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Congenital Hyperinsulinism Treatment & Management

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

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.

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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.

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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.

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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.

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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]

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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.

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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
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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)
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Contributor Information and Disclosures
Author

Robert S Gillespie, MD, MPH Physician, Department of Pediatrics, Cook Children's Medical Center

Disclosure: Received consulting fee from Alexion Pharmaceuticals for consulting.

Coauthor(s)

Stephen Ponder, MD, CDE Director, Division of Pediatric Endocrinology, Department of Pediatrics, Driscoll Children's Hospital; Professor of Pediatrics, Texas A&M Health Science Center College of Medicine

Stephen Ponder, MD, CDE is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, Pediatric Endocrine Society, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
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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 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 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.
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.
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.
 
 
 
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