A 45-year-old woman walks into your office and requests to be seen for a complaint of repeated hypoglycemia. The patient was recently discharged from a hospital in a different city, after a partial pancreatectomy for the same problem. She has her records with her, the details of which are confirmed in a telephone discussion with her previous physician who is puzzled by her problem.

Her symptoms began a year ago and consisted of sweating, palpitations and dizziness that resolved if she ate or drank. She had lost consciousness on a few occasions. Workup revealed high plasma insulin levels during hypoglycemia (including simultaneous glucose and insulin concentrations-- obtained during fasting -- of 28, 34 and 40 mg/dl and 600, 56 and 22 uU/ml respectively). CT scan showed enlargement of the tail of the pancreas, diagnosed as an insulinoma and a partial pancreatectomy was performed. The patient did well for two weeks after surgery, but now reports one week of recurrent symptoms. Past medical history includes occasional bouts of depression, and no current medications. The patient is single and lives with her mother and aunt.

The problem is recurrent hypoglycemia. What do you do next?

1. Review the earlier biochemical data. The previous workup demonstrates several interesting features:
   1. hyperinsulinemic hypoglycemia: This diagnosis is unquestionably confirmed by repeated laboratory measurements. It is most important that the hypoglycemia was found to be associated with high insulin levels. This finding is the most significant feature of the history obtained so far, in that it considerably narrows the differential diagnosis to exclude those causes of hypoglycemia that are not associated with elevated insulin levels (e.g. adrenal or pituitary insufficiency).

      We are most likely looking at one of the following diagnoses:

      • a residual insulinoma, not removed at the time of surgery
      • adult nesidioblastosis (hyperplasia of pancretic beta cells, most often seen neonatally)
      • factitious hypoglycemia (use of insulin or sulfonylureas)
      • immune causes of hypoglycemia.
   2. Plasma insulin concentrations that are excessively high. Although plasma insulin levels are expected to be high in most of the above diagnoses, the quantitative evaluation of the insulin levels is useful, because one of these is likely too high for an insulinoma (600 uU/ml).
2. Review the pathology. Still under review. Was sent out for other pathologists to review the possibility of nesidioblastosis (diffuse beta cell hyperplasia).
3. Get more clinical information. More findings on history or physical examination may help to sort out the possible diagnoses from the short list above.
   1. What happened to symptoms after surgery?
   2. A residual insulinoma would be expected to have similar symptoms to those that existed before surgery, since the basic cause remains in the residual pancreas. Partial removal of hyperplastic islets should result in some improvement in symptoms. Removal of some, but not all, insulinomas would have the same effect. (Unlikely etiology because insulinomas are rarely multiple).
   3. Family history of hypoglycemia?
   4. Some forms of nesidioblastosis are inherited.
   5. Is there a history suggestive of possible access to insulin or sulfonylureas?

      This possibility must always be kept in mind, no matter how unlikely it appears that the patient may be surreptitiously inducing hypoglycemia.

   6. Is there any evidence of autoimmune disease?

      Autoimmune causes of hypoglycemia are usually seen in the presence of other manifestations of autoimmunity, e.g., SLE, Graves disease.

      The following information is obtained:

      1. Symptoms disappeared for two weeks after surgery, then returned without change in severity.
      2. No family history of hypoglycemia.
      3. Aunt has diabetes. Further probing reveals that the aunt uses insulin.
      4. No history suggestive of autoimmune disease. No information on workup for autoimmune disease.
   7. Begin your workup.

      A number of possible tests could be used, however the simplest is to begin a prolonged fast (up to 72 hours) as an inpatient. Two thirds of insulinomas will develop hypoglycemia within the first 24 hours of the fast. This patient developed repeated severe hypoglycemia one to two times per day. Blood glucose levels dropped to a very low 28mg/dl. Most importantly, simultaneous blood samples for insulin and C-peptide were obtained. The following results were observed:

      Day/ Time	Mon/ 08:00	Tues/ 11:00	Wed/ 17:00		Normal Range
      glucose	28	35	32	mg/dl	70-110
      insulin	120	81	53	uU/ml	3-15
      C-peptide	0.3	0.4	0.2	pmol/ml	0.3-0.7