AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1938, Laidlaw coined the term nesidioblastosis, now termed persistent hyperinsulinemic hypoglycemia of infancy (PHHI), to describe the neodifferentiation of islets of Langerhans from pancreatic ductal epithelium. Severe recurrent hypoglycemia associated with an inappropriate elevation of serum insulin, C-peptide, and proinsulin defines this disorder. PHHI represents the most common cause of hyperinsulinism in neonates. If left untreated, PHHI can lead to brain damage or death secondary to severe hypoglycemia. Although PHHI 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. PHHI is often poorly responsive or unresponsive to medical management, necessitating 95% or near-total pancreatectomy.

Pathophysiology

In PHHI, the histologic abnormalities in pancreatic structure are heterogeneous but can be grouped into 2 broad categories: (1) focal adenomatous hyperplasia (found in one fourth to one third of cases) and (2) a 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.

Recent advances in elucidating the molecular basis of PHHI 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 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.

Frequency

United States

Few data are available regarding PHHI. An estimated incidence of 1 in 50,000 live births in a random-mating population has been reported.

International

Again, few data are available on PHHI. The incidence may be as high as 1 in 2500 live births in populations with high rates of consanguineous unions.

Mortality/Morbidity

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.

Sex

The diffuse form of PHHI 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.

Age

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

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Most patients with PHHI present shortly after birth with symptoms of hypoglycemia (eg, hunger, jitteriness, lethargy, apnea, seizures). Older children, in addition to the above 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 PHHI 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

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 PHHI.

• 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. PHHI 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 be quite variable in nature.

Causes

PHHI is a clinically, pathologically, and genetically heterogeneous disease.

• Most cases of PHHI are sporadic. In approximately 50% of cases, no known genetic abnormality is found.
• Familial forms of PHHI are rare but well documented. These cases of PHHI involve autosomal recessive or dominant defects in 4 genes.
• • Beta-cell high-affinity sulfonylurea receptor gene (ABCC8, also known as SUR1)
  • Inwardly rectifying potassium channel gene (KCNJ11, also known as Kir6.2)
  • Glucokinase gene (GCK, also called GK): Only 5 persons have been described with this mutation.
  • Glutamate dehydrogenase gene (GLUD1, also called GUD1): This gene is associated with hyperinsulinism with hyperammonemia. It is unclear whether this disorder (described below) is a variant of persistent hyperinsulinemic hypoglycemia of infancy or a distinct clinical entity.
• Recent data have helped elucidate the mechanism of the focal form of PHHI. 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 PHHI.
• 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.
• See the references by Glaser and Fournet for a more detailed treatment of the genetics of hyperinsulinism.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Transient hypoglycemia of the newborn
Erythroblastosis fetalis
Drug effect (eg, tocolytics, quinine)
Withdrawal of parenteral nutrition or dextrose-containing 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

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• 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 upon 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 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 are consistent with exaggerated insulin activity.
• Cortisol and growth hormone levels are usually elevated in specimens taken during an episode of hypoglycemia (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 PHHI.
• Urinary ketones, amino acids, and reducing-substances studies may be obtained to exclude other metabolic diseases. The results are expected to be within the reference range in cases of PHHI.
• 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 persistent hyperinsulinemic hypoglycemia of infancy. 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.

Imaging Studies

• Ultrasonography, CT scanning, or MRI may be used to search for a focal mass in the pancreas; however, in many cases, the lesion is too small to be visible. No form of imaging currently available reveals the diffuse form of PHHI.

Other Tests

• The need for IV glucose at a rate greater than 10 mg/kg/min to maintain normoglycemia suggests the diagnosis of PHHI.

Procedures

• Catheterization of the portal and pancreatic veins with venous sampling may help distinguish between focal and diffuse PHHI. This procedure is well described in the pediatric population.
• • In this procedure, a catheter is placed in the pancreatic venous system via a femoral vein or 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 PHHI 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.
• A test using intra-arterial calcium stimulation has been described in adults and to a lesser extent in children.
• • In this test, a rapid bolus of calcium gluconate is 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.
  • Pancreatic venous sampling has been studied more widely to date, especially in neonates, but 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 PHHI has been divided into focal and diffuse categories. In the focal form (comprising 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 PHHI, 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. The endoplasmic reticulum is well developed, and Golgi complexes are prominent. Results of macroscopic examination are normal.

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 PHHI. 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

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• The only major expert consensus document on PHHI was developed by The European Network for Research into Hyperinsulinism (ENRHI) (Aynsley-Green et al, 2000).
• Immediate treatment of hypoglycemia is essential. Patients may require continuous IV glucose infusion. Glucagon may also be administered emergently to maintain adequate blood glucose levels.
• Diazoxide (Hyperstat [IV], Proglycem [PO]) is an antihypertensive agent that relaxes smooth muscle in the peripheral arterioles.
• • 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 opposite that of 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 levels, and hyperosmolar nonketotic comas have been reported with diazoxide, especially with long-term use.
  • Patients should be monitored for hypotension while using diazoxide, 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 (Sandostatin, SMS 201-995) is a long-acting analogue of somatostatin. Octreotide 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 PHHI 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 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, such as angina pectoris. The adverse effects observed at these low doses have been minimal.
• 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 changing medications, 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.

Surgical Care

• 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. Surgical treatment is indicated if medical therapy does not maintain normoglycemia, if a discrete lesion can be identified, or if the patient or patient's 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.
• 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. However, most focal lesions are too small to identify by CT scanning, MRI, ultrasonography, or even intraoperative palpation. Pancreatic venous sampling or intra-arterial calcium stimulation may help identify a focal lesion (see Procedures).
• If a focal lesion is found before or during surgery, the lesion may be excised locally without further pancreatic resection. However, multiple focal lesions may be present. Intraoperative glucose monitoring during a trial of glucose-free 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.
  • 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. This approach is recommended.
  • 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 reported success in distinguishing focal pathology from diffuse pathology 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. In this procedure, the tail, body, 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. Resection of less than 95% of the pancreas is associated with a higher rate of treatment failure and need for reoperation. 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 remainatsubstantialrisk
  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 PHHI is limited. The extent of pancreatic resection necessary for optimal outcomes in adults is not known. Pancreatic resections ranging from 30-95% have been reported with widely variable 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.
• 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 resulting in immunosuppression or rejection. Since 1977, several centers have reported success in adults undergoing total pancreatectomy for severe pancreatitis or pancreatic tumors. Success in eliminating insulin requirements varies from 50-100%; in small series, this approach has been reported to prevent the development of diabetes for at least 13 years.
• • No cases of islet cell autotransplantation in patients with PHHI 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.

Consultations

• Pediatric endocrinologist
• Pediatric surgeon
• Dietitian (ideally, experienced in the care of diabetes because management of PHHI is similar to that of diabetes)
• Medical geneticist

Diet

• 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.

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.
  

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Diazoxide, octreotide, and nifedipine are the primary medications used in long-term treatment of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). Some authors also recommend using chlorothiazide in conjunction with diazoxide for a synergistic effect. All these drugs 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 PHHI, but their other therapeutic actions may become a burden in patients with PHHI, 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 PHHI. In addition, most agents have significant adverse effects, especially with long-term use. Nifedipine is a relatively new addition to the therapeutic armamentarium, and it appears to have considerably fewer adverse effects than the other agents.

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.

Drug Category: Insulin secretion inhibiting agents

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 persistent hyperinsulinemic hypoglycemia of infancy (PHHI), functional abnormalities are believed to exist in the 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 PHHI. 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 PHHI, chlorothiazide should be used in conjunction with diazoxide. It exerts a synergistic effect on inhibiting insulin secretion by activating a different potassium channel.

Drug Name	Chlorothiazide (Diuril)
Description	When combined with diazoxide, elicits synergistic effect on inhibiting insulin secretion by activating a different potassium channel. Also counteracts the salt and water retention induced by diazoxide.
Adult Dose	Not well defined for PHHI; the usual diuretic dose is 250-1000 mg PO/IV qd/qid; the dose for PHHI may be much smaller.
Pediatric Dose	7-10 mg/kg/d PO/IV divided bid
Contraindications	Documented hypersensitivity; anuria; hypokalemia
Interactions	May decrease effectiveness of anticoagulants, antigout agents, and sulfonylureas; effectiveness may be decreased by bile acid sequestrants, methenamine, and NSAIDs; may increase toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, diazoxide, digitalis, lithium, loop diuretics, methyldopa, muscle relaxants, and vitamin D; potentiates diuresis when coadministered with loop diuretics
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause hypercalcemia, hypomagnesemia, and increased plasma cholesterol levels; avoid IM or SC administration

Drug Name	Octreotide (Sandostatin)
Description	A peptide with pharmacologic action similar to somatostatin. More potent inhibitor of insulin, glucagon, and growth hormone secretion than somatostatin. Elicits diverse endocrine effects, including suppression of LH response to GnRH, decreased splanchnic blood flow, inhibition of release of serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, pancreatic polypeptide, and thyroid-stimulating hormone (TSH). Decreases gallbladder contractility and bile secretion. Used in PHHI primarily for its ability to inhibit insulin secretion.
Adult Dose	50 mcg SC tid initially; may increase dose to 500 mcg SC tid; doses of 300-600 mcg/d or higher seldom result in additional biochemical benefit
Pediatric Dose	1-10 mcg/kg/d SC divided q6-8h
Contraindications	Documented hypersensitivity
Interactions	May decrease absorption of PO administered drugs; may decrease blood levels of cyclosporine; patients may require dose adjustments of insulin, PO hypoglycemic agents, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balances while on this drug
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Associated with gallbladder sludging or gallstones, pancreatitis, hypothyroidism, and altered fat absorption; bradycardia, conduction abnormalities, arrhythmias, and ECG changes have been reported in patients taking octreotide for acromegaly; patients may experience hypoglycemia or hyperglycemia due to the alteration of multiple interrelated glucose regulatory pathways; diarrhea, nausea, and abdominal discomfort are common adverse effects

Drug Name	Nifedipine (Adalat, Procardia)
Description	Use of this drug in nesidioblastosis is relatively new, but initial reports suggest that it is effective and extremely well tolerated. 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 PHHI. A liquid formulation is not available commercially. The drug is supplied as a 10-mg liquid-in-gelcap. The contents may be aspirated with a syringe and needle to measure smaller doses, but it is very difficult to do so accurately, due to the extremely small volume of fluid in the gelcap. ER formulations have also been employed in PHHI.
Adult Dose	10-30 mg PO tid/qid
Pediatric Dose	0.25-2.5 mg/kg/d PO divided q6-8h
Contraindications	Documented hypersensitivity
Interactions	Caution with coadministration of any agent that can lower BP, including beta blockers and opioids; H2 blockers (eg, cimetidine) may increase toxicity; may increase serum levels of digoxin or quinidine; nifedipine levels may be affected by CYP3A4 inhibitors (eg, erythromycin, itraconazole) or inducers (eg, carbamazepine, rifampin)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	No adverse effects have been reported with use for PHHI in children; however, the number of reported cases is small and no data on long-term use are available; overdosage may result in hypotension; the most common adverse effects reported in adults during clinical trials at proportionately higher doses for angina pectoris were peripheral edema, dizziness, light-headedness, nausea, headache, flushing, and weakness; allergic hepatitis has occurred rarely; risk of measurement errors when removing drug from capsule for doses <10 mg; drug degrades upon removal from capsule and should not be withdrawn until ready for administration

Drug Category: Dextrose and glucose stimulators

Prompt-acting glycogenolysis is achieved with glucagon. Emergent blood glucose level elevation requires IV dextrose. Corticosteroids are rarely used for gluconeogenesis long term because of their risk of toxicity.

Drug Name	Glucagon
Description	Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Exerts opposite effects of insulin on blood glucose. Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). Increases hydrolysis of glycogen to glucose (glycogenolysis) in liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases force of contraction in heart and has a relaxant effect on GI tract.
Adult Dose	1 mg (1 U) IV/IM/SC
Pediatric Dose	<20 kilograms: 0.5 mg (0.5 U) IV/IM/SC or 20-30 mcg/kg; not to exceed 1 mg/dose >20 kilograms: Administer as in adults
Contraindications	Documented hypersensitivity; pheochromocytoma
Interactions	Effects of anticoagulants may be enhanced by glucagon (although onset may be delayed); monitor prothrombin activity and monitor for signs of bleeding in patients receiving anticoagulants; adjust dose accordingly
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor blood glucose levels in hypoglycemic patients until they are asymptomatic; glucagon is effective in treating hypoglycemia only if sufficient liver glycogen is present; because liver glycogen availability is necessary to treat hypoglycemic patients, glucagon has virtually no effect on patients in states of starvation, adrenal insufficiency, or chronic hypoglycemia

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit patient to a neonatal intensive care unit (NICU) or ICU until blood glucose levels are stabilized. Arrange for family and patient education to begin immediately.

Further Outpatient Care

• 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.

In/Out Patient Meds

• Home therapy must be individualized, usually involving one or more of the following:
• • Oral diazoxide, possibly in conjunction with oral chlorothiazide
  • Oral nifedipine
  • Subcutaneous octreotide
  • Subcutaneous glucagon (for emergency use)

Transfer

• 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.

Complications

• 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.
• 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.
• Complications of medical therapy primarily are related to adverse effects of medications (see Medication).

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 one 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. 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. Most series are limited by relatively short follow-up times, so 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 following resection of focal lesions.
  • Patient/family education 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 PHHI 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 exist, and the heterogeneity of the disease likely confounds many neurodevelopmental studies.

Patient Education

• Patients (if old enough) and family members should be taught how to use a home blood glucose monitor.
• Patients and family members should 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. Many areas of the United States still do not have 911 services. Family members should know the local emergency phone number if 911 service is not available in their area.
• Patients should wear a medical ID bracelet.
• A nutritionist should provide dietary education and meal-planning assistance.
• 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize and treat hypoglycemia
• Misdiagnosis of hypoglycemic seizure as epileptic seizure, resulting in inappropriate treatment with anticonvulsants and failure to treat with glucose
• Failure to diagnose PHHI, with resulting morbidity or mortality
• Failure to identify associated endocrine abnormalities, such as multiple endocrine neoplasia type I

Special Concerns

• Little is known about PHHI in pregnancy. One report describes a 36-year-old woman with PHHI treated successfully with octreotide during pregnancy.
• • The use of medications should be reviewed. Diazoxide is known to decrease fetal survival in animals, although this effect has not been documented in humans. Studies of octreotide and glucagon in pregnant animals have not shown harm to the fetus, even at doses far greater than those used in humans. These medications are classified as pregnancy category B. No adequate and well-controlled studies of these agents in pregnant women exist; therefore, these drugs 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 PHHI 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 the infant has persistent hypoglycemia.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Pancreatic specimen showing diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI) viewed at low power. The paler-staining cells are the neuroendocrine (islet) cells, which should be arranged in discrete islands within the acinar lobules. Acinar cells are the exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini-small glands. In PHHI, more of the neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
	View Full Size Image
Media type:  Photo

Media file 2:  Pancreatic specimen showing diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI) viewed at medium power. The paler-staining cells are the neuroendocrine (islet) cells, which should be arranged in discrete islands within the acinar lobules. Acinar cells are the exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini-small glands. In PHHI, more of the neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
	View Full Size Image
Media type:  Photo

Media file 3:  Pancreatic specimen showing diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI) viewed at high power. The paler-staining cells are the neuroendocrine (islet) cells, which should be arranged in discrete islands within the acinar lobules. Acinar cells are the exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini-small glands. In PHHI, more of the neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
	View Full Size Image
Media type:  Photo

Media file 4:  Normal pancreas. There are fewer of the 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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Sep 12, 2006