hypoglycaemia in the non-diabetic patient

see also:

• hypoglycaemia
• RCH guideline - hypoglycaemia in children

• hypoglycaemia in patients who are not taking oral hypoglycaemics or insulin is an uncommon presentation to ED
• Whipple's triad:
  • documentation of low blood sugar
  • presence of symptoms
  • reversal of these symptoms when the blood sugar level is restored to normal
• absence of Whipple's triad suggests hypoglycaemia is NOT the cause of symptoms

• CNS control to prevent fasting hypoglycaemia:
  • The CNS recruits neural circuits (many of which reside in the hypothalamus) that coordinate metabolic target organ function, including islet hormone secretion, insulin sensitivity, hepatic glucose production (HGP) and the generation of gluconeogenic substrates via adipose tissue lipolysis to provide the right amount of glucose to meet the metabolic demands of the circumstances
    • Agrp-expressing neurons in the arcuate nucleus of the hypothalamus (ARH^Agrp neurons) control food intake as well as peripheral insulin sensitivity
    • leptin receptor (Lepr)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH<up>Lepr</sup> neurons) are implicated in both energy expenditure and glucose disposal
    • cholecystokinin b receptor expressing VMHC^ckbr neurons in the ventromedial nucleus of the hypothalamus play an important role in maintaining glucose during normal activities, including the early part of the fasting period between the last meal of the day and waking up in the morning
      • unlike many other neural circuits, these neurons control glucose mobilization without altering food intake, body weight or energy expenditure
      • in the first four hours after you go to bed, these neurons ensure that you have enough glucose so that you don't become hypoglycemic overnight by directing the body to burn fat to produce glycerol and then glucose ¹⁾
    • overactivity results in hyperglycaemia

• hypoglycaemia is a common life-threatening issue in the newborn, especially small for dates infants, infants of diabetic mothers, erythroblastosis foetalis

• may occur in glycerol intoxication syndrome in young children
  • from drinking ice slush drinks made with glycerol ²⁾
  • manufacturers sometimes use glycerol instead of high sugar content to keep the slushy texture of slush ice drinks. These drinks are particularly marketed at children.
  • can cause reduced consciousness (drowsiness/coma), very low blood sugar levels with high lactic acid levels, and glycerol was found in their urine
• starvation-induced or stress-induced in children with inborn errors of metabolism:
  • inherited liver enzyme deficiencies that restrict hepatic glucose release:
    • deficiencies of glucose-6-phosphatase
    • fructose-1,6-diphosphatase
    • phosphorylase
    • pyruvate carboxylase
    • phosphoenolpyruvate carboxykinase
    • glycogen synthetase
  • inherited defects in fatty acid oxidation, including:
    • that resulting from systemic carnitine deficiency
    • inherited defects in ketogenesis (3-hydroxy-3-methylglutaryl-CoA lyase deficiency)
• following food:
  • galactosaemia
  • hereditary fructose intolerance
• accidental poisoning with oral hypoglycaemic agents
• excessive alcohol intake
• Reye's syndrome
• drugs (see under adults)
• nesidioblastosis (diffuse budding of insulin-secreting cells from pancreatic duct epithelium and pancreatic microadenomas of such cells) is a rare cause in infants and adults, but cases have been reported after gastric bypass surgery
• ingestion of too many unripe lychee, rambutan, longan or ackee on an empty stomach - these contain an amino acid which can cause hypoglycemia in children - more than 100 die each year in India

• overdose with oral hypoglycaemic agents or insulin
• anorexia nervosa / eating disorders
• excessive alcohol consumption
• severe liver disease - cirrhosis, hepatitis
• severe sepsis / septicaemia
• severe heart disease
• long term starvation or malnutrition
• insulinoma (rare)
• adrenal or pituitary hormone deficiencies
  • various causes
  • steroid withdrawal adrenal insufficiency
  • opioid‐induced central adrenal insufficiency (OIAI) ³⁾
• other drugs which may cause hypoglycaemia:
  • haloperidol, pentamidine, quinine, salicylates, and sulphonamides
  • phenothiazines, tricyclic antidepressants, SSRI/SNRI antidepressants, bishydroxycoumarin, p-aminobenzoic acid, propoxyphene, hypoglycin, carbamate insecticide, disopyramide, isoniazid, methanol, methotrexate, cytotoxic agents, organophosphates, didanosine, trimethoprim, 6-mercaptopurine, thiazides, thioglycolate, ritodrine, disodium ethylenediaminetetraacetic acid (EDTA), clofibrate, ACE inhibitors, and lithium carbonate

• hypopituitarism
• Addison's disease
• large non-islet cell tumour
  • most commonly retroperitoneal or mediastinal malignant mesenchymal tumors
  • tumor secretes abnormal insulinlike growth factor (large IGF-II), which does not bind to its plasma binding proteins.
  • this increase in free IGF-II exerts hypoglycemia through the IGF-I or the insulin receptors.
• acquired severe liver disease
• sepsis
• congestive cardiac failure
• acute kidney injury (AKI) / acute renal failure (ARF)
• severe dehydration and starvation (inanition)

• low plasma insulin:
  • ketotic hypoglycaemia of childhood
  • alcohol
  • some drugs (see above)
  • prolonged exercise
  • glycogen storage disease
  • ?glucagon deficiency
• high plasma insulin:
  • low plasma C peptide levels and presence of insulin antibodies:
    • insulin factitial hypoglycaemia
    • insulin autoimmune syndrome (rare)
  • elevated plasma C peptide levels and no insulin antibodies:
    • factitial sulphonylurea intake
    • insulinoma
      • may occur as an isolated abnormality or as a component of the multiple endocrine neoplasia type I (MEN) syndrome
    • insulin-receptor antibodies

• galactosaemia
• hereditary fructose intolerance
• Ackee fruit poisoning (Jamaican national fruit but unripe fruit contains hypoglycins and ingestion causes Jamaican vomiting sickness )

• early diabetes?
• alimentary hypoglycaemia (post-GIT surgery)
• gin and tonic
• rarely, insulinoma