Congenital hyperinsulinism

Overview
Congenital hyperinsulinism 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 present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years.

Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the pancreas to protect the brain from damage due to recurrent hypoglycemia.

Terminology
This condition has been referred to by a variety of names in the past 50 years. 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.

Types of congenital hyperinsulinism

 * Transient neonatal hyperinsulinism
 * Focal hyperinsulinism
 * Paternal SUR1 mutation with clonal loss of heterozygosity of 11p15
 * Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15
 * Diffuse hyperinsulinism
 * Autosomal recessive forms
 * SUR1 mutations
 * Kir6.2 mutations
 * Autosomal dominant forms
 * Glucokinase gain-of-function mutations
 * Hyperammonemic hyperinsulinism (glutamate dehydrogenase gain-of-function mutations)
 * Short chain acyl coenzyme A dehydrogenase deficiency
 * Carbohydrate-deficient glycoprotein syndrome
 * Beckwith-Wiedemann syndrome (thought to be due to hyperinsulinism but pathophysiology still uncertain: 11p15 mutation or IGF2 excess)

Common presentations and natural history
Manifestations of congenital hyperinsulinemic hypoglycemia vary by age and severity of the hypoglycemia. Hypoglycemia in early infancy can cause jitteriness, lethargy, cyanosis, unresponsiveness, hypothermia, or seizures. The most severe forms may cause macrosomia in utero, producing a large-for-gestational-age birth weight, often accompanied by enlargement of the heart and liver. Milder hypoglycemia in infancy causes hunger every few hours, with increasing irritability or lethargy if feeding is delayed.

Congenital hyperinsulinism often becomes apparent later in the first year of life, sometimes by a failure to tolerate increasing feeding intervals and an inability to sleep through the night. Sometimes an unusual stress like an illness precipitates a severe hypoglycemic episode.

Milder forms have occasionally been detected by investigation of family members of infants with severe forms. Adults with the mildest degrees of congenital hyperinsulinism may simply have a decreased tolerance for prolonged fasting.

The variable ages of presentations and courses suggest that some forms of congenital hyperinsulinism, especially those involving abnormalities of KATP channel function, can gradually worsen or improve with time.

The potential harm from hyperinsulinemic hypoglycemia appears to depend on the severity, frequency, and duration. Children who have prolonged or recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to their brains and may be developmentally delayed.

Diagnostic evaluation
When the cause of hypoglycemia is not obvious, the most valuable diagnostic information is obtained from a blood sample drawn during the 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, beta-hydroxybutyrate and ketones provide additional evidence of insulin excess. If this critical cannot be obtained during an early episode of spontaneous hypoglycemia, a diagnostic fast may be required.

An additional piece of evidence indicating hyperinsulinism is an usually high requirement for intravenous glucose to maintain adequate glucose levels. The minimum glucose required to maintain a plasma glucose above 70 mg/dl is referred to as the glucose infusion rate. 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.

Once the evidence indicates hyperinsulinism, the diagnostic efforts 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. Evidence for specific type can include responsiveness to some of the therapeutic measures. Genetic screening is now available within a useful time frame for some of the specific conditions.

It is usually 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 (PET scanning) is becoming the most useful imaging technique and usually indicates whether the entire pancreas is producing too much insulin or whether a focal area is to blame.

Treatment
Acute hypoglycemia is immediately reversed by raising the blood glucose, but in most forms of congenital hyperinsulinism hypoglycemia recurs and the therapeutic effort is directed toward preventing falls and maintaining a glucose above 70 mg/dl (3.9 mM). Some of the following measures are often tried:
 * shorter feeding interval (every 2 hours)
 * increased calorie density of formula (usually 24 calories per ounce instead of 20)
 * continuous feeding with formula through a nasogastric tube or gastrostomy, sometimes with added corn starch
 * continuous intravenous dextrose
 * hydrocortisone or other glucocorticoid
 * diazoxide by mouth
 * octreotide (a somatostatin analog) by subcutaneous injection or infusion
 * glucagon by continuous intravenous infusion
 * nifedipine or other calcium channel blocker
 * partial pancreatectomy

Each treatment has its limitations and disadvantages or hazards. Many of the treatments do not effectively maintain a satisfactory blood glucose in the more severe cases. Many of the treatments aggravate the poor feeding behavior that often accompanies severe congenital hyperinsulinism. It is hard for parents to continue frequent feedings for many months. Increased calories and corn starch may produce excessive weight gain. Unexpected interruptions of continuous feeding regimens can result in sudden, severe hypoglycemia. Insertion and maintenance of nasogastric tubes is distasteful to parents. Gastrostomy tube insertion requires a minor surgical procedure. Prolonged glucocorticoid use incurs the many unpleasant side effects of Cushing's syndrome. 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, and many of the Kir and SUR mutations are unresponsive. 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, incurring the infection and blood clot hazards of prolonged central venous lines. 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 simpler medical measures fail to provide prolonged normal blood sugar levels. For many decades, the most common surgical procedure was removal of about 95% of the pancreas. This cured some infants but not all, and some needed second procedures to remove even the last remnants. Insulin-dependent diabetes mellitus commonly develops, though in many cases it occurs many years after the pancreatectomy.

In the early 1990s it was discovered that a sizeable minority of cases of Kir and SUR 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 no long-term problems. The initial pancreatectomy became a prolonged process of repeated microscopic examination of small pieces removed from various parts of the pancreas while the infant was under anesthesia in the operating room, with an experienced surgeon and pathologist attempting to identify a focal region of overactive cells which could be completely removed.

The relative rarity of this condition and the difficulty of both diagnosis and treatment has resulted in only a few centers around the world developing the expertise to achieve optimal surgical outcomes for these infants: the Children's Hospital of Philadelphia, the Great Ormond Street Hospital for Children in London, as well as centers in Paris and Israel.