OVERVIEW

What is congenital hyperinsulinemic hypoglycemia?

Congenital hyperinsulinemic hypoglycemia, also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), familial hyperinsulinemic hypoglycemia, and primary islet cell hypertrophy (nesidioblastosis), is an autosomal genetic disorder. It is characterized by abnormal regulation of insulin secretion and is the most common cause of persistent hypoglycemia in newborns and infants.
The condition may manifest as life-threatening hypoglycemia on the first day after birth or as mild symptomatic hypoglycemia during childhood or adolescence (which may be difficult to recognize). Early identification, diagnosis, and treatment are crucial to prevent or minimize neurological damage caused by recurrent or prolonged episodes of hypoglycemia.

Is congenital hyperinsulinemic hypoglycemia common?

Congenital hyperinsulinemic hypoglycemia is uncommon. In Northern Europe, the incidence is approximately 1 case per 30,000 live births. In populations with a high prevalence of consanguineous marriages, such as Saudi Arabia and certain Ashkenazi Jewish communities, familial clustering is observed, with incidence rates as high as 1 case per 2,675 live births and 1 case per 3,200 live births, respectively. In China, only sporadic case reports exist, and there is currently no data on its incidence.

SYMPTOMS

What are the common manifestations of congenital hyperinsulinemic hypoglycemia?

Congenital hyperinsulinemic hypoglycemia mostly occurs in infants under 1 year of age. Most affected infants develop hypoglycemic symptoms within hours to days after birth, such as feeding difficulties, lethargy, tremors, muscle weakness (hypotonia), and in severe cases, life-threatening conditions. Its typical characteristic is excessive insulin secretion disproportionate to the hypoglycemic state, accompanied by low ketone bodies and low free fatty acid levels.

Due to recurrent hypoglycemia and hypoketonemia during the neonatal or infant period, the central nervous system of affected children may suffer severe damage, leading to intellectual impairment.

Congenital hyperinsulinemic hypoglycemia may also present as mild symptomatic hypoglycemia in childhood or adolescence after the age of 1, which can be difficult to recognize. The manifestations and severity of this condition vary significantly among different patients.

What serious consequences can congenital hyperinsulinemic hypoglycemia cause?

Acute hypoglycemia may lead to seizures, lethargy, or coma, and severe hypoglycemic episodes can be life-threatening. Recurrent hypoglycemia and hypoketonemia during the neonatal or infant period may cause severe damage to the central nervous system, resulting in epilepsy, intellectual disability, cognitive deficits, microcephaly, and other complications.

CAUSES

What is the cause of congenital hyperinsulinemic hypoglycemia?

Normally, when blood glucose levels decrease, only a small amount of insulin is secreted or none at all. Congenital hyperinsulinemic hypoglycemia disrupts the normal regulatory relationship between blood glucose and insulin secretion due to various gene mutations. Whether blood sugar is high or low, excessive insulin is secreted, leading to recurrent hypoglycemia or severe hypoglycemic episodes.

Who is commonly affected by congenital hyperinsulinemic hypoglycemia?

Congenital hyperinsulinemic hypoglycemia is frequently observed among recently married Saudi Arabians and certain Ashkenazi Jewish populations, with a tendency for familial clustering.

Is congenital hyperinsulinemic hypoglycemia contagious?

Congenital hyperinsulinemic hypoglycemia is not contagious; it is an inherited autosomal genetic disorder.

Is congenital hyperinsulinemic hypoglycemia hereditary?

Congenital hyperinsulinemic hypoglycemia is a hereditary disorder, classified as an autosomal genetic disease.

DIAGNOSIS

How is Congenital Hyperinsulinemic Hypoglycemia Diagnosed?

When diagnosing congenital hyperinsulinemic hypoglycemia, doctors primarily rely on the presence of inappropriately high insulin secretion during hypoglycemia. Specific criteria include:

• Recurrent hypoglycemic episodes in newborns or infants, with severe cases showing blood glucose levels below 2.2 mmol/L or even undetectable;

• Inappropriately elevated blood insulin and C-peptide levels during hypoglycemia;

• Abnormally low blood ketone levels during hypoglycemia, with urine ketones often negative;

• Increased glucose requirements (greater than 15 mg/kg/min or 2–4 times the usual glucose needs) to maintain blood glucose within a safe range (3.5–6.0 mmol/L);

• A rise in blood glucose ≥1.7 mmol/L after glucagon administration;

• Exclusion of other diseases causing hypoglycemia;

• Identification of mutated genes through genetic testing.

What Tests Are Needed for Congenital Hyperinsulinemic Hypoglycemia?

Common tests include fasting blood glucose, insulin, C-peptide, blood and urine ketones, growth hormone, cortisol, thyroid hormones, glucagon stimulation test, imaging studies, pancreatic histopathology, and genetic testing.

• Blood glucose, insulin, and C-peptide tests: Confirm hypoglycemia and hyperinsulinemia. C-peptide helps distinguish endogenous insulin overproduction (as in this condition) from exogenous insulin administration (e.g., insulin injections).

• Blood and urine ketone tests: Support diagnosis, as this condition shows low blood ketones and typically negative urine ketones.

• Growth hormone, cortisol, and thyroid hormone tests: Rule out hypoglycemia caused by pituitary, adrenal, or thyroid disorders.

• Glucagon stimulation test: Administer glucagon intravenously (0.03 mg/kg) during hypoglycemia and measure blood glucose and insulin at 10, 20, and 30 minutes. A glucose rise ≥1.7 mmol/L or insulin >80 mU/L at 30 minutes suggests hyperinsulinemia.

• Imaging studies: Such as pancreatic CT or MRI.

• Pancreatic histopathology: Helps determine pathological subtype and guide treatment.

• Genetic testing: Identifies mutated genes to confirm diagnosis and guide therapy.

What Precautions Should Be Taken During the Glucagon Stimulation Test for Congenital Hyperinsulinemic Hypoglycemia?

• Pre-test: Discontinue diazoxide for at least 5 days, and octreotide, glucagon, or corticosteroids for at least 24 hours. Fast for 6 hours before the test. A peripheral IV line is usually placed for drug administration and blood sampling.
• Post-test: Glucagon-induced hyperglycemia may trigger reactive insulin release, increasing hypoglycemia risk post-test. Stop IV glucose infusion 30–60 minutes before and during the test, but resume continuous glucose infusion immediately afterward. Monitor fingertip glucose and adjust IV glucose rate/concentration to prevent hypoglycemia.

TREATMENT

Which department should be consulted for congenital hyperinsulinemic hypoglycemia?

Pediatrics, Endocrinology.

Can congenital hyperinsulinemic hypoglycemia resolve on its own?

Some cases of congenital hyperinsulinemic hypoglycemia may resolve spontaneously. However, in most cases, long-term treatment is required.

How is congenital hyperinsulinemic hypoglycemia treated?

The primary treatment goals for congenital hyperinsulinemic hypoglycemia are to prevent acute neurological symptoms (such as seizures, lethargy, or coma) and long-term sequelae (such as epilepsy, cognitive deficits, or microcephaly) caused by prolonged or recurrent hypoglycemic episodes.

The short-term goal is to raise and maintain blood glucose levels within a safe range (above 3.9 mmol/L) through intravenous glucose and/or enteral nutrition. The long-term goal is to reduce insulin secretion through medication or surgery and maintain normal blood glucose levels to protect neurological function.

Methods for preventing and treating hypoglycemia include intravenous glucose infusion, intravenous glucagon (used in initial treatment or pre-surgery), and dietary therapy (frequent and regular feeding).

Treatment for hyperinsulinemia includes medication and surgery.

• Medications include:
  • Diazoxide (first-line treatment), 5–15 mg/kg/day, divided into 3 doses. If there is no response at doses exceeding 15 mg/kg/day, increasing the dose is often ineffective and may increase side effects. If no clear efficacy is observed within 48 hours of starting treatment, it is likely ineffective, and alternative treatments should be considered.
  • Octreotide, a somatostatin analog, is the second choice after diazoxide failure. It is usually combined with diazoxide, at 5–20 μg/kg/day, divided into 3 doses, or higher doses may be used.
  • Sirolimus may be tried in children unresponsive to diazoxide and octreotide.
  • Calcium channel blockers, such as nifedipine, theoretically inhibit insulin secretion and may help reduce doses of other medications, but there is currently insufficient data on their efficacy.
• Surgery: For infants older than a few weeks, if hyperinsulinemia is confirmed and hypoglycemia cannot be controlled with medication, surgical exploration is necessary. If blood glucose levels cannot be maintained within a safe range despite all medical treatments (medications, oral or intravenous glucose), surgery must be considered. Focal lesions can often be cured by resection, while diffuse lesions require subtotal pancreatectomy (removal of 95%–99% of the pancreas). Surgical options include laparoscopic and open surgery, with the former offering advantages such as faster recovery and less bleeding.

What are the common side effects of medications for congenital hyperinsulinemic hypoglycemia?

• The most common side effects of diazoxide include hirsutism (which can be severe) and edema (which can be managed with thiazide diuretics like hydrochlorothiazide). Other side effects include advanced bone age, pulmonary hypertension, edema, and heart failure, most of which resolve after discontinuation.
• Octreotide may slightly increase the risk of necrotizing enterocolitis and may affect height growth.

What are the common risks of surgical treatment for congenital hyperinsulinemic hypoglycemia?

The effectiveness of surgery depends on the specific condition and the extent of pancreatic resection. Common risks include:

• Surgical failure, which may require repeat surgery.
• Hyperglycemia, often requiring insulin therapy.
• After near-total pancreatectomy, most children experience impaired exocrine function, with about half having fat malabsorption. Symptoms include steatorrhea and poor weight gain, which can be improved with pancreatic enzyme replacement therapy.

Can congenital hyperinsulinemic hypoglycemia be completely cured?

A small proportion of cases may resolve spontaneously. For focal lesions, resection can cure the condition.

DIET & LIFESTYLE

What should patients with congenital hyperinsulinemic hypoglycemia pay attention to in their diet?

• For infants, frequent and regular feeding helps reduce the frequency and severity of hypoglycemic episodes and may decrease the need for intravenous glucose infusion.
• For older infants and children with mild conditions, frequent high-carbohydrate meals and nighttime uncooked cornstarch intake may help maintain normal blood glucose levels without requiring intravenous glucose.

PREVENTION

Can congenital hyperinsulinemic hypoglycemia be prevented?

Congenital hyperinsulinemic hypoglycemia is a genetic disorder, and prenatal genetic counseling can help reduce its occurrence.

How can patients with congenital hyperinsulinemic hypoglycemia prevent complications?

Early diagnosis, active treatment, and preventing recurrent hypoglycemia are key to avoiding complications.