-cells
[1]. CHI, can be transient or permanent, and could be associated with
overgrowth syndromes, birth asphyxia, IUGR, Rh isoimmunisation and
maternal diabetes mellitus [2].
Ketotic hypoglycemia (KH) is the most common
form of hypoglycemia beyond infancy, the exact etiopatho-genesis of
which still remains obscure [3,4]. KH readily responds to oral or
intravenous glucose administration without causing permanent
neurological sequelae with majority of children outgrowing this
condition with age. The development of KH after resolution of transient
CHI has not been widely reported. We report our observations on KH after
resolution of CHI.
After approval from the Institute’s Ethics Committee
the clinical data was collected from 142 children referred to our centre
with persistent hypoglycemia between 2009 and 2016. Diagnosis of CHI
(inappropriately high insulin and C-peptide and low Free Fatty Acids
(FFA) and 3- betahydroxyl butyrate) and KH (low insulin and C-peptide
with elevated FFA, 3-betahydroxybutyrate and normal cortisol during
hypoglycemia [glucose <45 mg/dL]) were made based on clinical and
biochemical parameters. Patients with CHI who developed KH subsequently
were included in the study.
Five children (all boys) developed KH subsequent to
resolution of CHI. Baseline characteristics of each child and time
interval for development of KH are shown in Web Table
I. The mean (SD) birthweight was 2.82 (0.45) kg and the mean age at
the time of initial presentation was 46.8 hours. All patients required
higher rates of glucose infusion [13.70 (1.57) mg/kg/min)] with a mean
(SD) glucose concentraion of 1.98 (0.72) mmol/L. The biochemcial screen
during hypoglycemia confirmed CHI (raised insulin concentration with
suppressed FFA and 3- betahydroxyl butyrate). Four children required
Diazoxide [7.38 (1.94) mg/kg/day] therapy which was discontinued at a
mean (SD) age of 11.2 (5.25) months. KH developed after a mean duration
of 6.7 months following resolution of CHI.
Our study revealed that some infants presenting with
transient CHI have an increased risk of developing KH later in
childhood. Majority of patients with CHI tend to be of transient nature
with some requiring diazoxide therapy for variable time periods [5].
KH is typically seen in toddlers who miss meals owing
to inter-current illness and develop hypoglycemia along with ketonemia
and ketonuria. In our study, all 5 children presented with KH during
intercurrent illneness. Christensen described failure of the adrenergic
stress response during episodes of KH [6]. One of our patients had low
cortisol but his short Synacthen test revelaed normal cortisol reserve.
Development of KH exclusively in males was a notable
feature of our study; similar to a previous study [9], which showed that
children of male gender and with low body weight have increased
susceptibility to KH [7]. However, the exact mechanism behind this
association; however, is unclear.
IUGR infants are known to be hypoinsulinemic,
secondary to placental insufficiency producing diminished transplacental
glucose transport which reduces protein and glycogen synthesis. Lower
plasma concentrations of insulin and glucose produces a marked reduction
in hepatic and muscle glycogen content [8]. The reason why only some
newborns with IUGR develop CHI is unclear. Small sample size and
retrospective nature were the major limitations of our study.
Patients with transient CHI need long term follow-up
to enable early identification and appropriate management of KH.
Contributors: PP: literature search, data
collection and manuscript review, act as guarantor; DG: editing the
manuscript, managed the patient; MD and SS: acquisition and
interpretation of data, managed the patients and edited the manuscript;
SS: manuscript review, manuscript editing, drafting the article and
revising the article critically for important intellectual content.
All authors reviewed and approved the manuscript for
publication. PP: will act as guarantor of the study.
Funding: None; Competing interest: None
stated.
References
1. Stanley CA. Perspective on the genetics and
diagnosis of congenital Hyperinsulinism disorders. J Clin
Endocrinol Metab. 2016;101:815-26.
2. Senniappan S, Arya VB, Hussain K. The molecular
mechanisms, diagnosis and management of congenital hyperinsulinism.
Indian J Endocrinol Metab. 2013;17: 19-30.
3. McQuarrie I. Idiopathic spontaneously occurring
hypoglycaemia in infants. Clinical significance of problem and
treatment.Am J Dis Child. 1954;87:399-428.
4. Pershad J, Monroe K, Atchison J. Childhood
hypoglycemia in an urban emergency department: epidemiology and a
diagnostic approach to the problem. Pediatr Emerg Care.1998;14:268-71.
5. Fafoula O, Alkhayyat H, Hussain K. Prolonged
hyperinsulinaemic hypoglycaemia in intrauterine growth retarded
newborns. Arch Dis Child Fetal Neonatal. 2006;Ed 91:F467.
6. Christensen NJ. Adrenergic mechanisms in selected
diseases: arterial hypertension, duodenal ulcer, primary depressive
illness, malignant tumors, and ketotic hypoglycemia. Metabolism.
1980;29:1190-7.
7. Daly LP, Osterhoudt KC, Weinzimer SA. Presenting
features of idiopathic ketotic hypoglycemia. J Emerg Med. 2003;25:39-43.
8. Hay WW Jr. The role of placental-fetal interaction in fetal
nutrition. Semin Perinatol.1991;15:424-33.