Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most of children diagnosed with isolated GHD presents with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

Analgesic activity of Phong Thap Dan tablets in animal models

Phong thap dan tablets are intended to treat low back pain. This study was carried out to evaluate theanalgesic effects of Phong thap dan tablets in experimental animals. The analgesic effects were evaluated inthree animal models: hot plate, mechanical stimulation and acetic acid-induced writhing test. Mice were dividedinto 4 groups given oral water, control drug (codein phosphate in hot plate and mechanical stimulation tests oraspirin in writhing test), Phong thap dan at 2.88 tablets (1.44 g) or 8.64 tablets (4.32 g)/kg b.w/day, respectively.Our results showed that Phong thap dan tablets at both doses increased the reaction time to thermal stimulation,increased the paw withdrawal latency and the force required to elicit a paw withdrawal and decreased thenumber of acetic acid-induced writhing movements in mice. There was no statistically significant differencebetween 2 doses of Phong thap dan tablets in three animal models. We conclude that Phong thap dan tabletsat the doses of 2.88 tablets and 8.64 tablets/kg b.w/day showed significant analgesic effect in animal models.

Secretin stimulation test and early diagnosis of gastrinoma in MEN1 syndrome: Survey on the MEN1 Florentine database

Context Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine cancer syndrome. Multiple gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) affect 30-80% of MEN1 patients, with the most common functioning GEP-NET being gastrinoma. Biochemical identification of hypergastrinemia may help to recognize the presence of gastrinomas before they are detectable by instrumental screening, enabling early diagnosis and start of therapy, preferably before tumor progression and metastases occurrence. Objective Evaluate the effectiveness of secretin stimulation test to precociously diagnose the presence of gastrin-secreting tumors. Design Results of secretin stimulation tests, performed between 1991 and February 2020, were retrospectively analyzed, as aggregate, in a cohort of MEN1 patients with GEP-NETs. Setting Data were extracted from the MEN1 Florentine database. Patients The study included 72 MEN1 patients with GEP-NETs who underwent a secretin stimulation test for the evaluation of gastrin secretion. Outcomes A positive secretin stimulation test was assumed with a difference between basal fasting serum gastrin (FSG) and the maximum stimulated value of gastrin over 120 pg/ml. Results The secretin stimulation test showed a secretin-induced hypergastrinemia in 27.8% (20/72) of patients with GEP-NETs, and a positive test in 18 cases. The test allowed the identification of a positively stimulated hypergastrinemia in 75.0% (3/4) of patients who presented a basal FSG within the normal range. Conclusions Diagnosis of gastrinoma is complex, difficult and controversial. Results of this study confirm that a positive secretin stimulation test allows early diagnosis of gastrinomas, even in the presence of borderline or normal levels of non-stimulated FSG.

When is a positive test for pediatric growth hormone deficiency a true positive test?

Given the low prevalence rate of growth hormone deficiency (GHD) and the high false positive rates for growth hormone stimulation tests, the probability of GHD in a child with short stature and positive growth hormone stimulation tests is 0.028 (about 1 in 36). Without further information, most positive growth hormone stimulation tests will be false positives. Further study may yield the necessary improvements in the diagnostic accuracy for GHD in children.

Insulin-like growth factor ternary complex components as biomarkers for the diagnosis of short stature

Objective The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. Design Boys and girls (n = 429, 0.7–16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis. Results All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups. Conclusion Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

An Effective Approach for Endocrine Dynamic Function Tests Workflow and Reporting Using Cerner Millennium®

Introduction/Objective Endocrine dynamic function testing (DFT), also known as hormone stimulation tests, are indispensable tools in the endocrine practice. Common pitfalls of ineffective testing and misdiagnosis are due to incorrect sample recordings, delay in sample collections and disorganized or confusing result presentation. Clinical and laboratory data deserves careful attention and discrepancies must be reviewed by a clinical biochemist before releasing results for proper patient diagnosis. The main objective of this Cerner DFT project is to design and implement Cerner Millennium applications for effective management and organized result reporting of hospital-wide DFT protocols. Methods/Case Report The DFT Cerner workflow is uniquely designed in-house and known as a pioneer build for Cerner Millenium. The design involves the use of Cerner Discern Analytics 2.0 and clinical modules to complete such a complex build. Five DFT panels are defined as care-sets with specific hormone discrete task assays (DTA). For each care-set, an ‘order sentence’ is created to produce the order priority rules. The DFT panels can only be requested as future orders in PowerChart and activated by the medical staff upon collection of the baseline sample. On Cerner PathNet, results are pre-verified by the medical technologists then auto-filtered in the clinical Review Queue (RQ) module for final verification and addition of comments by the biochemistry consultant. A word processing template is used to collate the results and present the summary of the DFT report where standardized canned comments are added using pre-defined codes. Results (if a Case Study enter NA) See Conclusion Section Conclusion The Cerner DFT project mproves the diagnosis and treatment of patients with hormone disorders. Before, there was a danger of misdiagnosis when samples are individually requested producing separate reports with no organized presentation. Report comments from the clinical biochemist consultant also served as good diagnostic guidance. This quality initiative has definitely improved the previous and long term issues of endocrine dynamic function tests.

38 Clinical features and echocardiographic parameters of relative adrenal insufficiency (RAI) among preterm infants: A five-year review

Primary Subject area Neonatal-Perinatal Medicine Background Infants born at low gestational age (GA) often present with a septic shock-like picture in the neonatal intensive care unit (NICU). Some of these premature infants are noticed to exhibit inadequate cortisol levels at such a time of stress, an entity termed ‘relative adrenal insufficiency’ (RAI), which is postulated to compromise the compensatory mechanisms and further circulatory collapse. Objectives To review the clinical features and echocardiographic parameters of RAI in preterm infants, and their correlation with adrenocorticotropic hormone (ACTH) stimulation tests in a quaternary NICU over 5 years. Design/Methods This is a single centre retrospective study. Infants born at < 32 weeks GA between January 2015 to June 2019, admitted to the British Columbia Women’s Hospital NICU (Vancouver, British Columbia), were reviewed. Infants who presented with a shock-like picture with a cortisol level at this time of stress of < 250 nmol/L were included. Infants who have received corticosteroid prior to cortisol collection were excluded. Results There were 798 infants < 32 weeks admitted to the BCWH NICU over a 5 year period, of which 284 had a spot cortisol drawn. We identified 45 eligible infants in our study (5.6% of NICU admissions). Their median (IQR) for GA, birth weight, cortisol level, and age of onset of RAI were 25 weeks (24, 26), 690 g (590, 815), 83 (58, 127), and 13 days of life (8, 24), respectively. Among these infants, 73% developed significant hypotension or respiratory failure (Table 1). 13 infants (28.9%) had echocardiogram performed at the time of cardiopulmonary deterioration, and all had normal left ventricular (LV) fractioning shortening (median [IQR]: 42% [38-49%]) and LV output (median [IQR]: 242 mL/kg/min [155-330 mL/kg/min]). Only 19 infants (42.2%) received hydrocortisone, with a median [range] treatment duration of 2 days [1–8]. Lower cortisol level was associated with lower GA at the presentation of RAI (p=0.049), but not predictive of adverse clinical and laboratory outcomes (Table 2). ACTH stimulation tests were performed in 20 (44.5%) infants and 3 (15%) were found to be abnormal, and results were not correlated with clinical features. Conclusion In our cohort, we identified 5% of NICU admission with RAI, based on the cut-off of cortisol < 250 nmol/L at the time of shock-like presentation. Lower cortisol level was associated with lower GA at the presentation of RAI. Further prospective study with a well-defined protocol is needed to understand the use of cortisol and its clinical implications.

Development and Internal Validation of a Predictive Model for Adult GH Deficiency Prior to Stimulation Tests

BackgroundThe diagnosis of adult GH deficiency (GHD) relies on a reduced GH response to provocative tests. Their diagnostic accuracy, however, is not perfect, and a reliable estimation of pre-test GHD probability could be helpful for a better interpretation of their results.MethodsEighty patients showing concordant GH response to two provocative tests, i.e. the insulin tolerance test and the GHRH + arginine test, were enrolled. Data on IGF-I values and on the presence/absence of other pituitary deficits were collected and integrated for the estimation of GHD probability prior to stimulation tests.ResultsAn independent statistically significant association with the diagnosis of GHD was found both for IGF-I SDS (OR 0.34, 95%-CI 0.18-0.65, p=0.001) and for the presence of other pituitary deficits (OR 6.55, 95%-CI 2.06-20.83, p=0.001). A low (<25%) pre-test GHD probability could be predicted when IGF-I SDS > +0.91 in the presence of other pituitary deficits or IGF-I SDS > -0.52 in the absence of other pituitary deficits. A high (>75%) pre-test GHD probability could be predicted when IGF-I SDS < -0.82 in the presence of other pituitary deficits or IGF-I SDS < -2.26 in the absence of other pituitary deficits.ConclusionThis is the first study that proposes a quantitative estimation of GHD probability prior to stimulation tests. Our risk class stratification represents a simple tool that could be adopted for a Bayesian interpretation of stimulation test results, selecting patients who may benefit from a second stimulation test and possibly reducing the risk of wrong GHD diagnosis.

Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report

Objectives: Gordon syndrome (GS), also known as pseudohypoaldosteronism type II, is a rare tubular disease characterized by hypertension, hyperkalemia, and metabolic acidosis. Its causative genes are CUL3, KLHL3, WNK1, and WNK4, and they are associated with varying severity of the disease. Herein, we report the first case of GS caused by a CUL3 mutation in a patient with short stature in Korea.Case presentation: A 7-year-old boy had hypertension, metabolic acidosis, and persistent hyperkalemia, which were initially detected during the evaluation of short stature. He was born small for gestational age at late preterm gestation. Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels. Genetic analysis revealed a heterozygous de novo mutation in the CUL3 gene (c.1377+1G > C in intron 9). Thus, a diagnosis of GS was made. The results of the endocrine function test (including growth hormone stimulation tests) were normal. After thiazide treatment, the patient’s electrolyte levels were normalized. However, he presented with persistent hypertension and short stature.Conclusions: GS should be considered in children with short stature, hypertension, and hyperkalemia, and early treatment may reduce complications.