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November 01, 2009
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Clinical Advances in Pediatric Endocrinology: Focus on: Hyperinsulinism (short version)

Clinical Advances in Pediatric Endocrinology; Focus on: Hyperinsulinism

Introduction

Update on Diagnosis and Treatment of Hyperinsulinemic Hypoglycemia
Mark A. Sperling, MD, and Charles A. Stanley, MD

Introduction


Hyperinsulinemic hypoglycemia is the most dangerous form of hypoglycemia. Insulin affects not only glucose metabolism, but also the metabolism of protein and fat. Notably, insulin suppresses the conversion of fat to ketone bodies, which are the ultimate source of fuel for muscles and the brain under circumstances of fasting and low glucose. Thus, hyperinsulinism not only results in hypoglycemia, but also prevents the body from providing any alternative source of fuel to substitute for glucose. For this reason, hyperinsulinemic hypoglycemia carries a very high risk of causing irreversible brain damage unless promptly diagnosed and treated. Some forms of the disorder respond well to medical management, but others may require near-total pancreatectomy to control blood glucose levels.

The molecular mechanism and pathology of congenital hyperinsulinism has taken approximately 50 years to understand, with particularly exciting developments occurring over the past 10-15 years. For example, the molecular mechanisms by which the chemical energy of glucose is coupled to the activity of the β-cell and the secretion of insulin have been significantly unraveled. This knowledge has subsequently led to insight on how the pathway of insulin secretion may become dysregulated. There is also the discovery that β-cells in the pancreas take up L-3,4-dihydroxyphenylalanine (L-DOPA), and that this uptake is increased in areas of the pancreas that harbor potentially curable focal lesions. This discovery applied to newer imaging techniques has resulted in the ability to characterize and localize a lesion before surgery and offers the potential for complete cure while leaving most of the pancreas intact. Despite these advancements, however, there is still room for improvement. For example, only about 50% of cases of hyperinsulinism are accurately diagnosed and the frequency of developmental delay and seizures continues to be between 25% and 50%.

This monograph will serve to update pediatric endocrinologists and pediatric endocrine nurses who care for children who have hypoglycemia. The history of the field will be reviewed, along with the potential causes of hyperinsulinism. Diagnostic methods and treatment strategies will also be discussed.

I thank Dr. Charles A. Stanley for his article, case, and discussions, which led to the development of this monograph. Readers can expect to be provided with the most up-to-date knowledge of the field of hyperinsulinism, as well as strategies to use this knowledge to improve their practice.

Mark A. Sperling, MD
Course Chair

Mark A. Sperling, MDCourse Chair: Mark A. Sperling, MD
Professor and Chair Emeritus
Department of Pediatrics
Children’s Hospital of Pittsburgh
Pittsburgh, Pennsylvania

Charles A. Stanley, MDCharles A. Stanley, MD
Professor of Pediatrics
University of Pennsylvania School of Medicine
Director of the Hyperinsulinism Center
Core Laboratory Director
Clinical Translational Research Center
The Children’s Hospital of Philadelphia
Philadelphia, PA

Update on Diagnosis and Treatment of Hyperinsulinemic Hypoglycemia


Mark A. Sperling, MD, and Charles A. Stanley, MD

Summary

Hypoglycemia due to genetic and non-genetic forms of hyperinsulinism (HI) make up the most common, as well as the most difficult to manage, disorders of hypoglycemia in pediatrics. Affected children are at high risk for seizures and irreparable brain damage if not promptly recognized and adequately treated. Some cases present as neonates with severe intractable hypoglycemia, but milder cases may escape detection until later in childhood or even until adult life. Recent discoveries have identified 8 genetic loci associated with congenital hyperinsulinism; these can have recessive, dominant, or sporadic patterns of inheritance. Testing for some of these genes is routinely available in commercial laboratories. In addition, there is increasing recognition that a prolonged neonatal form of hyperinsulinism can occur in association with disorders that cause perinatal stress, such as birth asphyxia and intrauterine growth retardation. Some forms of hyperinsulinism can be controlled well with medical therapy; others may require surgical near-total pancreatectomy. In more than half the cases that require surgery, the cause of the hyperinsulinism is an isolated focal lesion of the pancreas that is potentially curable by surgery. New methods for preoperative diagnosis and localization of such lesions, such as imaging by fluorine-18 L-3, 4-dihydroxyphenylalanine ([18F] L-DOPA) positron emission tomography (PET) scans, are becoming available.

Historical Note

Children with what we now recognize as congenital HI were first described in the early 1950s under the rubric of “idiopathic hypoglycemia of infancy.” In a subset of these cases, hypoglycemia could also be provoked by high-protein meals or by amino acids, particularly leucine. In the 1960s, the development of the first radioimmunoassays for insulin showed that idiopathic hypoglycemia was associated with dysregulation of insulin secretion. In the 1970s, it was suggested that these children had a problem in islet cell maturation evidenced by persistence of β-cells budding off the ductal epithelium, which was termed nesidioblastosis. However, subsequent investigations showed that this pattern of nesidioblastosis is a normal feature of the pancreas during the first several months after birth so this term should no longer be used. By the 1990s, it was appreciated that congenital HI could be inherited in either recessive or dominant fashion and the first genetic loci associated with HI were described. As discussed below, these discoveries of the genetic basis of HI led to rapid advances in clinical diagnosis and management of this challenging group of disorders.1-3

Clinical Features

Fasting hypoglycemia is the most important feature of HI. In severe cases, hypoglycemia occurs less than 1 or 2 hours after, or even in spite of, feeding. This reflects the potent action of insulin to increase the rates of glucose utilization while suppressing the rates of glucose production. Glucose infusion rates (GIR) needed to maintain normoglycemia in patients with HI usually are greater than 10–15 mg/kg/min and may exceed 20–30 mg/kg/min (5–6 times normal). Neonates with severe congenital HI are usually large-for-gestational age (LGA) at birth, due to the anabolic effect of insulin on fetal growth. Such infants are easily confused with infants born to diabetic mothers. Postprandial hypoglycemia is not usually a feature of HI; however, specific forms of HI are associated with protein-sensitive hypoglycemia, with or without leucine-sensitivity.1-3

Diagnosis

There are several criteria for making the diagnosis of HI (Table). The best method of diagnosing HI is a provocative fasting test to monitor the fuel and hormone responses to hypoglycemia. Opportunity should also be taken at times of spontaneous hypoglycemia episodes to obtain specimens for diagnosis. In HI in children, the problem is dysregulated insulin secretion with a lack of adequate suppression of insulin, rather than oversecretion. Therefore, serum levels of insulin may not be clearly elevated at times of hypoglycemia, so emphasis must be placed on demonstrating markers of excessive insulin effects on circulating fuels (free fatty acid and β-hydroxybutyrate) and the glycemic response to glucagon.4,5 Point-of-care meters for measuring plasma β-hydroxybutyrate, if available, in addition to blood glucose measurements by meter, are useful in evaluating suspected HI in real time. In some circumstances, additional biomarkers, such as insulin-like growth factor binding protein-1(IGFBP1), C-peptide, or proinsulin levels may provide useful information.6 6

Table. Hyperinsulinism Diagnosis Criteria

Variants of Hyperinsulinism: Genetic Forms

There are many major genetic and non-genetic forms of HI. Since 1995, 8 genetic loci have been associated with congenital HI.1,7 Defects in these loci involve steps in the pathways by which metabolic fuels “trigger” insulin release by increasing ATP levels to close the β-cell ATP-dependent potassium (KATP) channels, leading to depolarization of the β-cell plasma membrane (Figure 1). Note that diazoxide, the current drug of choice for medical treatment of HI, suppresses insulin secretion by binding to and activating KATP channel opening. Diazoxide is obviously not effective in patients with KATP channel mutations that cause complete loss of channel function. As discussed below, differences in phenotypes among the disorders can be helpful in pinpointing the underlying defect and defining therapeutic strategies.

Figure 1. Pathways of Insulin Secretion and Genetic Defects Causing Congenital Hyperinsulinism
Figure 1. Pathways of Insulin Secretion and Genetic Defects Causing Congenital Hyperinsulinism
Glucose and amino acids stimulate insulin release by generating ATP, which leads to closure of ATP-sensitive plasma membrane potassium channels, plasma membrane depolarization, activation of voltage-sensitive calcium channels, an increase of cytosolic calcium, and release of insulin from storage granules.

Source: Charles A. Stanley, MD

KATP-channel HI [inactivating mutations of the SUR1 (ABCC8) or Kir6.2 (KCNJ11) subunits of the β-cell KATP channel; 11p15]

There are 2 subunits of the KATP channel: SUR1, which is encoded by the gene ABCC8, and Kir6.2, which is encoded by the gene KCNJ11. Inactivating mutations in the genes for either of these subunits result in inactive channels and consequently dysregulated insulin secretion. Mutations in the channel can be inherited in either a dominant or a recessive fashion.

Recessive KATP-HI

This is responsible for most of the cases of severe, diazoxide-unresponsive, diffuse HI. Infants are often born LGA and present with hypoglycemia at birth. GIR can be very high (20–30 mg/kg/min). Although some cases may be managed with octreotide plus intensive tube feeding regimens, many require surgical near-total pancreatectomy.

Focal KATP-HI

Congenital focal lesions of β-cell adenomatosis are usually small, between 0.5 cm and 1 cm in diameter. They arise early in fetal development of the pancreas when a paternally-transmitted recessive KATP-channel HI mutation becomes duplicated due to loss of the normal maternal allele.8 A similar two-hit loss of heterozygosity mechanism is also responsible for many forms of cancer (eg, retinoblastoma). The phenotype is identical clinically to that of diffuse HI caused by recessive KATP mutations, ie, diazoxide is ineffective and affected infants often have high GIR and require surgery within a few weeks after birth.

Dominant KATP-HI

This is responsible for approximately half of the cases of diazoxide-unresponsive HI in whom a genetic defect can be found. Although some of those affected present with severe hypoglycemia in the neonatal period, other cases have few symptoms and may escape recognition even into adult life.9

GCK-HI (activating mutations of glucokinase; 7p15)

This is a relatively rare form of HI, but more cases continue to be reported, providing new information on the range of phenotype.10 The mutations are dominantly expressed, but approximately half of reported cases have de novo mutations. Although originally described as being responsive to diazoxide, it is increasingly recognized that plasma glucose may be difficult to normalize in this form of HI. This illustrates the fact that glucokinase (GCK) has a major effect on setting the β-cell glucose threshold for insulin release.

GDH-HI (also known as the hyperinsulinism-hyperammonemia syndrome; caused by activating mutations of glutamate dehydrogenase, GLUD1; 10q23)

This is one of the more common diazoxide-responsive forms of HI for which mutations have been identified.11 The mutations are dominantly expressed, but most patients have de novo mutations. Since glutamate dehydrogenase (GDH) is the site where leucine acts to stimulate insulin secretion, affected individuals are susceptible to protein-induced hypoglycemia and are hypersensitive to leucine-induced hypoglycemia. Patients have a high frequency of developmental delay and of absence seizures (generalized epilepsy), which seem not to be due to hypoglycemia, but may reflect effects of abnormal GDH function in the brain.12,13

SCHAD-HI (inactivating mutations of short-chain 3-hydroxy-acyl-CoA dehydrogenase, HADH; 4q22)

This is a rare recessive form of diazoxide-responsive HI that is caused by a deficiency of a mitochondrial enzyme involved in β-oxidation of short-chain fatty acids. The mechanism responsible for insulin dysregulation has not yet been elucidated. The disorder can be identified by metabolic tests showing increased plasma 3-hydroxy-butyryl-carnitine and urinary 2-hydroxy-glutarate.

In addition to the above, other rarer genetic HI defects have been described:

  • MCT-1 (dominant exercise-induced HI; caused by mutations that interfere with silencing of β-cell expression of a plasma membrane pyruvate carrier, monocarboxylate carrier 1, SLC16A1; 1p13.2).
  • UCP-2 HI (dominant inactivating mutations of the mitochondrial ATP-carrier, uncoupling protein 2, UCP2; 11q13).
  • HNF-4A (dominant inactivating mutations of the MODY1 gene, TCF14; 20q12); this defect later evolves into the MODY1 form of adult diabetes.7

Variants of HI: Acquired/Transient Forms

Perinatal stress HI

This is a transient form of congenital HI associated with birth asphyxia, small-for-gestational age (SGA) birthweight, or maternal toxemia/hypertension. Hypoglycemia may resolve within a few days but can last for several months. Most patients respond to diazoxide treatment. The mechanism is not understood, but the disorder is not uncommon and may occur in more than 10% of SGA infants.14

Other Types of Hyperinsulinemic Hypoglycemia or Mimickers of HI

Drug-induced HI and surreptitious insulin administration (Münchausen by proxy)

The possibility of hypoglycemia being induced by exogenous agents, such as oral sulfonylurea drugs (eg, glyburide) or injections of insulin, should be kept in mind even in very young children. Oral hypoglycemic agents may be ingested accidentally by young children, whereas insulin administration may be accidental or deliberate (syndrome of Münchausen by proxy). In the former setting, there will be release of both endogenous insulin and C-peptide secretion suggesting an insulinoma, whereas in the latter scenario, there will be suppressed levels of serum C-peptide at times of hypoglycemia [while serum insulin may be high or low, depending on the type of insulin administered (native human or animal insulin vs analogs of insulin) and their detectability with the assay employed]. Regardless, uncovering these causes requires the utmost vigilance and unusual perspicacity.

Insulinoma

Acquired tumors of the pancreas that release insulin are the most common cause of hypoglycemia in adults. Although rare, they occasionally occur in childhood. Most are benign, single islet cell adenomas; occasionally they may be associated with MEN1 mutations, which also can cause tumors of the pituitary.3

Congenital disorders of glycosylation (CDGs)

Some of the recessive disorders of glycosylation may have manifestations of hypoglycemia that involve or resemble HI. In some, such as CDG1a, the hypoglycemia responds to treatment with diazoxide; this particular defect interferes with synthesis of mannose and can be corrected with oral mannose supplementation. Others do not respond to mannose and also may not respond to diazoxide. The disorders can be screened for by testing for abnormal patterns of iso-electric focusing of plasma transferrin.15,16

Autoimmune hypoglycemia disorders

Hypoglycemia resembling HI has been reported due to insulin receptor activating antibodies or with antibodies against insulin itself. Although rare, these disorders have occasionally been demonstrated in children as young as 1 year. Although autoimmune hypoglycemia disorders mimic the physiological features of HI, failure to detect elevation of serum insulin levels and failure to respond acutely to suppression of insulin release with octreotide may provide clues to these unusual disorders.17

Molecular Diagnosis

Commercial laboratory tests for the most common genetic forms of congenital HI are available (ABCC8, KCNJ11, GLUD1, and GCK). In addition, HNF-4A (TCF14) testing is available under tests for MODY-type diabetes. These tests provide direct sequencing of coding regions and portions of flanking introns and can be selected based on clinical phenotype (eg, for a diazoxide-unresponsive case, tests for ABCC8 and KCNJ11 will be useful, but GCK should also be considered). Testing is particularly useful for preoperative diagnosis of focal vs diffuse HI. Testing may be definitive for diffuse HI if two known disease-causing recessive mutations of ABCC8 or KCNJ11 are found. The demonstration of a paternal-only recessive ABCC8 or KCNJ11 mutation can suggest possible focal HI; however, it does not exclude possible diffuse disease.

Histology of focal vs diffuse HI

The histology of diffuse HI shows an abnormality consisting only of nuclear enlargement in 5% to 10% of β-cells (3–4 times larger than surrounding cells).18,19 This can be very subtle and requires a pathologist experienced in congenital HI to interpret correctly. The histology of focal HI shows a single area of β-cell adenomatosis which may be as small as a few millimeters with normal-appearing islets in the surrounding tissue. (Visit www.EndocrineToday.com to view histological images of congenital and diffuse hyperinsulinism.)

Imaging for focal vs diffuse HI

Standard imaging procedures have not been useful in identifying or localizing focal adenomatosis lesions in infants (including CT, MRI, ultrasound, intra-operative ultrasound, octreoscan, etc). Invasive radiologic procedures are also not reliable, such as trans-hepatic portal vein insulin sampling or selective pancreatic arterial calcium stimulation/venous insulin sampling. Recently, good results have been obtained using [18F] L-DOPA PET scans.20 While this remains an experimental procedure in most countries, efforts should be made to make it available prior to surgery in infants with congenital diazoxide-unresponsive HI, because 50% or more of cases will have potentially curable focal lesions (Visit www.EndocrineToday.com to view [18F] L-DOPA PET scan images of congenital and diffuse hyperinsulinism.)

Plasma Glucose Standards for Diagnosis and Treatment of HI and Other Hypoglycemia Disorders

The goal of treatment is to maintain plasma glucose levels above 70 mg/dL. Successful treatment adequate to allow for management at home means achieving this goal for periods of fasting of at least 8–12 hours. For provocative tests of hypoglycemia, a plasma glucose level of 50 mg/dL is low enough to identify abnormalities of fuel and hormone responses and unlikely to provoke serious symptoms of hypoglycemia (except in disorders of fatty acid oxidation). Note that the common practice of using lower standards for diagnosis and treatment of hypoglycemia in neonates vs older children and adults is strongly discouraged. This is especially true in HI, since the levels of ketones and other fuels are suppressed by insulin, leaving no alternative source of energy to support brain metabolism when plasma glucose is low.

Emergent Treatment of HI

At the finding of hypoglycemia, while treatment must be given immediately, consideration should also be given to obtaining essential diagnostic information just before starting treatment. This involves drawing an extra amount of blood, referred to as a critical sample, for later determination of important fuels (ketones and free fatty acid) and hormones (insulin, cortisol, growth hormone, etc). Intravenous dextrose, 200 mg/kg, can be given (2 cc/kg of 10% dextrose solution). Continuous infusion of dextrose should then be given at a level sufficient to maintain plasma glucose above 70 mg/dL.

Chronic Medical Treatment of HI

Diazoxide

Diazoxide is the drug of first choice for treatment of HI, since it acts directly to open the KATP channel and suppress insulin secretion. It is not effective in severe KATP channel inactivating defects and may not be completely effective in GCK-HI. Responsive patients require 5–15 mg/kg/d divided into 1 or 2 doses. Since the half-life is 24–36 hours, patients can only be judged as unresponsive after being on 15 mg/kg/d for 4–5 days. Effectiveness should be assessed by a 10–14 hour fasting test prior to discharge. Adverse effects include fluid retention (which may require diuretics) and hypertrichosis (excess hair growth in non-sexual areas, eg forehead and back).

Octreotide

Octreotide acts downstream of the KATP channel complex to suppress insulin release and may be useful for short-term or, occasionally, for chronic therapy in patients who fail to respond to diazoxide. Since octreotide downregulates its own receptor, tachphylaxis and desensitization to the effect of the drug on blood sugar control make octreotide effective only rarely for long-term use. It may be given as 3–15 µg/kg/d divided into 3–4 doses, preferably starting with low doses and titrating up as needed. Adverse effects include altered intestinal motility, steatorrhea, gall stones, and rare instances of necrotizing enterocolitis.

Other drugs

Calcium channel blockers, glucocorticoids, growth hormone, and other insulin antagonists have been used to treat infants with HI but are not effective and usually not worth trying. Glucocorticoids, especially, are not helpful in treating hypoglycemia due to HI.

Dietary treatment

Tube feedings (nasogastric or gastrostomy) may be useful in some cases as a continuous infusion to maintain normal plasma glucose levels. Force feeding should be avoided to prevent development of GERD and feeding refusal behaviors. Cornstarch is not helpful in management of HI. For some types of HI that are associated with protein-sensitive hypoglycemia, high protein feedings should be avoided.

Surgical Management of HI

Because of the need to distinguish focal from diffuse HI, surgery for congenital HI requires both surgical and pathology teams with experience in dealing with these cases.21 In most centers, the disorder is encountered only rarely; thus, cases should be referred to centers that have established expertise. Prior to surgery, results of mutation analysis and [18F] L-DOPA PET scans may provide an indication of whether the disease is focal or diffuse and, if focal, where the lesion is located. At surgery, biopsies for frozen sections are taken of 3 regions of the pancreas (head, body, and tail) to assess whether there is evidence of diffuse disease. If not, careful search by inspection and palpation is done to identify a focal lesion. For diffuse disease, a 98% near-total resection is necessary to assure that hypoglycemia control improves. For focal disease, the lesion is resected locally, leaving as much unaffected pancreas intact as possible. For lesions in the head of the pancreas, a Roux-en-Y procedure may be necessary.

Visit www.EndocrineToday.com and click on the CME center to take post-test and obtain credit for this activity. Additional CME credit can be earned by viewing supplemental images and a case presentation with commentary.

References

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