Congenital Hyperinsulinism 

Updated: Dec 16, 2015
Author: Robert S Gillespie, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD 

Overview

Background

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) represents the most common cause of hyperinsulinism in neonates; currently, many authors prefer the term congenital hyperinsulinism (CHI). It was first identified in 1938, when Laidlaw coined the term nesidioblastosis to describe the neodifferentiation of islets of Langerhans from pancreatic ductal epithelium (a term since replaced by PHHI and CHI).[1]

Severe recurrent hypoglycemia associated with an inappropriate elevation of serum insulin, C-peptide, and proinsulin levels defines CHI. If left untreated, CHI can lead to brain damage or death secondary to severe hypoglycemia. Although it was initially thought to affect only infants and children, numerous cases have been reported in adults of all ages but at a much lower incidence. CHI is often poorly responsive or unresponsive to medical management, necessitating 95% or near-total pancreatectomy.

Pathophysiology

In CHI, the histologic abnormalities in pancreatic structure are heterogeneous but can be grouped into the following 2 broad categories:

  • Focal adenomatous hyperplasia (found in one fourth to one third of cases)

  • Diffuse abnormality of the islets

In the focal form, the histologically abnormal beta cells are limited to 1 or more focal areas, whereas in the diffuse form, the beta-cell abnormality is distributed throughout the pancreas.

Investigations into the molecular basis of CHI have led to the discovery of mutations in the sulfonylurea receptor and an inwardly rectifying potassium channel. However, approximately 50% of cases do not involve any currently known mutation.

Presumed structural or functional molecular abnormalities in the insulin secretory mechanism or glucose-sensing mechanism result in a failure to reduce pancreatic insulin secretion in the presence of hypoglycemia (serum glucose level < 60 mg/dL). Inappropriately high circulating insulin levels act to promote hepatic and skeletal muscle glycogenesis, causing a decrease in the amount of free glucose available in the bloodstream and suppression of the formation of free fatty acid (FFA), an alternative energy substrate for the brain.

The net effect is hypoglycemia, which results in physiologically appropriate adrenergic and neuroglycopenic symptoms, with severe neurologic dysfunction and frank seizure activity when central nervous system (CNS) glucose levels fall below 20-30 mg/dL.

Prolonged hypoglycemia causes death. Repeated episodes of severe, prolonged, sublethal hypoglycemia can result in permanent neurologic damage, including developmental delay, mental retardation, and focal CNS deficits. Therapy should be aimed at prevention of hypoglycemia to prevent morbidity and mortality.

Etiology

CHI is a clinically, pathologically, and genetically heterogeneous disease. Most cases are sporadic. In approximately 50% of cases, no known genetic abnormality is found. Familial forms of CHI are rare but well documented. Currently, the following 9 genes are associated with CHI[2, 3] :

  • ABCC8, also known as SUR1: Beta-cell high-affinity sulfonylurea receptor gene

  • KCNJ11, also known as Kir6.2: Inwardly rectifying potassium channel gene

  • GCK, also called GK: Glucokinase gene

  • GLUD1, also called GUD1: Glutamate dehydrogenase gene - This gene is associated with hyperinsulinism with hyperammonemia

  • HADH: 3-hydroxyacyl-coenzyme A dehydrogenase

  • SLC16A1: Solute carrier family 16, member 1

  • HNF4A: Hepatocyte nuclear factor 4-alpha

  • HNF1A: Homeobox A

  • UCP2: Uncoupling protein 2

Some data have helped elucidate the mechanism of the focal form of CHI. In the focal form, data have shown that a specific loss of maternal alleles occurs in the imprinted chromosome region 11p15 in the cells of the hyperplastic area, but no loss occurs in the normal pancreatic cells. This loss of heterozygosity results in a reduction to hemizygosity or homozygosity of the remaining paternal alleles that carry a mutation of ABCC8 (SUR1) or KCNJ11 (Kir6.2).

This abnormality occurs during embryonic development in a single pancreatic cell, resulting in a proliferative monoclonic lesion. However, other pancreatic cell lines not derived from this cell, as well as all other cells of the body, do not carry this genetic defect. The result is similar to uniparental disomy, but it occurs only in a clonal cell line and not constitutionally. This is a nonmendelian mechanism. This abnormality has not been observed in patients with the diffuse form of CHI.

High rates of consanguinity have been noted in some series. No known genetic abnormalities have been found in approximately half (in some series, the majority) of the patients studied, suggesting the existence of other mutations that have not yet been described. More detailed treatments of the genetics of hyperinsulinism have been published by Glaser et al[4] and Fournet et al.[5]

Adult-onset hyperinsulinemic hypoglycemia with pancreatic beta cell hypertrophy has been reported in adults undergoing Roux-en-Y gastric bypass surgery.[6] The relation between the operative procedure and the pancreatic disease remains poorly understood. Service et al theorize that gastric bypass may increase activity of beta-cell trophic factors.[6]

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Epidemiology

Few data are available on CHI. An estimated incidence of 1 in 50,000 live births in a random-mating US population has been reported. Worldwide, the incidence may be as high as 1 in 2500 live births in populations with high rates of consanguineous unions.

Age- and sex-related demographics

Patients with CHI usually present between birth and age 18 months, with most cases diagnosed shortly after birth. Cases of adult-onset forms of CHI are rare but well documented.

The diffuse form of CHI has a male-to-female ratio of 1.2:1. Focal lesions are found in a 1.8:1 male-to-female ratio. The overall male-to-female ratio is 1.3:1.

Prognosis

Cure

If a solitary focal lesion can be identified and excised, the patient usually maintains blood glucose levels within the reference range without the need for medication or continuous feedings.

Hypoglycemia often persists even after a 95-98% pancreatectomy. Hypoglycemia may be easier to control after partial pancreatectomy and may resolve months or years later or persist throughout life.

In a study of 101 patients, 50% of patients who underwent a 95% or greater pancreatectomy were cured (ie, they did not require medical or dietary treatment to maintain normoglycemia within the follow-up period of the study). The mean time from surgery to cure was 4.7 years.[7] However, in some series, 40-63% of patients managed with medical therapy alone had late remission of hypoglycemia. Later onset of disease is correlated with a higher likelihood of being able to discontinue medical therapy.

Future development of diabetes mellitus

Patients who undergo partial pancreatectomy are at high risk for developing diabetes mellitus later in life. The risk of diabetes mellitus appears to increase with the extent of pancreatic resection; however, the risk is significant even with conservative surgical procedures.

In one series, 14% of children with diffuse lesions developed diabetes mellitus, regardless of the surgical procedure performed. The mean time from surgery to development of diabetes mellitus was 9.6 years.[7] Because most series are limited by relatively short follow-up times, the lifetime incidence of diabetes mellitus is not well understood. Islet cell preservation and autotransplantation remain promising but untested therapies for patients who develop diabetes mellitus.

Diabetes mellitus is extremely rare after resection of focal lesions.

In a series of 3 patients treated without pancreatic resection, 2 developed impaired glucose tolerance, and one developed diabetes mellitus.[8] All 3 patients had mutations of the ABCC8 (SUR1) gene. The significance of this small series is uncertain, but the results suggest that development of impaired glucose tolerance may be part of the underlying disease process and not solely due to surgical reduction in islet cell mass.

Education of the patient and family and long-term follow-up are essential to prevent delays in the diagnosis of disease recurrence, glucose intolerance, or diabetes mellitus.

Neurodevelopmental outcome

In some series, a high frequency of mental retardation, developmental delay, and nonhypoglycemic seizures has been observed. These findings are generally attributed to minimal brain damage from early hypoglycemic events, although the existence of these disorders as inherent comorbid conditions with CHI has not been fully excluded. Other series, usually in conjunction with medication studies, have shown normal developmental progress in patients with PHHI.

Some data suggest that patients with early, severe disease treated with early, aggressive surgery have a better neurodevelopmental outcome. No comprehensive long-term studies of neurodevelopmental outcomes in patients with PHHI are available, and the heterogeneity of the disease likely confounds many neurodevelopmental studies.

Permanent neurologic dysfunction (eg, seizures, developmental delay, focal neurologic deficits) or death secondary to severe, prolonged hypoglycemia may occur if PHHI goes untreated or is inadequately treated.

Patient Education

A nutritionist should provide dietary education and meal-planning assistance. Patients (if old enough) and family members should be taught how to use a home blood glucose monitor. They should also understand the signs and symptoms of hypoglycemia and how to treat this condition with rapid-acting oral carbohydrates and subcutaneous glucagon.

Family members must understand the importance of prompt treatment of hypoglycemia to prevent severe complications or death. Family members should be instructed to call the local emergency medical service (EMS) if they are unable to treat a hypoglycemic episode or if the patient does not respond to treatment promptly. Family members should know the local emergency phone number if 911 service is not available in their area. Patients should wear a medical identification bracelet.

Patients and family members should be reminded to carry medications, a glucose meter, a rapid-acting carbohydrate source, and glucagon when traveling. Families should carry sufficient supplies for several extra days in case of unexpected travel delays.

Patients who have undergone surgery, as well as their family members, should be reminded of the risk of future development of diabetes mellitus and the importance of long-term follow-up. Failure to educate families about this potential late complication could result in a delay of diagnosis of diabetes mellitus if it occurs.

Genetic counseling with regard to risk of recurrence may be appropriate. Techniques for prenatal diagnosis are currently limited to investigational use but may be available at some medical centers.

 

Presentation

History

A number of symptoms are commonly observed in the history of patients with congenital hyperinsulinism (CHI).

Most patients with CHI (ie, persistent hyperinsulinemic hypoglycemia of infancy [PHHI]) present shortly after birth with symptoms of hypoglycemia (eg, hunger, jitteriness, lethargy, apnea, seizures). Older children, in addition to these symptoms, may also show diaphoresis, confusion, or unusual mood or behavior changes.

Hypoglycemia is persistent, requiring frequent or continuous glucose infusions or feedings to maintain adequate blood glucose levels.

Presenting symptoms of CHI reported in adults include confusion, headaches, dizziness, syncope, and loss of consciousness. The symptoms may be exacerbated by fasting and may improve after eating.

Physical Examination

A thorough physical examination is essential. The physical examination findings are usually normal when the patient is euglycemic. No characteristic visual, auscultatory, or tactile findings are associated with CHI.

The presence of hepatomegaly suggests a metabolic disorder, such as glycogen storage disease, galactosemia, or fructosemia. The presence of syndromic or dysmorphic features suggests a different diagnosis. CHI is not usually associated with a genetic syndrome or characteristic physical features.

Infants may be large for their gestational age because of the influence of chronic hyperinsulinism in utero. Older children and adults may have signs of residual neurologic damage from episodes of prolonged hypoglycemia. These signs may vary widely.

 

DDx

Diagnostic Considerations

Misdiagnosis of hypoglycemic seizure as epileptic seizure will result in inappropriate treatment with anticonvulsants and failure to treat with glucose. Consider associated endocrine abnormalities, such as multiple endocrine neoplasia type I.

In addition to these and the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Transient hypoglycemia of the newborn

  • Erythroblastosis fetalis

  • Drug effect (eg, tocolytics, quinine)

  • Withdrawal of parenteral nutrition or dextrose-containing intravenous (IV) fluid

  • Exogenous insulin administration (eg, Munchausen syndrome, Munchausen syndrome by proxy)

  • Ingestion of oral hypoglycemic agents

  • Hyperinsulinism with hyperammonemia

  • Hyperinsulinism-hyperammonemic syndrome

  • Insulin-secreting adenoma

  • Ketotic hypoglycemia

Differential Diagnoses

 

Workup

Laboratory Studies

A number of laboratory studies may be indicated in patients with congenital hyperinsulinism (CHI), also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI).

Serum glucose, ketone, and insulin levels should be obtained while the patient is hypoglycemic (serum glucose level < 60 mg/dL). The definition of hypoglycemia in neonates is dependent on gestational age, and the threshold may be lower than described here.

The finding of nonketotic hypoglycemia in association with elevated insulin levels (>10 µU/mL) and normal levels of free fatty acid (FFA) supports the diagnosis of hyperinsulinism. The insulin-to-glucose ratio may range from 0.4-2.7 (normal, < 0.3). Sustained glucose use rates in excess of 10 mg/kg/min (evidenced by the need to administer intravenous [IV] glucose at a rate higher than 10 mg/kg/min to maintain normoglycemia) are consistent with exaggerated insulin activity and suggestive of CHI.

Cortisol and growth hormone levels are usually elevated in specimens taken during an episode of hypoglycemia (as an appropriate and normal response to hypoglycemia) and are usually within the reference range during periods of normoglycemia.

Serum metabolic screens, pH, lactate, and ammonia studies may be obtained to exclude other metabolic diseases. The results are expected to be within the reference range in cases of CHI. Urinary ketone, amino acid, and reducing-substance studies may be obtained to exclude other metabolic diseases. The results of these are also expected to be within the reference range in cases of CHI.

Hyperinsulinism with hyperammonemia and elevated levels of FFA suggests a fatty acid oxidation disorder. Hyperinsulinism with hyperammonemia and normal levels of FFA suggest the diagnosis of hyperinsulinism with hyperammonemia, a clinically and genetically distinct variant of CHI. Patients with this disorder usually respond very well to medical therapy alone and are much less likely to require surgical intervention. The hyperammonemia is mild and not symptomatic.

Ultrasonography, CT, MRI, and PET

Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) have been used to search for a focal mass in the pancreas; however, in many cases, the lesion is too small to be visible by such techniques. These forms of imaging cannot identify the diffuse form of CHI.

A newer imaging technique has been developed that uses positron emission tomography (PET) in conjunction with coregistered abdominal CT (see the image below) to distinguish between focal and diffuse disease and, in the case of focal disease, localize the lesions.[9, 10] This technique uses a novel isotope, fluorine-18 L-3,4-dihydroxyphenylalanine (18 F-L-DOPA), for which neuroendocrine cells have a high affinity.

Combined positron emission tomography (PET)/comput Combined positron emission tomography (PET)/computed tomography (CT) scan of focal lesion in head of pancreas of infant with congenital hyperinsulinism. Uptake of 18F-L-DOPA glows brightly in head of pancreas (center), pinpointing abnormal cells in focal hyperinsulinism. Large glowing areas lower in image are kidneys, where 18F-L-DOPA is excreted. Image courtesy of Charles Stanley, MD, Children's Hospital of Philadelphia.

A large series at Children’s Hospital of Philadelphia found that the technique had a specificity of 96%, sensitivity of 85%, and positive predictive value of 96% for diagnosing a focal lesion. When a focal lesion was identified by PET scan, the concordance between imaging and anatomic findings was 100%.[11]

The18 F-L-DOPA isotope remains investigational and is technically complex to prepare. It is currently available at only a few centers worldwide. However, because of the remarkable results seen in preliminary published trials, physicians treating patients with CHI should strongly consider consultation with an expert at one of these centers.

Portal and Pancreatic Venous Sampling

Catheterization of the portal and pancreatic veins with venous sampling may help distinguish between focal and diffuse CHI. This procedure is well described in the pediatric population.

For venous sampling, a catheter is placed in the pancreatic venous system via a femoral vein or inserted by direct hepatic puncture to enter the portal vein. With the use of fluoroscopic guidance and IV contrast agents, the catheter is advanced into various pancreatic veins, and blood samples are taken to measure glucose, insulin, and C-peptide levels.

If a focal lesion is present, elevated insulin levels are expected in veins draining the area near the lesion, and insulin levels are expected to be within the reference range for CHI in other areas. If a diffuse lesion is present, insulin levels are expected to be high throughout the pancreatic venous bed.

In some cases, the results of this study are difficult to interpret, and correlation of results with pathologic findings remains imperfect. Pathologic examination remains the criterion standard for identification of focal disease. However, pancreatic venous sampling is one of few preoperative techniques available to identify focal lesions in patients in whom findings on conventional imaging are inconclusive.

Pancreatic venous sampling and intraoperative histologic studies should be strongly considered, because the identification of a focal lesion has profound implications for treatment and prognosis.

Intra-arterial Calcium Stimulation

A test using intra-arterial calcium stimulation has been employed in adults and, to a lesser extent, in children. In this test, a bolus of calcium gluconate is rapidly administered via a catheter in the celiac axis and the splenic, superior mesenteric, and gastroduodenal arteries. Blood samples are obtained through a catheter in the right hepatic vein before injection and at several intervals after injection. These blood samples are then tested for glucose, calcium, and insulin levels.

An excessive insulin response from calcium stimulation in a single artery suggests a focal lesion, and excessive poststimulation insulin secretion associated with all arteries suggests a diffuse form of hyperinsulinism.

Although pancreatic venous sampling has been studied more widely to date, especially in neonates, experience with intra-arterial calcium stimulation in children is increasing. Children’s Hospital of Philadelphia has reported on a large number of cases.

Histologic Findings

The histology of CHI has been divided into focal and diffuse categories. In the focal form (accounting for one fourth to one half of cases), the focal lesion contains isletlike cell clusters with ductoinsular complexes, hypertrophic cells, and giant nuclei. A well-developed endoplasmic reticulum and prominent Golgi complex are present, suggesting a high level of protein synthetic activity. Immunohistochemical staining shows an increased proportion of insulin-containing cells.

The focal lesion may occur in any part of the pancreas, although the tail and body are the most common locations. The focal lesion is commonly too small to be identified on imaging studies or palpated during surgery. Outside of the area of the focal lesion, the pancreas appears normal. Most patients with the focal form of PHHI have a solitary lesion; however, approximately one fourth of cases are multifocal (ie, contain 2 or more focal lesions).

In the diffuse form of CHI, findings throughout the pancreas are similar to those found within a focal lesion. Again, isletlike cell clusters with ductoinsular complexes, hypertrophic cells, and enlarged, hyperchromatic nuclei are observed; endocrine cells also occur individually (see the images below). The endoplasmic reticulum is well developed, and Golgi complexes are prominent. Results of macroscopic examination are normal.

Normal pancreas. There are fewer paler-staining ne Normal pancreas. There are fewer paler-staining neuroendocrine (islet) cells, and they are arranged in more discrete islands. Image courtesy of Tom Milligan, MD, Driscoll Children's Hospital, Corpus Christi, Tex.
Pancreatic specimen showing congenital hyperinsuli Pancreatic specimen showing congenital hyperinsulinism (CHI) viewed at low power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyp Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at medium power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyp Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at high power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.

These histologic findings have also been observed in infants and older children with no known abnormalities of glucose homeostasis.

Some authors suggest that this microscopic appearance may be part of a normal developmental process and that other functional abnormalities may exist in the patient with CHI. Persistent hyperinsulinism, then, may represent a derangement of the developmental process or the extreme end of a spectrum of endocrine cell function. Other authors suggest that these histologic findings may be associated with infants of diabetic mothers or stressed, growth-retarded premature infants.

 

Treatment

Approach Considerations

Admit patients with congenital hyperinsulinism (CHI), or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), to an intensive care unit (ICU) or a neonatal ICU (NICU) until blood glucose levels are stabilized. Arrange for family and patient education to begin immediately.

Newborns with persistent hypoglycemia should be transferred to the NICU for stabilization, monitoring, and further diagnostic evaluation. Other patients should be transferred to a specialized center if appropriate monitoring, therapy, and consultation cannot be provided at the facility to which the patient initially presents.

Diazoxide, octreotide,[12] and nifedipine are the primary medications used in long-term treatment of CHI. Chlorothiazide is sometimes used in conjunction with diazoxide for a synergistic effect.

Despite many years of experience and extensive reports in the literature, surgical therapy remains frustrating. Rates of initial failure to control hypoglycemia are high, followed by, paradoxically, high rates of subsequent development of diabetes mellitus.[13]

The most dangerous complication is hypoglycemia with resultant brain damage or death if not treated promptly. Hypoglycemia may occur even with optimal medical and surgical treatment; therefore, glucose monitoring and patient/family education are essential.

Pharmacologic Therapy

The only major expert consensus document on CHI was developed by The European Network for Research into Hyperinsulinism (ENRHI).[14]

Immediate treatment of hypoglycemia is essential. Patients may require continuous intravenous (IV) glucose infusion. Glucagon may also be administered emergently to maintain adequate blood glucose levels.

Diazoxide, octreotide, and nifedipine are the primary medications used in long-term treatment of CHI. All 3 are used widely for other indications, and diazoxide and octreotide are associated with increased serum glucose levels as a well-known adverse effect. Their hyperglycemic action is beneficial in the treatment of CHI, but their other therapeutic actions may become a burden in patients with CHI, who lack the conditions the drugs were originally intended to treat.

For example, diazoxide, primarily used as an antihypertensive, may cause hypotension in the normotensive child with CHI. In addition, most agents have significant adverse effects, especially with long-term use. Complications of medical therapy are primarily related to these adverse effects.

Different doses for each drug have been used in different centers. The exact medication regimen, including doses and selection of drugs, must be highly individualized on the basis of therapeutic response, adverse-effect tolerance, and individual factors (eg, patient acceptance of subcutaneous injections). Many patients require years of drug therapy, and regular reassessment and dose adjustments are required.

Because of the potential for significant adverse effects with long-term administration of these agents, patient adherence to the medication regimen may be suboptimal. The best way to ensure good adherence is by having open discussions with patients about the risks and benefits of the drugs, by scheduling regular follow-up appointments, and by tailoring drug regimens for each patient.

Diazoxide is related to the thiazide class of drugs but has no diuretic action. It promotes opening of the potassium adenosine triphosphate (ATP) channel, which inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release. (This effect is the opposite of that exerted by the sulfonylurea drugs used in diabetes mellitus, which close the ATP channel.)

Diazoxide causes sodium and water retention and should be used cautiously in patients with congestive heart failure or poor cardiac reserve. Hypertrichosis, coarsening of the facies, decreased serum immunoglobulin G (IgG) levels, and hyperosmolar nonketotic comas have been reported with diazoxide, especially with long-term use.

Patients should be monitored for hypotension while receiving diazoxide therapy, especially during IV administration, because blood pressure may drop rapidly. Usually, oral diazoxide is used for the treatment of hypoglycemia.

Some authors recommend using chlorothiazide in conjunction with diazoxide for a synergistic effect. Chlorothiazide activates a different potassium channel, and its diuretic action helps counteract the salt and water retention associated with diazoxide therapy.

Octreotide is a long-acting analogue of somatostatin that has a wide array of endocrinologic functions, including inhibition of insulin release. Octreotide therapy may avert or postpone the need for surgery. Most patients develop tolerance to octreotide over time, requiring increased doses. Experience with long-term use of octreotide in patients with CHI is limited.

Suppression of growth hormone and decreased linear growth may be important adverse effects of octreotide, and the patient’s growth parameters should be monitored carefully during octreotide therapy. Gallbladder sludging and gallstones have been reported as a late complication in patients who are taking octreotide. Octreotide suppresses thyroid-stimulating hormone (TSH), but clinical hypothyroidism is very rare. Mild diarrhea and abdominal bloating are common and, usually, transient adverse effects.

Nifedipine, a later addition to the therapeutic armamentarium, is a calcium channel blocker that helps reduce the influx of calcium into beta cells, which is a necessary step for insulin secretion. This effect occurs with doses much lower than those traditionally used for other indications (eg, angina pectoris). Nifedipine appears to have considerably fewer adverse effects than the other agents do.[15]

Patients should use a home glucose meter to monitor glucose levels. A physician should review the results periodically to assist in adjusting medications. More frequent glucose monitoring may be necessary during illness, when medications are changed, or after dose adjustments. During illness, when oral intake is lower, patients may be at higher risk for hypoglycemia.

Patients with persistent vomiting or diarrhea may require hospital admission for IV glucose administration until they are able to tolerate oral intake. Continuous feeding by a nasogastric or gastrostomy tube may be helpful in some patients to maintain adequate blood glucose levels. Continuous feeding is particularly useful during sleep.

Pancreatectomy

Surgical treatment is indicated if medical therapy does not maintain normoglycemia, if a discrete lesion can be identified, or if the patient or the family is unable or unwilling to comply with medical therapy. In one study, 50% of patients with congenital hyperinsulinism required pancreatectomy to obtain adequate glucose control.[7] Although most centers routinely perform extensive pancreatectomy, one center in Israel has reported success with a consistently nonsurgical approach.[16]

The distinction between focal and diffuse lesions is critical in planning surgical intervention. Every effort should be made, both before and during surgery, to identify or rule out a focal lesion. Because of the difficulty in detecting many small lesions, multiple techniques should be employed. Finding a focal lesion can potentially prevent unnecessary pancreatic resection, which can help prevent future development of diabetes mellitus, with its well-known and devastating morbidity and mortality.

If a focal lesion can be identified and excised, the prognosis is excellent. Most patients maintain reference-range serum glucose levels without the need for medication or dietary intervention.18 F-L-DOPA PET scanning may be very helpful in identifying a focal lesion, most of which are too small to locate with other imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography. Pancreatic venous sampling or intra-arterial calcium stimulation may also help identify a focal lesion (see Workup).

If a focal lesion is found before or during surgery, it may be excised locally without further pancreatic resection. However, multiple focal lesions may be present. Intraoperative glucose monitoring during a trial of glucose-free intravenous (IV) fluids may guide the surgeon in determining the need to search for additional lesions. The patient’s ability to maintain normoglycemia without IV glucose suggests that no hypersecretory foci remain.

The recommended surgical approach involves taking multiple biopsy samples from different parts of the pancreas (head, body, isthmus, and tail). These samples are sent for frozen-section evaluation to help determine intraoperatively whether the pathology is diffuse or focal. Inspection and palpation of the pancreas may also help localize a focal lesion. In a series of 53 patients with a focal lesion, 8 did not have an apparent focal lesion on18 F-L-DOPA PET scan, but all were identified intraoperatively, avoiding unnecessary and harmful near-total pancreatectomy.[11]

The finding of abnormal beta-cell nuclei in all specimens suggests a diffuse lesion, for which extensive pancreatectomy is indicated. In contrast, if only one specimen contains abnormal beta-cell nuclei, a focal lesion may be present.

Nuclear abnormalities include greatly increased size or abnormal (crescent or ovoid) shapes of beta cells. Since these histologic findings also occur in some persons without hyperinsulinemic hypoglycemia, clinical confirmation of hyperinsulinism and hypoglycemia before surgery is essential.

Some investigators have reportedly achieved success in distinguishing focal pathology from diffuse pathology by using mean nuclear radius and nuclear crowding indices of beta cells in pancreatic specimens. Studies suggest that this procedure, which is currently investigational, could be performed intraoperatively to determine the extent of pancreatic resection required.

If no focal lesion is found, the surgeon performs a partial pancreatectomy. Extensive experience with varying degrees of pancreatic resection in infants and children has been reported. Although some controversy remains, the 95% or subtotal pancreatectomy is the most widely accepted procedure for infants and children; resection of less than 95% of the pancreas is associated with a higher rate of treatment failure and need for reoperation.

In a 95% pancreatectomy, the tail, the body, the uncinate process, and most of the head of the pancreas are removed, leaving a portion of pancreas to the right of the common bile duct and a thin rim along the second portion of the duodenum and the pancreaticoduodenal arteries.

The more aggressive 98% pancreatectomy removes all but a few small islands of pancreatic tissue along the pancreaticoduodenal arteries. This procedure is associated with a higher rate of diabetes mellitus postoperatively; however, patients with lesser degrees of pancreatic resection also remain at substantial risk for future development of diabetes mellitus.

Some authors advocate a more conservative initial procedure, with reoperation later if hypoglycemia persists. Future advances in medical therapy may provide better glycemic control with fewer side effects, permitting less radical pancreatic resection.

Regardless of the procedure used, hypoglycemia may recur, and the patient may require continued medical therapy. Reoperation with additional pancreatic resection may be indicated if optimal medical management cannot provide adequate glycemic control. In refractory cases, which are rare, total resection of the pancreas has been performed.

In infants, surgery is usually performed within the first 2 months of life. Laparoscopic procedures can be done in all age groups.

Published material on the surgical management of adult CHI is limited. The extent of pancreatic resection necessary for optimal outcomes in adults is not known. Pancreatic resections ranging from 30% to 95% have been reported, with widely varying results. Until more data are available, some authors have suggested a more conservative resection of the pancreas as the initial procedure in adults, with possible reoperation if adequate glycemic control is not achieved.

Early complications of surgery include bleeding and wound infection. Late complications of surgical treatment include pancreatic exocrine insufficiency and glucose intolerance or frank diabetes mellitus.

Islet cell autotransplantation

Some authors advocate cryopreservation of islet cells from the resected portion of the pancreas for possible future autotransplantation if the patient develops diabetes mellitus. In theory, this process would cure diabetes without the need for immunosuppression or risk of rejection, as is observed in pancreatic or islet cell allotransplants.

Since 1977, several centers have reported success using this approach in adults and children undergoing total pancreatectomy for severe pancreatitis or pancreatic tumors.[17, 18] Success in eliminating insulin requirements varies from 29 -100%; in small series, this approach has been reported to prevent the development of diabetes for at least 13 years.[19]

No cases of islet cell autotransplantation in patients with CHI have been published to date. However, some patients (or their families, in the case of infants) have elected to have islet cell cryopreservation performed, in anticipation of future developments in this area.

Ethical, technical, and safety considerations related to this therapy have not been fully developed, but the concept appears promising, especially given the rapid progress being made in islet cell allotransplantation. Patients or their families should consider islet cell preservation for possible future autotransplantation, as the knowledge base continues to develop.

Treatment of Pregnant Patients

Little is known about CHI in pregnancy. One report describes a 36-year-old woman with PHHI treated successfully with octreotide during pregnancy.[20]

The use of medications should be reviewed. Diazoxide is known to decrease fetal survival in animals; this effect has not been documented in humans. Studies of octreotide and glucagon in pregnant animals have not shown fetal harm, even at doses far greater than those used in humans. These medications are classified as pregnancy category B. No adequate studies of these agents in pregnant women exist; therefore, they should be used with caution and only if clearly needed. The safety of nifedipine in pregnancy has not been established.

Pregnancy frequently causes disturbances of glucose metabolism. Because both hypoglycemia and hyperglycemia pose considerable risks to the fetus, patients should practice diligent glucose monitoring with regular medical follow-up. Therapeutic modalities should be individualized and adjusted as indicated.

Early prenatal care and close follow-up are essential. Referral to a maternal-fetal medicine specialist or high-risk pregnancy clinic should be considered.

Prenatal diagnosis by measurement of amniotic fluid insulin, C-peptide, and glucose levels has been described, but very limited data are available.

Infants of mothers with CHI should be closely monitored for hypoglycemia by physical examination and blood sampling. If possible, arranging delivery at a facility with a NICU may be prudent to facilitate prompt treatment in the event that the infant has persistent hypoglycemia.

Dietary Measures

A diet of 3 meals and 3 snacks daily helps maintain adequate serum glucose levels. Patients should avoid fasting (eg, skipping meals and scheduled snacks), because hypoglycemia may develop quickly.

A high-protein, high-carbohydrate diet is preferred. The carbohydrates provide the most long-acting source of glucose to counter the continuous release of insulin, and concurrent protein helps prolong this effect.

Patients should always have access to a rapid-acting carbohydrate, such as glucose tablets, glucose gel, fruit juice, hard candy, or sugar cubes. Uncooked cornstarch may be used to provide additional carbohydrates, and it may be helpful in preventing fasting hypoglycemia during sleep if administered at bedtime.[21]

Activity

Regular activity should be encouraged, with appropriate precautions.

Patients or parents should always carry a supply of rapid-acting carbohydrate (eg, glucose tablets or gel, sugar cubes, fruit juice, hard candy) to use in case of hypoglycemia.

Patients should increase their carbohydrate intake when increased exertion is anticipated, such as before strenuous exercise.

Consultations

Consultations with the following professionals should be obtained as needed:

  • Pediatric endocrinologist

  • Pediatric surgeon

  • Dietitian (ideally, one who is experienced in the care of diabetes; dietary management of CHI is related to that of diabetes)

  • Medical geneticist

Long-Term Monitoring

Patients should have regular follow-up visits with a pediatric endocrinologist to review blood glucose levels, diet, growth, and medication side effects. Patients should record blood glucose levels and bring these records to follow-up visits or use a home glucose meter with a memory that can be downloaded.

Home therapy must be individualized and usually involves 1 or more of the following:

  • Oral diazoxide, possibly in conjunction with oral chlorothiazide

  • Oral nifedipine

  • Subcutaneous octreotide

  • Subcutaneous glucagon (for emergency use)

 

Medication

Medication Summary

Diazoxide, octreotide, and nifedipine are the primary medications used in long-term treatment of congenital hyperinsulinism (CHI), or persistent hyperinsulinemic hypoglycemia of infancy (PHHI).[22] Some authors also recommend using chlorothiazide in conjunction with diazoxide for a synergistic effect. Most of these agents have significant adverse effects, especially with long-term use. Nifedipine appears to have considerably fewer adverse effects than the others.

Patients may require continuous intravenous (IV) glucose infusion. Glucagon may also be administered emergently to maintain adequate blood glucose levels.

Glucose-Elevating Agents

Class Summary

Insulin secretion may be altered by various mechanisms. Diazoxide inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release, which elevates blood glucose levels. Octreotide is a peptide with pharmacologic action similar to that of somatostatin, which inhibits insulin secretion.

In CHI, functional abnormalities are believed to exist in the adenosine triphosphate (ATP)-sensitive potassium channels (composed of the sulfonylurea receptor [SUR gene abnormality] and the potassium channel pore protein [Kir6.2 gene abnormality]). These channels initiate depolarization of the beta-cell membrane and opening of calcium channels. The resultant increase in intracellular calcium triggers insulin secretion. Calcium channel blockers block the action of these calcium channels, decreasing insulin secretion.

Nifedipine is the only calcium channel blocker for which clinical trials have been performed in patients with CHI. The use of other calcium channel blockers given in liquid formulations or by alternative drug-delivery systems remains a promising area for future research. Thiazide diuretics also inhibit insulin secretion.

In CHI, chlorothiazide should be used in conjunction with diazoxide. It exerts a synergistic effect on inhibiting insulin secretion by activating a different potassium channel.

In addition to the agents described above, prompt-acting glycogenolysis is achieved with glucagon. Emergent blood glucose level elevation requires IV dextrose. Corticosteroids are rarely used for gluconeogenesis in the long term, because of their risk of toxicity.

Octreotide (Sandostatin)

Octreotide is a peptide with a pharmacologic action similar to that of somatostatin. It is a more potent inhibitor of insulin, glucagon, and growth hormone secretion than somatostatin. It elicits diverse endocrine effects, including suppression of luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH), decreased splanchnic blood flow, and inhibition of release of serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, pancreatic polypeptide, and thyroid-stimulating hormone (TSH).

Octreotide decreases gallbladder contractility and bile secretion. It is used in CHI primarily for its ability to inhibit insulin secretion.

Diazoxide (Proglycem)

Diazoxide is an antihypertensive agent that relaxes smooth muscle in the peripheral arterioles. It is related to the thiazide class of drugs but has no diuretic action. It inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release.

Diuretics, Thiazide

Class Summary

Some authors recommend using chlorothiazide in conjunction with diazoxide for a synergistic effect.

Chlorothiazide (Diuril)

When combined with diazoxide, chlorothiazide elicits a synergistic effect on inhibiting insulin secretion by activating a different potassium channel. It also counteracts the salt and water retention induced by diazoxide.

Cardiovascular, Other

Class Summary

Use of nifedipine in CHI is relatively new, but initial reports suggest that it is effective and extremely well tolerated.

Nifedipine (Adalat, Procardia, Nifediac, Nifedical XL)

Nifedipine, a later addition to the therapeutic armamentarium, is a calcium channel blocker that helps reduce the influx of calcium into beta cells, which is a necessary step for insulin secretion. This effect occurs with doses much lower than those traditionally used for other indications (eg, angina pectoris). Nifedipine appears to have considerably fewer adverse effects compared with other agents.[13]

Most information on adverse effects of, and interactions with, nifedipine has been obtained from studies of adults using the drug for angina pectoris at proportionately higher doses than those used in children for CHI.

A liquid formulation is not available commercially. The drug is supplied as a 10-mg liquid-in-gelcap. To measure smaller doses, the contents may be aspirated with a syringe and needle, but it is very difficult to do this accurately because of the extremely small volume of fluid in the gelcap. Extended-release (ER) formulations have also been employed in CHI.

Dextrose (Glutol, Enfamil Glucose, Similac Glucose, Glutose 15)

Dextrose is used for prompt elevation of serum glucose. It is a monosaccharide that is absorbed from the intestine and then distributed, stored, and used by the tissues. Parenterally injected dextrose is used in patients unable to sustain adequate oral intake. Direct oral absorption results in a rapid increase in blood glucose concentrations. Dextrose is effective in small doses, and no evidence indicates that it may cause toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake in a small volume of fluid.

Glucagon (GlucaGen)

Glucagon, a polypeptide hormone, is produced by pancreatic alpha cells of the islets of Langerhans. Its effects on blood glucose are the opposite of those exerted by insulin. Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis).

Glucagon increases hydrolysis of glycogen to glucose (glycogenolysis) in the liver, in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract.