Background: The acid-labile subunit (ALS) is a crucial factor in the tertiary complex. IGF-I and IGFBP-3 are routinely measured during the diagnostic work-up for growth hormone deficiency (GHD). The aim of the study is to evaluate the relevance of serum ALS as an additional biomarker in the diagnosis of GHD. Methods: Ninety-one children undergoing standard diagnostic work-up for GHD were included in this retrospective study. Inclusion criteria were evidence-based auxological cutoffs, IGF-I and IGFBP-3 <−2 SDS at first presentation, at least 1 growth hormone (GH) stimulation test, and IGF-I, IGFBP-3, and ALS measurements on the same day. Statistical analysis was performed by ROC as well as by odds ratio calculations. Results: Forty-seven of 90 participants presented with peak GH values under the cutoff of 7 ng/mL. AUC from a model containing only IGF-I was 0.76 and 0.68 when using only ALS. A model containing IGF-I, IGFBP-3, and ALS (AUC = 0.77) did not improve the result compared to the combination of IGF-I/IGFBP-3 (0.77) or IGF-I/ALS (0.76). Furthermore, the variation in the outcome (GH peak </≥7) explained by IGF-I only amounts to 20.4%, while that explained by IGFBP-3 and ALS is only 10.6 and 7.8%, respectively. The sensitivity to diagnose GHD at respective concentrations of −2.0 SDS was 48% for IGF-I, 38% for IGFBP-3, and only 8% for ALS. Conclusion: Determination of serum ALS alone or in combination with IGF-I and IGFBP-3 did not improve definition of biochemical GHD in a cohort of short children and adolescents with suspected growth disorder. However, performance of IGFBP-3 in this context was not statistically superior to ALS.

1.
Le Roith
D
,
Bondy
C
,
Yakar
S
,
Liu
JL
,
Butler
A
.
The somatomedin hypothesis: 2001
.
Endocr Rev
.
2001
;
22
(
1
):
53
74
. .
2.
Kaplan
SA
,
Cohen
P
.
Review: the somatomedin hypothesis 2007: 50 years later
.
J Clin Endocrinol Metab
.
2007
;
92
(
12
):
4529
35
.
3.
Baxter
RC
.
Insulin-like growth factor binding proteins in the human circulation: a review
.
Horm Res
.
1994
;
42
(
4–5
):
140
4
. .
4.
Janosi
JB
,
Ramsland
PA
,
Mott
MR
,
Firth
SM
,
Baxter
RC
,
Delhanty
PJ
.
The acid-labile subunit of the serum insulin-like growth factor-binding protein complexes. Structural determination by molecular modelling and electron microscopy
.
J Biol Chem
.
1999
;
274
(
33
):
23328
32
.
5.
GH Research Society
.
Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society
.
J Clin Endocrinol Metab
.
2000
;
85
:
3990
3
.
6.
Grimberg
A
,
DiVall
SA
,
Polychronakos
C
,
Allen
DB
,
Cohen
LE
,
Quintos
JB
, et al
Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency
.
Horm Res Paediatr
.
2016
;
86
(
6
):
361
97
. .
7.
Blum
WF
,
Alherbish
A
,
Alsagheir
A
,
Awwa
AE
,
Kaplan
W
,
Koledova
E
, et al
The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders
.
Endocr Connect
.
2018
;
7
(
6
):
212
22
.
8.
Murray
PG
,
Dattani
MT
,
Clayton
PE
.
Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence
.
Arch Dis Child
.
2016
;
101
(
1
):
96
100
. .
9.
Guzzetti
C
,
Ibba
A
,
Pilia
S
,
Beltrami
N
,
Di Iorgi
N
,
Rollo
A
, et al
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
.
Eur J Endocrinol
.
2016
;
175
(
1
):
41
7
. .
10.
Binder
G
,
Huller
E
,
Blumenstock
G
,
Schweizer
R
.
Auxology-based cut-off values for biochemical testing of GH secretion in childhood
.
Growth Horm IGF Res
.
2011
;
21
(
4
):
212
8
. .
11.
Boquete
HR
,
Sobrado
PG
,
Fideleff
HL
,
Sequera
AM
,
Giaccio
AV
,
Suárez
MG
, et al
Evaluation of diagnostic accuracy of insulin-like growth factor (IGF)-I and IGF-binding protein-3 in growth hormone-deficient children and adults using ROC plot analysis
.
J Clin Endocrinol Metab
.
2003
;
88
(
10
):
4702
8
. .
12.
Cianfarani
S
,
Boemi
S
,
Spagnoli
A
,
Cappa
M
,
Argirò
G
,
Vaccaro
F
, et al
Is IGF binding protein-3 assessment helpful for the diagnosis of GH deficiency?
Clin Endocrinol
.
1995
;
43
(
1
):
43
7
. .
13.
Cianfarani
S
,
Tondinelli
T
,
Spadoni
GL
,
Scire’
G
,
Boemi
S
,
Boscherini
B
.
Height velocity and IGF-I assessment in the diagnosis of childhood-onset GH insufficiency: Do we still need a second GH stimulation test?
Clin Endocrinol
.
2002
;
57
:
161
7
.
14.
Cianfarani
S
,
Liguori
A
,
Boemi
S
,
Maghnie
M
,
Iughetti
L
,
Wasniewska
M
, et al
Inaccuracy of insulin-like growth factor (IGF) binding protein (IGFBP)-3. Assessment in the diagnosis of growth hormone (GH) deficiency from childhood to young adulthood: association to low GH dependency of IGF-II and presence of circulating IGFBP-3 18-kilodalton fragment
.
J Clin Endocrinol Metab
.
2005
;
90
(
11
):
6028
34
.
15.
Blum
V
,
Alherbish
A
,
Alsagheir
A
,
El Awwa
A
,
Kaplan
W
,
Koledova
E
, et al
(2018). The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders
.
Endocr Connect
.
2018
;
7
(
6
):
212
22
.
16.
Barrios
V
,
Argente
J
,
Muñoz
MT
,
Pozo
J
,
Chowen
JA
,
Hernández
M
.
Diagnostic interest of acid-labile subunit measurement in relationship to other components of the IGF system in pediatric patients with growth or eating disorders
.
Eur J Endocrinol
.
2001
;
144
(
3
):
245
50
. .
17.
Grandone
A
,
Miraglia del Giudice
E
,
Cirillo
G
,
Abbondanza
C
,
Cioffi
M
,
Romano
T
, et al
Clinical features of a new acid-labile subunit (IGFALS) heterozygous mutation: anthropometric and biochemical characterization and response to growth hormone administration
.
Horm Res Paediatr
.
2014
;
81
(
1
):
67
72
. .
18.
Juul
A
,
Møller
S
,
Mosfeldt-Laursen
E
,
Rasmussen
MH
,
Scheike
T
,
Pedersen
SA
, et al
The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency
.
J Clin Endocrinol Metab
.
1998
;
83
(
12
):
4408
15
. .
19.
Fukuda
I
,
Hizuka
N
,
Itoh
E
,
Yasumoto
K
,
Ishikawa
Y
,
Murakami
Y
, et al
Acid-labile subunit in growth hormone excess and deficiency in adults: evaluation of its diagnostic value in comparison with insulin-like growth factor (IGF)-I and IGF-binding protein-3
.
Endocr J
.
2002
;
49
(
3
):
379
86
. .
20.
Grote
FK
,
van Dommelen
P
,
Oostdijk
W
,
de Muinck Keizer-Schrama
SM
,
Verkerk
PH
,
Wit
JM
, et al
Developing evidence-based guidelines for referral for short stature
.
Arch Dis Child
.
2008
;
93
(
3
):
212
7
. .
21.
Gleiss
A
,
Lassi
M
,
Blümel
P
,
Borkenstein
M
,
Kapelari
K
,
Mayer
M
, et al
Austrian height and body proportion references for children aged 4 to under 19 years
.
Ann Hum Biol
.
2013
;
40
(
4
):
324
32
. .
22.
Ranke
MB
, editor.
Diagnosis of growth hormone deficiency and growth hormone stimulation tests
. In:
Diagnostics of endocrine function in children and adolescents
.
Basel
:
Karger
;
2003
. p.
107
28
.
23.
Friedrich
N
,
Wolthers
OD
,
Arafat
AM
,
Emeny
RT
,
Spranger
J
,
Roswall
J
, et al
Age- and sex-specific reference intervals across life span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 ratio measured by new automated chemiluminescence assays
.
J Clin Endocrinol Metab
.
2014
;
99
(
5
):
1675
86
. .
24.
Bidlingmaier
M
,
Friedrich
N
,
Emeny
RT
,
Spranger
J
,
Wolthers
OD
,
Roswall
J
, et al
Reference intervals for insulin-like growth factor-1 (IGF-I) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations
.
J Clin Endocrinol Metab
.
2014
;
99
(
5
):
1712
21
. .
25.
Ertl
DA
,
Gleiss
A
,
Sagmeister
S
,
Haeusler
G
.
Determining the normal range for IGF-I, IGFBP-3, and ALS: new reference data based on current internal standards
.
Wien Med Wochenschr
.
2014
;
164
(
17–18
):
343
52
. .
26.
Wagner
IV
,
Paetzold
C
,
Gausche
R
,
Vogel
M
,
Koerner
A
,
Thiery
J
, 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
(
3
):
389
97
. .
27.
Schemper
M
.
Predictive accuracy and explained variation
.
Stat Med
.
2003
;
22
(
14
):
2299
308
. .
28.
Schilbach
K
,
Bidlingmaier
M
.
Laboratory investigations in the diagnosis and follow-up of GH-related disorders
.
Arch Endocrinol Metab
.
2019 Nov–Dec
;
63
(
6
):
618
29
. .
29.
Morrison
KM
,
Bidlingmaier
M
,
Stadler
S
,
Wu
Z
,
Skriver
L
,
Strasburger
CJ
.
Sample pre-treatment determines the clinical usefulness of acid-labile subunit immunoassays in the diagnosis of growth hormone deficiency and acromegaly
.
Eur J Endocrinol
.
2007
;
156
(
3
):
331
9
. .
30.
Tillmann
V
,
Buckler
JM
,
Kibirige
MS
,
Price
DA
,
Shalet
SM
,
Wales
JK
, et al
Biochemical tests in the diagnosis of childhood growth hormone deficiency
.
J Clin Endocrinol Metab
.
1997
;
82
(
2
):
531
5
. .
31.
Shen
Y
,
Zhang
J
,
Zhao
Y
,
Yan
Y
,
Liu
Y
,
Cai
J
.
Diagnostic value of serum IGF-1 and IGFBP-3 in growth hormone deficiency: a systematic review with meta-analysis
.
Eur J Pediatr
.
2015
;
174
(
4
):
419
27
. .
32.
Frystyk
J
,
Freda
P
,
Clemmons
DR
.
The current status of IGF-I assays: a 2009 update
.
Growth Horm IGF Res
.
2010
;
20
(
1
):
8
18
. .
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