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Insights into Neonatal Hyperinsulinism

Kelly, Andrea M.D.*; Alter, Craig M.D.*; Thornton, Paul M.D.*

CME Review Articles: Pediatric Endocrinology
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Hyperinsulinism (HI) is the most common cause of hypoglycemia in the newborn period and can be transient or persistent. Neonatal HI can cause significant morbidity and mortality if not recognized and carefully treated. Successful treatment of hyperinsulinism can be painstaking. Management demands 1) rigorous attention to blood glucose monitoring, 2) an attempt to restore normal or near-normal fasting tolerance, 3) preservation of a child’s ability and desire to feed, 4) establishment of a manageable home regimen that allows normal childhood development, and 5) alertness to the psychosocial stresses chronic illness imposes upon a family of a child. The discovery of a number of the genetic mutations responsible for congenital hyperinsulinism is allowing a more methodical and thoughtful approach to diagnosis and management. Identification of autosomal recessive mutations of the sulfonylurea receptor/potassium channel complex and of autosomal dominant gain of function mutations of glutamate dehydrogenase and glucokinase has provided powerful insight into the mechanism of the disease as well as into normal regulation of insulin secretion. Unfortunately, much has yet to be learned: uncharacterized forms of hyperinsulinism remain and the limited therapeutic armament is frequently ineffective.

Division of Pediatric Endocrinology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.

This article is the 3rd of 36 that will be published in 2001 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned appear following the Table of Contents.

Address correspondence to: Andrea Kelly, M.D., Division of Pediatric Endocrinology, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104. Phone: 215-590-1666; Fax: 215-590-1605; E-Mail: kellya@email.chop.edu.

*The authors have disclosed no significant financial or other relationship with any commercial entity.

Unlabeled/investigational uses of a commercial product are discussed in this CME review article.

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Introduction

Learning Objectives:

* Distinguish the major genetic forms of persistent neonatal hyperinsulinism (HI) with respect to their clinical manifestations and prognosis.

* Describe how best to confirm a diagnosis of HI.

* Explain the pharmacological options for treating HI and the role of surgery when medical treatment is unavailing.

Hyperinsulinism (HI) is the most common cause of recurrent hypoglycemia in infancy [1]. In the general population, the incidence ranges from one in 27,000 in the Irish population (unpublished data, Paul Thornton) to one in 40,000–50,000 in Finland and the Netherlands [2,3]. In the Saudi Arabian population consanguinity has led to incidences as high as one in 3,000 [4]. Recognition of the various genetic forms of HI whose symptoms may be mild and dependent upon environmental triggers has begun to dispel the notion that inherited HI is a diagnosis of infancy and childhood. Even into adulthood, individuals are now being diagnosed with inherited forms of HI.

For the over forty years since the original description of the syndrome of idiopathic hypoglycemia of infancy by McQuarrie in 1954, the pathophysiology of hyperinsulinism has been laden with confusion and subject to controversy. McQuarrie differentiated idiopathic hypoglycemia of infancy from “true” HI because not all affected children had either a β-cell tumor or diffuse hyperplasia of β-cells [5,6]. The term nesidioblastosis, used interchangeably with the term HI, had previously been coined to describe the histologic features that revealed persistence of a diffuse proliferation of islet cells budding from ducts in infants with HI [7]. This term, however, was later abandoned because this persistence of a fetal distribution of β-cells has been found in euglycemic neonates and infants [8–10]. In addition, improved insulin assays and the development of the glucagon stimulation test have allowed the documentation of inappropriately elevated insulin concentrations or action at the time of hypoglycemia in infants who would otherwise have not been considered to have HI by McQuarrie’s standards [6,11,12]. In 1956, Cochrane described a family with protein-induced hypoglycemia and considered the disorder to reflect leucine-sensitivity [13]. Later the cause of this leucine-sensitive hypoglycemia of infancy and childhood was found to be hyperinsulinism [14,15], and concern arose that all children with HI were protein-sensitive. Drash and Wolff presented diazoxide as a treatment for leucine-sensitive hypoglycemia in 1964 [16], but it was not effective for all HI cases and the use of glucocorticoids and low protein diets in treatment of HI persisted. Pancreatectomy and later octreotide, a long-acting somatostatin analogue, were the only hopeful but often unsuccessful alternatives.

Until the discovery in 1994 of linkage of some familial cases of HI to chromosome 11, an understanding of the pathophysiology of HI stagnated [17]. Defects of the potassium channel were subsequently uncovered in these HIaffected individuals. In the five years since that discovery, a number of genetic defects responsible for the inability of the β-cell to regulate insulin secretion have been identified. Mutations of the β-cell sulfonylurea receptor (SUR1) and its inwardly rectifying potassium channel (Kir6.2) [3,18–23], of glutamate dehydrogenase (GDH) [24–28], and of glucokinase (GK) [29] have all been associated with HI. Their clinical manifestations vary and have likely contributed to the confusion regarding pathophysiology and management of HI. Identification of these defects has provided insight into approach and management of HI-affected children and has greatly expanded the understanding of insulin secretion.

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Etiology

The definition of neonatal hypoglycemia has been heavily debated. Beyond day of life one, serum glucose less than 50 mg/dL is abnormal and when recurrent must be investigated. Hypoglycemia due to HI is particularly dangerous because the brain is deprived of its alternative fuels (ketones and lactate) that normally are available by the time prolonged fasting causes hypoglycemia; excessive insulin suppresses not only glycogenolysis but also gluconeogenesis, lipolysis, fatty acid oxidation, and ketogenesis. Affected children can be deceptively asymptomatic, display subtle signs such as poor feeding or intermittent lethargy, or develop the more severe symptoms of apnea or seizures, all the while placing their developing brains at risk of injury. A study by Koh revealed that although a child clinically appears asymptomatic at the time of hypoglycemia, neurologic changes could be detected [30]. Recurrent or prolonged hypoglycemia can cause permanent brain damage; a child with hypoglycemia must be treated promptly, and a search for the etiology must be undertaken.

The differential diagnosis of neonatal hypoglycemia includes not only HI, but also hypopituitarism and growth hormone deficiency, disorders of glycogenolysis and gluconeogenesis, and fatty acid oxidation disorders. With hypoglycemia due to HI, the serum insulin concentration may not be elevated, but suppressed IGFBP-1 (<120 ng/mL), free fatty acids (<1.5 mmol/L), and ketones (β-hydroxybutyrate < 1.5mmol/L) and a glycemic response to glucagon (>30 mg/dL increase in serum glucose with injection of 1 mg glucagon) will document excessive insulin action [6,11,12,31,32]. Affected infants frequently have high glucose infusion requirements, but others have only fasting intolerance. Neonatal hypopituitarism can mimic HI, and provocative testing for growth hormone, adrenal, and thyroid function may be necessary. Neonatal HI can be transient or permanent.

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Transient

Transient HI is associated with maternal diabetes and neonatal stress. Infants of diabetic mothers are born hyperinsulinemic and can be large for gestational age or of normal birth weight and develop hypoglycemia. Their HI resolves after a few days but can be severe enough to require intravenous dextrose and drug therapy.

Infants born small for gestational age, prematurely, to mothers with hypertension, or asphyxiated can have HI. The etiology of the dysregulated insulin secretion is not understood. This form of HI resolves in a few days to weeks but can last a few months and may require pharmacological intervention in addition to intravenous dextrose [33,34].

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Persistent

Persistent HI has previously been referred to as nesidioblastosis and leucine sensitive hypoglycemia of infancy and childhood. These terms, however, are inaccurate generalizations that do not apply to all the various forms of HI. With the recognition of specific HI-causing genetic mutations, the terminology has become more precise. Thus far, recessive and dominant mutations in four different genes have been associated with persistent HI: the sulfonylurea receptor (SUR1), the potassium channel (Kir6.2) (which together encode the KATP channel), glutamate dehydrogenase (GDH), and glucokinase (GK).

To understand the effects of these genetic defects, a basic understanding of the regulation of insulin secretion is necessary. Glucose-regulated insulin secretion is mediated by KATP-dependent and -independent pathways. The known sites of HI-causing defects occur in the KATPdependent pathway, which will be reviewed here (Fig. 1).

In the normal resting state of the β-cell, open KATP channels and the Na+-K+ ATPase pump maintain the β-cell plasma membrane in a hyperpolarized state to suppress insulin secretion. Closure of KATP channels raises intracellular potassium to cause depolarization of the β-cell plasma membrane. Voltage-dependent calcium channels then open, calcium influx occurs, and intracellular calcium concentrations rise to activate insulin secretion. This KATP-dependent pathway is regulated by the phosphorylated energy state of the β-cell. An increase in the ATP to ADP ratio works on the SUR1 to close the potassium channel. After glucose enters the β-cell through the GLUT2 transporter, it is phosphorylated by glucokinase (GK), the rate-limiting step in glucose metabolism. GK activity is controlled by the ambient glucose concentration and thus serves as the “glucosensor” of the β-cell. Beyond this rate-limiting step, further metabolism of glucose through glycolysis generates ATP leading the SUR1 to close the potassium channel and ultimately effect insulin secretion [35]. Stimulation of GDH activity is also thought to generate ATP and stimulate insulin secretion through the KATP-dependent pathway (mechanism to be further described under GDH-HI). The KATP channel-independent pathway is not completely understood but is demonstrated by glucose-stimulated insulin secretion above and beyond that induced by depolarization of the β-cell membrane and increased intracellular calcium concentrations. This pathway involves kinase A and C activation. The role of this pathway in HI remains to be explored.

Both tolbutamide and diazoxide act upon SUR1 to respectively stimulate and inhibit the KATP-dependent insulin secretion pathway. The natural ligand for the KATP channel remains to be identified.

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KATP-HI

KATP-HI arises from mutations in either of the two functional subunits of the β-cell ATP-regulated potassium channel (KATP). The β-cell KATP is composed of four SUR1 subunits and four inwardly rectifying Kir6.2 subunits; these subunits are encoded adjacently on chromosome 11p [22,36,37]. Loss of KATP activity, from mutations that inhibit either channel formation or activity, allows the β-cell plasma membrane to be constitutively depolarized; inappropriate calcium influx and insulin secretion that is not controlled by ambient glucose concentrations result.

To date, two pathologic mechanisms with two different inheritance patterns have been described for KATP-HI [38,39]. The first mechanism causes a diffuse disease in which all β-cells of the pancreas abnormally secrete insulin. This form is inherited in a typical autosomal recessive fashion, and heterozygous family members are unaffected by HI. The second mechanism arises sporadically and gives rise to a focal cluster of β-cells with abnormal KATP channels, surrounded by normal β-cells. This focal form arises from inheritance of an abnormal paternal SUR1 allele that affects all cells. However, in the focal lesion, a loss of heterozygosity for the maternal allele at 11p15 has occurred. The normal maternal SUR1 gene is lost, and a maternally imprinted tumor suppressor gene (H19) is also lost. Insulin-like growth factor –2 continues to be expressed by the β-cell. The sum of these events likely allows clonal expansion of β-cells expressing the paternally inherited abnormal KATP [39–42]. Autosomal dominant forms of KATP-HI have yet to be clearly identified.

Nearly 50 mutations of the SUR1 have thus far been described; two of these mutations account for almost 90% of the KATP-HI individuals of Ashkenazi Jewish descent, an ethnic population in whom HI is relatively prevalent [3,18–23,43,44]. The Finns and Saudi Arabians are two other populations in whom KATP-HI has been reported more commonly than in other ethnic backgrounds. The majority of cases in Finland can be explained by a novel point mutation in exon 4 of SUR1 that is inherited homozygously or in compound heterozygous form with another SUR1 mutation. This mutation generates nonfunctional channels and continuous insulin secretion, which likely account for the severe phenotype in patients with this mutation [3].

Correlations of phenotype with genotype have otherwise been difficult to make because, in this relatively rare disease, individuals who are homozygous for mutations are also rare. The diffuse and focal KATP-HI forms are clinically indistinguishable and are associated with severe HI. Affected infants are generally large for gestational age and suffer hypoglycemia within the first few days of life. Most patients with KATP-HI are diazoxide-unresponsive. This unresponsiveness is attributed to an inability of diazoxide to act on its target, namely, the KATP channels. Decreased numbers of KATP channels at the cell membrane, altered responsiveness to phosphated energy, or completely inactivated channels may all prevent diazoxide from inhibiting KATP channel closure. Octreotide can sometimes attenuate excessive insulin secretion, but frequently these infants require pancreatectomy. All these therapies are besieged with adverse effects and complications, which will be discussed later.

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GDH-HI

GDH-HI is due to gain of function mutations of the mitochondrial enzyme glutamate dehydrogenase. This enzyme is a homohexamer and is encoded on chromosome 11. It is responsible for the conversion of glutamate to α-ketoglutarate, a reversible reaction. It is allosterically activated by leucine and allosterically inhibited by GTP [45–52]. Thus far, mutational analysis of GDH from GDH-HI affected individuals has revealed mutations that localize to a region considered a site of interaction of GDH with GTP; this region is encoded by exons 11 and 12 [25]. These mutations likely impair GDH interaction with GTP:in vitro studies reveal decreased sensitivity of mutant GDH to inhibition by GTP [26] (Fig. 1).

GDH-HI is also referred to as the hyperinsulinism / hyperammonemia syndrome (HI / HA) and may be inherited autosomal dominantly or arise sporadically. Affected newborns are of normal birth weight and generally do not present with hypoglycemia until later in infancy. Their HI is characterized by subtle defects in fasting but potentially severe hypoglycemia with ingestion of protein. The extent of hypoglycemic symptoms is variable, and some individuals, although symptomatic, only have been diagnosed with GDH-HI after an affected family member had been identified. Affected individuals also have persistent hyperammonemia from which they are asymptomatic despite serum ammonium concentrations that are 2–5 times above the normal range. Serum ammonium concentrations are not affected by protein intake. Because their SUR1 is intact, individuals with GDH-HI are diazoxide-responsive, although cases of diazoxide unresponsiveness have been reported [24–28].

Concomitant hyperinsulinism and hyperammonemia are proposed to arise from impaired GTP inhibition of GDH allowing upregulated GDH activity. Figures 1 and 2. In the β-cell, GDH activity generates α-ketoglutarate, which enters the Kreb Cycle to produce ATP; ATP can then act on the KATP to effect insulin release. Impaired sensitivity of GDH to GTP inhibition allows unopposed leucine stimulation of this reaction. With protein ingestion, leucine, which often accounts for 10% of the amino acid content of ingested protein, is available to stimulate GDH activity and inappropriate insulin secretion. As a result, consumption of protein provokes hypoglycemia. Recently, Maechler and Wollheim suggested that GDH activity stimulates insulin secretion through the reverse reaction that generates glutamate; glutamate in turn stimulates exocytosis of insulin [53]. The actual direction of the reaction has yet to be determined, but the hyperammonemia of GDH-HI would suggest that in the hepatocyte the direction of the reaction favors oxidative deamination of glutamate to α-ketoglutarate. Hyperammonemia would then arise from 1.) depletion of the glutamate stores necessary for N-acetylglutamate production, a necessary co-factor in the urea cycle and 2.) from excessive ammonia production from upregulated deamination of glutamate by GDH (Fig. 2).

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GK-HI

GK-HI is due to gain of function mutations of glucokinase (GK) [29]. GK, a low affinity hexokinase, is considered the “glucose sensor” of the β-cell. GK governs the initial step in the pathway of β-cell glucose metabolism, which is necessary for glucose-mediated insulin secretion. Its sigmoidal substrate concentration dependency with its steep slope assures that it detects small changes in glucose concentration. The inflection point for insulin secretion curve normally occurs at a glucose concentration of 45–72 mg/dL (2.5–4.0 mmol/L), and its Km is 108–198 mg/dL (6–11 mmol/L) [54,55].

One family with GK-HI has thus far been reported; transmission was autosomal dominant. Their GK mutation caused increased affinity of GK for glucose. As a result, the threshold for insulin secretion was lowered: higher rates of glycolysis were achieved at lower glucose concentrations and therefore higher rates of insulin secretion occurred at any plasma glucose concentration. Unlike with other forms of HI, insulin secretion in this GK-HI family was suppressed beyond the “new” lower limit, and serum blood glucose stabilized at 40 mg/dL with fasting [29].

GK-HI is a relatively mild form of HI when compared with KATP-HI and has variable degrees of symptoms. Three of the affected family members were not diagnosed with GK-HI until adulthood; two of them had symptoms dating from adolescence. The two children, however, suffered hypoglycemic seizures. As expected, GK-HI is diazoxideresponsive as diazoxide exerts its effects through the KATP which is distal to GK action.

Loss of function mutations of GK are associated with a form of maturity-onset diabetes of the young (MODY) [56]. Just as this discovery has increased the search of families affected by the GK form of MODY, awareness of HI-causing GK mutations is likely to increase identification of GK-HI in individuals with hypoglycemia.

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Other Genetic Defects

Despite the identification of these genetic forms of HI, the molecular etiologies responsible for about 50% of HI-affected individuals have yet to be identified [38]. At least one other dominant form of HI exists [57,58].

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Diagnosis

As previously described the diagnosis of HI depends upon demonstrating increased insulin concentrations at the time of hypoglycemia. Serum insulin concentrations, however, are not consistently elevated and cannot be relied upon to make the diagnosis of HI. Instead, one must demonstrate increased insulin action with suppressed free fatty acids, ketones, and IGFBP-1 and a glycemic response to glucagon at the time of hypoglycemia. The work-up is further complicated by the recognition that signs of excess insulin action may be subtle, particularly in GDH-HI. As compared to children with other forms of HI, children with GDH-HI may have relatively long, but still abnormal, fasting tolerances in addition to their protein-induced hypoglycemia.

Once the diagnosis of HI is confirmed, diagnostic studies to delineate the form are necessary. Serum ammonium will be elevated in GDH-HI, although whether GDH mutations can give rise to HI without hyperammonemia remains to be determined. Tests of leucinesensitivity and oral protein challenges will be abnormal in GDH-HI (unpublished data) [59,60].

KATP-HI can be quite severe and demands taking advantage of the recognition of diffuse and focal forms. Transhepatic portal venous sampling permits localization of a focal lesion prior to surgery but requires the patient be subjected to controlled hypoglycemia during the procedure; such work is under investigation in Europe [61]. At the Children’s Hospital of Philadelphia acute insulin responses to the secretagogues calcium and tolbutamide are being explored to differentiate focal from diffuse disease: the diffuse form is not expected to respond to tolbutamide while the focal form is [62]. Arterial stimulation venous sampling can then be used to localize the focal lesion to the head, body or tail of the pancreas; this procedure does not require the maintenance of hypoglycemia [63].

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Treatment

Treatment of children with HI has changed dramatically over the years and with the recognition of the responsible genetic defects is destined to further mature. The ultimate goal of treatment is cure. However, unless a focal lesion is present, this goal currently remains unattainable. The aim, thus, becomes to prevent hypoglycemia in the context of a normal feeding regimen. A normal fasting tolerance is often difficult to obtain, particularly in children with KATP –HI, but periods between feeds can often be extended with pharmacological interventions or surgery. KATP-HI can be so severe that despite these measures, continuous gastric feeds/dextrose are necessary. Attempts to devise a medical regimen that is manageable for caretakers and allows the child to develop appropriately should be a priority.

The drugs that are available to treat HI are limited to diazoxide, octreotide, calcium-channel blockers, and glucagon.

Diazoxide primarily activates the KATP-channel through SUR1 to inhibit insulin secretion. The therapeutic dose range is 5–15 mg/kg/day in two to three divided oral doses. Infants with transient HI frequently can be successfully treated with diazoxide, and often a low dose is sufficient. Generally, diazoxide is effective in GDH-HI but may not completely protect against hypoglycemia associated with ingestion of pure protein. GK-HI also seems to respond to diazoxide. KATP-HI is frequently resistant to diazoxide even at high doses. Correlations of genotype and diazoxide-responsiveness in KATP-HI have yet to be made. Other forms of HI whose molecular etiology remains unknown have also been reported to respond to diazoxide.

Side effects of diazoxide are primarily cosmetic but fluid retention can also occur. Fluid retention is more common in children treated with large fluid volumes to maintain euglycemia; it can be significant enough to cause congestive heart failure. A mild diuretic (hydrochlorothiazide) can be initiated empirically in those children at high risk. Monitoring of electrolytes is necessary to screen for fluid retention/hyponatremia as well as hypokalemia that can complicate diuretic therapy. Diazoxide also causes hypertrichosis which resolves within several months after withdrawal of therapy. Rarely leukopenia and thrombocytopenia have been reported side effects.

Nifedipine, a calcium channel blocker, has recently been used with some success in children with severe HI refractory to diazoxide [64,65]. Nifedipine is thought to antagonize voltage dependent calcium channels to inhibit insulin release. The effective oral dose is 0.25–2.5 mg/kg/day divided over every eight hours. A low dose is initiated and then progressively increased to effect. Experience with nifedipine is limited. Unpublished experience from major medical centers suggests nifedipine rarely works. Blood pressure monitoring is necessary, but otherwise limited experience suggests nifedipine is quite safe.

Octreotide is a long-acting somatostatin analog. It activates β-cell potassium channels to inhibit insulin secretion. This agent has the disadvantage of requiring injection and, as a result, is initiated if diazoxide fails. It can be given by continuous intravenous or subcutaneous infusion or by intermittent subcutaneous injection. Doses of 5–40 μg/kg/day have been used in the past but doses above 20 μg/kg/day are unlikely to be effective [66]. Potential side effects include growth hormone, TSH, and ACTH suppression as well as altered gut motility and cholelithiasis.

Glucagon antagonizes insulin action by mobilizing hepatic glycogen stores, thereby decreasing the glucose requirement of a patient with HI. A dose of 1 mg/day given continuously as an intravenous infusion can be used as a temporizing measure, e.g., while awaiting surgery, but experience with its use on a chronic basis is limited. Some centers titrate the dose between 5 and 10 μg/kg/hr. As a powerful insulin secretagogue, glucagon has the theoretical capacity of exacerbating excessive insulin secretion. Side effects include nausea, vomiting, and inhibition of gastric acid and pancreatic enzyme secretion.

Pancreatectomy is indicated for children who fail medical therapy. Focal lesions account for at least 30–50% of cases of KATP-HI and with an experienced, multi-disciplinary staff can potentially be cured with focal resection. Unlike adenomas, these lesions do not disrupt the normal architecture of the pancreas and are difficult for the surgeon to detect grossly. A localization procedure performed prior to pancreatectomy can guide the surgeon, but successful resection of a focal lesion will require hours of multiple biopsies, attentive microdissection, and intra-operative examination of tissue by a pathologist with experience with β-cell hyperplasia. In addition, focal lesions are frequently found in the head of the pancreas, a difficult area to resect without causing damage to important nearby structures such as the bile ducts.

Diffuse KATP-HI often necessitates 95–99% subtotal pancreatectomy. If a pancreatectomy is undertaken, no less than a 95% pancreatectomy should be performed because dysregulated insulin secretion from the residual β-cell mass can cause persistent hypoglycemia despite this large resection. Although the ultimate goal of surgery is cure, pancreatectomy may only decrease β-cell mass sufficiently to allow more effective medical management. Repeat pancreatectomies are sometimes necessary to control hypoglycemia and are frequently complicated by the development of diabetes mellitus.

The risks of pancreatectomy are diabetes mellitus and pancreatic exocrine insufficiency. These will be discussed under complications.

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Complications

Neurologic sequelae of hypoglycemia include seizures and permanent brain damage. Seizures are related to acute hypoglycemia, and generally will not recur if euglycemia is maintained unless significant brain damage has occurred. The degree, duration, and frequency of hypoglycemia needed to cause permanent brain damage are not welldefined, but with at least 20% of children with HI beset with significant brain damage, the importance of prompt and complete intervention cannot be over-emphasized [67].

Prolonged hospitalization can impair bonding and socialization. The diagnostic work-up, attempts at medical intervention, surgery, post-operative recovery, re-assessment and re-institution of medical therapies require weeks of hospitalization. During these weeks of nasogastric tubes and intravenous lines, affected children may have limited access to parents and environmental exploration. Creating a stimulating inpatient environment may decrease the risk of these developmental lags, but certainly involvement with early intervention programs is warranted. Studies of long-term development in HI-affected children are currently underway.

Feeding issues in HI-affected children are multi-factorial and can be a serious problem. Prolonged intravenous and nasogastric tube feedings aimed at preventing hypoglycemia can seriously interfere with an infant learning to feed. Medications, such as diazoxide, octreotide, and post-operative analgesia, can suppress the appetite. Abdominal surgery can disrupt gut motility to cause disinterest in food. Infants should always be encouraged to take oral feeds. Nasogastric feeds should be reserved for children who do not take sufficient feeds with ample intervention or who depend upon continuous feeds to maintain euglycemia. If necessary, feeding intervention programs should be involved early.

Inherent to any abdominal surgery are post-operative complications. Pancreatitis, pseudocyst formation, and duodenal hematoma are specific complications of pancreatectomy that prolong recovery. Transient hyperglycemia frequently occurs after 95% pancreatectomy, may require low dose insulin, and can last from days to months.

Permanent diabetes mellitus can occur immediately post-operatively from a large resection or can be of late onset. Permanent diabetes mellitus is more likely to occur the greater the extent of the resection; individuals who have had local resection of a focal lesion are unlikely to develop permanent diabetes mellitus. Late –onset diabetes mellitus may be uncovered at the time of puberty when an antiinsulin state unmasks decreased β-cell reserve. Decreased β-cell mass may manifest as intermittent hyperglycemia even while episodes of hypoglycemia still recur. In one series, two of eight patients who had undergone pancreatectomy for HI developed diabetes mellitus. However, two of six medically managed patients (i.e., no surgery) had depressed insulin responses to glucose stimulation [68].

The development of diabetes mellitus as a late complication of subtotal pancreatectomy may not be completed related to decreased β-cell mass from resection. Abnormal β-cells undergo early apoptosis and may account not only for the gradual improvement of HI but for the development of diabetes mellitus when a critical minimum mass has been reached [69]. In addition, abnormal KATP-HI channels cause “glucose blindness”: dysregulated insulin secretion occurs not only with hypoglycemia but also with hyperglycemia [68].

Pancreatic exocrine insufficiency complicating pancreatectomy is usually subclinical. Poor growth or diarrhea is an indication for further evaluation for malabsorption. Replacement digestive enzymes can be used if necessary.

As with any chronic disease, HI can be emotionally burdensome for the family. Hospitalization of a newborn infant for months, interference with bonding, multiple studies and interventions that cause the infant discomfort, parental guilt with regard to the genetics of their child’s disease or to delayed diagnosis, other familial and financial responsibilities, and intensive home regimens can overwhelm families. Psychosocial support systems that address these issues are vital to the successful management of patients with HI. A suggestion as simple as encouraging leisure can be a welcome relief to parents who think they are not “permitted” to leave the bedside.

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HI in the New Millennium

The new genetics of HI has opened many doors to an improved understanding of insulin secretion and to better approaches to diagnosis and management. As the basic mechanisms of insulin secretion are unraveled and new HI-causing genetic mutations are identified, therapeutic interventions are sure to improve the lives of HI-afflicted children and their families. [68]

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References

1. Stanley CA; Hyperinsulinism in infants and children. Pediatr Clin N Am 1997; 44:363–74.
2. Bruining G; Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr 1990; 2:758–65.
3. Otonkoski T, Ammala C, Huopio H, et al.: A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. Diabetes 1999; 48:408–15.
4. Mathew PM, Young JM, Abu-Osba YK, et al.: Persistent neonatal hyperinsulinism. Clin Pediatr 1988; 27:148–51.
5. McQuarrie I: Idiopathic spontaneously occurring hypoglycemia in infants. Clinical significance of problem and treatment. Am J Dis Child 1954; 87:399–428.
6. Stanley CA, Baker L: Hyperinsulinism in infants and children: diagnosis and therapy. Adv Pediatr 1976; 23:315–55.
7. Laidlaw G:. Nesidioblastoma, the islet tumor of the pancreas. Am J Pathol 1938; 14:125–34.
8. Rahier J, Fält K, Müntefering H, et al.: The basic structural lesion of persistent neonatal hypoglycaemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of B-cells? Diabetologia 1984; 26:282–9.
9. Rahier J: Relevance of endocrine pancreas nesidioblastosis to hyperinsulinemic hypoglycemia. Diabetes Care 1989; 12:164–6.
10. Goossens A, Gepts W, Saudubray JM, et al.: Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 1989; 13:766–75.
11. Finegold DN, Stanley CA, Baker L; Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 1980; 96:257–9.
12. Stanley CA, Baker L: Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics 1976; 57:702–11.
13. Cochrane WA, Payne WW, Simpkiss MJ, Woolf LI: Familial hypoglycemia precipitated by amino acids. J Clin Invest 1955; 35:411–22.
14. Fajans SS, Floyd FC, Knopf RF, et al.: A difference in the mechanism by which leucine and other amino acids induce insulin release. J Clin Endocr Metab 1967; 27:1600–6.
15. Grumbach M, Kaplan S: Amino acid and alpha keto acid induced hyperinsulinsim in the leucine-sensitive type of infantile and childhood hypoglycemia. J Pediatr 1960; 57:346–62.
16. Drash A, Wolff F: Drug therapy in leucine-sensitive hypoglycemia. Metabolism 1964; 13:487.
17. Glaser B, Chiu KC, Anker R, et al.: Familial hyperinsulinism maps to chromosome 11p14–15.1, 30 cM centromeric to the insulin gene. Nat Genet 1994; 7:185–8.
18. Thomas P, Ye YY, Lightner E: Mutations of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996; 5:1809–12.
19. Thomas P, Wohllk N, Huang E: Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1996; 59:510–8.
20. Nestorowicz A, Wilson BA, Schoor KP, et al.: Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 1996; 5:1813–22.
21. Nestorowicz A, Inagaki N, Gonoi T, et al.: A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 1997; 46:1743–8.
22. Aguilar-Bryan L, Bryan J: The molecular biology of ATP-sensitive K+ channels. Endocr Rev 1999; 20:101–35.
23. de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, et al.: Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999; 340:1169–75.
24. Weinzimer SA, Stanley CA, Berry GT, Yudkoff M, Tuchman M, Thornton PS: A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr 1997; 130:661–4.
25. Stanley CA, Fang J, Kutyna K, et al.: Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. Diabetes 2000; 49:667–73.
26. Stanley CA, Lieu YK, Hsu BYL, et al.: Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998; 338:1352–7.
27. Miki Y, Tomohiko T, Obura T, Kato H, Yanagisawa M, Hayashi Y: Novel misense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome. J Pediatr 2000; 136:69–72.
28. Yorifuji T, Muroi J, Uematsu A, Hiramatsu H, Momoe T: Hyperinsulinism-hyperammonemia syndrome caused by mutant glutamate dehydrogenase accompanied by novel enzyme kinetics. Hum Genet 1999; 104:476–9.
29. Glaser B, Kesavan P, Heyman M, et al.: Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998; 338:226–30.
30. Koh T, Aynsley-Green A, Tarbit M, Eyre J: Neural dysfunction during hypoglycaemia. Arch Dis Child 1988; 63:1353–8.
31. Katz LEL, Smith MSS, Stanley CA, Cohen P: Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia due to hyperinsulinism [Abstract #538-presented orally]. In Society for Pediatric Research, San Diego, 1995.
32. Stanley CA, Anday EK, Baker L, Delivoria-Papadopolous M: Metabolic fuel and hormone responses to fasting in newborn infants. Pediatrics 1979; 64:613–9.
33. Collins JE, Leonard JV, Teale D, et al.: Hyperinsulinaemic hypoglycaemia in small for dates babies. Arch Dis Childhood 1990; 65:1118–20.
34. Collins JE, Leonard JV: Hyperinsulinsim in asphyxiated and small-for-dates infants with hypoglycaemia. Lancet 1984; 2:311–3.
35. Shepherd R, Cosgrove K, O’Brien R, Barnes P, Ammala C, Dunne M: Hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000; 82:F87–97.
36. Inagaki N, Gonoi T, Clement J, et al.: Reconstitution of IK-ATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 1995; 270:1166–70.
37. Aguilar-Bryan L, Nichols CG, Wechsler SW, et al.: Cloning of the β cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268:423–6.
38. Glaser B, Thornton P, Otonkoski T, et al.: Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000; 82:F79–86M.
39. Rahier J, Guiot Y, Sempoux C: Persistent hyperinsulinaemic hypoglycemia of infancy: a hetereogenous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 2000; 82:F108–12.
40. de Lonlay P, Fournet JC, Rahier J, et al.: Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997; 100:802–7.
41. Ryan F, Devaney D, Joyce C, et al.: Hyperinsulinism: molecular aetiology of focal disease. Arch Dis Child 1998; 79:445–7.
42. Verkarre V, Fournet JC, de Lonlay P, et al.: Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998; 102:1286–91.
43. Thomas PM, Cote GJ, Wohllk N, et al.: Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995; 268:426–9.
44. Nestorowicz A, Glaser B, Wilson B, et al.: Genetic heterogentiy in familial hyperinsulinism. Hum Mol Genet 1998; 7:1119–28.
45. Bryla J, Michalik M, Nelson J, Erecinska M; Regulation of the glutamate dehydrogenase activity in rat islets of langerhans and its consequence on insulin release. Metabolism 1994; 43:1187–95.
46. Zaleski J, Wilson DF, Erecinska M: β-2-Aminobicyclo-(2.2.1)-heptane-2-carboxylic acid. A new activator of glutaminase in intact rat liver mitochondria. J Biol Chem 1986; 261:14091–4
47. Zaleski J, Wilson DF, Erecinska M: Glutamine metabolism in rat hepatocytes. Stimulation by a nonmetabolizable analog of leucine. J Biol Chem 1986; 261:14082–90.
48. Sener A, Malaisse WJ: L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Nature 1980; 288:187–9.
49. Sener A, Malaisse-Lagae F, Malaisse WJ: Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid. Proc Natl Acad Sci USA 1981; 78:5460–4.
50. Malaisse WJ: Insulin biosynthesis and secretion in vitro. In International Textbook of Diabetes Mellitus, edited by Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, pp. 261–83, Chichester, John Wiley & Sons 1992.
51. Gylfe E: Comparison of the effects of leucines, non-metabolizable leucine analogues and other insulin secretogogues on the activity of glutamate dehydrogenase. Acta Diabet Lat 1976; 13:20–4.
52. Colman RF: Glutamate dehydrogenase (bovine liver). In A Study of Enzymes, edited by Kuby SA, pp. 173–92, New York, CRC Press 1991.
53. Maechler P, Wollheim CB: Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature 1999; 402:685–9.
54. Matschinsky F: A lesson in metabolic regulation inspored by the gluokinase glucose sensor paradigm. Diabetes 1996; 45:223–41.
55. Matschinsky F, Liang Y, Kesavan P, et al.: Glukokinase as pancreatic beta-cell glucose sensor and diabetes gene. J Clin Invest 1993; 92:2092–8.
56. Froguel P, Aouali H, Vionnet N, et al.; Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med 1994; 328:697–702.
57. Kukuvitis A, Deal C, Arbour L, Polychronakos C: An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. J Clin Endocrinol Metab 1997; 82:1192–4.
58. Thornton PS, Satin-Smith MS, Herold K, et al.: Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. J Pediatr 1998; 132:9–14.
59. Kelly A, Ferry RJ, Grimberg A, Koo-McCoy S, Stanley CA: Acute insulin responses to leucine: a diagnostic tool for the hyperinsulinism/hyperammonemia syndrome. Pediatr Res 1999; 45:92A.
60. Hsu BYL, Kelly A, Thornton PS, et al.: Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr 2001 (in press).
61. Dubois J, Brunelle F, Touati G, Sebag B, et al.: Hyperinsulinism in childen: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcomes in 25 cases. Pediatr Radiol 1995; 25:512–6.
62. Grimberg A, Ferry RJ, Kelly A, et al.; Acute insulin responses to tolbutamide and glucose distinguish diffuse versus focal forms of congenital hyperinsulinism due to sulfonylurea receptor mutations. 81st Annual Meeting of the Endocrine Society 1999, San Diego, OR12–3.
63. Ferry RJ, Kelly A, Grimberg A, et al.: Insulin responses to peripheral intravenous and intrahepatic arterial calcium stimulation in diffuse vs. focal forms of congenital hyperinsulinism due to mutations of the SUR1 sulfonylurea receptor. J Pediatr 2000; 137:239–46.
64. Eichmann D, Hufnagel M, Quick P, Santer R: Treatment of hyperinsulinaemic hypoglycaemia with nifedipine. Eur J Pediatr 1999; 158:204–6.
65. Bas J, Darendeliler F, Demirkol D, Bundak R, Saka N, Gunoz H: Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Eur Endocrinol Metab 1999; 12:873–8.
66. Thornton PS, Alter CA, Katz LE, Baker L, Stanley CA: Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism [see comments]. J Pediatr 1993; 123:637–43.
67. Aynsley-Green A, Hussain K, Hall J, et al.: Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000; 82:F98–107.
68. Liebowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, Landau H: Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission—high incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab 1995; 80:386–92.
69. Glaser B, Ryan F, Donath M, et al.: Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene. Diabetes 1999; 48:1652–7.
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