User:Adam Harangozó (NIHR WiR)/sandbox/CH

Congenital hyperinsulinism (CHI or '''HI) is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion. Congenital forms of hyperinsulinemic hypoglycemia can be transient or persistent, mild or severe. These conditions are often present at birth and most become apparent in early infancy. Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects. '''

Signs and symptoms
'''Hypoglycemia in early infancy can cause jitteriness, lethargy, unresponsiveness, or seizures. The most severe forms may cause macrosomia in utero, producing a large birth weight, often accompanied by abnormality of the pancreas. Milder hypoglycemia in infancy causes hunger every few hours, with increasing jitteriness or lethargy. Milder forms have occasionally been detected by investigation of family members of infants with severe forms, adults with the mildest degrees of congenital hyperinsulinism have a decreased tolerance for prolonged fasting.'''

Other presentations are:   '''The variable ages of presentations and courses suggest that some forms of congenital hyperinsulinism, especially those involving abnormalities of KATP channel function, can worsen or improve with time. The potential harm from hyperinsulinemic hypoglycemia depends on the severity, and duration. Children who have recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to the brain. '''
 * Dizziness
 * Intellectual disability
 * Hypoglycemic coma
 * Cardiomegaly

As CHI is a congenital condition, an infant usually starts to show signs and symptoms within the first few days of life, although very occasionally symptoms may appear later in life. It is often difficult to identify signs and symptoms of CHI because they are often confused with typical behaviours of new-borns and infants.

CHI may present in several ways; common symptoms of hypoglycaemia include:

Older children and adults’ symptoms may also include headaches, confusion and feeling dizzy
 * Irritability
 * Lethargy (excessive sleepiness)
 * Jitteriness/tremors
 * Tachycardia or bradycardia
 * Abnormal breathing patterns/apnoea
 * Hypothermia
 * Abnormal feeding behaviour (not waking for feeds, not sucking effectively, appearing unsettled and demanding very frequent feeds especially after a period of feeding well)
 * High pitched cry
 * Hypotonia (Loose/floppy muscles)
 * Pale/pallor/cyanosis (bluish coloured skin)
 * Sweating

Parents often describe initial concerns or symptoms such as their infants “not feeding well, being sleepy and jittery”.

More severe symptoms, such as seizures (fits or convulsions), can occur with a prolonged or extremely low blood sugar level. If the blood sugar level is not corrected, it can lead to loss of consciousness and potential brain injury.

A simple blood sugar measurement is essential if there are any symptoms of  hypoglycaemia.

Cause
Hyperinsulinism (HI) or congenital hyperinsulinism (CHI) can be a genetic or acquired condition. Acquired CHI may be secondary to factors around birth, such as growth restriction of the fetus, less oxygen to the baby or maternal diabetes. Together, these are often called perinatal stress induced HI. They are typically present in the first 24 hours of life but often resolve by two weeks of age.

In contrast to the resolving perinatal stress induced low blood sugars, CHI can also be due to a genetic cause. Therefore, genetic testing should be considered in children in whom acquired CHI is unlikely. This typically includes those not responding to first line medication diazoxide. A genetic cause is also possible in children responding to diazoxide but where low sugars persist beyond the first 4 months of life.

There are many different genetic forms of CHI which can be present in isolation or as part of a wider condition, called a syndrome.

Isolated forms
Isolated hyperinsulinism occurs in the majority of individuals with CHI. The most common genetic cause is a change in one or both copies of a gene that instructs the building of the potassium channel (ABCC8 and KCNJ11). This channel normally regulates insulin production from the β-cell in the pancreas in response to sugar levels in the blood. A change or fault in the channel leads to uncontrolled and excessive production of insulin. These changes in the ABCC8/KCNJ11 genes can be inherited in a dominant or recessive manner. In the dominant form, a single (monoallelic) change inherited from one parent (or arising spontaneously) causes diffuse CHI. In diffuse CHI, the whole pancreas is affected. Dominant CHI may be mild and respond to diazoxide or severe and diazoxide unresponsive. Some changes in the ABCC8 and KCNJ11 genes are not inherited dominantly but are inherited recessively. In these families each parent carries one copy of a faulty gene, but are themselves unaffected. A child will develop CHI if they inherit two copies of the faulty ABCC8/KCNJ11 gene, one from each parent. Recessively-inherited changes in the ABCC8/KCNJ11 genes cause diffuse CHI which typically does not respond to diazoxide. In some cases, a paternal copy of the faulty gene is inherited by the child which occurs in combination with a loss of the mother’s normal copy of the gene in the pancreas. This gives rise to focal CHI where only one part of the pancreas (called a focal lesion) produces excess insulin.

If CHI is severe and not responsive to medicines, rapid testing of the ABCC8 and KCNJ11 genes is recommended. This helps to identify the possibility of focal CHI early in the course of the illness. Following a genetic finding, specialised positron emission tomography (PET) scanning using the radiotracer 18-fluoro-dopa can be used to localise the focal abnormality (lesion) for surgical removal. Genetic testing is also helpful to determine if two copies of faulty ABCC8/KCNJ11 genes are inherited – these indicate a diagnosis of diffuse CHI that may not respond to diazoxide. Such cases require treatment with alternative medications such as octreotide and may need surgical removal of most of the pancreas. Therefore, early rapid genetic testing is important to guide the medical and surgical management of children with severe CHI. Results from CHI genetic testing are preferably analysed by molecular genetics laboratories experienced and specialised in CHI.

Another common genetic cause of CHI results from changes in the gene for the enzyme glutamate dehydrogenase (GDH). This genetic form of CHI is also known as GDH-CHI or GLUD1-CHI. These gene changes are inherited dominantly but may also arise spontaneously. In this condition, ammonia levels in blood are mildly raised. Children and adults with GDH-CHI often respond to diazoxide. An excess of proteins in the diet can bring about low sugars, so a good carbohydrate to protein ratio is advisable. There are many other genetic causes of isolated CHI. Examples include changes in the genes that make the enzymes hydroxyacyl-CoA dehydrogenase gene (SCHAD-CHI) and glucokinase (GCK-CHI). More recently, changes in hexokinase 1 (HK1), another enzyme similar to glucokinase has been identified to cause both mild and severe forms of illness.

Syndromic forms
Syndromic CHI is less common than isolated CHI. Data from patient registries suggest a prevalence of less than 1% among reported cases. In syndromic CHI, genetic causes are common. Beckwith-Wiedemann Syndrome (BWS), an overgrowth syndrome is a well-recognized form of syndromic CHI. Other syndromes that commonly feature CHI include Kabuki syndrome and Turner syndrome. Most individuals with syndromic CHI respond to treatment with diazoxide and CHI may resolve over time. However, CHI with BWS can be severe and be unresponsive to usual therapy.

Diagnosis
'''In terms of the investigation of congenital hyperinsulinism, valuable diagnostic information is obtained from a blood sample drawn during hypoglycemia, detectable amounts of insulin during hypoglycemia are abnormal and indicate that hyperinsulinism is likely to be the cause. Inappropriately low levels of free fatty acids and ketones provide additional evidence of insulin excess. An additional piece of evidence indicating hyperinsulinism is a usually high requirement for intravenous glucose to maintain adequate glucose levels, the minimum glucose required to maintain a plasma glucose above 70 mg/dl. A GIR above 8 mg/kg/minute in infancy suggests hyperinsulinism. A third form of evidence suggesting hyperinsulinism is a rise of the glucose level after injection of glucagon at the time of the low glucose. '''

'''Diagnostic efforts then shift to determining the type- elevated ammonia levels or abnormal organic acids can indicate specific, rare types. Intrauterine growth retardation and other perinatal problems raise the possibility of transience, while large birthweight suggests one of the more persistent conditions. Genetic screening is now available within a useful time frame for some of the specific conditions. It is worthwhile to identify the minority of severe cases with focal forms of hyperinsulinism because these can be completely cured by partial pancreatectomy. A variety of pre-operative diagnostic procedures have been investigated but none has been established as infallibly reliable. Positron emission tomography is becoming the most useful imaging technique. '''

Clinical diagnosis
CHI is due to dysregulation of secretion of the hormone insulin from beta-cells in the pancreas. Insulin is present in the blood at the time of hypoglycemia rather than being suppressed. This can be difficult to measure due to fluctuation in insulin levels. The diagnosis of CHI is made on the basis of increased insulin action and/or inadequate suppression of plasma insulin during a time of hypoglycemia. Increased insulin action can be demonstrated by increased glucose requirement (e.g., > 8 mg/kg/minute in a newborn compared to normal of 4-6 mg/kg/minute. Another sign of excess insulin action is suppressed blood levels of free fatty acids and ketones (beta-hydroxybutyrate) during hypoglycemia. The clinical diagnosis is also supported by a large blood glucose rise after glucagon administration at the time of hypoglycemia.  Glucagon is another hormone secreted from the pancreas that opposes insulin action and stimulates the release of glucose from liver glycogen stores. Measurement of insulin, c-peptide (which is co-secreted with insulin) free fatty acids and ketones together with a glucagon stimulation test can be performed during the spontaneous time of hypoglycemia or during hypoglycemia induced by a period of supervised and monitored fasting. In newborn infants, there is a time of transitional hypoglycaemia due to hyperinsulinism for the first  after birth 72 hours. Hence the clinical diagnosis is best established after 72 hours of age. Assessing blood ammonia and acylcarnitine profile, urinary metabolic profiles, in addition to provocative responses to protein and amino acids (leucine) may be helpful in defining the subtype of CHI.

Treatment
The goal of treatment in hyperinsulinism is to prevent hypoglycemia-induced brain damage, thus, the goal of therapy is to maintain the plasma glucose in the normal range [>70 mg/dL (3.9 mmol/L)]. The first step is the restoration of plasma glucose to the normal range after acute hypoglycemia, followed by prevention of recurrent episodes of hypoglycemia, which is common in congenital hyperinsulinism;. This is best accomplished with intravenous dextrose initially.

Once the diagnosis of CHI has been established, including determination of the genotype and phenotype, whenever possible, specific treatment should be initiated. Some of the following measures are often tried:

• Nutritional measures: continuous carbohydrate administration through the enteral route (nasogastric tube or gastrostomy), including continuous dextrose or formula feedings.

• Medications that inhibit insulin secretion: Diazoxide, somatostatin analogues including Octreotide and lanreotide

• Medications that oppose the effects of insulin: Glucagon

• Surgery to remove part or almost all of the pancreas (Pancreatectomy)

'''Corn starch[ citation needed] can be used in feeding; unexpected interruptions of continuous feeding regimens can result in sudden hypoglycemia, gastrostomy tube insertion (requires a minor surgical procedure) is used for such feeding. Prolonged glucocorticoid use incurs the many unpleasant side effects of Cushing's syndrome, while diazoxide can cause fluid retention requiring concomitant use of a diuretic, and prolonged use causes hypertrichosis. Diazoxide works by opening the KATP channels of the beta cells. Octreotide must be given by injection several times a day or a subcutaneous pump must be inserted every few days, octreotide can cause abdominal discomfort and responsiveness to octreotide often wanes over time. Glucagon requires continuous intravenous infusion, and has a very short half-life.'''

'''Nifedipine is effective only in a minority, and dose is often limited by hypotension. Pancreatectomy (removal of a portion or nearly all of the pancreas) is usually a treatment of last resort when the less-drastic medical measures fail to provide prolonged normal blood sugar levels. For some time, the most common surgical procedure was removal of almost all of the pancreas; this cured some infants but not all. Insulin-dependent diabetes mellitus commonly develops, though in many cases it occurs many years after the pancreatectomy. Later it was discovered that a sizeable minority of cases of mutations were focal, involving overproduction of insulin by only a portion of the pancreas. These cases can be cured by removing much less of the pancreas, resulting in excellent outcomes with fewer long-term problems.'''

Diazoxide, a KATP channel opener, that inhibits insulin secretion by binding to the sulfonylurea 1 (SUR1) component of the KATP channel, is the only drug with regulatory approval for the treatment of CHI and the first line of therapy for this condition. To prevent complications from diazoxide-induced fluid retention, diuretic therapy is typically initiated concomitantly with diazoxide. Dose selection and dose escalation should be carefully considered weighing the response and potential for side effects. Because of its long half-life it may take up to 5 days to achieve a full therapeutic effect. An important next step is the assessment of the responsiveness to diazoxide, which has important diagnostic and therapeutic implications. Responsiveness to diazoxide is defined by the demonstration that the cardinal feature of HI, hypoketotic hypoglycemia, is corrected by treatment. This is best assessed by a fasting test demonstrating that the child can fast for 12-18 hours with plasma glucose ≥ 70 mg/dL (3.9 mmol/L) or that plasma betahydroxybutyrate increases to > 1.8 mmol/L before plasma glucose decreases below 50-60 mg/dL (2.8-3.3 mmol/L) during fasting. Lack of responsiveness to diazoxide suggests the possibility that the CHI is due to inactivating mutation(s) in the genes encoding the KATP channels which accounts for up to 90% of cases of diazoxide-unresponsive CHI. For these cases, rapid genetic testing of the genes ABCC8 and KCNJ11 is critical to determine the likelihood of focal CHI.

Surgery is the treatment of choice for focal CHI, but before surgery, it is important to localize the lesion. These lesions are not visible using conventional imaging techniques such as ultrasound, computed tomography (CT) scan, and magnetic resonance imaging (MRI) However, specialized imaging using 18-F-L 3,4 dihydroxyphenylalanine (18F DOPA) positron emission tomography (PET) scan is almost 100% accurate in localizing a focal lesion. Expert assessment of the pancreatic histology during surgery using frozen biopsies and surgical expertise are key for the success of the surgery. The reported cure rate for focal CHI is 97%.

For non-focal diazoxide-unresponsive cases, treatment options are limited. Off-label use of the somatostatin analogue octreotide has been the long-standing second line of treatment for CHI, but its effectiveness is limited by the development of tachyphylaxis. Is important to note that in countries where diazoxide is not available, octreotide may be the first line of therapy. Because of its association with potentially fatal necrotizing enterocolitis, octreotide use in very young infants should be carefully considered weighting the risk versus the potential benefits. Octreotide is administrated as a subcutaneous injection typically every 6 hours but it can also be administrated continuously through a subcutaneous pump. Long-acting somatostatin analogues, octreotide LAR (administrated intramuscularly) and lanreotide (administered as a deep subcutaneous injection), are a convenient option for older children. An alternative treatment approach for diazoxide-unresponsive cases that are either not eligible or unresponsive to somatostatin analogues is the use of a continuous infusion of dextrose through a gastrostomy tube. Typically, dextrose 20% is used and because of tolerance, the maximal glucose infusion rate administrated through this route is 10 mg/kg/min. Continuous intragastric dextrose is also used in combination with octreotide, an approach that allows for the use of less frequent dosing of octreotide and avoidance of tachyphylaxis. Another option preferred by some centers includes the administration of carbohydrate supplemented formula feedings intermittently or continuously by a gastrostomy tube. A near-total pancreatectomy is indicated when medical therapy fails.

Ongoing monitoring of glycemic control, therapy-associated side effects, and of growth and development are part of the treatment plan. Children who have undergone ≥ 50% pancreatectomy are monitored for diabetes and pancreatic insufficiency.

Multiple new therapies for CHI are under development and promise to make possible a personalized approach to treatment of children with CHI in an effort to improve their long-term outcome. Therapies currently in clinical trials include: a peptide antagonist of the GLP-1 receptor, a short-acting soluble glucagon analogue, a long-acting glucagon analogue, a selective non-peptide somatostatin receptor 5 agonist, and an allosteric inhibitor of the insulin receptor.

Outcomes
The outcomes of individuals with CHI are affected by the disease process itself, including consequences of delayed diagnosis, the side effects of therapy, and the effectiveness of treatment.

Side effects of therapy are common in children treated with diazoxide and somatostatin analogues, affecting up to 50% of treated patients with various degree of severity. Surgical outcomes are excellent for children with the focal form of CHI with a cure rate of 97%. However, up to 50% of children with the diffuse form of the disease that undergo a near-total pancreatectomy continue to have hypoglycemia after surgery requiring additional therapy. Overtime, these children developed insulin dependent diabetes and pancreatic insufficiency. Ninety-one percent of children who had undergone a near-total pancreatectomy require insulin by age 14 years.

The frequency of neurodevelopmental and neurobehavioral problems in children with hyperinsulinism is as high as 40-50% across different patient types  and countries. Therefore neurodevelopmental assessments should be performed throughout childhood, even in those children who have outgrown or have undergone surgical cure of the disease.

Epidemiology
The incidence of CHI is variable. It ranges from 1:2500 in people where cousin marriages are common to 1:50,000 in other people. These numbers may be inaccurate as they are based on small numbers of children with CHI admitted to hospitals. The incidence of persistent forms of CHI have been reported in the UK to be 1:28,389. In Finland, the incidence has been reported to be 1:13,500. The incidence of transient forms of CHI has been reported at 1:7400. However, perinatal stress induced hyperinsulinism is relatively common and so the figure is predicted to be higher. The true incidence of CHI will not be known until newborn screening services are developed for CHI.

The natural history of CHI varies with the severity of illness and whether or not CHI is transient. Children with severe CHI are often unresponsive to medical treatment and may require pancreatic surgery. Although surgery is more likely in those with genetic forms of CHI, there appears to be reduction in severity over time, encouraging some clinicians to maintain normal glucose levels by a combination of medications such as octreotide and carbohydrate rich feeds. Similarly, some children with changes in genes making up the potassium channel (ABCC8/KCNJ11) showed a reduction in severity.

Changes in single copy of the ABCC8/KCNJ11 genes can be inherited by dominant transmission, i.e., transmission from an affected parent to the child. In such children, remission can happen, although variably. In this group, some children and adults may also develop high blood sugar and diabetes in later life. Similarly, a change from low to high blood sugar can also be seen in those with changes in HNF1A and HNF4A genes.

The natural history of CHI goes beyond the problem of hypoglycemia. An important consequence of early life hypoglycemia is brain injury. Delays in childhood development have been reported in up to 50%, particularly in those with severe CHI. Feeding problems are also reported commonly by parents. Feeding problems appear to be more frequent in children with severe CHI and may continue over long periods.

The natural history of CHI includes the onset and progress of treatment related side effects. In the short term, diazoxide may cause life threatening pulmonary hypertension but this happens only in a minority of cases. More commonly, many on diazoxide develop excess body hair or a change in facial features over a long time. Children with focal forms of CHI treated by limited surgery to the pancreas are usually cured and have no residual pancreas problems. By contrast, those having more extensive surgery, for example subtotal pancreatectomy, invariably develop diabetes requiring insulin by late childhood or adolescence. In the period after pancreatic surgery, they often have a combination of low and high sugars before frank diabetes. About half of such individuals develop the need for pancreatic enzyme supplements.

History
Congenital hyperinsulinism (CHI) has been referred to by a variety of names; nesidioblastosis and islet cell adenomatosis were favored in the 1970s, beta cell dysregulation syndrome or dysmaturation syndrome in the 1980s, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) in the 1990s.

Symptomatic hypoglycemia caused by insulin was first recognized in 1922 when one of the first diabetes patients ever treated with insulin was found “climbing the walls” due to hypoglycemia induced by insulin. The first description of children with congenital hyperinsulinism was made in 1954 by Dr Irvin McQuarrie in his presidential address to the American Pediatric Society. McQuarrie termed the disorder “idiopathic hypoglycemia of infancy” and several of his patients required removal of most of their pancreas to control their hypoglycemia. McQuarrie suggested the disorder might be genetic, since hypoglycemia ran in families of some of his patients; however, he incorrectly believed that insulin was not the cause, since no insulin-producing tumors were found in the pancreas of patients. The following year, Cochrane and colleagues in Toronto reported that hypoglycemia in some, but not all, cases of idiopathic hypoglycemia could be provoked by protein or by certain individual amino acids, especially leucine. “Leucine-sensitive” hypoglycemia provided the first indication that amino acids, as well as glucose, could be important stimulators of insulin release.

CHI is sometimes incorrectly referred to as “nesidioblastosis”, based on the appearance of the pancreatic tissue showing insulin cells arising from ductal structures. However, the term was discarded when it was shown that nesidioblastosis was merely a common feature of the pancreas in early infancy. It is now well recognised that CHI is a disorder of beta-cell insulin regulation due to genetic mutations.

In 1964, Drash and colleagues reported that diazoxide, an antihypertensive that suppresses insulin secretion, controlled hypoglycemia in some children with CHI; currently, this is the only FDA-approved drug for treatment of hyperinsulinism.

In 1996, mutations causing CHI were discovered in the genes (ABCC8, KCNJ11) that encode the K-ATP channel which serves a key role in glucose-stimulated insulin secretion. Shortly thereafter, mutations in glucokinase (GCK) and glutamate dehydrogenase (GLUD1) were also identified to cause HI. The list of CHI genes has now grown to over 30. Rapid genetic testing for the most common CHI genes has become part of standard diagnosis and can be helpful in identifying infants likely to have a focal form of CHI that can be cured by surgical removal. In 2003, it was shown that radioactive 18-fluoro-DOPA PET scans could assist surgeons locate and resect focal CHI tumors.

Patient advocacy organizations
Patient advocacy organizations dedicated to improving the lives of people born with congenital hyperinsulinism play an important role in supporting people with the disease and their families, participating in and funding research on CHI, and raising awareness of the condition. For example Congenital Hyperinsulinism International is a globally focused patient advocacy organization dedicated to improving the lives of people born with congenital hyperinsulinism. They are a member of the Chan Zuckerberg Initiative's Rare as One Network, which is a group of patient led organizations that have launched collaborative research networks.

Patient registries
People with congenital hyperinsulinism can participate in a patient reported registry called the HI Global Registry. By submitting a survey on their experiences to the registry, people with CHI can help research on the condition.