Notes on hypoglycaemia

Whipple’s triad. Whipple’s 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 Whipple’s 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 beta-hydroxybutyrate: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 IGF-II/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 Whipple’s 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.