Causes of hypoglycemia are varied, but it is seen most often in diabetic patients. Hypoglycemia may result from medication changes or overdoses, infection, diet changes, metabolic changes over time, or activity changes; however, no acute cause may be found. Other causes include alimentary problems, idiopathic causes, fasting, insulinoma, endocrine problems, extrapancreatic causes, hepatic disease, and bariatric surgery, along with additional miscellaneous etiologies.
In a multicenter, retrospective cohort study, Riegger et al reported that independent risk factors for intraoperative hypoglycemia in children include age under 5 years, weight for age below the fifth percentile, American Society of Anesthesiologists status of III or above, the presence of a gastric or jejunal tube, poor feeding, and abdominal surgery. Eighty percent of hypoglycemia cases were in children under age 5 years and in youngsters weighing under 20 kg. [4]
A study by van Furth et al indicated that both dumping syndrome and post–bariatric surgery hypoglycemia can be attributed to a common etiology, with glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) being key to the development of each. The investigators point out that L-cells, which secrete GLP-1 and PYY, are affected by bariatric surgery, with, for example, an increase in L-cells in the perianastomotic jejunum occurring after Roux-en-Y gastric bypass. [5]
Fasting hypoglycemia
Nesidioblastosis is a rare cause of fasting hypoglycemia in infants and an extremely rare cause in adults. This condition is characterized by a diffuse budding of insulin-secreting cells from pancreatic duct epithelium and pancreatic microadenomas of such cells.
Causes of fasting hypoglycemia usually diagnosed in infancy or childhood include inherited liver enzyme deficiencies that restrict hepatic glucose release (deficiencies of glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphorylase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, or glycogen synthetase).
Inherited defects in fatty acid oxidation, including those resulting from systemic carnitine deficiency and inherited defects in ketogenesis (3-hydroxy-3-methylglutaryl-CoA lyase deficiency), cause fasting hypoglycemia by restricting the extent to which nonneural tissues can derive their energy from plasma free fatty acids (FFA) and ketones during fasting or exercise. This results in an abnormally high rate of glucose uptake by nonneural tissues under these conditions.
Several cases of nesidioblastosis were reported recently after gastric bypass surgery.
Drugs
Ethanol (including propranolol plus ethanol), haloperidol, pentamidine, quinine, salicylates, and sulfonamides ("sulfa drugs") have been associated with hypoglycemia. Other drugs that may be related to this condition include oral hypoglycemics, phenylbutazone, insulin, bishydroxycoumarin, p-aminobenzoic acid, propoxyphene, stanozolol, hypoglycin, carbamate insecticide, disopyramide, isoniazid, methanol, methotrexate, tricyclic antidepressants, cytotoxic agents, organophosphates, didanosine, chlorpromazine, fluoxetine, sertraline, fenfluramine, trimethoprim, 6-mercaptopurine, thiazide diuretics, thioglycolate, tremetol, ritodrine, disodium ethylenediaminetetraacetic acid (EDTA), clofibrate, angiotensin converting enzyme (ACE) inhibitors, and lithium.
A study by Fournier and colleagues indicates that treatment for pain with the opioid analgesic tramadol increases a patient’s risk of being hospitalized for hypoglycemia. Information from the United Kingdom Clinical Practice Research Datalink and the Hospital Episode Statistics database was analyzed for 28,110 patients who were newly prescribed tramadol and 305,924 individuals who were newly prescribed codeine, all for noncancer pain, with 11,019 controls also included in the study. Using case-control, cohort, and case-crossover analysis, the investigators found that tramadol increased the risk of hospitalization for hypoglycemia by more than three-fold, with the risk particularly elevated in the first 30 days of treatment. The actual risk was small, however, occurring in about 7 patients per 10,000 annually. [6, 7]
A study by Eriksson et al indicated that in patients with type 2 diabetes undergoing second-line treatment, the combination of metformin and sulfonylurea carries a greater risk for severe hypoglycemia, cardiovascular disease, and all-cause mortality than does the combination of metformin and dipeptidyl peptidase-4 inhibitor (DPP4i). [8]
Similarly, a study by Gautier et al found that patients with type 2 diabetes treated with metformin plus insulin secretagogues (such as sulfonylurea or glinide) were more likely to experience hypoglycemia than were those treated with metformin plus DPP4i while starting insulin. Both groups achieved similar glycemic control. [9]
Surreptitious sulfonylurea use/abuse
Factitious, or self-induced, hypoglycemia can be seen in healthcare workers or in relatives who care for diabetic family members at home. [10] (See Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus for further discussion, including the diagnostic use of C-peptide levels and HbA1c.)
Exogenous insulin
Surreptitious use of insulin may be seen, typically among those likely to have access to insulin. Measurement of insulin level along with C-peptide is very crucial in making this diagnosis.
Endogenous insulin or insulin-receptor–mediated hypoglycemia
Sources of endogenous insulin include insulin-producing tumors of pancreas and non–beta-cell tumors.
Insulin-producing tumors of pancreas
Islet cell adenoma or carcinoma (insulinoma) is an uncommon and usually curable cause of fasting hypoglycemia and is most often diagnosed in adults. It may occur as an isolated abnormality or as a component of the multiple endocrine neoplasia type I (MEN I) syndrome.
Carcinomas account for only 10% of insulin-secreting islet cell tumors. Hypoglycemia in patients with islet cell adenomas results from uncontrolled insulin secretion, which may be clinically determined during fasting and exercise. Approximately 60% of patients with insulinoma are female. Insulinomas are uncommon in persons younger than 20 years and are rare in those younger than 5 years. The median age at diagnosis is about 50 years, except in patients with MEN syndrome, in which the median age is in the mid third decade of life. Ten percent of patients with insulinoma are older than 70 years.
Non–beta-cell tumors
Hypoglycemia may also be caused by large non–insulin-secreting tumors, most commonly retroperitoneal or mediastinal malignant mesenchymal tumors. The 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. The hypoglycemia is corrected when the tumor is completely or partially removed and usually recurs when the tumor regrows.
Reactive hypoglycemia
Reactive hypoglycemia can be idiopathic, due to alimentary problems, or a result of congenital enzyme deficiencies.
Alimentary hypoglycemia is another form of reactive hypoglycemia that occurs in patients who have had previous upper gastrointestinal (GI) surgical procedures (gastrectomy, gastrojejunostomy, vagotomy, pyloroplasty) and allows rapid glucose entry and absorption in the intestine, provoking excessive insulin response to a meal. This may occur within 1-3 hours after a meal. Very rare cases of idiopathic alimentary hypoglycemia occur in patients who have not had GI operations.
Congenital enzyme deficiencies include hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood. In hereditary fructose intolerance and galactosemia, an inherited deficiency of a hepatic enzyme causes acute inhibition of hepatic glucose output when fructose or galactose is ingested. Leucine provokes an exaggerated insulin secretory response to a meal and reactive hypoglycemia in patients with leucine sensitivity of childhood.
Other causes of hypoglycemia include the following, singly or in combination (eg, chronic renal failure and sulfonylurea ingestion):
Autoimmune hypoglycemia: Insulin antibodies and insulin receptor antibodies
Hormonal deficiencies: Hypoadrenalism (cortisol), hypopituitarism (growth hormone) (in children), glucagons deficiency (rare), and epinephrine (very rare)
Critical illnesses: Cardiac, hepatic, and renal diseases; sepsis with multiorgan failure
Exercise (in patients with diabetes treated with diabetes medications)
Pregnancy
Renal glycosuria
Ketotic hypoglycemia of childhood
Adrenal insufficiency
Hypopituitarism
Starvation
Artifact