Download Congenital hyperinsulinism

Seminars in Fetal & Neonatal Medicine (2005) 10, 369e376
www.elsevierhealth.com/journals/siny
Congenital hyperinsulinism
K. Hussain*
The Institute of Child Health, Unit of Biochemistry, Endocrinology and Metabolism,
University College London, 30 Guilford Street, London WC1N 1EH, UK
KEYWORDS
Congenital
hyperinsulinism;
Hypoglycaemia;
Insulin;
Glucose;
Potassium channels;
SUR1;
KIR6.2
Summary Congenital hyperinsulinism is a cause of persistent hypoglycaemia in
the neonatal period. It is a heterogeneous disease with respect to clinical
presentation, molecular biology, genetic aetiology and response to medical
therapy. The clinical heterogeneity may range from severe life-threatening disease
to very mild clinical symptoms. Recent advances have begun to clarify the
molecular pathophysiology of this disease, but despite these advances treatment
options remain difficult and there are many long-term complications. So far
mutations in five different genes have been identified in patients with congenital
hyperinsulinism. Most cases are caused by mutations in genes coding for either of
the two subunits of the b-cell KATP channel (ABCC8 and KCNJ11). Two histological
subtypes of the disease e diffuse and focal e have been described. The
preoperative histological differentiation of these two subtypes is now mandatory
as surgical management will be radically different. The ability to distinguish diffuse
from focal lesions has profound implications for therapeutic approaches, prognosis
and genetic counselling.
ª 2005 Elsevier Ltd. All rights reserved.
Introduction
Congenital hyperinsulinism (CHI) is the most
common cause of persistent and recurrent hypoglycaemia in the neonatal period. For decades,
the disease was thought to be due to ‘nesidioblastosis’. This term, which was first used by
Laidlaw, describes the persistence of a diffuse
* Tel.: C44 20 7 905 2128; fax: C44 20 7 404 6191.
E-mail address: [email protected]
and disseminated proliferation of islet cells budding off from the pancreatic ductal tissue.1
However, it is now quite clear that nesidioblastosis is a common feature of the pancreas in
normoglycaemic neonates.2 Neonatal onset CHI is
a major risk factor for development of severe
mental retardation and epilepsy.3
Biochemically, CHI is characterized by inappropriate and unregulated insulin secretion from pancreatic b-cells. The biochemical profile at the time
of hypoglycaemia reflects the metabolic actions of
insulin. The dysregulated and uncontrolled release
1744-165X/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2005.03.001
370
of insulin from the b-cells reflects the final manifestation of a number of different processes that
alter intracellular biochemical pathways of the bcell, thereby generating abnormal signals for the
secretion of insulin.4 These abnormalities perturb
the normal physiological mechanisms which normally ensure that the amount of insulin secreted is
directly related to the ambient blood glucose
concentration. CHI is characterized by the presence of insulin and c-peptide concentrations that
are inappropriately high for the level of blood
glucose. A ‘normal’ insulin level for normoglycaemia is usually inappropriate in the presence of
hypoglycaemia, especially taken in the context of
high glucose requirement to maintain normoglycaemia.5 There appears to be very little correlation
between circulating levels of insulin at presentation and the severity of hypoglycaemia.5
Recent advances have begun to unravel the
pathophysiology of this intriguing disease as well
as providing an understanding of the normal
physiological and biochemical mechanisms regulating insulin secretion from pancreatic b-cells. It
is now clear that CHI is a heterogeneous disorder
with respect to clinical presentation, histology,
molecular biology and genetics.6 The histological
differentiation of focal and diffuse forms of CHI
has radically changed the surgical approach to this
disease, and the focal form of the disease can now
be cured by partial pancreatectomy.7,8 So far,
mutations in five different genes have been described which lead to dysregulated insulin secretion from b-cells.9e13 Despite these advances the
genetic defect is still unknown in about 50% of
cases.
Clinical presentation and diagnosis
Typically, CHI presents in the neonatal period,
usually within the first few days of birth, although
it can present later in infancy and childhood.14
Neonates will present with specific symptoms
(such as fits) or non-specific symptoms (lethargy,
irritability, poor feeding) of hypoglycaemia. Macrosomia may be a feature in some patients, but not
all neonates with CHI are macrosomic. The hypoglycaemia in CHI is persistent and recurrent, and in
most cases normoglycaemia can only be maintained by giving large volumes of intravenous
glucose. CHI can occur in preterm babies, in which
case it appears to be more severe and aggressive.15 Hypertrophic cardiomyopathy is a common
clinical finding in patients with CHI, but the
underlying mechanism for this is unclear.
K. Hussain
Hyperinsulinism can also be transient. The
transient form is associated with infants born to
mothers with diabetes mellitus (gestational
and insulin-dependent), in infants with Beckwithe
Weidemann syndrome, in intrauterine growth retardation babies, and in babies subjected to
perinatal asphyxia.16 Transient hyperinsulinism
may also occur in babies where there is no
predisposing factor.17 The mechanisms causing
transient hyperinsulinism in these conditions are
not clear.
Hyperinsulinism may also be a manifestation of
a rare syndrome such as Kabuki, Costello or Turner’s syndrome (Hussain K, unpublished observations) or congenital disorders of glycosylation18
and some undiagnosed syndromes.19
Foregut dysmotility and gastro-oesophageal reflux is common in CHI.20 The pathophysiology of
the gut dysmotility and the gastro-oesophageal
reflux is unclear. Infants may show poor sucking
and swallowing, retching, vomiting, and intestinal
dilatation; feeding problems are compounded by
the use of nasogastric or gastrostomy feeds, which
delay the establishment of normal feeding patterns, taste, and ‘orality’. In severe cases, the
deprivation of oral stimulation may require months
of rehabilitation with skilled speech and language
therapists.
The biochemical hallmark of CHI is hyperinsulinaemic, hypoketotic, hypofattyacidaemic hypoglycaemia. These biochemical abnormalities reflect
the metabolic actions of insulin. The unregulated
insulin secretion causes increased glucose disposal
in insulin-sensitive tissues such as the liver (hepatomegaly on clinical examination), adipose tissue
and skeletal muscle, and simultaneously inhibits
glucose production. There is also higher glucose
demand in the absence of alternative fuels. This is
reflected in the increased glucose clearance rate
(above the normal of 5 mg/kg/min) required to
maintain normoglycaemia. The serum cortisol
counter-regulatory hormone levels are blunted in
hyperinsulinaemic hypoglycaemia due to the lack
of drive from the hypothalamicepituitary axis, and
replacement therapy with glucocorticoids does not
seem to affect the severity of the disease.21
In most cases the diagnosis of CHI is relatively
straightforward, but in difficult cases other supportive evidence is required: for example, decreased serum levels of insulin growth factor
binding protein 1 (IGFBP-1) (as insulin suppresses
the transcription of the IGFBP-1 gene),22 a positive
glycaemic response to intramuscular/intravenous
glucagon at the time of hypoglycaemia (a clear
increment in blood glucose concentration despite
severe hypoglycaemia),23 and a positive glycaemic
Congenital hyperinsulinism
response to octreotide with a concomitant reduction in the glucose infusion rate required to
maintain normoglycaemia.
371
KIR 6.2
(KCNJ11gene)
SUR 1
(ABCC8 gene)
ATP/ADP
Pathophysiology of CHI
Under normal physiological conditions the pancreatic b-cells are exquisitely sensitive to the plasma
glucose concentration and secrete appropriate
amounts of insulin. Pancreatic b-cells possess
a signal transduction system whereby metabolic
changes in the b-cell are linked to regulated insulin
secretion.24 The metabolic changes are linked to
regulated insulin secretion by potassium channels
(KATP) located in the pancreatic b-cell membrane.25
Each KATP channel consists of a heteromultimeric
complex of at least two proteins designated SUR1
(ABCC8 gene) and KIR6.2 (KCNJ11 gene).26 The
functional integrity of both of these proteins is
necessary for potassium channel movement, and
the genes responsible for them have been localized very closely to each other on the short arm of
chromosome 11 (11p14-15.1). Under normal physiological conditions the KATP channels maintain the
electrical potential of the b-cell membrane. The
metabolism of glucose in the b-cell increases
the ratio of ATP/ADP, which has the effect of
closing the KATP channels. This in turn causes the
opening up of voltage-gated calcium channels,
which regulate the entry of calcium into the bcell. The entry of calcium is thought to be the final
stimulus for insulin exocytosis.25 Fig. 1 illustrates
the role of KATP channels and voltage-gated calcium
channels in regulating insulin secretion.
Although KATP channels have an essential role in
linking the metabolism of glucose to the secretion
of insulin, there is now evidence that there may
well be other mechanisms of insulin secretion: the
so-called KATP channel-independent pathways of
insulin secretion.27
The commonest genetic cause of persistent CHI
is an abnormality of the KATP channels.28 A number
of mutations in the ABCC8 and KCNJ11 genes have
been defined, particularly in children with the
familial forms of CHI.9,10 These mutations impair
the function of the KATP channel by affecting
channel density, channel expression, channel trafficking from the Golgi apparatus and endoplasmic
reticulum, channel gating properties and channel
activity in response to changes in the concentrations of intracellular nucleotides.
Rare causes of CHI include gain-of-function
mutations (autosomal dominant) in the genes encoding the enzymes glucokinase (GK) and glutamate
GLUCOSE
Ca2+
Ca2+
Mitochondria
Pancreatic β-cell
EXOCYTOSIS
Figure 1 KATP channels link glucose metabolism to
regulated insulin secretion. The KATP channel responds
to changes in the concentration of intracellular nucleotides such as ATP/ADP. Glucose metabolism in the
pancreatic b-cell increases the ATP/ADP ratio. This has
the effect of closing the KATP channels, allowing the
entry of calcium. The entry of calcium is the trigger for
exocytosis of insulin. The commonest causes of CHI are
mutations in the genes (ABCC1 and KCNJ11) that
regulate the function of the two proteins of the KATP
channels (SUR1 and KIR6.2, respectively).
dehydrogenase (GDH).11,12 CHI due to abnormalities in these enzymes is usually less severe and
often presents late.
GK is a key glycolytic enzyme that functions as
a glucose sensor in the pancreatic b-cell, where it
governs glucose-stimulated insulin secretion. GK
mutations alter the threshold of glucose-stimulated
insulin release and glucose homeostasis. The gainof-function mutation in glucokinase causes increased affinity of glucokinase for glucose, with
increased rates of glycolysis at low blood glucose
concentrations. This then increases insulin secretion at any given blood glucose concentration.
GDH is a mitochondrial enzyme that catalyses
the oxidative deamination of glutamate to aketoglutarate plus ammonia, using NAD or NADP
as cofactor. The a-ketoglutarate then enters the
Kreb’s cycle to produce ATP. The syndrome of
hyperinsulinism/hyperammonaemia (HI/HA) is associated with dominantly expressed missense mutations in GDH. HI/HA mutations impair GDH
sensitivity to its allosteric inhibitor GTP, resulting
in a gain of enzyme function and increased
sensitivity to its allosteric activator leucine. The
clinical picture is characterized by postprandial
hypoglycaemia following protein meals, as well as
fasting hypoglycaemia. Plasma ammonia levels are
increased to 3e5 times normal, but the mechanism
of this is unclear.
Another novel form of CHI recently described is
due to autosomal recessive mutations in the gene
encoding the enzyme short-chain L-3-hydroxyacylCoA dehydrogenase (SCHAD).13,29 This enzyme is
372
involved in the penultimate pathway of fatty acid
b-oxidation. This defect provides the first clue to
the in vivo dysregulation of insulin secretion by
defects in the metabolism of fatty acids. The
precise mechanism of dysregulated insulin secretion in children with SCHAD deficiency is not
understood.
Management
Neonatal CHI is one of the most difficult diseases
to manage in paediatric endocrinology. Patients
should be referred to centres that have the
necessary experience and expertise in managing
this condition. These patients will require frequent
and accurate blood glucose monitoring with
prompt diagnosis and aggressive management of
the hypoglycaemia. The goals of management
include preventing hypoglycaemic brain damage,
allowing normal psychomotor development, establishing a normal feeding pattern (content and
frequency for the age of the child), ensuring
normal tolerance to fasting for age without developing hypoglycaemia, and maintaining family
integrity.
Medical management
The immediate imperative is to give sufficient
glucose to maintain blood glucose concentrations
above 3.5 mmol/L. Adequate carbohydrate can be
provided as intravenous glucose in high concentrations, together with a nasogastric feeding tube
for regular feeds. Glucose polymer can be added
to the enteral feed to increase the carbohydrate
intake but should be used with caution in neonates
at risk of necrotizing enterocolitis. Some infants
may require the insertion of a gastrostomy for
regular and frequent feeds.
Infusion rates in excess of 4e6 mg/kg/min are
usually necessary. Rarely, infusion rates O20 mg/
kg/min may be needed.30 The delivery of concentrated glucose infusions will require the insertion
of an umbilical venous catheter or central venous
access.
Having stabilized the blood glucose concentration, it is then imperative to determine whether
the patient will respond to the conventional
medical therapy. If there is no response to medical
therapy the only other option is surgical.
The mainstay of medical therapy is diazoxide.
This drug works by locking onto the intact SUR
component of the KATP channel. By keeping the
channel open it stops insulin secretion. CHI due to
abnormalities in the enzymes GK, GDH and SCHAD
K. Hussain
all respond to diazoxide, as these do not involve
defects in KATP channels. However, patients with
mutations in the KATP channel may not respond to
diazoxide. The major side-effect of diazoxide in
the short term is fluid retention. In the long term
hirsutism is the main cosmetic side-effect. Chlorothiazide is used in conjunction with diazoxide for
its hyperglycaemic action as well as to counteract
the fluid-retaining properties of diazoxide.31
Given the role of the voltage-gated calcium
channels in regulating insulin secretion, the use
of a calcium-channel antagonist such as nifedipine
has been proposed.32 However, despite several
case reports documenting nifedipine-responsive
CHI,33 the overall response to nifedipine has been
disappointing.
Glucagon and octreotide have several different
roles in the management of an infant with CHI.
Intramuscular glucagon (1 mg) can be used in the
acute management of hypoglycaemia due to hyperinsulinism when intravenous access is unavailable. Glucagon acutely stimulates glycogenolysis,
but also has actions on gluconeogenesis, lipolysis,
protein degradation, amino acid catabolism and
ketogenesis. Onset of action of glucagon is within
10e15 min. A subcutaneous or intravenous continuous infusion of glucagon (in combination with
octreotide) is used in the short term to maintain
stability until further investigations are planned.
High doses of glucagon (O20 mg/kg/h) can cause
paradoxical insulin secretion, which leads to worsening of the hypoglycaemia in patients with CHI.34
Octreotide is an analogue of somatostatin and is
used in the short- and long-term management of
patients with CHI. Somatostatin and its analogues
inhibit insulin secretion by activation of somatostatin receptor 5, which is mediated by stimulation
of the G-coupled proteins.35 Octreotide can be
administered by subcutaneous injection or as
a continuous subcutaneous infusion. Octreotide
also causes the inhibition of the release of several
hormones, including growth hormone (GH), serotonin, gastrin, vasoactive intestinal polypeptide
(VIP), secretin, motilin, pancreatic polypeptide,
ACTH, and thyroid-stimulating hormone (TSH). The
suppression of GH (including insulin-like growth
factors) and thyroid hormones may lead to stunting
of growth, although in clinical practice this does
not seem to be a problem. Octreotide can decrease gallbladder contractility and bile secretion
leading to steatorrhoea, cholestasis, hepatic dysfunction and cholelithiasis. Blood flow to the
splanchnic circulation is decreased by octreotide,
hence it must be used cautiously in babies at risk
of necrotizing entercolitis. Resistance to octreotide therapy can occur even at high doses.
Congenital hyperinsulinism
373
The medications used in the treatment of CHI
are summarized in Table 1.
Surgical management
Those children who fail to respond to medical
therapy will require surgery. The extent of surgery
will depend on the histological subtype of CHI. Two
histological subtypes of CHI e diffuse and focal e
have been described.2 The diffuse form is characterized by changes of b-cell hypertrophy and
hyperplasia throughout the whole pancreas. The
diffuse form is classically associated with defects
in SUR1 and KIR6.2.
The focal lesion is confined to one region of the
pancreas and is distinct from an insulinoma.36 It is
associated with a unique combination of events,
with somatic loss of the maternal allele on the
short arm of chromosome 11, in a child harbouring
an SUR1 or a KIR6.2 mutation on the paternal
allele.37,38 The juxtaposition of SUR1 and several
imprinted genes on chromosome 11p15 appears to
be responsible for this unique genetic mechanism
of disease. About 40e50% of infants will have the
focal form of the disease.
It is now imperative to identify those children
with the focal disease, as their management will
Table 1
be radically different compared to those with
diffuse disease. Those with focal disease will
require a limited pancreatectomy with the aim of
resecting only the focal lesion and preserving as
much normal pancreatic tissue as possible. On the
other hand those with diffuse disease will usually
require a near-total pancreatectomy.
Pancreatectomy is not without risk and is not
a procedure to be undertaken lightly. Some children remain hypoglycaemic despite this, when
a further attempt can be made to control the
condition by diazoxide therapy. In a minority of
cases, a total pancreatectomy may be necessary to
control the severe hyperinsulinism. The risk of
developing diabetes mellitus following a near-total
pancreatectomy remains high.39
The typical diffuse form of the disease can now
be identified by performing a laparoscopic tail
biopsy of the pancreas (Hussain K et al., unpublished observation). Current methods of localizing
focal lesions include intrahepatic pancreatic portal
venous sampling40 and the intra-arterial calcium
stimulation test.41 Even more recently 18F-fluoro-Ldopa PET (positron emission tomography) has been
successfully used to localize the focal domain.42
This has many advantages over the highly invasive
pancreatic venous sampling and intra-arterial calcium stimulation tests.
Summary of the dietary, medical and surgical management of different forms of CHI
Medication
Route of
administration
Dose
Mechanism of action
Side-effects
Diazoxide
Oral
5e20 mg/kg/day
divided into
two or three
doses
Agonist of the
KATP channel
Fluid retention, hypertrichosis,
hyperuricaemia, eosinophilia,
leukopenia, rarely hypotension
Chlorothiazide
(used in
conjunction with
diazoxide)
Oral
7e10 mg/kg/day
divided into two
doses
Activation of KATP
channels; synergistic
response with
diazoxide
Hyponatraemia, hypokalaemia
Nifedipine
Oral
0.25e2.5
mg/kg/day
divided into
three doses
Calcium channel
blocker
Hypotension
Glucagon
SC/IV infusion
(Goctreotide)
1e20 mg/kg/h
Increases
glycogenolysis and
gluconeogenesis
Nausea, vomiting,
paradoxical insulin
secretion; skin rashes
Octreotide
SC/IV
continuous
infusion 6e8
hourly SC
injections
(Gglucagon)
5e25 mg/kg/day
Multiple actions in
the b-cell (see text)
Suppression of GH, TSH, ACTH,
glucagons; Diarrhoea,
steatorrhoea, cholelithiasis,
abdominal distension,
growth suppression,
tolerance
GH, growth hormone; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotrophic hormone.
374
Table 2
K. Hussain
Summary of medical therapy used for the management of CHI
Type of CHI
Diet
Medical
Surgical
Diffuse (KATP channel defect in
SUR1 or KIR6.2)
High calorie/frequent
feeding
D/C/N/G/O
Near-total
pancreatectomy
Focal (KATP channel defect in paternal
SUR1 or KIR6.2 with loss of heterozygosity)
High calorie/frequent
feeding
D/C/N/G/O
Limited
pancreatectomy
Glutamate dehydrogenase (GDH)
up-regulation
Protein
restriction/high calorie
D
No surgery
Glucokinase (GK) up-regulation
High calorie
D
No surgery
SCHAD deficiency
High calorie
D
No surgery
D, diazoxide; C, chlorothiazide; N, nifedipine; G, glucagon; O, octreotide.
The medical and surgical treatment of CHI is
summarized in Table 2.
Mice knockout models of KATP channels
and CHI
Three mouse models have been developed to
understand the role of KATP channels in the
regulation of insulin secretion. These models include homozygous KIR6.2ÿ/ÿ knockout mice,43 the
expression of a dominant negative mutant KIR6.2
subunit that reduces or eliminates KATP channel
activity44 and SUR1 knockout.45
Transgenic mice are only mildly hypoglycaemic
at birth, but become hyperglycaemic within 4
weeks as a result of b-cell destruction.44 The
deletion of SUR1 or KIR6.2 from mouse pancreatic
b-cells has unexpectedly little or no effect on
glucose homeostasis, in contrast to the predicted
hypoglycaemic phenotype seen in humans. The
knockout animals do not have persistent hyperinsulinaemic hypoglycaemia despite the abolition
of KATP channels. They may have a compensation
mechanism using an as-yet-undefined KATP-independent regulatory pathway to maintain nearnormal insulin and blood glucose concentrations.
The reasons for the lack of correlation between
the mouse and human phenotypes with CHI are not
entirely clear.
Natural history of CHI
There is now some evidence to show that the
natural history of CHI is a slow progressive loss of
b-cell function, and this may be due to the
increased b-cell apoptosis.46 It has been shown
that patients with CHI who have had their pancreas
removed, and who have mutations in the ABCC8
(SUR1) gene, have increased number of apoptotic
cells in focal lesions.47 The precise mechanism of
apoptosis is unclear but may be related to the
increased intracellular calcium concentrations as
a result of unregulated calcium entry.48
A unique example of the natural history of CHI is
illustrated by the dominant heterozygous missense
mutation (E1506K) in the sulphonylurea receptor
ABCC8 gene in a large Finnish family.49 In the
infancy period heterozygous E1506K carriers of this
mutation have a mild form of CHI which is responsive to diazoxide.49 In early adulthood this
mutation causes loss of insulin secretory capacity
with glucose intolerance, and then in middle age
diabetes mellitus develops. The underlying mechanism of how this mutation causes the development of diabetes mellitus over time is thought to
be related to apoptosis, but this is unproven.
Neurological outcome
Neurological outcome depends on age at presentation. Although there are no studies documenting
the frequency, severity, and duration of persistent
hyperinsulinaemic hypoglycaemia which results in
brain injury, neonates with medically unresponsive
CHI are at an increased risk of neurological
damage.3 Other factors which increase the risk of
brain damage include delay in establishing the
diagnosis and the need for surgical treatment.50
There seems to be no difference in neurological
outcome between diffuse or focal CHI presenting
in the neonatal period.3
Conclusions
CHI is a cause of persistent and recurrent hypoglycaemia in the newborn period. In order to
prevent brain damage the hypoglycaemia must be
managed promptly. The differentiation of focal and
Congenital hyperinsulinism
diffuse disease is now imperative as management is
different for the two forms. Evidence is emerging
that some forms of CHI may be associated with slow
progressive loss of b-cell function. Mice knockout
models of CHI are phenotypically different from
the human phenotype.
Practice points
CHI is a cause of persistent hypoglycaemia
in the neonatal period
The biochemical profile is one of hypofattyacidaemic, hypoketotic hyperinsulinaemic hypoglycaemia (no alternative
substrates for the brain to use); hence
management of the hypoglycaemia must
be prompt in order to avoid brain damage
The surgical management of the focal form
of CHI is different from that of the diffuse
form
Infants with CHI should be referred to
a centre that has the expertise and
experience to manage these patients
Research directions
Understanding the genetic basis of CHI in
the remaining 50% of patients
Understanding the mechanisms leading to
transient hyperinsulinism
Developing new therapeutic interventions
for children with diffuse disease so that
near-total pancreatectomy can be avoided
Understanding why mouse models of CHI
are phenotypically different from the
human phenotype
Acknowledgements
Research at the Institute of Child Health and Great
Ormond Street Hospital for Children NHS Trust
benefits from research and development funding
received from the NHS Executive.
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