primary and secondary insensitivity to growth hormone in short children otto mehls university...

Primary and Secondary Insensitivity to Growth Hormone in Short Children

Otto Mehls

University Hospital for Childen and Adolescents

Devision of Pediatric Nephrology

Heidelberg, Germany

Reasons for Short Stature : Insulin-like Growth Factor Deficiency

Hypothalamic dysfunction

Pituitary GHD

GH insensitivity A. Primary GH insensitivity

1. GH receptor defect

B. Secondary insensitivity 1. Malnutrition 2. Liver disease 3. Chronic disease like chronic kidney disease

(CKD)

Growth Hormone Receptor

GH action on liver and extrahepatic tissue

Molecular defects resulting in severe primary IGF deficiency

after Rosenfeld 2009

Severe Primary IGF Deficiency

I. GHR abnormalities1. Mutations/deletions of the GHR affecting the extracellular domain of

the GHR and resulting in decreased GH binding

2. Mutations/deletions of the GHR affecting the ability of the GHR to dimerize

3. Mutations/deletions of the GHR affecting the transmembrane domain of the receptor and resulting in defective anchoring in the cell membrane

4. Mutations/deletions of the GHR affecting the intracellular domain and signaling

Molecular defects resulting in severe primary IGF deficiency

after Rosenfeld 2009

Severe Primary IGF DeficiencyContinuation

II. Post-GHR signaling defects1. Mutations of STAT5b resulting in defective or absent GH signal

transduction

III. Mutations/deletions of IGF-I1. Deletions of IGF-I

2. Mutations of the IGF-I resulting in bioinactive IGF-I

IV. Defects of IGF transport and/or clearance1. Mutations/deletions of –ALSIGF, resulting in defective IGF transport

and rapid IGF clearance

V. IGF resistance1. Mutations of the IGF1R, resulting in decreased sensitivity to IGF-I

Secondary GH insensitivity/resistance

Example : Chronic renal failure

Effect of Forced Feeding in Infants on PD Heidelberg Experience

27 infants, age < 2 years. 22 NG tube, 5 PEGMean energy intake 100 % RDA, protein intake 125 % RDA

BMI SDS

Months on Tube Feeding

0 3 6 9 12 15 18 21 24

SD

S

-3

-2

-1

0

Height SDS

0 3 6 9 12 15 18 21 24

SD

S

-3

-2

-1

0

Initial BMI > -2 SDS

Initial BMI < -2 SDS

Months on Tube Feeding

Initial BMI > -2 SDS

Initial BMI < -2 SDS

Effect of Gastrostomy Feeding in ESRD ChildrenNottingham Experience

Treatment: 20 PD, 2 HD patients

Age at gastrostomy: 2.3 (0.2-10.3) years

Observation period: 14.5 (2.5 - 56) months

Mean Energy Intake: 115 % RDA (98-155%)S

DS

Coleman et al. NDT 1998

Resistance to GH/IGF in CKD• Serum concentration of GH increased, metabolic

clearance decreased Haffner et al, J Clin Invest 93, 1163-71, 1994

• GH pulsatility disturbed Schaefer et al, J Pediatr 119, 568-77

• GH receptor expression decreased Tönshoff et al, J Clin Endocrinol Metab 82, 1007-13, 1997

• Signal transduction of GHR impairedSchaefer et al, J Clin Invest 108, 467-75, 2001

• IGF-I production decreasedBlum et al, Pediatr Nephrol 5, 539-44, 1991

• IGF activity decreased by binding proteinsTönshoff et al, J Pediatr 370, 28-34, 1990

• Endorgan (postreceptor) resistance to GH and IGF-I

Mak and Pak, Kidney Int 50, 40-6, 1996

Resistance to GH/IGF in CKD• Serum concentration of GH increased, metabolic

clearance decreased Haffner et al, J Clin Invest 93, 1163-71, 1994

• GH pulsatility disturbed Schaefer et al, J Pediatr 119, 568-77

• GH receptor expression decreased Tönshoff et al, J Clin Endocrinol Metab 82, 1007-13, 1997

• Signal transduction of GHR impairedSchaefer et al, J Clin Invest 108, 467-75, 2001

• IGF-I production decreasedBlum et al, Pediatr Nephrol 5, 539-44, 1991

• IGF activity decreased by excess of binding proteinsTönshoff et al, J Pediatr 370, 28-34, 1990

• Endorgan (postreceptor) resistance to GH and IGF-I

Mak and Pak, Kidney Int 50, 40-6, 1996

Derangements of Somatotropic Hormone Axis in CRF

Post-R Defect

Improvement of response to GH following dayly hemodialysis

Fischbach et al ,Ped Neph 2006Fischbach et al, Pediatr Nephrol 2006

• General clinical problem: Some short patients respond better to GH treatment than others.

• Why ? What is the reason ?

• Prediction possible ?

First year response to daily growth hormone treatment in males with IGHD Bakker et al JCEM 93,352, 2008

Prediction of Growth Hormone (GH)-Response

in Short Children with CKD

O. Mehls, A. Lindberg, R. Nissel, D. Haffner, A. Hokken-Koelega, M. B. Ranke

Submitted to JCEM

Design

Data from 208 prepubertal children on conservative treatment or dialysis from a large pharmaco-epidemiological survey (KIGS)

Independent control Data from 67 similar CKD patients registered at the Dutch Growth Research Foundation

Statistical Analysis

Multiple linear regression analysis fitted by least squares and REG procedure in the SAS computer program.

Variation of response to GH was expressed in terms of Studentized residuals.

Regression equation variables used for prediction

Parameterestimate

Rank Partial R2 Variablesignificance

Intercept (constant)

13.3

Age at start (years)

-0.38 1 0.203 < 0.001

Weight SDS at start

0.39 2 0.062 < 0.001

Hereditary renal disorder

-1.16 3 0.039 0.0008

GFR (ml/min x 1.73 m²)

0.023 4 0.039 0.0005

Log dose GH (mg/kg per week)

1.04 5 0.022 0.0090

Cumulative R² 0.37

Error SD (cm) 1.6

Studentized Residuals

Residual = observed height velocity(HV) – predicted HV) / Standard error of predicted HV

= index of responsiveness

Individual Prediction

●

o

Identification of Non-Responders

Dutch non responders= Dutch patients

with HV SDS < 0.0

Summary

• Primary resistance to GH resulting in very low or defective IGF1 is explained by various molecular defects of the GH receptor and along its signaling pathway

• Secondary resistance to GH is due to functional, reversible defects of the GH-IGF axis

• Low , normal or high response to GH treatment can be seen from Bakker charts or predicted using KIGS prediction models.

Reasons for Short Stature : Insulin-like Growth Factor Deficiency

Hypothalamic dysfunction Pituitary GHD GH insensitivity

A. Primary GH insensitivity 1. GH receptor defect

B. Secondary insensitivity 1. Malnutrition 2. Liver disease 3. Chronic disease

Primary defects of IGF synthesis Primary defects of IGF transport/clearance IGF resistance

Studentized Residuals vs. predicted height velocity

KIGS Dutch Controls

Growth Response to GH ( Height SDS) 1st YearAccording to Primary Renal Disease

Prepubertal Patients

H

eigh

t S

DS

1st

yea

r

Growth Response to GH ( Height SDS) 0-2yearsAccording to Primary Renal Disease

Prepubertal Patients

Hei

ght

SD

S 2

yea

rs

Short stature in children with CKD:-Variable diagnosis -Varable renal function-Variable response to GH

Aim: -Prediction of individual growth response and identify non-responders

Clinical problem

rGH Treatment Efficacy in Prepubertal Children with CRIGerman GH in CRI Study Group

Haffner et al. J Am Soc Nephrol 1998

74 CRI, 29 dialysis patients from 27 centers, observation up to 5 years

DialysisDialysis

CRICRI

Years of Observation

Hei

ght

SD

S

Schaefer et al. Pediatr Nephrol 1996; 10:288–93

Impact of Renal Function on Prepubertal Growth320 children with congenital CKD

Hei

gh

t (c

m)

404 100

Age (years)

150

90

100

110120

130

140

80

70

60

6 82

9075502510

50

Moderate CRFGFR > 25 ml/min/1.73 m2

404 100

Age (years)

150

90

100

110120

130

140

80

70

60

6 82

9075502510

50

Severe CRFGFR < 25 ml/min/1.73 m2

First year response to dayly growth hormone treatment according to primary disease

Bakker et al JCEM 93,352, 2008

Growth of uremic rats is impaired by reduced food intake and uremia ,

but reduced food intake might only be associated with poor growth

Growth of uremic rats is impaired by reduced food intake and uremia,

but reduced food intake might only be associated with poor growth

Studentized Residuals

Residual = observed height velocity(HV) – predicted HV) / Standard error of predicted HV = index of responsiveness Patients with an observed height velocity (HV) of < 0.0 height velocity SDS were excluded to allowidentification of non-responders by the model.

Statistical Analysis

Multiple linear regression analysis fitted by least squares and REG procedure in the SAS computer program.

The hierarchy of predicting factors was derived by the all-possible regression approach as described for other prediction models.

Differences were expressed in terms of Studentized residuals.