GHD IN CHILDREN test and treatment 555.pptx

Gh

1. EVALUATION AND MANAGEMENT GHD IN CHILDREN

2. BIOCHEMICAL ASSESSMENT IGF1 IGFBP3 GH GHBP IGF GENERATION TESTS TESTS OF GH – IGF 1 AXIS

3. Serum IGF-II IGFBP-2 Acid-labile subunit levels GH secretagogues Useful in combination OTHER TESTS

4. Neonatal hypoglycemia+ Metabolic disorder -VE Random GH measurement – polyclonal RIA <20 mg/L IGFBP-3 measurement is valuable using a highly sensitive hGH -ELISA the median GH concentration cutoff value of 7 μg /L, when measured with the same assay, sensitivity (100%) and specificity (98%) RANDOM GH

5. Hospital admission overnight-blood sampling every 20 min Superior reproducibility Differentiates poorly between GH deficient & normal short children Lower sensitivity, fails to identify 57% of children GH neurosecretory dysfunction : An abnormal 24-h GH secretory profile (reduced GH pulses & amplitude) ( low IGF 1, auxology , bone age delay of at least 2 yrs & a N GH stim test) Should only be considered IF clinical presentation is strongly consistent with GHD Structural abnormalities of the pituitary gland on MRI Pharmacological stimulation test is normal. Spontaneous GH Secretion (GHRS recommends against using the same)

6. Urinary GH : Prerequisites: Timed urinary collection / GH assay of high sensitivity/ N Renal function Advantages Relative ease of performance / noninvasive nature / only single measurement Disadvantages Wide inter individual variation & lack of age & sex-related reference ranges GH

7. PRINCIPLE: Provocative stimuli + post peak GH Several validated GH stimulation tests PROVOCATIVE TESTS

8. Considerable variation in the cut offs by different medical societies Assay-specific cutoffs are recommended But…. published & well-validated data-available only for selected assays/conditions

9. Re-examined the cut-offs for the diagnosis of GHD For 6 currently available commercial immunoassays & for a MS based assay In 52 children (without GHD) + 44 children with GHD and treated with GH HT SDS Calculated Wagner IV, Paetzold C, Gausche R, et al. Clinical evidence-based cutoff limits for GH stimulation tests in children with a backup of results with reference to mass spectrometry. Eur J Endocrinol 2014;171:389–97.

10. No gold standard Non physiological Poorly reproducible Types of provocation stimuli Sex steroid priming Cut-off levels - diagnosis -Arbitrary cut offs Assay related problems Lack of normative data GH PROVOCATIVE TEST

11. 50% GH is bound to GHBP in circulation binds to GH in a site-specific manner. Interference - avoided by use of antibodies that bind to epitopes different from the receptor binding site.

12. GH - several isoforms and isomers. Most common GH variant is the 22 kD GH,GH-1 or GH-N 20 kD isoform displays longer half-life but lower potency than 22 kD GH Different isoforms of GH are secreted in Parallel

13. Polyclonal or monoclonal antibodies? current consensus is to “go specific” no disease is known that only affects a single isoform Assay standardization and comparability as well as harmonization of cutoff values are considered more important than measurement of multiple GH isoforms . Recommendation is to limit detection to the 22 kD pituitary GH A further source of confusion in the past was that some laboratories reported GH concentrations in activity ( mU /L), whereas others used mass units (mg/L). The existence of various conversion factors between the 2 added to the confusion. “Go permissive or go specific?”

14. Potential cross-reactants : other members of the GH gene family- placental GH, placental lactogens,prolactin . Different standard preparations for calibration of GH immunoassays Currently, all GH assays should be calibrated to the international reference standard 98/574 (National Institute for Biological Standards and Control), a rGH preparation of high purity LAB REPORTING -GH concentrations : Activity ( mU /L) or Mass units (mg/L) with Various conversion factors between the 2 . All GH concentrations – measured/reported in mass units(MG/L).

15. To improve standardization: GH reference preparation- rhGH presently 88/624- potency of 3 IU = 1 mg When reporting assay data- a clear statement of methodology Clinician, using any assay- aware of its methodology, its limitations, and its performance An assay that measures 22-kDa hGH , using monoclonal antibodies, is recommended.

16. Ghigo et al have conducted the most comprehensive study to date comparing 10 different GH stimulation tests in 472 children without GHD. Mean peak GH concentrations varied between tests from 9.7 mg/L to 61.8 mg/L. Excluding combined stimulation tests, all the tests incorrectly classified some subjects as GH deficient. Using a cut-off of 7 mg/L, false positive rates varied between 8.9% and 23.7%, depending on the test used, and increased to 14.9–49% when the cut-off was increased to 10 mg/L.

17. Nutritional status Concomitant medication ( e.g. glucocorticoids , psychotropic drugs, etc.) Psychosocial conditions Confounding factors

18. Screening -IGF-I/IGFBP-3 levels Confirmation- GH provocation tests after excluding hypothyroidism Isolated GHD- 2 GH provocation tests (sequential or on separate days) IN CNS pathology, h/o irradiation, MPHD, or a genetic defect: One GH test + evaluation of other pituitary function At times GHD may evolve over yrs- Hence rpt GH testing in few yrs may be reqd STEPS

19. GH-RH + Arginine (inhibits somatostatin ) Most accurate BMI-specific (<25, 25–30, and >30 kg/m2) cutoffs have been determined

20. IGF-I - a stable marker of an individual’s GH levels Fluctuate much less compared with GH IGF-I levels start decreasing after they peak in puberty Sex only minor influence- Peaks earlier in girls than in boys, esp if corrected for Tanner stage Consensus statement recommends sex-specific reference values for children but age-specific reference intervals are sufficient for adults Stable over a wide range of BMIs Disconnect between GH and IGF-I in obesity (increased hepatic GH sensitivity in overweight and obese ) IGF-1

21. Similar to GHBP – SIX IGFBPs So dissociate IGFBP from IGF 1 Block IGFBP Binding sites using IGF2 Type I diabetes, liver cirrhosis, chronic renal failure, and anorexia nervosa Increased IGFBP levels relative to IGF-I Assay standardization - 2008 when recombinant international IGF-I std preparation 02/254- established

22. Difference between assays: Interference by IGFBPs Cross-reactivity to related molecules IGF-II, present in high quantities Method of calibration -major source of variation in the mass spectrometry study PROBLEMS WITH IGF Sensitivity 73% / 30% Specificity 95%/ 98%

23. INDIA- Clonidine commonly used ITT –other test used Rarely glucagon used

24. ALL 3 conditions: auxological criteria Hypothalamic-pituitary defect [ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk], tumor or irradiation Deficiency of at least one additional pituitary hormone NEWBORN with hypoglycemia with serum GH > 5 µg/L + deficiency of at least one additional pituitary hormone and/or the classical imaging triad (ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk) GH PROVOCATIVE TESTING NOT REQD IF…

25. Failed GH Provocative tests should not be relied as sole criteria for diagnosis 2 tests can be performed sequentially on same day Harmonized assay using std preparations Sex steroid priming prior to provocative GH testing in pre-pubertal boys > 11 , girls > 10 yrs with adult height prognosis within -2 SD of the reference population mean. 2 mg (1 mg for body weight <20 KG) Oral beta estradiol 2 days prior to test 50-100 mg im depot testo 1 wk prior in boys

26. Following features should be recorded: MRI ideally in 2-mm slices with and without contrast Pituitary height and/or volume Anatomy of the stalk Position of the posterior pituitary Isolated GHD or MPHD +/- Genetic defects

27. PERSISTENT GHD GHD+ MPHD / Structural defect/ genetic mutation RE EVALUATION OF AXIS: GHD + deficiency of only one additional pituitary hormone idiopathic isolated GHD isolated GHD with a small/ectopic posterior pituitary patients post-irradiation TRANSITIONAL CARE

28. After a trial of at least 1 month off GH treatment Serum IGF-I Measurement- initial test IF IGF1 Low -- -then provocative testing

29. IF PT IS OFF GH FOR FEW MONTHS: Beginning a perhaps ½ the adolescent dose and decreasing the dose every few months as one move toward the adult dose is safe and effective. PT OFF GH > 6 months : starting at the adult dose, perhaps 0.3-0.8 mcg per day (total dose) is appropriate and titrating the dose upward . Rx in Adolescents AND Adults

30. Available since 1985 Cadaveric GH stopped due to reports of CJD Goal of Rx: Normalize height during childhood and adolescence Attain an adult height within the normal range and within the target height range (genetic potential) rGH

31. GHD Chronic renal failure (1995) Turner Syndrome (1993) PraderWilli Syndrome (2000) Small for gestational age without catch-up growth (2001) Idiopathic short stature (2003) Short stature homeobox containing gene ( Shox ) deficiency (2006) Noonan Syndrome (2007) INDICATIONS

32. Presence of the isoform of the GH receptor gene that lacks exon 3 may have a small benefit (increased height velocity) at the initiation of rhGH therapy, but not a significant impact in adult height Polymorphisms in the IGF binding protein 3 (IGFBP-3) promoter region: First-year growth velocity of patients with the AA genotype was 13.0 cm compared to 10.8 cm in those with the CC genotype RESPONSE TO THERAPY

33. Weight-based or body surface area (BSA)-based GH dosing Initial GH dose of 0.16-0.24 mg/kg/week (22-35 µg/kg/day) subcutaneous Dose approved by the FDA is 25-100 mcg/kg/day Preferably in the evening – mimics physiological secretion Started at the youngest possible age to achieve the greatest growth response IGF 1 BASED GH DOSING GH DOSING

34. Monitor at 6 month intervals Measurement of serum IGF-I levels as a tool to monitor adherence Look for Adverse effects (intracranial hypertension, slipped capital femoral epiphysis, and scoliosis ) re-assessment of adrenal & thyroid axes after initiation of GH (MPHD) Glucose metabolism Dose to be reduced if IGF1 rises above limit To stop if growth velocity attained is below 2-2.5 cm/year FOLLOW UP

35. If a prepubertal patient initially responds well rhGH treatment, but then fails to achieve the expected height velocity of the pubertal growth spurt, they may benefit from a temporary increase in rhGH dose (e.g., to 70-100 mcg/kg/day) PUBERTY

36. Headache-most common-benign idiopathic intracranial hypertension (formerly known as pseudotumor cerebri ) increased intraocular pressure slipped capital femoral epiphysis Worsening of pre existing scoliosis Pancreatitis transient gynecomastia an increase in the growth and pigmentation of nevi Carpal tunnel syndrome Edema Arthralgia A dverse effects

37. Acquired GHD due to primary malignancy: Shared decision-making- patient, family, oncologist, & treating endocrinologist after discussing potential effect of GH treatment on the timing of second neoplasm occurrence After completion of tumor therapy & no evidence of ongoing tumor, a std waiting period of 12 months to establish "successful therapy" of the primary lesion for GH initiation . GH & NEOPLASIA

38. Type Of Delivery System Discomfort With Injections Cost Of Treatment, Socioeconomic Status Lack Of Communication/Training Poor Understanding Of Disease And Consequences Of Missed Doses Requirement For Long-term Treatment, Lack Of Immediate Clinical Improvement Peer Or Psychosocial Pressure (E.G., During Adolescence) Poor adherence to GH therapy

39. Injection pain is one of the major factors that influence compliance. Optimization of the preservative and buffer content of a liquidGH formulationmay reduce injection pain and, hence, improve patient compliance

40. rhIGF -I, as a twice-daily sc injection 200-400 mcg / g/day for the long-term treatment of growth failure in children with severe primary IGF-I deficiency and in children with GH gene deletions who have developed neutralizing antibodies to GH . Severe primary IGF-I deficiency is defined by a height SD score less than 3.0 and a basal IGF-I SD score less than 3.0 and normal or elevated growth hormone (GH). Severe primary IGF-I deficiency includes patients with mutations in the GH receptor (GHR), post- GHRsignaling pathway, and IGF-I gene defects. FDA approval RIGF 1

41. Lft altered Acromegaloid facies Antibodies 10% hypoglycemia

42. Bioequivalent GH products Combined GH/IGF-I product Sustained-release GH preparation Treating patients with GH - non-FDA-approved indications- Crohn disease, cystic fibrosis & glucocorticoid dpdt pts NEWER THERAPEUTICS :

43. THANK YOU

44. 1) in the neonate: hypoglycemia prolonged jaundice microphallus or traumatic delivery 2) cranial irradiation 3) head trauma or central nervous system infection 4) consanguinity and/or affected family member 5) craniofacial midlineabnormalities POINTERS

45. Early onset of growth failure Positive family history and possible consanguinity Height more than 3 sd below the mean Extremely low GH response to provocation tests, including GHRH Very low IGF-I and IGF-BP3 levels POINTERS TO GENETIC DISORDERS

46. Routine use of GH in every child with height SDS < -2.25 is not recommended Children who meet FDA criteia for ISS- GH after shared decision making/cost eff /risk vs benefits follow-up assessment of benefit in height SDS and psychosocial impact 12 months after GH initiation and dose optimization. dose of 0.24 mg/kg/week, with some patients requiring up to 0.47 mg/kg/week ISS

47. (1) screening: auxological parameters and low IGF-I concentration (2) causes of secondary IGF-I deficiency must be excluded, including under-nutrition, hepatic disease, and GHD (3) circulating levels of GH-binding protein (GHBP): very low or undetectable levels suggest Laron syndrome/GHIS while normal levels are non-informative (4) IGF-I generation test and mutation analyses can be helpful, but have limitations PIGFD/GHIS

48. trial of GH therapy before initiating IGF-I for patients with unexplained IGF-I deficiency IGF-I dose of 80-120 µg/kg BID. 150-180 µg/kg once daily administration of IGF-I 20 minutes after a carbohydrate-containing meal or snack, and education of patients/families on the symptoms and risk of hypoglycemia associated with IGF-I treatment

49. rare disorder IGF-I treatment is indicated With both ht and IGF-I levels <-3 SD FDA approved INDICATIONS: IGF-I gene deletion or inactivating mutation GHR gene mutation or post-receptor signal transduction defects GH-inactivating antibodies Low IGF-I levels : GHD, under-nutrition, chronic glucocorticoid use, hypothyroidism, and chronic illness Treatment directed at the cause of secondary IGFD should be sought, rather than IGF-I therapy. While some authors have suggested that many children with ISS have IGF-I deficiency, and would be better served if treated with IGF-I rather than GH, there are no data to support this hypothesis. In fact, treating a GH-sufficient child with IGF-I may suppress endogenous GH production, decrease production of IGF-I, and reduce delivery of GH to growing bone . PIGFD

50. BONE AGE > 1 YR- X ray left wrist < 1 YR- x-rays of the knee and ankle MRI Intracranial tumours Optic nerve hypoplasia / septooptic dysplasia Structural or developmental anomaly RADIOLOGY

51. Richmond E, Rogol ADTreatment of growth hormone deficiency in children, adolescents and at the transitional age, Best Practice & Research Clinical Endocrinology & Metabolism (2016)

52. Recent relevant population standards available. Standards updated-Based- Population secular trend. Growth data : Expressed as SD scores NOT percentiles. To correctly evaluate height velocity, there is a need for longitudinal velocity standards. Biological markers -Body composition, BMD and bone markers - not discriminatory INTERPRETATION OF GROWTH DATA