

“…Recently, Wagner et al (35), re-evaluated the cut-off value in diagnosis of GHD, using ROC analysis and Youden index, in 44 GHD children and 52 controls tested with arginine, ITT and glucagon. They identified 7.09 µg/L as the cut-off point where the rate of correct classification was at its maximum.…”

Pitfalls of Insulin-like Growth Factor-I and Growth Hormone Assays

“…Total GH as well as the different GH isoforms exhibit a remarkable preanalytical stability. 5 Furthermore, a recent study demonstrated that 22 kD GH concentrations as measured by an immunoassay did not change over a period of more than 10 years when samples were stored at À80 C. 6 Traditionally, the preferred matrix to measure GH is serum, but most of the currently available assays can also be used with plasma samples. Even though GH sample handling is easy, there are plenty of other factors that make measuring GH and interpreting measured GH concentrations a challenge.…”

Performance criteria for reference measurement procedures and reference materials

“…It was also shown that a mass spectrometry based candidate RMP targeting peptides originating from digested hGH did not correlate well on clinical samples with the end user measurement procedures. Further investigations on peptides from tryptic digest confirmed the lacking correlation of this candidate RMP and end user measurement procedures [14]. The relative residuals of the correlation plots could reach 30% and more depending on the individual sample and the concentration range.…”