Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism

INTRODUCTION — Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants and children. HI is characterized by dysregulated insulin secretion and is classified into three main types: a transient form related to perinatal stress, monogenic forms due to single-gene defects, and those associated with syndromes (such as Beckwith-Wiedemann syndrome). The clinical characteristics, severity of hypoglycemia, and duration of treatment vary among the different types of HI. However, all forms of HI share a high risk of hypoglycemia-induced brain damage and developmental delays [1].

Prompt recognition and initiation of appropriate therapy in a timely manner is essential to minimize the risk of poor neurologic outcomes.

An overview of the pathophysiology, genetics, clinical features, and diagnosis of HI will be presented here. The treatment, complications, and long-term outcomes of HI are discussed in more detail separately. (See "Treatment and outcomes of congenital hyperinsulinism".)

EPIDEMIOLOGY — The estimated incidence of congenital (monogenic) HI is approximately 1 in 28,000 to 50,000 live births in the general population and is as high as 1 in 2700 in certain consanguineous populations [2-4].

Perinatal stress-induced HI (PSHI) is a distinct category of HI that is caused by physiologic stress in the perinatal period. The incidence of PSHI is probably high among at-risk infants. A study of 514 neonates identified as being at risk of hypoglycemia found that 51 percent had hypoglycemia (plasma glucose <47 mg/dL) and 19 percent had severe hypoglycemia (plasma glucose <36 mg/dL) [5]. Two-thirds of the neonates had risk factors for PSHI, including being born small for gestational age or being a late preterm infant.

PATHOGENESIS — Insulin secretion by pancreatic beta cells is triggered when plasma glucose increases above a threshold of approximately 85 mg/dL in humans. Glucose enters the beta cells through glucose transporters and is metabolized to generate adenosine triphosphate (ATP). The subsequent increase in ATP-to-adenosine diphosphate (ADP) ratio triggers closure of the ATP-sensitive potassium (K_ATP) channel, which leads to membrane depolarization. This depolarization results in opening of voltage-dependent calcium channels, and the increase in cytosolic calcium triggers insulin secretion. Defects in these pathways lead to dysregulated insulin secretion, resulting in HI (figure 1).

TYPES OF HYPERINSULINISM

Perinatal stress-induced hyperinsulinism — Perinatal stress-induced HI (PSHI) is a transient form of HI in neonates caused by perinatal stressors such as placental insufficiency or birth asphyxia. Clinical features suggesting risk for PSHI include intrauterine growth retardation or small for gestational age, congenital heart disease, and history of intrauterine infection or maternal preeclampsia (table 1) [6]. Infants with PSHI are more likely to be male and have been delivered by cesarean delivery [7]. The mechanism for PSHI remains unknown but may involve fetal hypoxia [8].

PSHI is typically responsive to diazoxide and resolves within the first three to six months of life. However, infants with severe perinatal stress and cholestasis may have a more prolonged HI that is not responsive to diazoxide [9].

Monogenic forms of hyperinsulinism — Mutations in 10 genes associated with insulin secretion and beta cell development result in congenital HI (table 2). The most common forms are discussed below.

KATP-HI — The most common and severe form of monogenic HI is due to dysfunction of the adenosine triphosphate-sensitive potassium channel (K_ATP), known as K_ATP-HI (MIM #256450; #601820). Approximately 90 percent of individuals with diazoxide-unresponsive HI will have a K_ATP defect [10]. It is caused by inactivating mutations of the ABCC8 or KCNJ11 genes, which encode the two subunits of the K_ATP channel, SUR-1 and Kir6.2, respectively [11,12]. Mutations in ABCC8 and KCNJ11 can be inherited in a dominant or recessive pattern.

Mutations interfere with channel expression, trafficking, or function and result in abnormal glucose regulation, as manifested by:

●Severe fasting hypoglycemia, due to failure of decreasing glucose concentrations to suppress insulin secretion.

●Postprandial hyperglycemia, due to impaired glucose-stimulated insulin secretion [13].

●Hypoglycemia, due to excessive insulin secretion in response to a protein load (protein-induced hypoglycemia) [14]. This is a characteristic of K_ATP-HI, as well as glutamate dehydrogenase-related HI (GDH-HI), as discussed below.

For clinical purposes, it is useful to categorize K_ATP-HI on the basis of response to treatment or on histology (table 2 and algorithm 1):

●Diazoxide responsiveness – Diazoxide is a K_ATP channel opener that exerts its action through binding to SUR-1 and helps to distinguish among the genetic and clinical subtypes of K_ATP-HI:

•Diazoxide-unresponsive – Most patients with K_ATP-HI do not respond to diazoxide. These infants tend to be born large for gestational age and have more severe HI, requiring high glucose infusion rates to maintain euglycemia. Approximately one-half of these infants have a focal form of HI, as discussed below.

•Diazoxide-responsive – A small subset of children with K_ATP-HI do respond to diazoxide. They have dominant mutations in KCNJ11 or ABCC8 and tend to have milder hypoglycemia [15]. These infants have the diffuse form of HI.

●Histologic type – K_ATP-HI can also be classified by histologic type into focal and diffuse forms, which are found in approximately equal proportions (picture 1). Distinguishing between the diffuse and focal forms is essential, given the divergent treatment options and outcomes, as outlined below.

•Focal – Focal K_ATP-HI does not respond to diazoxide, but surgical resection of the focal lesion is curative. This form of HI is characterized by a discrete area of beta cell proliferation or adenomatosis. The pathophysiology of this form features a "two hit" mechanism [16,17]. First, a paternally inherited recessive mutation in the ABCC8 or KCNJ11 genes is present, and second, there is somatic loss of the maternally inherited 11p15 chromosomal region, which results in paternal uniparental disomy (figure 2). The maternal 11p15 region contains tumor-suppressor genes, and their loss allows for the proliferation of beta cells, which forms the focal lesion.

•Diffuse – For patients with diffuse K_ATP-HI, medical management is the mainstay of treatment; palliative surgery is reserved for the most severe cases. Diffuse K_ATP-HI is characterized by hyperactivity of beta cells with nuclear enlargement throughout the pancreas [18]. Diffuse K_ATP-HI is caused by biallelic recessive mutations or, less commonly, dominant mutations.

In a large series of infants and children undergoing pancreatectomy for HI, 55 percent were found to have focal HI and 45 percent had diffuse HI [19]. Genetic testing is the best means of differentiating between the two forms prior to surgery. (See 'Further evaluation' below.)

Other monogenic forms — Other monogenic forms of congenital HI are less common, and most have recognizable clinical and biochemical characteristics (table 2).

●GDH-HI – GDH-HI (also known as hyperinsulinism-hyperammonemia syndrome; MIM #606762) is caused by activating mutations of the GLUD1 gene, which encodes GDH [20]. GDH is a key enzyme in the beta cell pathway of amino acid-stimulated insulin secretion.

GDH-HI is characterized by fasting hypoglycemia, as well as severe protein-induced hypoglycemia [21,22]. Plasma ammonia levels are tonically elevated to three to five times the upper limit of normal, but the typical symptoms of hyperammonemia are absent in these patients [23]. Approximately two-thirds of mutations arise de novo, while the remaining one-third are inherited in an autosomal dominant manner. Children with GDH-HI have a high rate of seizures (most commonly absence), learning disabilities, and behavioral disorders such as attention deficit hyperactivity disorder [24]. These neurologic issues appear to be unrelated to either the hypoglycemia or hyperammonemia. Although children with GDH-HI respond well to diazoxide, they must also be counseled to add carbohydrates and fat when eating protein.

●Glucokinase (GCK)-HI – GCK-HI (MIM #602485) is caused by dominant activating mutations in the GCK gene, which catalyzes the first step of glucose-mediated insulin secretion [25].

Children with GCK-HI have variable degrees of hypoglycemia, ranging in severity from mild to severe enough to warrant near-total pancreatectomy [26,27]. In addition to fasting hypoglycemia, these children show exaggerated insulin responses to oral and intravenous glucose [28]. Response to diazoxide is variable, and patients often require additional therapies such as continuous feedings/dextrose or somatostatin analogs [26]. Conversely, inactivating mutations of GCK are a cause of neonatal diabetes or maturity-onset diabetes of the young.

●HNF4A- and HNF1A-HI – Inactivating mutations of the genes encoding two hepatic nuclear factors, HNF4A and HNF1A, result in a diazoxide-responsive form of HI [29,30]. These transcriptions factors have long been recognized as a cause of monogenic diabetes of the youth (MODY1 and MODY3, respectively). Penetrance is variable as only one-third of patients may have a positive family history [31]. Affected infants are commonly macrosomic and present with hyperinsulinemic hypoglycemia, which typically resolves during the first decade of life [32]. However, progressive deterioration of beta cell function places them at risk of diabetes later in life. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Monogenic diabetes (formerly called maturity onset diabetes of the young)'.)

●SCHAD-HI – SCHAD-HI (short-chain 3-hydroxyacyl coA dehydrogenase-HI; MIM #609975) is caused by recessive mutations in the HADH gene [33]. It is associated with protein-induced hypoglycemia.

●UCP2-HI – UCP2-HI (uncoupling protein 2-HI) is caused by dominant mutations in the UCP2 gene [34]. It is associated with relatively mild hypoglycemia.

●MCT1-HI – MCT1-HI (monocarboxylic acid transporter 1-HI; MIM #610021) is caused by recessive mutations in the SLC16A1 gene [35]. In this disorder, hypoglycemic episodes are triggered by anaerobic exercise.

●HK1-HI – Mutations in noncoding regions of HK1 lead to aberrant expression of hexokinase (HK1) in the beta cell with resulting HI [36,37]. Affected individuals have normal birth weights, and the majority are responsive to diazoxide.

Syndromic hyperinsulinism — HI is associated with several syndromes (table 3):

●Beckwith-Wiedemann syndrome – Beckwith-Wiedemann syndrome (MIM #130650) is an overgrowth disorder characterized by macroglossia, abdominal wall defects, and hemihypertrophy. It is caused by genetic and epigenetic changes on the imprinted region of chromosome 11p15 [38]. HI is considered a cardinal feature of Beckwith-Wiedemann syndrome and occurs in approximately 50 percent of cases. In the majority of cases, the HI is mild and resolves within the first one to two years of life. However, children with Beckwith-Wiedemann syndrome due to paternal uniparental isodisomy have a more severe and persistent form of HI, which may require pancreatectomy [39]. (See "Beckwith-Wiedemann syndrome".)

●Kabuki syndrome – Kabuki syndrome (MIM #147920; MIM #300867) is characterized by dysmorphic facial features, skeletal and dermatoglyphic abnormalities, intellectual disability, and short stature [40]. Dominant de novo mutations in the KMT2D and KDM6A genes lead to Kabuki syndrome. Increasingly, hypoglycemia due to HI is recognized as part of the syndrome [41,42]. Response to diazoxide is variable, and some patients have required treatment with somatostatin analogs.

CLINICAL PRESENTATION — The classic presentation of HI is at birth. Infants with HI are large for gestational age and have severe hypoglycemia, which requires a high glucose infusion rate, ie, >10 mg/kg/min. However, the clinical spectrum of HI is wide and patients may present with normal birth weight, require minimal dextrose support, or present outside of infancy. Clinical features can suggest certain forms (table 2 and table 3):

●Large for gestational age – K_ATP-HI, HNF4A-HI, Beckwith-Wiedemann syndrome, Sotos syndrome

●Small for gestational age – Perinatal stress-induced HI (PSHI)

●Congenital heart disease – PSHI, Kabuki syndrome, Turner syndrome

●Dysmorphic features – Syndromic forms

Children with the diffuse form of HI are more likely to present with higher birth weights and require a higher glucose infusion rate [43]. In contrast, only 50 percent of children with focal HI are born large for gestational age, and focal cases are more likely to present with hypoglycemic seizures after discharge from the birth hospital. However, there is significant overlap in features, so clinical presentation alone cannot be used to distinguish between the diffuse and focal forms of HI.

EVALUATION — Infants and children with suspected HI should be evaluated according to the guidelines recommended by the Pediatric Endocrine Society [44]. The mainstay of the evaluation is collection of a "critical sample" at the time of hypoglycemia. This sample of key hormones and metabolic fuels may be obtained with a spontaneous episode of hypoglycemia or through a controlled diagnostic fast. Additionally, the glycemic response to glucagon must be assessed via a glucagon stimulation test. The evaluation process for hypoglycemia is discussed in a separate topic review. (See "Approach to hypoglycemia in infants and children".)

DIAGNOSIS — The laboratory evidence for HI includes a detectable insulin and/or C-peptide, suppressed beta-hydroxybutyrate (BOHB) and free fatty acids (FFA), and a glycemic response to glucagon at the time of hypoglycemia (table 4).

●Suppressed BOHB and FFA – Insulin suppresses lipolysis and ketogenesis, resulting in inappropriately low levels of BOHB and FFA at the time of hypoglycemia. A BOHB concentration of <1.8 mmol/L has a sensitivity and specificity for HI of 100 percent [45]. A plasma FFA concentration of <1.7 mmol/L has a sensitivity and specificity of 87 and 100 percent, respectively.

●Detectable insulin or C-peptide – When plasma glucose is <50 mg/dL (2.8 mmol/L), any detectable amount of insulin is abnormal. However, a detectable insulin level is not necessary to make the diagnosis of HI and an undetectable insulin level does not rule out HI, given the limitations and variable sensitivity of insulin assays [46]. The sensitivity and specificity for HI of detectable plasma insulin at the time of hypoglycemia are 82.2 and 100 percent, respectively [45]. Similarly, a C-peptide concentration ≥0.5 ng/mL is evidence that insulin secretion is not appropriately suppressed in response to decreasing glucose concentrations. The sensitivity and specificity of a plasma C-peptide concentration of ≥0.5 ng/mL are 88.5 and 100 percent, respectively.

●Glycemic response to glucagon – A rise in glucose of ≥30 mg/dL after administration of glucagon is consistent with HI because it reflects excessive insulin action on the liver. Insulin suppresses hepatic glycogenolysis, which leads to inappropriately high reserves of glycogen in the liver at the time of hypoglycemia. Using this threshold, the sensitivity and specificity of this test to detect HI are 89 and 100 percent, respectively [45].

In neonates, panhypopituitarism must be excluded. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — Other insulin-mediated disorders should be considered, particularly in children presenting after the first year of life. In the majority of cases, these alternative diagnoses can be ruled out through history and laboratory testing.

●Neonatal panhypopituitarism – In neonates with panhypopituitarism, the biochemical response to fasting and the glucagon stimulation test are indistinguishable from neonatal HI. Panhypopituitarism should be suspected in neonates with hypoglycemia who have midline defects (eg, choanal atresia or cleft palate) or microphallus. Of note, low cortisol and growth hormone on the critical sample are not sufficient to diagnose adrenal insufficiency or growth hormone deficiency [47]. Therefore, if panhypopituitarism is suspected, the appropriate stimulation testing should be done to confirm the diagnosis prior to starting treatment. (See "Diagnosis of growth hormone deficiency in children" and "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

●Sulfonylurea ingestion – Ingestion of sulfonylureas such as glipizide or glyburide should be considered in a child with hypoglycemia who has access to these drugs. The biochemical profile of sulfonylurea-induced hypoglycemia is identical to that of congenital HI. (See "Causes of hypoglycemia in infants and children", section on 'Ingestions'.)

●Factitious hypoglycemia – Factitious or induced hypoglycemia refers to intentional administration of insulin or an oral hypoglycemic administration by a parent, caregiver, or by the child him- or herself. The diagnosis should be suspected in children with severe hypoglycemia that has an abrupt onset and does not have consistent triggers such as fasting or illness. Because insulin and C-peptide are secreted in equimolar amounts by the beta cell, an insulin:C-peptide ratio >1 suggests exogenous insulin administration. Specialized insulin assays and sulfonylurea toxicology studies are often necessary to confirm this diagnosis [48]. (See "Medical child abuse (Munchausen syndrome by proxy)" and "Approach to hypoglycemia in infants and children", section on 'Low ketones and low free fatty acids'.)

●Insulinoma – Insulinomas are insulin-secreting islet cell tumors and are typically benign. They sometimes occur in the setting of multiple endocrine neoplasia type 1. These tumors are a rare cause of hypoglycemia in children. They should be suspected when persistent and recurrent hypoglycemia presents in adolescence, although cases have occurred in children as young as two years old. (See "Insulinoma".)

FURTHER EVALUATION — Patients with HI confirmed by laboratory testing should undergo a trial of diazoxide, with further steps depending on the result (algorithm 1).

Trial of diazoxide — Diazoxide responsiveness is typically the starting point for distinguishing congenital HI phenotypes since those who do not respond to diazoxide will often require surgery. Dosing of diazoxide, a "safety fast" protocol to determine diazoxide responsiveness, and other considerations are discussed separately. (See "Treatment and outcomes of congenital hyperinsulinism", section on 'Diazoxide trial'.)

Genetic testing — For all patients who do not respond to diazoxide, a blood sample should be sent promptly for mutation analysis of the ABCC8 and KCNJ11 genes, using a laboratory that offers expedited service with a rapid (four- to seven-day) turnaround time. A listing of clinical laboratories that perform this testing is available at the Genetic Testing Registry website.

Genetic testing is essential for patients with diazoxide-unresponsive HI because approximately 90 percent of these children have K_ATP-HI [10] and more than 50 percent of those with K_ATP-HI have the focal form, which is cured through surgery. A single paternally inherited recessive mutation in the ABCC8 or KCNJ11 genes has a positive predictive value of 94 percent for focal HI [10]. The interpretation of the findings from genetic testing is complicated by the fact that many mutations are novel. Therefore, information may not be available regarding whether the mutation is dominant or recessive or likely to be diazoxide-responsive. In these cases, referral to a specialized HI center may be necessary.

For children with diazoxide-responsive HI, genetic testing is less urgent but is still valuable because it can aid in prognosis and family planning and guide duration of treatment. It should be noted that mutations are only identified in 50 percent of patients with diazoxide-responsive HI [10].

Imaging — Routine imaging of the pancreas in children diagnosed with HI is not recommended. Those patients with suspected focal HI should be referred to a specialized HI center to undergo an 18-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography (PET) scan. (See "Treatment and outcomes of congenital hyperinsulinism".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in infants and children".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and clinical importance – Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants and children. HI results in severe and recurrent hypoglycemia, as well as an inability to make ketone bodies, a crucial alternative fuel for the brain. Therefore, children with HI are at high risk of neurologic damage and developmental deficits. Prompt recognition and appropriate treatment of HI is essential for the best neurologic outcome.

●Causes of HI

•Pathogenic categories – There are three main types of HI: perinatal stress-induced (table 1), monogenic forms due to single-gene defects (table 2), and those associated with syndromes (such as Beckwith-Wiedemann syndrome) (table 3). (See 'Types of hyperinsulinism' above.)

•Monogenic forms – Inactivating mutations of adenosine triphosphate-sensitive potassium (K_ATP) channel on the beta cell, encoded by the ABCC8 and KCNJ11 genes, cause the most common and severe form of HI. Most commonly, this type of HI does not respond to diazoxide.

K_ATP-HI occurs in a diffuse form, involving the beta cells throughout the pancreas, as well as a focal form, in which there is a localized area of beta cell proliferation. The focal form can be cured through surgical resection of the lesion, whereas surgery for the diffuse form is palliative only. Genetic testing offers the best means of differentiating the focal from the diffuse form. (See 'KATP-HI' above and 'Genetic testing' above.)

●Diagnostic criteria – The laboratory criteria for HI includes evidence of insulin action at the time of hypoglycemia (plasma glucose <50 mg/dL) (table 4):

•Suppressed beta-hydroxybutyrate (BOHB; <1.8 mmol/L)

•Suppressed free fatty acids (FFA; <1.7 mmol/L)

•A glycemic response to glucagon (increase in plasma glucose >30 mg/dL)

The presence of any detectable insulin (>2 uIU/mL) or C-peptide (0.5 ng/mL) confirms the diagnosis of HI, but undetectable insulin or C-peptide do not exclude the diagnosis. (See 'Diagnosis' above.)

●Further evaluation – Further evaluation is designed to identify children who can be managed with diazoxide, as well as others with focal disease for which surgery is curative:

•Diazoxide trial – Patients with HI confirmed by laboratory testing should undergo a trial of diazoxide, with further steps depending on the result (algorithm 1). (See 'Trial of diazoxide' above.)

•Genetic testing – Genetic testing is essential for any child with HI who does not respond to diazoxide, because these children have a high likelihood of having K_ATP-HI. Mutations in the K_ATP genes, ABCC8 and KCNJ11, are found in 90 percent of cases that are not diazoxide-responsive. More than 50 percent of patients with recessive mutations in these genes will have focal HI, for which surgery is curative. (See 'Genetic testing' above.)

•Imaging – If the focal form is suspected based on lack of response to diazoxide followed by genetic testing results, the child should be referred to a specialized HI center for an 18-fluoro-dihydroxyphenylalanine positron emission tomography (PET) scan. (See 'Imaging' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Agneta Sunehag, MD, PhD, and Morey W Haymond, MD, who contributed to an earlier version of this topic review.