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BMJ Case Rep. 2010; 2010: bcr08.2009.2174.
Published online Feb 8, 2010. doi:  10.1136/bcr.08.2009.2174
PMCID: PMC3030263
Rare disease
Congenital hyperinsulinism with hyperammonaemia
Alex Pschibul, Jörg Müller, and Hubert Fahnenstich
St Elisabethen Hospital, Paediatrics, Feldbergstr 15, Lörrach, 79359, Germany
Correspondence to Alex Pschibul, apschibul/at/web.de
Congenital hyperinsulinism is considered to be the most frequent cause of persistent recurrent hypoglycaemia in infants. The clinical presentation and response to pharmacological treatment may vary significantly depending on the underlying pathology. We report a case of a female infant with mild but early onset of recurrent hypoglycaemia. Metabolic workup revealed hyperinsulinism combined with mild hyperammonaemia as well as elevation of α-ketoglutarate in urine. Genetic testing demonstrated a de novo mutation in exon 7 of the glutamate dehydrogenase gene on chromosome 10. Episodes of hypoglycaemia responded to treatment with diazoxide. The differential diagnosis, pathophysiology and treatment of congenital hyperinsulinism is discussed.
Congenital hyperinsulinism (CHI), previously termed “nesidioblastosis”, is considered to be the most frequent cause of persistent recurrent hypoglycaemia in infants. Incidence is estimated 1:40,000 births in central Europe. In ethnic groups with high proportions of consanguineous parents, the incidence can be as high as 1:2500.1,2 The clinical presentation varies depending on the underlying pathology with respect to both the severity of hypoglycaemia as well as in the response to pharmacological treatment.
Sixty per cent of CHI are diagnosed within the first 3 days of life, with the remaining 40% being diagnosed later; 85% of the remainder are diagnosed in months 2–12, and 15% after the first year of life.3 Clinical symptoms include seizures, pallor, muscle weakness, cyanosis and cardiac failure, but neonates may be asymptomatic (20%).3
CHI is an important diagnosis to consider in neonatal hypoglycaemia as it is an important cause of severe neurodevelopmental impairment.
A female infant (weight 2700g (small for gestational age, SGA), length 47 cm, occipitofrontal circumference (OFC) 32 cm) was born at 38+6 weeks to a 33-year-old G1/P1 by elective caesarean section. There was no maternal history of unexplained primary sterility, spontaneous abortions or peri/neonatal deaths as well as no maternal health issues during pregnancy and no suggestion of maternal diabetes mellitus or gestational diabetes. Postnatal adaptation was normal with APGAR scores of 9, 10 and 10 after 1, 5 and 10 min, respectively. Early medical examination did not reveal any abnormalities. On the first day of life, the infant showed hypoglycaemia with blood glucose values between 1.7–2.2 mmol/l despite early feeding with maltodextrine. Blood glucose values normalised on an intravenous glucose infusion. During the following days ongoing intravenous glucose administration was necessary despite increased oral feeding. The initial metabolic workup included cortisol, insulin, growth hormone, lactate and ammonia. These bloods were sampled at a glucose concentration of 2.7 mmol/l. The results were normal other than a slight hyperammonaemia at 141 μmol/l (controlled 159 μmol/l). A screen for inborn errors of metabolism showed no distinctive features.
With a presumed diagnosis of prolonged transient hyperinsulinism secondary to growth restriction we began treatment with hydrocortisone (2 mg twice daily), which stabilised blood glucose values with normal feeding.
At the age of 8 weeks hydrocortisone medication was terminated. Blood glucose values remained within the normal range, ammonia was slightly elevated at 92 μmol/l.
The infant was readmitted at the age of 5½ months for observation after a fall to the floor from a “babysafe” carry system. Clinical examination was inconspicuous. Sensorimotor development as well as growth was normal for its age. No neurological symptoms appeared until discharge 2 days later.
Three hours after returning back home, an episode of abnormal jerky movements of the head with an empty gaze was observed over a period of 5 min. Feeding had been normal that morning with 180–200 ml formula milk every 4–5 h plus a half portion of porridge. On admission to hospital, the blood glucose concentration was measured at 2.2 mmol/l. A computed tomography (CT) scan of the skull excluded acute intracranial haemorrhage and the electroencephalogram (EEG) recordings showed no pathologic activity. Intensified metabolic workup showed the following results.
Investigations
At blood glucose concentration of 3.0 mmol/l:
  • Insulin 14.8 mU/l
  • Growth hormone 10.1 μg/l (reference 0.5–3.5 μg/l)
  • Ammonia 170 μmol/l (reference 18–74 μmol/l)
  • No elevated β-OH-butyrate and aceto-acetate in plasma
  • Acyl-carnitine profile normal
  • Urine: No ketone bodies, α-ketoglutarate mildly elevated at 450 mmol/mol creatinine.
At blood glucose concentration of 2.2 mmol/l:
  • No elevated β-OH-butyrate or aceto-acetate in plasma
  • Free fatty acids not elevated
  • Urine: α-ketoglutarate elevated at 710 mmol/mol creatinine.
Box 1 lists the diagnostic criteria for CHI.
Box 1 Diagnostic criteria for congenital hyperinsulinism3
  • Need for glucose administration >10 mg/kg/min to keep blood glucose values stable.
  • Insulin > 3 mU/l during hypoglycaemia with paired blood glucose value < 2 mmol/l.
  • Free fatty acids in plasma <600 μmol/l, ketone bodies in blood <0.1mmol/l, no ketonuria.
  • Administration of glucagon (30 μg/kg subcutaneously/intramuscularly) leads to an elevation of blood glucose values.
  • Concomitant hyperammonaemia should be considered and ammonia values checked.
Carbohydrates were supplemented up to 20 g/kg/day by oral feeding of formula milk with 15% maltodextrine plus intravenous glucose infusion, according to a theoretical glucose demand of 14 mg/kg/min.
Although the relevant blood samples could not be taken in real hypoglycaemia (defined as blood glucose <2 mmol/l), the insulin concentration demonstrated was inappropriately high given the low blood glucose concentration. Furthermore the suppression of lipolysis and ketogenesis seen are characteristic of congenital hyperinsulinism.
The concomitant hyperammonaemia and elevation of α-ketoglutarate seen in urine are indicative of a defect of the glutamate dehydrogenase.4
Box 2 lists the differential diagnosis for CHI
Box 2 Differential diagnosis for congenital hyperinsulinism
  • Transient hyperinsulinism of the neonate (as seen in the infant of a diabetic mother, large for gestational age (LGA) infants, asphyxia, sepsis, rhesus incompatibility, etc).
  • Beckwith–Wiedemann syndrome: macrosomia, microcephalus, omphalocele, auricular notch.
  • Lack of short-chain-L-3-hydroxylacetyl-CoA-dehydrogenase (SCHAD): elevation of C4-OH-carnitine.
  • Lack of growth hormone.
  • Glycogen storage disease type 0: glycogene synthetase deficiency in the liver.
  • Insulinoma: very rare in childhood.
In our patient the acyl-carnitine-profile was normal, ruling out SCHAD (lack of short-chain-L-3-hydroxylacetyl-CoA-dehydrogenase) as an important differential diagnosis. Growth hormone values were elevated due to a counter-regulatory rise caused by hypoglycaemia.
Treatment
After the diagnosis of CHI was established, treatment was commenced with diazoxide 5 mg/kg/day orally, increasing to 10 mg/kg/day after 3 days.
Following treatment we observed an elevation of pre- and post-prandial blood glucose concentrations up to the normal range (fig 1).
Figure 1
Figure 1
Clinical course. BGL, blood glucose concentration; GI, glucose infusion.
Outcome and follow-up
Neurodevelopmental follow-up examination until the age of 2 years was normal. Blood glucose values remained stable on diazoxide medication.
To understand the background of CHI, the physiologic regulation of the pancreatic β-cell has to be understood:
  • The intracellular ATP:ADP ratio is dependent upon the intracellular concentration and metabolism of energy-rich metabolites such as glucose and glutamate.
  • A low ATP:ADP ratio opens the KATP sodium channel stabilising the cell membrane potential at –70mV (fig 2A).
    Figure 2
    Figure 2
    (A) Normal pancreatic β-cell, low intracellular glucose concentration. (B) Normal pancreatic β-cell, high intracellular glucose concentration.
  • A high ATP:ADP ratio leads to an inactivation of this sodium channel, causing membrane depolarisation and, via an opening of voltage dependant calcium channels, secretion of insulin (fig 2B).
The molecular mechanism of hyperinsulinism is caused by the impairment of either the intramembranous or intracellular proteins of the pancreatic β-cell (table 1).
Table 1
Table 1
Different forms of congenital hyperinsulinism (modified after Meissner and Maytapek5)
  • Impairment of intramembranous proteins (fig 3):
    Figure 3
    Figure 3
    Impairment of the KATP channel of the pancreatic β-cell.
    • Impairment of the KATP channel itself, consisting of the channel protein Kir6.2 and the sulfonylurea receptor SUR1, cause a defect of cell membrane stabilisation in spite of a low ATP:ADP ratio. This leads to spontaneous membrane depolarisation and insulin secretion.
    • Both relevant genes (>100 known mutations) are coded next to each other on chromosome 11p15. Approximately 60% of all CHI depend on an impairment of these genes causing severe, early manifestation of symptoms.
    • This type of CHI is not responsive to diazoxide, which is a direct opener of the KATP channel. In 35% of CHI, this mutation is only expressed in focal hyperplastic pancreas cells rather than diffusely. This hyperplasia can be demonstrated by L-DOPA-PET and it can be amenable to focal pancreatic surgery. In the case of diffuse pancreatic involvement, subtotal resection of the pancreas is possible.1
  • Impairment of intracellular proteins (fig 4) with two recognised forms:
    Figure 4
    Figure 4
    Impairment of intracellular proteins of the pancreatic β-cell.
    • First, mutation of the GCK gene on chromosome 7 may lead to an increased activation of glucokinase, the key enzyme of glycolysis. This causes a high intracellular ATP:ADP ratio even at low concentrations of intracellular glucose.5
    • Second, mutation of the GLUD1 gene on chromosome 10 may lead to an increased activation of glutamate dehydrogenase, a mitochondrial matrix enzyme, leading to an increased ATP:ADP ratio in the β-cell by metabolism of glutamate via the citrate cycle. In the liver, activation of GLUD1 results in an increased oxidation of glutamate to ammonia and α-ketoglutarate as well as depletion of N-acetylglutamate, therefore decreasing the activity of the carbamyl-phosphate-synthetase, the first enzyme of the urea cycle. This causes concomitant mild hyperammonaemia, typically in the range of 100–200 μmol/l, and therefore this is often clinically asymptomatic.
    • Furthermore, hypoglycaemia might be induced by leucine administration, as the glutamate dehydrogenase is allosterically activated by leucine, a circumstance that might be of diagnostic as well as of therapeutic use.1,6
    • The integrity of the KATP-channel in these conditions explains their good response to diazoxide administration.
In our patient a heterozygotic sporadic mutation (GLUD1 exon 7 c.965G>A p.Arg322His) was detected which was not present in the parents.
Pathological mutations of the same region have been described previously, firstly in a domain encoded by exons 11 and 127 and subsequently in a second domain encoded by exons 6 and 7.6 Our case demonstrated the latter mutation. All these mutations impair the sensitivity of the enzyme to allosteric inhibition by GTP. In a study of 48 examined cases, all of the affected patients were heterozygous, and 75% had the mutation de novo rather than inherited.7
It has been previously reported8 that some family members are not recognised as being affected until adult life. Some carriers of disease causing mutations have even been described as asymptomatic.8
The genetic basis of many sporadic cases of CHI remains unclear, suggesting that further genes might be affected in CHI.1,2
In our case the metabolic investigations were done during low blood glucose concentrations but not during a severe hypoglycaemic episode because an intravenous glucose infusion had already been commenced before blood sampling. This resulted in hormone values (for example, insulin) which were difficult to interpret. This is a common scenario in neonatal practice because of the importance of early correction of profound hypoglycaemia to prevent neurological sequelae. It is therefore crucial to consider hyperinsulinism early in the diagnostic process when treating infants with hypoglycaemia.
Learning points
  • Congenital hyperinsulinism is considered the most common cause of persistent recurrent hypoglycaemia in infants.
  • There is a broad spectrum of underlying pathology.
  • Concomitant hyperammonaemia suggests a defect in glutamate dehydrogenase activity.
Acknowledgments
Metabolic diagnostics were carried out by the Stoffwechselzentrum Heidelberg, Germany. Genetic testing was carried out by IntraGen GmbH Bonn, Germany.
Footnotes
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.
1. Meissner T, Maytapek E. Kongenitaler Hyperinsulinismus Diagnose und Behandlung. Monatsschr Kinderheilkd 2005; 153: 483–92.
2. Rabl W, Mohnke K. “Nesidioblastose”- Von der molekularen Pathophysiologie zur Therapie. Heidelberg Leipzig: Johann Ambrosius Barth Verlag (Edition J&J), 1999.
3. Working group for paediatric metabolic disorders in the German Society of Child Medicine And Youth Medicine Recommendations regarding diagnostics and therapy of the congenital hyperinsulinism (CHI). APS; 2008 [cited 30 June 2008. http://www.aps-med.de/APS-P05.asp.
4. De Lonlay P, Benelli C. Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. Pediatr Res 2001; 50: 353–7. [PubMed]
5. Meissner T, Maytapek E. Genetische Grundlagen der kongenitalen Hyperinsulinismus. Dtsch Arztebl 2000; 97: A2533–6.
6. MacMullen C, Fang J, Hsu B, et al. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab 2001; 86: 1782–7. [PubMed]
7. Stanley C, 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. [PubMed]
8. Stanley C, Lieu Y, Hsu B, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998; 338: 1352–7. [PubMed]
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