Hypoglycemia in adults without diabetes mellitus: Diagnostic approach
- F John Service, MD, PhD
F John Service, MD, PhD
- Emeritus Professor of Medicine
- Mayo Clinic College of Medicine
- Adrian Vella, MD
Adrian Vella, MD
- Professor of Medicine
- Mayo Clinic
Hypoglycemia is an uncommon clinical problem in patients not being treated for diabetes mellitus. It can occur in the fasting or postprandial state. In any case of hypoglycemia, regardless of the cause, the diagnosis can usually be established by appropriate blood tests at the time of the spontaneous occurrence of hypoglycemia, if such an event occurs in the presence of medical personnel (table 1).
If the patient is not symptomatic when seen, the diagnostic strategy is to replicate conditions in which hypoglycemia would be expected if a hypoglycemic disorder exists. A prolonged supervised fast, which can last as long as 72 hours, has been the best established and probably most reliable test for the evaluation of hypoglycemia occurring in the food-deprived state. For patients with postprandial hypoglycemia, however, a mixed-meal test is the preferred provocative procedure.
This topic will review the approach to the nondiabetic patient with hypoglycemia. The clinical manifestations, diagnosis, and causes of hypoglycemia, in general, are discussed separately (table 2 and table 3). The evaluation and management of hypoglycemia in patients with drug-treated diabetes mellitus is also reviewed separately. (See "Hypoglycemia in adults: Clinical manifestations, definition, and causes" and "Diagnostic dilemmas in hypoglycemia: Illustrative cases" and "Management of hypoglycemia during treatment of diabetes mellitus".)
CANDIDATES FOR EVALUATION
The presence of a hypoglycemic disorder in a person without diabetes should not be suspected solely on the basis of a low plasma glucose concentration [1,2], as this observation is necessary but insufficient for a diagnosis and, in some cases, may be misleading. Only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia. Given documentation of Whipple's triad, detailed laboratory evaluation is usually required in a healthy-appearing patient, whereas hypoglycemia may be readily recognized as part of the underlying illness or its treatment (or prescribing/dispensing error) in an ill or medicated patient (table 2). (See "Hypoglycemia in adults: Clinical manifestations, definition, and causes", section on 'Clinical manifestations'.)
Whipple's triad includes the following:
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- Placzkowski KA, Vella A, Thompson GB, et al. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab 2009; 94:1069.
- Service FJ, O'Brien PC, McMahon MM, Kao PC. C-peptide during the prolonged fast in insulinoma. J Clin Endocrinol Metab 1993; 76:655.
- O'Brien T, O'Brien PC, Service FJ. Insulin surrogates in insulinoma. J Clin Endocrinol Metab 1993; 77:448.
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- Service FJ, O'Brien PC. Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia. J Clin Endocrinol Metab 2005; 90:4555.
- Perros P, Henderson AK, Carter DC, Toft AD. Lesson of the week. Are spontaneous hypoglycaemia, raised plasma insulin and C peptide concentrations, and abnormal pancreatic images enough to diagnose insulinoma? BMJ 1997; 314:496.
- Lupsa BC, Chong AY, Cochran EK, et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore) 2009; 88:141.
- Grossman AB, Reznek RH. Commentary: imaging of islet-cell tumours. Best Pract Res Clin Endocrinol Metab 2005; 19:241.
- Noone TC, Hosey J, Firat Z, Semelka RC. Imaging and localization of islet-cell tumours of the pancreas on CT and MRI. Best Pract Res Clin Endocrinol Metab 2005; 19:195.
- Thompson SM, Vella A, Thompson GB, et al. Selective Arterial Calcium Stimulation With Hepatic Venous Sampling Differentiates Insulinoma From Nesidioblastosis. J Clin Endocrinol Metab 2015; 100:4189.
- Thompson SM, Vella A, Service FJ, et al. Impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selective arterial calcium stimulation with hepatic venous sampling for preoperative localization of occult insulinoma. Surgery 2015; 158:162.
- CANDIDATES FOR EVALUATION
- APPROACH TO TESTING
- Clinical evaluation
- Laboratory testing
- - Fasting evaluation
- - Postprandial evaluation
- - 72-hour fast
- Test endpoints and duration
- Ending the fast
- Interpretation of data
- - Plasma insulin
- - Plasma C-peptide
- - Plasma beta-hydroxybutyrate
- - Glycemic response to glucagon
- Determining the cause of hypoglycemia
- LOCALIZING STUDIES
- Radiologic studies
- Arterial calcium stimulation
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS
- Who should be evaluated?
- Interpretation of test results