Notes on hypoglycaemia

Whipples triad. Whipples triad refers to the presence of (1) symptoms, signs, or
both, consistent with hypoglycaemia; (2) low plasma glucose concentration; and (3)
resolution of the symptoms and/or signs with administration of glucose/after
glucose concentration is raised. The endocrine society recommends that only in
those with Whipples triad. Exception would be a patient who is unable to
communicate symptoms.
Symptoms of hypoglycaemia. Symptoms of hypoglycaemia develop at a mean
plasma glucose concentration of approximately 3 mmol/L. Symptoms of
hypoglycaemia can be divided into neuroglycopenic (a result of low glucose in
brain), and neurogenic (autonomic; symptoms and signs due to sympathoadrenal
discharge triggered by hypoglycaemia). Demonstration of a glucose level > 3.9
mmol/L is strong evidence that symptoms of a patient is not due to hypoglycaemia.
Biochemical workup in non-DM patient. The endocrine society recommends:
(1) Measurement of plasma glucose, insulin, C-peptide, proinsulin, and betahydroxybutyrate:
Glucose < 3 mmol/L, in the presence of one or more of below:
Insulin >= 3 mIU/L
C-peptide >= 0.2 nmol/L
Proinsulin >= 5 pmol/L
3-hydroxybutyrate <= 2.7 mmol/L
Indicates endogeneous hyperinsulinism;
(2) Observe the plasma glucose response to 1 mg of glucagon intravenously
Glucose rise of >= 1.4 mmol/L after IV glucagon indicate mediation by
insulin or by an IGF
(3) Screen for oral hypoglycaemic agent
(4) Formally re-create the circumstance which symptomatic hypoglycaemia
occurs:
Fasting, up to 72 hours After a mixed meal (a glucose tolerance test
should not be used)
(5) In patient where hyperinsulinaemic hypoglycaemia is confirmed:
Workup after (1) negative screen for OHA, (2) no circulating insulin
antibody
(6) Workup for hyperinsulinaemic hypoglycaemia:
Locate insulinoma by: CT, MRI, USG(transabdominal, endoscopic), ASVS
Causes of hypoglycaemia. Causes can be divided into where the subject is
ill/medicated or seemingly well. Where the subject is well, the diagnosis of
endogeneous hyperinsulinism (tumor, nesidioblastosis, dumping syndrome,
autoimmune insulin syndrome, secretagogue, etc), and accidental, surreptitious or
malicious causes should be considered. In addition to the above, in the ill or
medicated, the differential diagnosis includes drugs (insulin, OHA, alcohol, others#),

critical illness (organ failure, sepsis), hormone deficiency (cortisol, glucagon,

adrenaline), and non-islet cell tumor.
Drugs that causes hypoglycaemia (other than OHA). Quinine, indomethacin,
glucagon, pentamidine, gatifloxacin, and cibenzoline are known to cause
hypoglycaemia. Artesunate and lithium has also been reported to cause
hypoglycaemia.
Non-islet cell tumors. Non-islet cell tumors produces incompletely processed IGFII/pro-IGF-II which had much lower affinity with binding proteins, and as such leads
to higher endogeneous bioactivity. A normal total IGF-II level may be observed
though IGF-II/IGF-I ratio is elevated, GH is suppressed, free IGF-II level is elevated.
Post-gastric bypass. In these patients hypoglycaemia occurs in the post-prandial
period and is more often due to nesidioblastosis.
Prolonged fasting. Procedure as follows:
(1) Discontinue all non-essential medication, allow to drink calorie-free
beverages, ensure that patient is active during waking hours
(2) Collect specimens every 6 hours. When glucose drop to < 3.3 mmol/L,
increase the frequency of sampling to every 1-2 hours
(3) End the fast when glucose levels drop to< 2.5 mmol/L, with symptoms and/or
signs. The decision to end the fast is not by glucose level alone because
some healthy may have low glucose level during prolonged fasting. The level
may be < 3 mmol/L if the patient had unequivocal demonstration of
Whipples triad previously.
(4) Laboratory glucose, not POCT, should be used to guide further investigations
in this test.
(5) After the fast, a complete set of investigation should be taken (including OHA
screen) and glucagon 1.0 mg IV administered and glucose monitored q10
minutes for three times.
Mixed-meal diagnostic test. Procedure as follows:
(1) Mixed meal similar to what the patient reports has caused symptoms
(2) Collect plasma glucose/insulin/C-peptide/proinsulin before, and every 30
minutes after ingestion for 300 minutes.
(3) Refrain from treating the patient with glucose (unless absolutely necessary)
to observe the response to hypoglycaemia
Outcomes. After curative surgery, the recurrence rate is 7% for patients without
MEN-1 and 21% for those with MEN-1, recurrences before 4 year suggest fracture of
the insulinoma during resection.
Arterial-stimulated venous sampling. Selective pancreatic arterial calcium injections,
with measurement of venous catheterization, is considered positive when there is a

> 2-fold increase of insulin over baseline, or > 5 fold increase for contemporary
assays.
Insulin assay. Sandwich, particle-enhanced chemi-luminescent assay is used for
insulin in Abbott platform.