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Practical management of hyperinsulinism in infancy
HYPERINSULINISM
Practical management of hyperinsulinism in
infancy
A Aynsley-Green, K Hussain, J Hall, J M Saudubray, C Nihoul-F�k�t�,
P De Lonlay-Debeney, F Brunelle, T Otonkoski, P Thornton, K J Lindley
Abstract
Hyperinsulinism in infancy is one of the
most di
Ycult problems to manage in con-
temporary paediatric endocrinology. Al-
though
the
diagnosis
can
usually
be
achieved without di
Yculty, it presents the
paediatrician with formidable day to day
management problems. Despite recent
advances in understanding the patho-
physiology of hyperinsulinism, the neuro-
logical outcome remains poor, and there is
often a choice of unsatisfactory treat-
ments, with life long sequelae for the child
and his or her family. This paper presents
a state of the art overview on management
derived from a consensus workshop held
by the European network for research into
hyperinsulinism (ENRHI). The consensus
is presented as an educational aid for pae-
diatricians and childrens nurses. It o
Vers
a practical guide to management based on
the most up to date knowledge. It presents
a proposed management cascade and
focuses on the clinical recognition of the
disease, the immediate steps that should
be taken to stabilise the infant during
diagnostic investigations, and the princi-
ples of denitive treatment.
(Arch Dis Child Fetal Neonatal Ed 2000;82:F98F107)
Keywords: hyperinsulinism; treatment; hypoglycaemia;
neurological damage; cation channels
Hyperinsulinism is the most common cause of
persistent
or
recurrent
hypoglycaemia
in
infancy.
1
It is a major cause of neurological
damage and life long handicap, and the fact
that the incidence of such damage (in up to
20% of survivors) has changed little during the
past 20 years
2 3
reects the major di
Yculties in
managing the disease.
Until recently, the pathogenesis of hyperin-
sulinism remained an enigma,
4
but during the
past ve years there has been an explosion of
knowledge concerning the molecular genetics
and the membrane physiology of the condition,
which has given not only new insights into its
cause,
5
but has also opened up new concepts of
treatment.
6 7
It is now clear that the uncontrolled release
of insulin is the nal manifestation of a number
of di
Verent processes that either alter intra-
cellular biochemical pathways of the pancreatic
cell (thereby generating abnormal signals for
the secretion of insulin
8
), or alter the transport
of cations across the cell membrane. These
abnormalities perturb the stimulussecretion
coupling mechanisms that normally ensure
that the amount of insulin secreted is directly
related
to
the
ambient
blood
glucose
concentration.
8
Therefore, hyperinsulinism is characterised
by the presence of insulin concentrations that
are inappropriately high for the concentration
of blood glucose. A normal insulin concen-
tration for normoglycaemia is inappropriate in
the presence of hypoglycaemia!
Despite the new knowledge of pathogenesis,
the management of the disease still presents the
paediatrician with a choice of unsatisfactory
treatments that have major long term implica-
tions for the child and his or her family.
Because of the urgent need to improve prog-
nosis, the European network for research into
hyperinsulinism (ENRHI) was created in 1997
through the support of the European Union.
The network brings together leading basic and
clinical scientists from seven European coun-
tries to encourage collaboration, generate new
scientic data, and from these, to dene a con-
sensus guide to management.
A workshop was held in Finland in May
1999 to consider the latter, and this paper
reects the debate that occurred. As in any
other area of medicine, consensus was achieved
for many of the components of the manage-
ment cascade. Nonetheless, controversy still
surrounds other aspects, and these are dened
and considered below. Further areas of clinical
research that need to be developed are also
highlighted.
Background
Hyperinsulinaemic hypoglycaemia has previ-
ously masqueraded under a variety of di
Verent
descriptive names, including idiopathic hy-
poglycaemia of childhood, leucine sensitive
hypoglycaemia, neonatal insulinoma, pancre-
atic microadenomatosis, nesidioblastosis, per-
sistent hyperinsulinaemic hypoglycaemia of
infancy, and congenital hyperinsulinism. Both
sporadic and familial forms of the disease are
recognised, the former having an estimated
incidence in western Europe of one in 50 000
Arch Dis Child Fetal Neonatal Ed 2000;82:F98F107
F98
The London Centre for
Paediatric
Endocrinology and
Metabolism, Great
Ormond Street
Hospital for Children
NHS Trust, London
WC1N 3JH and the
Institute of Child
Health, University
College, London
WC1N 1EH, UK
A Aynsley-Green
K Hussain
K J Lindley
The Institute of
Molecular Physiology
and Department of
Biomedical Science,
University of She
Yeld,
She
Yeld S10 2TN, UK
J Hall
The Metabolic Unit of
Pediatrics and
Departments of
Radiology and
Surgery, Hospital
Necker Enfants
Malades, 75015 Paris,
France
J M Saudubray
C Nihoul-F�k�t�
P De Lonlay-Debeney
F Brunelle
Hospital for Children
and Adolescents and
the Hartman Institute
Transplantation
Laboratory, 000140
University of Helsinki,
Finland
T Otonkoski
The National Centre
for Inherited
Metabolic Disorders,
The Childrens
Hospital, Temple
Street, Dublin 1,
Ireland
P Thornton
On behalf of the
European Network for
Research into
Hyperinsulinism
(ENRHI)
Correspondence to:
Professor A Aynsley-Green,
The Institute of Child
Health, University College
London, 30 Guilford Street,
London WC1N 1EH, UK births.
9
In isolated European communities,
including parts of Finland, the disease inci-
dence is much higher
10
; the highest incidence is
found
in
societies
with
high
rates
of
consanguinity.
11
In these cultures, particularly
in the Arabian peninsular, the incidence may
be as high as one in 2500 births.
10 11
Clinical presentation and immediate
management
Most infants with hyperinsulinism present
during the 1st postnatal days, with others dur-
ing the 1st year. Rarely, older children present
de novo with symptoms of hypoglycaemia. Fig-
ure 1 shows the age distribution in one large
series of cases.
12
Hyperinsulinism can be associated with well
dened
clinical
conditions.
1316
Thus,
the
Beckwith-Wiedemann syndrome manifests a
transient hyperinsulinism and these babies
have pathognomonic physical signs including
exomphalos,
macroglossia,
and
transverse
creases of the ear lobes. This disease and the
hyperinsulinism caused by maternal diabetes,
rhesus incompatibility, perinatal asphyxia,
13
and maternal glucose and drug treatment dur-
ing delivery will not be considered further in
this paper.
Infants with hyperinsulinism might have a
characteristic appearance with macrosomia,
strongly resembling the infant of a diabetic
mother. The appearance suggests the occur-
rence of prenatal hyperinsulinism. However,
not all infants have this appearance, and some
of the most di
Ycult management problems
arise in infants born of normal or low birth
weight, including preterm infants.
17
The rst clinical manifestations of hyperin-
sulinism include non-specic features such as
oppiness, jitteriness, poor feeding, and
lethargy. More dramatically, the infants may
have seizures, coma, and even averted neonatal
death.
18
The importance of accurately measuring
blood glucose in the presence of any of these
symptoms cannot be overemphasised.
Considerable
controversy
surrounds
the
denition
of
neonatal
and
infantile
hypoglycaemia.
1921
Pragmatically, any infant
with
a
persistent
measurement
of
blood
glucose less than 2.6 mmol/litre (as measured
by an accurate laboratory method and not a
bedside screening test), particularly when
accompanied by symptoms, should be the
focus of particular attention, and the diagnosis
of hyperinsulinism considered. Any persistent
hypoglycaemia, whether symptomatic or not,
needs investigation and treatment
Blood must be drawn and saved at the time
of hypoglycaemia (together with the next urine
sample passed) for assay of the substances
listed in table 1.
A baby who cannot maintain normoglycae-
mia despite frequent enteral feeds (if necessary
via a nasogastric feeding tube) needs to have
the support of an intravenous glucose infusion
to prevent neuroglycopenia. It should com-
mence at the normal neonatal and infantile
hepatic production rate of glucose; namely,
between 46 mg/kg/min. The infusion rate
should then be titrated upwards as necessary to
maintain the blood glu