Congenital Hyperinsulinaemic Hypoglycaemia: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Sylwia Krawczyk
,
Karolina Urbanska
,
Natalia Biel
,
Michal Jakub Bielak
,
Agata Tarkowska
,
Robert Piekarski
,
Andrzej Igor Prokurat
,
Malgorzata Pacholska
,
Iwona Ben-Skowronek

Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of persistent hypoglycaemia in infants and children with incidence estimated at 1 per 50,000 live births. Congenital hyperinsulinism (CHI) is symptomatic mostly in early infancy and the neonatal period. Symptoms range from ones that are unspecific, such as poor feeding, lethargy, irritability, apnoea and hypothermia, to more serious symptoms, such as seizures and coma. During clinical examination, newborns present cardiomyopathy and hepatomegaly. The diagnosis of CHI is based on plasma glucose levels <54 mg/dL with detectable serum insulin and C-peptide, accompanied by suppressed or low serum ketone bodies and free fatty acids.

  • congenital hyperinsulinaemic hypoglycaemia
  • congenital hyperinsulinism
  • ABCC8
  • neonatal hypoglycaemia

1. Introduction

Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of persistent hypoglycaemia in infants and children [1]. It is characterised by dysregulated insulin secretion from pancreatic β-cells despite low glucose levels [2]. It can be either congenital or acquired. Congenital hyperinsulinism mutations in genes related with the regulation of insulin secretion have been described. These genes are ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, HNF1A, HK1, PGM1 and PMM2 (Table 1) [3][4]. Congenital forms of hyperinsulinism (CHI) can be divided into the following two main groups: channelopathies defects in ion channels located on β-cells membrane and metabolopathies defects in the metabolic pathways leading to increased insulin release. The most common mutations are those affecting the KATP channel genes–ABCC8 (36.8%) and KCNJ11 (5.9%) (Figure 1) [5]. Some of the cases of HH are associated with genetic syndromes; Beckwith–Wiedemann syndrome is the most common [6]. The incidence of CHI is estimated at 1:50,000 live births, but in some populations, such as Finland or Saudi Arabia, the incidence reaches from 1:2500 to 1:3000 live births [7]. Transient forms of HH are secondary to conditions such as perinatal asphyxia, intra-uterine growth retardation, erythroblastosis fetalis, maternal diabetes mellitus or the administration of intravenous glucose during labor [6].
Figure 1. The regulation of insulin release and gene mutations involved in CHI pathogenesis. Glucose enters pancreatic β-cell via glucose transporter 2 (GLUT-2). It is then phosphorylated by glucokinase. The product of glycolysis–pyruvate is a substrate of the tricarboxylic acid cycle in mitochondria. The tricarboxylic acid cycle product is ATP. An increase in ATP levels leads to a sequence of KATP channel closure, membrane depolarisation, opening of voltage-dependent Ca2+ channels, Ca2+ influx and eventually insulin exocytosis. Glutamate dehydrogenase (GDH) catalyses the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. Further processes lead to amino acid-induced insulin secretion. PGM1 and PMM2 are responsible for glycosylation. Monocarboxylate transporter 1 (MCT1) catalyses the transport of monocarboxylates–pyruvate and lactate. Enhanced MCT1 expression increases pyruvate metabolism in the tricarboxylic acid cycle. Created with BioRender.com, accessed on 22 September 2022.
Table 1. Genes in CHI pathogenesis.
Gene Full Gene Name Diazoxide Responsiveness
ABCC8 ATP-Binding Cassette Subfamily C Member 8 Yes/No
KCNJ11 Potassium Inwardly-Rectifying Channel Subfamily J Member 11 No
GLUD1 Glutamate Dehydrogenase 1 Yes
GCK Glucokinase Yes/No
HADH Hydroxyacyl-CoA Dehydrogenase Yes
SLC16A1 (MCT-1) Solute Carrier Family 16 Member 1 (Monocarboxylate Transporter Subtype 1) Yes/No
UCP2 Uncoupling Protein 2 Yes
HNF4A Hepatocyte Nuclear Factor 4A Yes
HNF1A Hepatocyte Nuclear Factor 1A Yes
HK1 Hexokinase 1 Yes
PGM1 Phosphoglucomutase 1 No
PMM2 Phosphomannomutase 2 Yes

2. Pathophysiology and Symptoms of CHI

The KATP channel reacts to an increased concentration of ATP (caused by glucose metabolism) by closure of the channel. This leads to β-cell membrane depolarisation and opening of the voltage-dependent Ca2+ channel. The increase in intracellular Ca2+ triggers insulin secretion [8]. The KATP channel consists of four sulphonylurea receptor 1 (SUR1) subunits, encoded by ABCC8, and four inward-rectifier potassium channel (Kir6.2) subunits, encoded by KCNJ11 [9]. The most severe forms of HH are caused by an inactivating mutation of the ABCC9 and KCNJ11 genes, which together are responsible for 36–70% of CHI cases [10][11].
Insulin decreases blood glucose concentrations by driving it into the insulin-sensitive tissues and inhibiting gluconeogenesis and glycolysis [2]. Insulin also inhibits lipolysis and ketone body synthesis. Therefore, in hyperinsulinaemic hypoglycaemia, the brain cannot be supplied with alternative energy sources. The combination of hypoketonaemic hypoglycaemia may lead to brain damage [5]. CHI is symptomatic mostly in early infancy and the neonatal period. Severe hypoglycaemia may even cause seizures or/and coma. The newborns are usually too big for their gestational age as a consequence of the high insulin level acting as a growth factor in utero [11]. Less specific symptoms of hypoglycaemia in the neonatal period include poor feeding, lethargy, irritability, apnoea and hypothermia [2]. In clinical examination, some newborns present cardiomyopathy and hepatomegaly [9].

3. Diagnosis of HH

An infant’s glucose blood concentration at birth amounts to 70% of the maternal levels. Within 1 h, it may decrease to 20–25 mg/dL. Then, over the next hours and days, it begins to rise [12]. The diagnostic criteria for patients with HH are based on the clinical presentation and biochemical profile. Plasma glucose levels of less than 54 mg/dL are accompanied by detectable serum insulin, detectable C-peptide, suppressed or low serum ketone bodies and suppressed or low serum concentrations of free fatty acids. The supportive evidence is a glucose infusion rate of >8 mg/kg per minute which is required to maintain normoglycaemia [9]. In the case of an unclear cause of hypoglycaemia, a glucagon test is performed. In this test, glucagon is administered intravenously at a dose of 0.03 mg/kg, and then blood glucose is measured at 0, 10, 20 and 30 min. CHI is diagnosed when the blood glucose level is higher than 30 mg/dL [9].
Histologically, CHI is divided into three types–diffuse, focal and atypical [13]. Focal lesions are responsible for 30–40% of congenital hyperinsulinaemic hypoglycaemia (CHH). Abnormal pancreatic cells are limited to a single location. The diffuse form of CHH accounts for 60–70% cases. The pathological β-cells are disseminated throughout the pancreas. The atypical form is described as a mosaic pattern of the two previous forms [6]. The gold standard in determining the form of HH is fluorine-18-dihydroxyphenyloalanine positron emission tomography ((18)F-DOPA PET). The sensitivity and specificity of (18)F-DOPA PET or PET/CT in differentiating between focal and diffuse CHI is 89% and 98%, respectively [14]. Rapid genetic testing of KATP channel genes allows for determining the histological subtype of the disease. It should be considered in diazoxide-unresponsive cases before performing (18)F-DOPA PET. The biallelic or single dominant KATP channel disease-causing variant confirms the diffuse form of HH, while a paternally inherited recessive KATP channel variant is linked to the focal form with a sensitivity of 97% [15][16][17].

Differential Diagnosis

The causes of neonatal hypoglycemia can be divided into four main groups: hyperinsulinism, inborn metabolic errors, counter-regulatory hormone deficiency and increased glucose requirement (Table 2) [18].
Table 2. Main causes of neonatal hypoglycaemia.
Transient neonatal hypoglycemia caused by hyperinsulinism
  • Infant of diabetic mother
  • Decreased pancreatic β-cell sensitivity to glucose levels
  • Maternal hyperglycemia during pregnancy
  • Maternal hyperglycemia caused by glucose infusions before or during labor
  • Maternal drugs (anti-diabetic drugs, beta-blockers, antiarrhythmic drugs, interferon, valproic acid)
  • Delayed feeding
  • Excessive insulin administration during treatment of neonatal hyperglycemia
Patent neonatal hypoglycemia Inborn metabolic errors (impaired gluconeogenesis):
  • Carbohydrate metabolism errors
  • Amino-acid metabolism errors
  • Fatty acid metabolism errors
  • Organic acidurias
Congenital hyperinsulinism:
  • ABCC8 and KCNJ11 mutations
  • Glutamate dehydrogenase mutations
  • Pancreatic β-cell hyperplasia
  • Erythroblastosis
  • Beckwith-Wiedemann syndrome
  • Sotos syndrome
Counter-regulatory hormone deficiency:
  • Hypopituitarism
  • Growth hormone deficiency
  • Adrenal insufficiency
  • Hypothyroidism
Increased glucose requirement:
  • Sepsis
  • Hypothermia
  • Hypoxia
  • Polycythemia
  • Cyanotic heart disease
  • Exchange transfusion
  • Intrauterine growth restriction
  • Prematurity
  • Mother starvation before labor
The majority of neonatal hypoglycemia cases are caused by delayed metabolic adaptation after birth. Some patients require high glucose infusions for a week or more until they develop physiological metabolic processes [19].
Metabolic or hormonal etiology should be suspected in low-risk cases or unusual severity of hypoglycemia [19]. Most of these causes can be excluded or confirmed with laboratory testing [19][20][21][22][23] (Table 3). The critical samples for laboratory investigations should be obtained at the time of a hypoglycaemic episode [19].
Table 3. Suggested laboratory investigations of the critical samples (taken during a hypoglycaemic episode) for differential diagnosis of neonatal hypoglycaemia.
Suggested Investigations in Differential Diagnosis
Complete blood count
Arterial blood gas
Blood glucose
Lactate
Pyruvate
Alanine
Glycerol
Ketone bodies
Plasma insulin
Free fatty acids
C-peptide
Plasma total and free carnitine, acylcarnitine profile
Ammonia
Electrolytes, blood urea nitrogen, creatinine
Uric acid
Growth hormone
Cortisol
Thyroid hormones
IGF-1
Galactosaemia screen
Ketones and organic acids in urine

This entry is adapted from the peer-reviewed paper 10.3390/jcm11206020

References

  1. Senniappan, S.; Shanti, B.; James, C.; Hussain, K. Hyperinsulinaemic Hypoglycaemia: Genetic Mechanisms, Diagnosis and Management. J. Inherit. Metab. Dis. 2012, 35, 589–601.
  2. Roženková, K.; Güemes, M.; Shah, P.; Hussain, K. The Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia. J. Clin. Res. Pediatr. Endocrinol. 2015, 7, 86.
  3. Galcheva, S.; Demirbilek, H.; Al-Khawaga, S.; Hussain, K. The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism. Front. Endocrinol. 2019, 10, 111.
  4. Kostopoulou, E.; Shah, P. Hyperinsulinaemic Hypoglycaemia—An Overview of a Complex Clinical Condition. Eur. J. Pediatr. 2019, 178, 1151–1160.
  5. Rahman, S.A.; Nessa, A.; Hussain, K. Molecular Mechanisms of Congenital Hyperinsulinism. J. Mol. Endocrinol. 2015, 54, R119–R129.
  6. Gϋemes, M.; Rahman, S.A.; Kapoor, R.R.; Flanagan, S.; Houghton, J.A.L.; Misra, S.; Oliver, N.; Dattani, M.T.; Shah, P. Hyperinsulinemic Hypoglycemia in Children and Adolescents: Recent Advances in Understanding of Pathophysiology and Management. Rev. Endocr. Metab. Disord. 2020, 21, 577.
  7. Lord, K.; De León, D.D. Hyperinsulinism in the Neonate. Clin. Perinatol. 2018, 45, 61–74.
  8. Shimomura, K.; Maejima, Y. KATP Channel Mutations and Neonatal Diabetes. Intern. Med. 2017, 56, 2387.
  9. Shah, P.; Rahman, S.A.; Demirbilek, H.; Güemes, M.; Hussain, K. Hyperinsulinaemic Hypoglycaemia in Children and Adults. Lancet Diabetes Endocrinol. 2017, 5, 729–742.
  10. Takasawa, K.; Miyakawa, Y.; Saito, Y.; Adachi, E.; Shidei, T.; Sutani, A.; Gau, M.; Nakagawa, R.; Taki, A.; Kashimada, K.; et al. Marked Clinical Heterogeneity in Congenital Hyperinsulinism Due to a Novel Homozygous ABCC8 Mutation. Clin. Endocrinol. 2021, 94, 940–948.
  11. De Franco, E.; Saint-Martin, C.; Brusgaard, K.; Knight Johnson, A.E.; Aguilar-Bryan, L.; Bowman, P.; Arnoux, J.B.; Larsen, A.R.; May, S.; Greeley, S.A.W.; et al. Update of Variants Identified in the Pancreatic β-Cell KATP Channel Genes KCNJ11 and ABCC8 in Individuals with Congenital Hyperinsulinism and Diabetes. Hum. Mutat. 2020, 41, 884–905.
  12. Adamkin, D.H. Neonatal Hypoglycemia. Semin. Fetal Neonatal Med. 2017, 22, 36–41.
  13. Galcheva, S.; Al-Khawaga, S.; Hussain, K. Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia. Best Pract. Res. Clin. Endocrinol. Metab. 2018, 32, 551–573.
  14. Treglia, G.; Mirk, P.; Giordano, A.; Rufini, V. Diagnostic Performance of Fluorine-18-Dihydroxyphenylalanine Positron Emission Tomography in Diagnosing and Localizing the Focal Form of Congenital Hyperinsulinism: A Meta-Analysis. Pediatr. Radiol. 2012, 42, 1372–1379.
  15. Hewat, T.I.; Johnson, M.B.; Flanagan, S.E. Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease. Front. Endocrinol. 2022, 13, 1484.
  16. Snider, K.E.; Becker, S.; Boyajian, L.; Shyng, S.L.; MacMullen, C.; Hughes, N.; Ganapathy, K.; Bhatti, T.; Stanley, C.A.; Ganguly, A. Genotype and Phenotype Correlations in 417 Children with Congenital Hyperinsulinism. J. Clin. Endocrinol. Metab. 2013, 98, E355–E363.
  17. Mohnike, K.; Wieland, I.; Barthlen, W.; Vogelgesang, S.; Empting, S.; Mohnike, W.; Meissner, T.; Zenker, M. Clinical and Genetic Evaluation of Patients with KATP Channel Mutations from the German Registry for Congenital Hyperinsulinism. Horm. Res. Paediatr. 2014, 81, 156–168.
  18. Vain, N.E.; Chiarelli, F.; Palermo, T.; Isidro, S.; Mejía, R.; Aires, B.; Sanatorio Trinidad Palermo, H. Neonatal Hypoglycaemia: A Never-Ending Story? Neonatology 2021, 118, 522–529.
  19. Deshpande, S.; Platt, M.W. The Investigation and Management of Neonatal Hypoglycaemia. Semin. Fetal Neonatal Med. 2005, 10, 351–361.
  20. Thornton, P.S.; Stanley, C.A.; De Leon, D.D.; Harris, D.; Haymond, M.W.; Hussain, K.; Levitsky, L.L.; Murad, M.H.; Rozance, P.J.; Simmons, R.A.; et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J. Pediatr. 2015, 167, 238–245.
  21. Adamkin, D.H. Metabolic Screening and Postnatal Glucose Homeostasis in the Newborn. Pediatr. Clin. 2015, 62, 385–409.
  22. Ghosh, A.; Banerjee, I.; Morris, A.A.M. Recognition, Assessment and Management of Hypoglycaemia in Childhood. Arch. Dis. Child. 2016, 101, 575–580.
  23. Douillard, C.; Mention, K.; Dobbelaere, D.; Wemeau, J.L.; Saudubray, J.M.; Vantyghem, M.C. Hypoglycaemia Related to Inherited Metabolic Diseases in Adults. Orphanet J. Rare Dis. 2012, 7, 26.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback