Glucose is of essential, fundamental importance for brain metabolism.
The major source of glucose to the brain is the blood supply; and, a
fall in the blood glucose level may lead to severe encephalopathy.
Hypoglycemia (blood glucose, <45 mg/dl; in neonates, <30 mg/dl),
is a common nonspecific problem in severely ill neonates and young
children irrespective of the illness. In adults, there are varied
causes of hypoglycemia but are noted most often in diabetic patients
and are usually secondary to changes in medication or overdoses,
infection or changes in diet or activity. Other causes include islet
cell/extrapancreatic tumors, adrenal insufficiency, hypopituitarism,
severe hepatic dysfunction, sepsis or starvation. The most frequent
causes of persisting neonatal hypoglycemia are hormonal disturbances,
e.g., hyperinsulinism or hypopituitarism, or regulatory disturbances
(e.g., ketotic hypoglycemia or glycogen storage disorders). Various
etiologies of genetic hypoglycemias are classified according to the
time of manifestation
[Table 5].
[29]
The laboratory investigations during symptomatic hypoglycemia should
include blood counts, C-reactive protein (CRP), liver function tests,
creatine kinase (CK), uric acid, triglycerides, blood gases and
electrolytes, lactate, and ammonia, ketones in urine, organic acids (in
first urine sample after hypoglycemia), plasma amino acids, carnitine
and acylcarnitines, plasma insulin, C-peptide, glucagons, cortisol,
IGF-1 and isoelectric focussing for transferrin (if indicated).
[Figure 2]
presents an overview of a biochemical approach to the diagnosis of
hypoglycemia, which focuses primarily on the disease caused by
inherited neurometabolic disorders. The presence of
non-glucose-reducing substances in the urine is characteristic of
untreated classical galactosemia and hereditary fructose intolerance.
This can be determined at the bedside by testing a few drops of urine
with Benedict's test and the glucose strip (Uristix). A positive
Benedict's test with a negative test with uristix for glucose indicates
that the reducing substance is not glucose. Patients with galactosemia
show other evidences of hepatocellular dysfunction and hereditary
fructose intolerance is associated with marked lactic acidosis.
The
normal physiological response to decreased glucose production is
increased mitochondrial fatty acid b-oxidation and the production of
ketones. Accordingly, increased urinary ketones provide an indirect
evidence of whether hypoglycemia is the result of inadequate production
or overutilization of glucose. In older infants, children and adults,
the absence of ketones in urine is usually a strong indication of
increased glucose utilization. Increased glucose utilization
(hypoketotic hypoglycemia) occurs as a result of either hyperinsulinism
or of primary or secondary defect in fatty acid oxidation. The two
situations are distinguishable by measuring plasma free fatty acid
levels. One of the physiological effects of insulin is inhibition of
hormone-sensitive lipase in adipose tissue. Low free fatty acid levels
during hypoglycemia are a strong indication of abnormally elevated
insulin levels. The timing of the hypoglycemia and other laboratory
findings render differentiation of this condition relatively simple.
Hyperinsulinemic hypoglycemia occurs due to insulin hypersecretion by
the Islets of Langerhans
More Details.
Focal islet cell hyperplasia is associated with mutation of
sulfonylurea receptor (SUR1) or inwardly rectifying potassium channel
(Kir.2) genes. A few cases of syndromic hyperinsulinemia such as
hyperinsulinism associated with Usher syndrome type Ic, congenital
disorder of glycosylation (CDG) Ia or Ib, Beckwith Wiedemann's
syndrome, Perlman's or Sotos' syndrome have been described. Infants
with mutations in glutamate dehydrogenase gene (GLUD I) present with
recurrent hypoketotic hypoglycemia, elevated plasma insulin and
persistent hyperammonemia.
Most hypoglycemias associated with permanent hepatomegaly occur due to an inherited metabolic disorder.
[30]
All conditions, acquired or inherited, associated with severe liver
failure can result in severe hypoglycemia, which appears after 2-3 h of
fasting and manifests with moderate lactic acidosis and no ketosis.
When hepatomegaly is the most prominent feature without hepatic
insufficiency, deficiencies of glucose-6-phosphatase (GSD I), fructose
1,6-bisphosphastase (FBP), glycogen debrancher (GSD III) or glycogen
synthase (GSD 0) should be considered as the most probable diagnosis.
In GSD I, laboratory examination typically shows lactic acidosis,
hyperuricemia, hypertriglyceridemia and hypophosphatemia. Hypoglycemia
is characteristically unresponsive to glucagon administration. A
distinguishing feature of this disorder is a significant increase in
plasma lactate in response to glucagon. In FBP deficiency, however, the
response to glucagon is preserved. An oral glucose test can
differentiate GSD I from GSD III. A moderate increase in blood lactate
is observed in GSD III, whereas blood lactate drops precipitously in
GSD I. The rare glycogen synthase deficiency presents with fasting
hypoglycemia, ketosis and postprandial hyperlactacidemia. A definitive
diagnosis of these disorders requires measurement of the relevant
enzymes. Respiratory chain disorders can present with hepatic failure
and hypoglycemia.
Hypoglycemia is a prominent secondary
metabolic phenomenon in all mitochondrial fatty acid b-oxidation
defects. The diagnosis can be confirmed by demonstrating the presence
of high concentration of C6-C10 dicarboxylic acids (adipic, suberic and
sebacic acids) and the characteristic acylcarnitines in plasma during
acute decompensation. Fasting hypoglycemia and marked hepatomegaly
associated with early-onset renal tubular dysfunction characterised by
polyuria, hypophosphatemic rickets, hyperchloremic metabolic acidosis,
and severe growth retardation is typical of Fanconi-Bickel syndrome.
This condition is caused by mutation in GLUT 2 gene coding for the
hepatic-type glucose transporter.
Patients with genetic
endocrine disorders due to defects such as growth hormone (GH) gene
deletion, mutation in GH-releasing hormone (GHRH) receptors,
insulin-like growth factor-1 (IGF-1) defects or malformations of the
hypothalamic area leading to multiple pituitary hormone deficiencies
can present with fasting hypoglycemia. Hypoglycemic responsiveness to
glucagon is variable-mild, absent or dramatic-the latter response being
similar to that observed in hyperinsulinism. Hypoglycemia associated
with isolated adrenocorticotrophic hormone (ACTH) deficiency is rare.
Glucagon deficiency can also be associated with hypoglycemia.
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