Congenital Hyperinsulinism
Paul S Thornton
Clinical Director of the Hyperinsulinism Programme
Children's Hospital of Philadelphia
Congenital Hyperinsulinism is the most frequent cause of severe,
persistent hypoglycaemia in newborn babies and children. In most
countries it occurs in approximately 1/25,000 to 1/50,000 births.
About 60% of babies with hyperinsulinism develop hypoglycemia
during the first month of life. An additional 30% will be diagnosed
later in the first year and the remainder after that. With early
treatment and aggressive prevention of hypoglycaemia, brain damage
can be prevented. However, brain damage can occur in up to 50%
of children with hyperinsulinism if their condition is not recognized
or if treatment is ineffective in the prevention of hypoglycaemia.
This article will explain the different forms of hyperinsulinism.
The mechanisms of each type of hyperinsulinism will be outlined
and will include the genetic defects responsible and their mode
of inheritance. Treatment options and recent advances in diagnosis
will be presented.
Mechanisms of Disease
Insulin is the most important hormone for controlling the concentration
of glucose in the blood. As food is eaten, blood glucose rises
and the pancreas secretes insulin to keep the blood glucose in
the normal range. Insulin acts by driving glucose into the cells
of the body. This action of insulin has two effects 1) maintaining
blood glucose between 3.3mmol/L to 5mmol/L (60 to 90 mg/dl) and
2) storing glucose particularly as glycogen in the liver. Once
feeding is completed and the glucose levels fall, insulin secretion
is turned off, allowing the stores of glucose in glycogen to be
released into the bloodstream to keep blood glucose normal. In
addition, with the switching off of insulin secretion, protein
and fat stores become accessible and can be used instead of glucose
as sources of fuel. In this manner, whether one eats or is starved
(fasted), blood glucose levels remain in the normal range and
the body has access to energy at all times.
With hyperinsulinism, however, this close regulation of blood
glucose and insulin secretion is lost. The pancreas, which is
responsible for insulin secretion, is blind to the blood glucose
level and makes insulin regardless of the blood glucose concentration.
As a result, the child with hyperinsulinism can develop hypoglycaemia
at any time but particularly when fasting. In the most severe
form of hyperinsulinism this glucose blindness causes frequent,
random episodes of hypoglycaemia. With one of the rarer forms
of hyperinsulinism, hypoglycaemia is related to protein ingestion.
Hyperinsulinism causes a particularly damaging form of hypoglycaemia
because it denies the brain of all the fuels on which it is critically
dependent. These fuels are glucose, ketones, and lactate. The
usual protective measures against hypoglycaemia, such as conversion
of protein to glucose (called gluconeogenesis) and conversion
of fat into ketones (called fatty acid oxidation and ketogenesis)
are prevented by insulin. Once the brain cells are deprived of
these important fuels, they can not make the energy they need
to work and so they stop working. This loss of function may result
in seizures and coma and if prolonged may result in death of the
cells. It is this cell demise which causes the damage which manifests
as learning disabilities, cerebral palsy, blindness or even death.
Causes of Hyperinsulinism
A number of causes exist. Some forms will resolve and are considered
transient. Others arise from genetic defects and persist for life.
These genetic forms of hyperinsulinism do not go away, but in
some cases, may become easier to treat as the child gets much
older.
Transient hyperinsulinism
Babies who are born small for gestational age, or prematurely,
may develop hypoglycaemia due to excessive insulin secretion.
In addition, infants in whom fetal distress occurred due to lack
of oxygen to the brain may also have hypoglycaemia from hyperinsulinism.
The cause of this inappropriate insulin secretion is unclear,
but it can last a few days to months. Once recognized, this form
of hyperinsulinism is usually easy to treat. Many affected infants
will not have hypoglycaemia once they are fed every 3-4 hours.
In the more severely affected children, intravenous glucose is
needed to prevent hypoglycaemia. Rarely, drug therapy is required;
in which case, diazoxide is usually a very effective treatment.
Children with this form of hyperinsulinism should have a fasting
study done whilst off all medications , to prove that the hyperinsulinism
was transient.
A small number of babies born to mothers with diabetes mellitus
may have hyperinsulinism. This hyperinsulinsim tends to occur
if the mother's diabetes was not under good control. The mother's
high blood glucose levels are transmitted across the placenta
to the fetus. The fetus compensates by secreting extra insulin.
This step-up in insulin secretion does not cause hypoglycaemia
while the fetus is inside the mother, but after birth, the constant
supply of high glucose from the placenta is gone and the blood
sugar in the newborn falls precipitously. This form of hyperinsulinism
should resolve within a few days of intensive intravenous drip
feeding of glucose. Once the hypoglycaemia resolves, it should
never recur.
Persistent Hyperinsulinism
Although the persistent forms of hyperinsulinism are uncommon,
a number of different genetic defects causing hyperinsulinism
have recently been recognized. In the past, before the different
genetic forms of hyperinsulinism were recognized, hyperinsulinism
was referred to by many names, including nesidioblastosis, islet
cell dysregulation syndrome, idiopathic hypoglycaemia of infancy,
Persistent Hyperinsulinaemic Hypoglycemia of Infancy (PHHI) and
Congenital Hyperinsulinism. With the identification of the genes
responsible for these disorders, the naming of the different forms
of hyperinsulinism has become more exact.
KATP -HI Diffuse or Focal Disease
The KATP form of HI is considered the classic form of hyperinsulinism
and previously was known as "nesidioblastosis" or "PHHI".
It is usually found in newborns who have larger than normal birth
weights (many weigh above 9lbs) and occurs in the first days of
life. It is called KATP-HI because its genetic cause is due to
defects in either of two genes that make up the potassium channel
(called KATP channel) in the insulin secreting beta-cells of the
pancreas. These two genes are the SUR1 gene and the Kir6.2 gene.
Normally, when the beta cell senses that glucose levels are elevated,
the KATP channel commences insulin secretion. When the KATP channel
is defective, inappropriate insulin secretion occurs and causes
hypoglycemia.
Two forms of KATP-HI exist: diffuse KATP-HI and focal KATP-HI.
When these mutations are inherited in an autosomal recessive manner
(one mutation in the gene inherited from each parent, neither
of whom is affected) they cause diffuse disease, meaning every
beta-cell in the pancreas is abnormal. Recently autosomal dominant
mutations (a mutation in a single copy of the gene causes disease
and whichever parent has the mutation will also have the disease)
have been found in the KATP channel and also cause diffuse disease.
When a loss of heterozygosity (inheritance of a mutation from
the father and loss of the mother's good gene from a few cells
in the pancreas) occurs a focal lesion arises. Abnormal beta cells
are limited to this focal lesion and are surrounded by normal
beta-cells. The beta-cells of the focal lesion have lost the mother's
normal KATP channel and are only able to express the father's
defective KATP channel.
Children with either form of KATP-HI are identical in their appearance
and behavior. They tend to have significant hypoglycaemia within
the first few days of life and require large amounts of glucose
to keep their blood glucose normal. They may have seizures due
to hypoglycaemia. Diazoxide is usually an ineffective treatment
for these children because diazoxide works on the broken KATP
channel and it cannot fix the broken channels. Other drugs have
been used to treat KATP-HI but are also usually poorly effective.
Octreotide given by injection every 6 to 8 hours or by continuous
infusion and nifedipine may be successful in the short term. Glucagon
may be given by intravenous infusion to stabilize the blood sugar
as a temporizing measure. Some centres advocate a very intensive
regimen of feeding every two hours and four to six injections
a day of octreotide or continuous octreotide by subcutaneous pump.
We prefer the surgical approach. With the recent discovery of
diffuse and focal KATP-HI, attempts to differentiate these two
forms are very important: surgical therapy will cure focal HI
but not diffuse HI (see below).
GDH-HI
GDH-HI has also been known as the Hyperinsulinism/Hyperammonaemia
Syndrome (HI/HA), leucine-sensitive hypoglycaemia, and diazoxide-sensitive
hypoglycaemia. GDH-HI is caused by a mutation in the enzyme glutamate
dehydrogenase (GDH). It is inherited in either an autosomal dominant
manner or may arise as a sporadically new mutation in a child
with no family history. GDH plays an important role in regulating
insulin secretion stimulated by amino acids (especially leucine).
Individuals with GDH-HI develop hypoglycaemia after eating a high
protein meal. GDH-HI affected individuals can have significant
hypoglycaemia if they eat protein (for instance eggs or meat)
without eating sugar containing foods such as bread, juice or
pasta. GDH-HI is also associated with elevated blood concentrations
of ammonia, which is derived from protein. These high ammonia
levels, however, do not appear to be harmful in GDH-HI.
Patients with GDH-HI often present later that KATP channel HI.
Typically, not until three to four months of age when they wean
from low protein containing breast milk to infant formula. Others
do not have recognizable hypoglycaemia until they sleep overnight
without a middle of the night feed or after they start higher
protein-containing solid foods such as yoghurt. The frequency
of hypoglycaemia is usually less than that associated with KATP-HI.
In addition, GDH-HI can be successfully treated with diazoxide
and the avoidance of pure protein loads. Most children with GDH-HI
will do very well once recognized, but if the diagnosis is delayed,
they may also suffer brain damage from untreated hypoglycemia.
GK-HI
Three families are now known with mutations of the enzyme glucokinase.
This defect was inherited in an autosomal dominant fashion but
likely can arise sporadically. Glucokinase is the "glucose
sensor" for the beta-cell. It tells the beta-cell how high
the blood glucose is and when to secrete insulin. Glucokinase
mutations that cause hyperinsulinism instruct the beta-cell to
secrete insulin at a lower blood glucose than is normal. Like
GDH-HI, GK-HI can be treated with diazoxide. Genetic tests for
the GK gene are available in only a few centers.
Others
Other forms of hyperinsulinism are known to exist, but the genetic
mutations responsible have yet to be identified. Their clinical
features and response to therapy vary.
Diagnosis
The diagnosis of hyperinsulinism may be quite difficult if one
relies on demonstrating an elevated blood insulin concentration
at the time of hypoglycaemia because insulin levels fluctuate
widely over time in patients with hyperinsulinism. Other signs
and chemical markers must be used to provide clues to excess insulin
action and are often easier to demonstrate. Hypoglycaemia which
occurs while an infant is on a glucose infusion is strongly suggestive
of HI. Other clues to excess insulin action are low free fatty
acids and ketones at the time of hypoglycaemia. Another indicator
of excess insulin can be demonstrated by the glucagon stimulation
test. Glucagon is a hormone that opposes insulin action and stimulates
release of glucose from liver glycogen stores. A rise in blood
glucose after glucagon administration at the time of hypoglycaemia
is a sensitive marker for hyperinsulinism. Ketones, free fatty
acids, and the glucagon stimulation test may all be performed
if a random episode of hypoglycaemia occurs. A fasting study is
sometimes required to provoke hypoglycaemia and confirm the diagnosis
of HI.
The identification of genetic defects responsible for hyperinsulinism
and the improved understanding of the mechanism of abnormal insulin
secretion have permitted the development of insulin secretion
studies aimed at identifying the specific type of hyperinsulinism
a child may have. The acute insulin response studies (AIRs) are
performed by serially administering intravenous injections of
glucose and drugs (calcium, tolbutamide which stimulates insulin
secretion through SUR1 and leucine, an amino acid) over a short
period of time. Insulin measurements are taken just prior to and
for 5 minutes after the infusions. The specific pattern of insulin
responses to these agents can help delineate the genetic defect
affecting the beta-cell.
If a focal lesion is suspected based upon the acute insulin response
studies, an attempt to identify the location of the lesion in
the pancreas can be undertaken. Localization of the lesion helps
the surgeon identify the lesion in the pancreas and may avoid
subjecting needlessly an infant with a focal lesion to a 95% pancreatectomy.
One of the localization studies available is called pancreatic
arterial stimulation venous sampling (ASVS). ASVS involves placement
of a catheter (a long intravenous line) into the artery of the
leg. Through this catheter the radiologist injects calcium into
each of the three arteries that supplies blood to the various
regions of the pancreas (head, body, and tail). Through an intravenous
line inserted into the child's neck, blood samples are obtained
to measure the insulin coming out of the pancreas. An increase
in insulin secretion, after injection of calcium into one of the
three arteries, suggests the location of the focal lesion (head,
body, or tail).
Transhepatic Portal Venous Sampling (THPVS) is another procedure
designed to localize the site of a focal lesion. A catheter is
inserted through the skin, into the liver, and into the veins
of the pancreas. Blood samples for insulin are obtained throughout
the various regions of the pancreas. The location of the focal
lesion is suggested by the region of the pancreatic venous system
with the highest insulin concentrations.
Treatment
Prompt treatment of hypoglycaemia due to hyperinsulinism is essential
to prevent brain damage. Unlike other hypoglycaemia-causing conditions
in which alternative fuels, such as ketones or lactate, may be
available for the brain during periods of hypoglycaemia, hyperinsulinism
prevents the production of these fuels and leaves the brain without
a source of energy. Hypoglycaemia can be treated by giving a carbohydrate-containing
drink by mouth or if severe, by giving glucose through the vein
or by injecting glucagon. A child with a feeding tube can have
glucose given through the tube. The goal of treatment is to prevent
hypoglycaemia while the child has a normal feeding pattern for
age with a little extra safety built in, e.g., a one year old
who normally would not eat overnight for 10-12 hours should be
able to fast for at least 14 -15 hours on a successful medical
regimen.
Medications used to treat hyperinsulinism include diazoxide, octretide,
and glucagon:
Diazoxide. Diazoxide is given by mouth 2-3 times per day. The
dose varies from 5 to 20mg/kg/day. Usually, if 15 mg/kg/day does
not work, higher doses will not work. Diazoxide acts on the KATP
channel to prevent insulin secretion. It is generally effective
for infants with stress-induced hyperinsulinism, infants with
GDH-HI or GK-HI, and in a subgroup of infants whose basic defect
is not known. Diazoxide rarely works in children KATP-HI.
Side effects of diazoxide include fluid retention, a particular
problem for the newborn which has received large amounts of intravenous
glucose to maintain the blood glucose in the normal range. A diuretic
medication (hydrochlorthiazide or chlorthiazide) is sometimes
used with diazoxide in anticipation of such a problem. Diazoxide
also causes a cosmetic problem of excessive hair growth of the
eyebrows, forehead, and back. This hair growth resolves several
months after diazoxide therapy is stopped. Shaving the hair occasionally
may be necessary and does not intensify hair growth.
Nifedipine. This is an oral medication, used to treat high blood
pressure, that blocks calcium entry into the cells. In theory,
it should work well to prevent hypoglycaemia, however in practice
it rarely does. There are several publications indicating its
success but overall most people who treat larger groups of children
with HI say that it works in less than 10 % of patients.
Octreotide. Octreotide is a drug that also inhibits insulin secretion.
It is administered by injection. It can be given periodically
throughout the day by subcutaneous injection or may be administered
continuously under the skin by a pump that is commonly used for
insulin therapy in individuals with diabetes. Octreotide is often
very effective initially, but its initial effectiveness may wane
with time and it becomes less effective. In addition more is not
always better as the higher the dose (higher than 20 -40 microgramms/kg/day)
the less effective it may become. Side effects include alteration
of gut motility, which may cause poor feeding. It may also cause
gallstones and very rarely may produce hypothyroidism, and short
stature. As with any injection, risks of pain, infection, and
bruising exist.
Glucagon. Glucagon stimulates release of glucose from the liver.
It is given through a vein or by injection under the skin or into
the muscle. Glucagon can be used in cases of emergency when a
child with hyperinsulinism has low blood glucose and cannot be
fed. It can also be given in the hospital as a continuous infusion
through a vein. It is most effective as a holding therapy while
the child is prepared for surgery.
Surgery
Children with diffuse KATP-HI commonly require 95-99% pancreatectomies.
These surgeries are not always curative, and KATP-HI children
who have undergone such surgeries may continue to require frequent
feeds and medications to prevent hypoglycemia. They also may need
repeat surgeries. The hope with such surgery is to lessen the
intense medical regimen that otherwise would be needed to protect
the child from recurrent, severe hypoglycaemia.
In children with focal KATP channel HI, surgery to remove only
a small part of the pancreas is the procedure of choice. This
requires a team of endocrinologists, pathologists and surgeons,
specialized in this procedure. Therefore it is generally only
available in the major centres treating patients with hyperinsulinism.
The majority of patients with Focal HI will be cured or will not
require any medical therapy after the surgery. This is in stark
contrast to those with diffuse disease in whom medical therapy
after surgery is the rule.
Focal lesions can be cured with surgery. The difficulty, however,
is that many focal lesions are found in the head of the pancreas.
The immediate surroundings of the pancreatic head include important
structures such as the bile ducts and duodenum. Successfully resecting
a lesion in the head of the pancreas without harming these other
important structures may sometimes be impossible.
Outcome
Prognosis is greatly influenced by the form (severity) of hyperinsulinism
an affected child has. The most severe long term complication
is brain damage. Even in the centres most experienced in treating
children with hyperinsulinism, rates of up to 20% of the children
suffer permanent damage. For all children, the development of
permanent learning disabilities is difficult to predict and depends
not only on the frequency of low blood glucose but also the duration
of a hypoglycemic episode. In addition to learning disabilities,
stroke like symptoms or cerebral palsy can occur. Strabismus (turned
in eye) or blindness may also be caused by hypoglycaemia.
Children with diffuse disease who have a 95-99% pancreatectomy
will continue to be at risk for hypoglycaemia. Occasionally a
second or third surgery may be required. The hypoglycemia post
surgery is usually easier to control than prior to surgery. Diabetes
in both the immediate post-operative period and in the long term
is a greater risk in patients with diffuse disease. Failure to
absorb the food from the gut may be a problem due to loss of the
enzymes produced by the pancreas for digestion of food. This may
require enzyme replacement.
Children with focal lesions that are successfully resected with
partial pancreatectomies are cured of their disease and are not
anticipated to have an increased risk of diabetes mellitus or
of food mal-absorption
Technically less disabling, but a very serious problem, are feeding
difficulties. There is a lot of debate about the cause of these
difficulties. The two main theories currently discussed are a
primary problem in abnormal gut motility due to the genetic defect
responsible for hyperinsulinism. This in theory should only therefore
be found in patients with diffuse disease. Because it is found
in both diffuse and focal disease, the second possibility is that
feeding difficulties commonly occur as a result of the therapy
of the hyperinsulinism. Long term tube feeds and the use of intravenous
fluids without oral feeding, designed to prevent hypoglycaemia,
may hinder the child from learning how to feed by mouth during
the critical first two to three months of life. Later, excessive
weight associated with forced tube feeding to prevent hypoglycemia
may suppress the appetite and thus prevent the child from developing
the desire to eat. Attempts should be made to encourage the child
to feed by mouth from birth in addition to whatever other therapies
are required, and early intervention by a feeding specialist should
be implemented, to decrease the risk of development of feeding
problems. In this manner, feeding difficulties will be reduced
dramatically.
Children with HI/HA and other forms of hyperinsulinism which
are diazoxide responsive tend to do well long-term but will need
occasional in-hospital monitoring of home regimens to insure safety
and for dose adjustments. The elevated blood ammonia concentrations
do not seem to cause problems in GDH-HI.
Finally, but equally important, are the stresses for the family.
Prolonged hospitalizations requiring parents to be away from home
or work, and intense home medical regimens can be quite taxing
for the family. Support of family, friends, and medical staff
is critical for helping the parents and siblings through the difficulties.
A medical regimen and a feeding schedule which are manageable
for the families without compromising the safety of the child
are also important so as to decrease the burden on the family.
