In children and younger adults, the differential diagnosis of hyperinsulinemic hypoglycemia is broader. Insulinoma in childhood and factitious illness by proxy (usually parents) are extraordinarily rare. Most frequently, hyperinsulinemic hypoglycemia in childhood is caused by generalized -cell dysfunction resulting in pathological insulin secretion. The etiology of some sporadic and familial cases of hyperinsulinism has been elucidated recently, but many cases remain unexplained. Histologically verified nesidioblastosis or -cell hyperplasia with clinical onset in adults have been described in the literature.

We present here three patients with recurrent episodes of hyperinsulinemic hypoglycemia. The diagnostic procedures are analyzed with regard to their usefulness in establishing the correct diagnosis.

Three days before admission, the young woman complained about nervousness and profuse sweating in the morning. The symptoms resolved spontaneously after breakfast. At the day of admission, the woman felt nervous and diaphoretic again. Five hours after lunch, she became confused and lost consciousness. The advised family practitioner observed a generalized seizure. Intravenous application of diazepam terminated the seizure, but the patient remained unconscious.

Hypoglycemia of 1.1 mmol/l (20 mg/dl) was revealed as the cause of coma when she reached the emergency room. Intravenous application of glucose resulted in immediate improvement of her mental state.

The insulin level obtained during hypoglycemia was 173 pmol/l (normal 58­172) and the insulin/glucose ratio was 1.3 (normal <0.3), indicating hyperinsulinism. Simultaneously measured C-peptide was 2,380 pmol/l (normal 300­900). Due to inappropriate elevation of insulin and C-peptide during hypoglycemia, insulinoma was suspected.

A second seizure with apnea occurred 2 days later, requiring cardiopulmonary resuscitation. The seizure resolved promptly after intravenous application of glucose. A computed tomographic scan of the abdomen was normal, in particular there was no discernible tumor in the pancreas.

The woman's medical history was unremarkable. She was married and had three children. Before marriage, she had worked as a nurse. Intake of any medication or alcohol consumption was denied. Physical examination and laboratory testing were unremarkable. Because of the biochemical and clinical setting, the differential diagnosis of factitious illness was discussed, but any intake of oral antidiabetic drugs was denied repeatedly. A psychiatric consultation did not reveal any mental abnormality.

A 72-hour fast followed by exercise was carried out without occurrence of hypoglycemia. Regulation of insulin and C-peptide during glucose tolerance test and tolbutamide stimulation test were normal. A transhepatic portal vein catheterization was performed for further evaluation and revealed 3 localizations with peaks of insulin and C-peptide. Due to simultaneously elevated levels of glucagon at these locations, a superselective catheterism of veins draining the pancreas with physiological undiluted insulin peaks was suspected.

The patient was discharged without definite diagnosis of these unexplained hypoglycemic episodes. Some weeks later, the patient's husband found sulfonylurea medication at home. Hypoglycemic episodes never occurred in the follow-up.

Blood glucose measurement revealed recurrent hypoglycemic episodes (glucose levels 1.9­3.6 mmol/l) as the likely cause for his symptoms. Correction of low glucose levels by glucose administration always relieved symptoms. The general practitioner therefore stopped oral antidiabetic medication. Because recurrent hypoglycemic episodes persisted despite the discontinuation of sulfonylurea therapy 4 months earlier, the patient was admitted for further evaluation.

The patient's past medical history revealed coronary artery bypass surgery performed 17 years before admission because of a three-vessel coronary artery disease and two hospitalizations for pneumonia several years ago. His current medications included atenolol, phenprocoumon, and nifedipine. Inspection of his medications ruled out inadvertent intake of sulfonylurea. Ingestion of alcohol and glyburide was denied repeatedly. No weight gain had been noted.

Physical examination was unremarkable, and laboratory testing revealed a plasma fasting glucose of 7.2 mmol/l (130 mg/dl), C-peptide 1.68 nmol/l (normal 0.26­1.32), and HbA_1c 6.5% (normal 4.0­6.1). Other laboratory values were within the normal range.

A diagnostic 72-hour fast was initiated, and symptomatic hypoglycemia occurred after 24 hours of fasting. Plasma glucose was 2.7 mmol/l (48.6 mg/dl), and the level of simultaneously obtained insulin was 255 pmol/l (normal 21­243). The insulin/glucose ratio of 0.8 (normal <0.3) indicated hyperinsulinism. C-peptide during hypoglycemia was 3,250 pmol/l (normal 260­1,320), suggesting insulinoma or sulfonylurea administration. In an urine obtained immediately after the hypoglycemic episode, metabolites of glyburide (4-trans- and 3-cis-hydroxyglyburide) could be detected by high-performance liquid chromatography (Figure 1).

Figure 1. Chormatograms of urine samples. a, Patient in Case 2, urine obtained immediately after hypoglycemia; b, Control after oral administration; c, Healthy control after ingestion of coffee and vitamins. Peaks: 1 = metabolite 2

Self-administration of glyburide was denied by the patient even when he was confronted with the positive result of the sulfonylurea screening test. Therefore, another 72-hour fast was performed without any occurrence of hypoglycemia. Screening for sulfonylureas after the 72-hour fast was negative in urine and serum, and hypoglycemic episodes never occurred during follow-up.

The patient's past medical history was unremarkable. Intake of any medication and alcohol consumption was denied. She worked as a designer in a fashion shop. Physical examination and laboratory investigation were unremarkable.

A 72-hour fast was initiated, and symptomatic hypoglycemia (1.6 mmol/l) occurred after 24 hours. Simultaneously obtained insulin was 79.6 pmol/l (normal 21­243) and C-peptide was 0.75 nmol/l (normal 0.26­1.32). Inappropriately elevated insulin and C-peptide (insulin/glucose ratio 0.4 and molar ratio of insulin to C-peptide of 0.11) indicated insulinoma or sulfonylurea intake as the most likely diagnosis.

Urine screening for sulfonylurea during hypoglycemia was negative. A computed tomographic scan of the pancreas was normal, but endosonographic examination demonstrated a 17 x 18 mm mass in the tail of the pancreas. Endosonographic needle aspiration did not reveal any malignancy, and octreotid scintigraphy showed enrichment in the tail of the pancreas.

Exploratory surgery of the pancreas including intraoperative ultrasonography was performed, but no pancreatic mass could be detected. Partial pancreatectomy of the tail was performed. Histopathologic examination of the removed pancreas specimens did not reveal insulinoma, nesidoblastosis, or any other pathological finding.

Recurrent hypoglycemic episodes persisted postoperatively. A therapeutic intervention with diazoxide, an ATP-sensitive K+ channel opener, was refused by the patient because of potential side effects (hypertrichosis).

Re-evaluation after 5 years showed persistence of recurrent hypoglycemic episodes and a 5 kg weight gain. Screenings for sulfonylureas during hypoglycemic episodes were repeatedly negative, and a pancreatic mass can still not be detected either by computed tomographic scan or by magnetic resonance imaging.

Inappropriately elevated serum levels of insulin and C-peptide during hypoglycemia are characteristic features of both conditions. In contrast, hypoglycemia caused by exogenous insulin administration is associated with a high serum insulin level and a low serum C-peptide. Molar ratio of insulin to C-peptide in a hypoglycemic patient in excess of 1.0 is indicative of exogenous insulin administration. A ratio less than 1.0 is found in both insulinoma and sulfonylurea intake.¹

Determination of insulin antibodies to prove exogenous insulin administration is not recommended because of the high degree of purity of current insulin preparations and the lack of specificity.²

Several unnecessary laparotomies and partial pancreatectomies because of erroneous diagnosis of insulinoma involving patients with surreptitious sulfonylurea overdosages have been reported in the literature. One patient died due to postoperative bleeding after unnecessary operative exploration.³ Therefore, determination of sulfonylurea in serum or urine by high-performance liquid chromatography is helpful in the diagnostic work-up of patients with hypoglycemic episodes and is a powerful tool to prevent unnecessary diagnostic and therapeutic procedures. Sulfonylurea screen in urine or serum should be established routinely before invasive evaluation for insulinoma.

Self-administration of oral antidiabetic medication can be inadvertent or factitious. Inadvertent administration may be discovered by careful inspection of and detailed interview regarding current medication and is encountered mainly in elderly patients.⁴ Reasons for factitious sulfonylurea ingestion are usually not disclosed in the literature, but the history of any possible access to oral antidiabetic medication should induce a high level of suspicion.

Case 1, involving the young woman who worked as a health care professional before marriage, is a typical example of possible factitious ingestion of oral antidiabetic drugs. History of diabetes mellitus with sulfonylurea treatment, as described in Case 2, is another instance in which the possibility of factitious or inadvertent sulfonylurea ingestion should be considered. Co-occurrence of insulinoma and diabetes mellitus is extraordinarily rare.⁵ Other features of factitious intake of antidiabetic drugs include a history of psychiatric disorders and abrupt onset of severe symptoms without milder warning symptoms.⁶ In childhood, factitious illness by proxy (usually parents) must also be considered.⁷

Failure to obtain serum or urine during hypoglycemia for sulfonylurea screening in patients with factitious illness may result in unnecessary and potentially dangerous diagnostic procedures, as described in Case 1, even though clinical symptoms were very suggestive for insulinoma.

Today, standardized procedures for the assay and identification of sulfonylureas are available.⁸ Urine or serum examination by high-performance liquid chromatography and comparison with external standards allows detection of any sulfonylurea with satisfactory precision and sensitivity.⁹

In Case 2, glyburide's two major metabolites (4-trans- and 3-cis-hydroxyglyburide) were detected by liquid chromatography after extraction with n-hexane-dichloromethane. The mobile phase was acetonitrile-0.038 M phosphate buffer (pH 7.5), and the UV detection wavelength was 203 nm. Figure 1a shows the chromatogram of the patient's urine obtained immediately after hypoglycemia. The two peaks represent the metabolites of glyburide. A urine sample from a volunteer after oral administration of 5 mg glyburide revealed the same peaks (Figure 1b), and urine from a volunteer after ingestion of coffee and vitamins served as negative control (Figure 1c).

The young woman described in Case 3 complained about persistence of hypoglycemic episodes after partial pancreatectomy because of a suspected insulinoma. Biochemical constellation of insulinoma without anatomically identifiable tumor needs further consideration. Preoperative and intraoperative procedures to localize insulinoma (solitary adenoma in 80­90%) have been debated extensively in the literature.

Although virtually every imaging technique has been advocated for preoperative localization of insulinoma, none has proved sufficiently reliable. Localization of insulinoma by usual imaging procedures fails in 40­60% of patients. Endoscopic ultrasonography in experienced hands and trans-hepatic portal vein sampling seem to be favorable methods, with a sensitivity of about 80%.^10,11

However, surgical exploration is necessary even if preoperative localization failed. Resection of pancreas without anatomical localization of the tumor intraoperatively is controversial. Some authors recommend small left pancreatic resection to distinguish insulinoma from -cell hyperplasia or nesidioblastosis.¹² However, extensive resection would cause considerable morbidity and mortality and may even result in endocrine and exocrine pancreatic insufficiency.

In younger patients with hyperinsulinemic hypoglycemia, the possibility of generalized -cell dysfunction resulting in pathological regulation of insulin secretion has to be considered. In general, hyperinsulinemic hypoglycemia in these cases is familial and occurs in neonates or childhood, but age of onset and severity of symptoms can vary markedly.¹³

In some cases of familial hyperinsulinism, genetic etiology has been identified recently. An activating glucokinase mutation can result in hyperinsulinism by pathological regulation of glucose-dependent insulin secretion.¹⁴ During prolonged fasting in patients with activating glucokinase mutation, the glucose concentration does not fall below 2.0 mmol/l. Therefore, this diagnosis does not seem to be very likely in Case 3, in which the patient had a documented plasma glucose value as low as 1.2 mmol/l.

Mutations in the -cell sulfonylurea-receptor (SUR1) gene or inward-rectifying potassium-channel (Kir 6.2) gene were found in other patients with familial hyperinsulinism, in whom insulin secretion is uncoupled from glucose metabolism.^15,16 In these cases, plasma glucose may be lower than 2.0 mmol/l. Nesidoblastosis or -cell hyperplasia is a well recognized cause of persistent hyperinsulinism in neonates, but some cases with onset in adulthood are described in the literature.^17,18

Hyperinsulinemic hypoglycemia remains a diagnostic challenge, and some cases remain unexplained at the present time.

Very few cases of recurrent hypoglycemic episodes remain unexplained at the present time, but the molecular basis of these dysfunctions will probably be elucidated in the near future. Since these mutations are rare and the techniques necessary to reveal such defects have to be established in specialized laboratories, the general applicability of these techniques is limited.