Congenital Hyperinsulinism - Treatment

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 K_ATP 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.