Diagnostic dilemmas in hypoglycemia: Illustrative cases

INTRODUCTION — Insulinomas are rare tumors that may present a diagnostic dilemma for the clinician. The classic diagnostic test for an insulinoma has been the 72-hour fast. There are two reasons to perform a prolonged supervised fast:

●To confirm the presence of a hypoglycemic disorder (by demonstrating low venous glucose concentrations at the time of symptoms and resolution of these symptoms with reversal of hypoglycemia). In this setting, measurement of serum insulin, C-peptide, and proinsulin helps establish the mechanism of hypoglycemia [1,2].

●To determine the mechanism of hypoglycemia when the presence of a hypoglycemic disorder has already been established.

This distinction is important because the criteria for ending a fast will differ. If the presence of a hypoglycemic disorder is already established, a fast can be stopped when glucose is <55 mg/dL (<3 mmol/L) even in the absence of hypoglycemic symptoms. This is because at these concentrations, endogenous insulin secretion should be suppressed [3].

If a patient has a spontaneous episode of symptomatic hypoglycemia that is fortuitously observed and confirmed with laboratory testing, a 72-hour fast is not needed. The 72-hour fast is also unnecessary in the rare patient with insulinoma who has exclusively postprandial symptoms; in such cases, hypoglycemia is evaluated during a mixed-meal test.

The presence of inappropriately high serum insulin, C-peptide, and proinsulin concentrations at the time of symptomatic and confirmed hypoglycemia in a patient who has a negative test for insulin secretagogues (sulfonylureas or meglitinides) establishes the diagnosis of insulinoma.

We consider the following values (measured in highly sensitive assays) as inappropriately high in a symptomatic patient with serum glucose concentration <55 mg/dL (<3 mmol/L) (table 1). (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

●Serum insulin – ≥3 microU/mL (immunochemiluminometric assay [ICMA])

●Serum C-peptide – ≥0.6 ng/mL (≥200 pmol/L)

●Serum proinsulin – ≥5 pmol/L

When the serum insulin and C-peptide values are lower, determination of markers of insulin action such as serum beta-hydroxybutyrate and the serum glucose response to intravenous glucagon at the end of the fast may provide important diagnostic information [1]. In normal subjects who fast for 72 hours, serum beta-hydroxybutyrate concentrations rise, and liver glycogen stores are mobilized. In contrast, in patients with an insulinoma who continue to secrete insulin, serum beta-hydroxybutyrate concentrations remain low (2.7 mmol/L or less) and serum glucose concentrations increase by more than 25 mg/dL (1.4 mmol/L) 30 minutes after the intravenous administration of 1 mg glucagon. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

The cases described below highlight some of the problems that may be encountered during the evaluation of patients suspected of having an insulinoma or in the management of those with a biochemically confirmed insulinoma.

CASE 1 — A 41-year-old female was referred for evaluation of repeated episodes of sweating, slurred speech, tremulousness, and confusion during the last nine months that could be aborted by eating. On one occasion, she was unresponsive to questions and thrashing about in bed. Capillary glucose measured by emergency personnel was 31 mg/dL (1.7 mmol/L), and she improved after intravenous glucose administration.

After fasting for 24 hours, she became diaphoretic and confused. Serum values at that time were as follows:

●Glucose – 32 mg/dL (1.8 mmol/L)

●Insulin – 6.5 microU/mL (39 pmol/L)

●C-peptide – 1.6 ng/mL (533 pmol/L)

●Proinsulin – 84 pmol/L

●Beta-hydroxybutyrate – 0.1 mmol/L

●Glucose increase after glucagon – 64 mg/dL (3.6 mmol/L)

●Sulfonylurea – Negative

Ultrasonography and spiral computed tomography (CT) of the abdomen showed a 1.5 cm lesion in the head of the pancreas. The location of the tumor was confirmed by intraoperative ultrasonography (see "Insulinoma"). The patient underwent enucleation of the insulinoma; pathologic examination confirmed the preoperative diagnosis of insulinoma.

Comment — This is a classic case of insulinoma. The patient was healthy but had episodes of neuroglycopenia. Whipple's triad (symptoms of hypoglycemia, low serum glucose concentrations at the same time, and relief of symptoms by glucose administration) was satisfied. That the hypoglycemia was caused by endogenous insulin was confirmed by the high serum insulin, C-peptide, and proinsulin concentrations and supported by the low serum beta-hydroxybutyrate concentration and the small rise in serum glucose after intravenous glucagon administration.

The tumor was detected by our preferred techniques: ultrasonography and spiral CT of the abdomen (see "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms"). Confirmation of the location was established by intraoperative ultrasonography. In this instance, enucleation was the surgical procedure of choice.

CASE 2 — A 29-year-old male with a past history of primary hyperparathyroidism (single parathyroid adenoma) was referred for evaluation of hypoglycemia. During the last year, he had repeated episodes of tremor, sweating, and confusion, usually after physical exertion; the symptoms were relieved by eating. The patient's father and three paternal aunts had primary hyperparathyroidism; in addition, a distant cousin had hyperparathyroidism and a benign pancreatic tumor.

During his initial evaluation, he had symptoms of hypoglycemia, at which time the following serum values were obtained:

●Glucose – 25 mg/dL (1.4 mmol/L)

●Insulin – 100 microU/mL (600 pmol/L)

●C-peptide – 8.5 ng/mL (2800 pmol/L)

●Proinsulin – 44 pmol/L

●Beta-hydroxybutyrate – 0.1 mmol/L

●Glucose increase after glucagon – 29 mg/dL (1.6 mmol/L)

●Sulfonylurea – Negative

Ultrasonography of the abdomen was uninterpretable. A spiral CT of the abdomen showed a 3 cm mass in the head of the pancreas consistent with an insulinoma. Intraoperative ultrasonography confirmed the presence of a mass in this location and revealed multiple small nodules in the body and tail of the pancreas. He underwent enucleation of the dominant mass in the head of the pancreas and distal subtotal pancreatectomy. Pathologic examination of the resected pancreatic tissue revealed multiple islet cell adenomas.

Comment — This is a case of insulinoma in a patient with multiple endocrine neoplasia type 1 (MEN1). Although the majority of patients with insulinoma have a solitary adenoma, multicentric islet cell adenomas are the rule in patients with MEN1 [4,5]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

Because neither ultrasonography nor palpation at surgery may be sufficiently sensitive to detect all small tumors, resection of most of the distal pancreas with enucleation of any tumors elsewhere in the pancreas is often indicated [6]. Alcohol ablation may be reasonable for small or unresectable tumors and can ameliorate symptoms in selected cases [7]. (See "Insulinoma", section on 'Treatment'.)

MEN1 should be considered in all patients with a personal or family history of hyperparathyroidism (or pituitary tumor) who have an insulinoma. These patients are at risk for multiple insulinomas; as a result, they usually require extensive pancreatic surgery to extirpate all the hyperfunctioning islet tissue.

CASE 3 — A 44-year-old female was referred for evaluation of recurrent syncope for five years. These episodes were characterized by premonitory symptoms of headache and slurred speech followed by suddenly finding herself on the floor. A "full-blown" episode could be aborted by eating. She had no family history of diabetes, but her boyfriend was taking a sulfonylurea drug for type 2 diabetes mellitus.

Three years ago, she had an 80 percent pancreatectomy, but no insulinoma was found. She was asymptomatic for four months after the operation, but her symptoms then recurred. She was treated with prednisone but became hyperglycemic, at which time glipizide and metformin were added. The prednisone (10 mg every other day) was discontinued three days and the glipizide (5 mg/day) and metformin (500 mg twice daily) two days before she came to our institution seeking another pancreatic operation. At that time, her serum glucose concentration was 50 mg/dL (2.8 mmol/L) 12 hours after her last meal.

The results of an outpatient fasting study were:

●Glucose – 38 mg/dL (2.1 mmol/L)

●Insulin – 9 microU/mL (54 pmol/L)

●C-peptide – 1.5 ng/mL (490 pmol/L)

●Proinsulin – 33 pmol/L

●Beta-hydroxybutyrate – 0.2 mmol/L

●Glucose increase after glucagon – 32 mg/dL (1.8 mmol/L)

When the fast was ended, she had no symptoms or signs of hypoglycemia. Ultrasonography and spiral CT of the abdomen were normal. Serum samples sent for analysis of sulfonylurea revealed the presence of glipizide, the concentrations being 473 and 853 ng/mL, respectively, when the serum glucose concentrations were 50 and 38 mg/dL (2.8 and 2.1 mmol/L); no other sulfonylureas were detected.

The patient did not acknowledge that she had continued to take glipizide. We therefore considered it possible, though unlikely, that her hypoglycemia was not due to glipizide. She then underwent an inpatient 72-hour supervised fast that was completely normal. The serum values were:

●Glucose – 50 mg/dL (2.8 mmol/L)

●Insulin – Undetectable

●C-peptide – 0.5 ng/mL (159 pmol/L)

●Proinsulin – 3 pmol/L

●Beta-hydroxybutyrate – 4.5 mmol/L

●Glucose increase after glucagon – 8 mg/dL (0.4 mmol/L)

●Sulfonylurea – Negative

Comment — The initial biochemical data in this patient were consistent with endogenous hyperinsulinemia but were undoubtedly due to glipizide (see "Factitious hypoglycemia"). It is unlikely that glipizide would be measurable in high and increasing concentrations 48 hours or more after the last dose. The serum insulin, C-peptide, proinsulin, and beta-hydroxybutyrate concentrations in patients with hypoglycemia due to a sulfonylurea drug ingestion may be very similar to those in patients with an insulinoma. It is therefore essential to measure sulfonylureas in the same blood sample drawn for the other measurements. Liquid chromatography tandem mass spectrometry can detect both first- and second-generation agents and repaglinide at low dose.

Another noteworthy point in this case is that the initial fasting study was ended despite the patient being asymptomatic. When a fast is ended on the basis of a low serum glucose concentration in the absence of symptoms or signs of hypoglycemia, the results should be interpreted with caution because, in some normal young women, serum glucose concentrations may fall to 30 to 40 mg/dL (1.7 to 2.2 mmol/L) with no symptoms [8,9]. Furthermore, some patients with an insulinoma may appear normal when their serum glucose concentrations are low; when the serum glucose is then raised, it may be apparent that the patient did not have normal mental function when hypoglycemic. The decision to end the fast can, therefore, be difficult. A Mini-Mental State Examination may help establish a cognitive baseline to compare with repeat examination during a supervised fast [10].

Although the patient continued to deny surreptitious administration of glipizide, a diagnosis of sulfonylurea-induced hypoglycemia was suspected. The basis for this diagnosis was the detection of glipizide in serum, a negative supervised 72-hour fast when sulfonylurea was undetectable in serum, and the patient's access to a sulfonylurea drug.

CASE 4 — A 27-year-old male was referred by his local clinician for evaluation of hypoglycemia found incidentally during an assessment for peptic ulcer disease. During the last four months, he had several episodes of weakness and feeling "shaky inside" late in the evening. During the night, he would periodically drink soda. When symptomatic, reflectance meter blood glucose values measured by the patient using equipment purchased for his seven-year-old daughter (diagnosed with type 1 diabetes one year earlier) had been in the range of 40 to 50 mg/dL (2.2 to 2.8 mmol/L). Serum values after an overnight fast were:

●Glucose – 36 mg/dL (2.0 mmol/L)

●Insulin – 140 microU/mL (840 pmol/L)

●C-peptide – <0.1 ng/mL (<33 pmol/L)

●Proinsulin – 0.9 pmol/L

The low serum C-peptide and proinsulin values indicate that the hyperinsulinemia (140 microU/mL [840 pmol/L]) was due to exogenous insulin administration. The patient's daughter was being treated with a split-mixed insulin program; her mother administered the morning dose and her father the evening dose. When confronted with the evidence for factitial hypoglycemia due to insulin self-administration, the patient adamantly denied he was injecting himself.

Comment — This is a case of surreptitious insulin injection, which almost always occurs in patients with ready access to insulin. The diagnosis of factitial hypoglycemia due to insulin administration should be suspected if the serum insulin concentration exceeds 100 microU/mL (600 pmol/L) when the patient is hypoglycemic. It is confirmed if the serum C-peptide and proinsulin concentrations are low. It is important to appreciate that insulin analogs may not always be detected by a given insulin immunoassay, and exogenous insulin use should be suspected when the patient has access to insulin and C-peptide is suppressed even when insulin is not markedly elevated. It is important for the clinician to know which insulin assay is used and whether it measures human insulin, insulin analogs, or both. (See 'Case 5' below.)

A serum insulin/C-peptide molar ratio of more than 1.0 has been suggested as identifying factitial hypoglycemia due to insulin administration [11]. This is in contrast to ratios of 0.2 at the end of a supervised fast in patients with an insulinoma and in normal subjects [12]. In most patients with factitial hypoglycemia due to insulin administration, the discrepancy between the serum insulin (as long as the assay can detect the insulin or insulin analog used) and C-peptide concentrations is so great that determination of the molar ratio is superfluous. (See "Factitious hypoglycemia".)

CASE 5 — A 54-year-old female presented for evaluation of postprandial hypoglycemia. Ten years previously she was diagnosed with necrotizing fasciitis and diabetes. After the fasciitis resolved, she was maintained on insulin therapy for approximately four years. She discontinued insulin approximately six years ago after achieving significant body weight loss. Hypoglycemia was documented in the postprandial period on at least two prior occasions. She had blood drawn at the endocrine testing center during a typical episode. Serum values were as follows:

●Glucose – 51 mg/dL (2.8 mmol/L)

●Insulin – 2.2 microU/mL (13.2 pmol/L)

●C-peptide – 0.2 ng/mL (70 pmol/L)

●Proinsulin – 1 pmol/L

●Beta-hydroxybutyrate – 0.1 mmol/L

●Glucose increase after glucagon – 60 mg/dL (3.3 mmol/L)

●Sulfonylurea – Negative

Due to clinical suspicion of exogenous insulin use, the laboratory used a mass spectrometric analysis to demonstrate the presence of aspart insulin (442 pmol/L) present at the time of hypoglycemia.

Comment — Many insulin immunoassays do not reliably detect insulin analogs [13]. Therefore, in situations where both C-peptide and insulin are suppressed, the use of insulin analogs should be suspected. This is especially true in patients with a prior history of insulin use or patients who have other access to insulin. (See "Factitious hypoglycemia".)

CASE 6 — A 43-year-old female underwent Roux-en-Y gastric bypass (RYGB) three years ago for the treatment of medically complicated obesity. At the time, she had type 2 diabetes treated with metformin monotherapy, as well as hypertension. She weighed 290 lbs (131.5 kg) prior to surgery. The postprocedure recovery was uncomplicated, and nadir body weight was reached 13 months after surgery. The patient experienced a remission of her diabetes within weeks of the procedure. Some weight regain occurred subsequently, and at presentation, the patient weighed 230 lbs (104 kg). For the past year, she has been troubled by symptoms of tachycardia, tremor, and diaphoresis, which typically occur within an hour or two of food ingestion. These symptoms were brought to the patient's attention when she required assistance at work after an episode of altered mentation (by report). A home reflectance glucose meter regularly shows glucose readings between 30 to 50 mg/dL (1.7 to 28 mmol/L) at the time of symptoms. The patient subsequently underwent a meal challenge where she consumed a meal likely to provoke her symptoms. The results obtained after a pancake breakfast are shown in the table (table 2).

Comment — The results of this test show the pitfalls of testing in patients after RYGB; it is unclear how often a "positive" test can be provoked in patients after RYGB if a high carbohydrate test meal is used. Similarly, patients who are post-RYGB should not consume a test meal with calories in liquid form, as this is likely to precipitate symptoms of dumping. Thus, careful counseling and reinforcement of dietary adherence are essential after bariatric surgery [14,15].

This case also highlights the importance of not uniformly applying the same criteria for endogenous hyperinsulinism in the fasted and postprandial states [16]. Rather, in the postprandial state, insulin concentrations represent the net sum of secretion and clearance. Within 120 minutes after meal ingestion, insufficient time has elapsed to clear all secreted beta cell polypeptides from the peripheral circulation [17].

The patient subsequently underwent a standardized (350 cal) solid, mixed-meal test (30 percent fat, 15 percent protein, 55 percent carbohydrate) according to an established protocol in the endocrine testing center, and the results obtained are shown in the table (table 3).

During retesting, the patient had postprandial blood glucose values between 60 to 70 mg/dL (3.3 to 3.9 mmol/L). However, these were not accompanied by symptoms of neuroglycopenia and could reflect normal values in this setting. In such cases, we usually recommend reinforcement of an appropriate post-bariatric diet alone [14]. Importantly, in such patients, extended distal pancreatectomy has not been shown to have durable effects on patient symptoms [18]. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Mixed meal test for postprandial hypoglycemia'.)

CASE 7 — A 68-year-old male was referred for evaluation of dizzy spells, which were subsequently shown to coincide with confusion, slurred speech, and altered mentation. On four or five occasions, these episodes were associated with fingerstick glucose values below 60 mg/dL (3.3 mmol/L). During an episode in the doctor's office, his glucose was 45 mg/dL (2.5 mmol/L), and C-peptide and insulin were inappropriately unsuppressed. An abdominal CT with intravenous contrast was negative. The patient was then admitted for a 72-hour fast, which was completely negative with a terminal glucose of 68 mg/dL and no symptoms of neuroglycopenia.

The following day, the patient had an episode of spontaneous hypoglycemia where glucose was 55 mg/dL (3 mmol/L) with an insulin level of 271 microU/mL and a C-peptide of 5 ng/mL (1655 pmol/L). Because of the disproportion of the insulin concentrations to the C-peptide concentrations, insulin antibodies were measured and found to be present in high titer (5.05 nmol/L; normal <0.02). The antibodies had high affinity to insulin labeled with radioisotope, indicating immune-mediated hypoglycemia secondary to insulin-binding antibodies.

At the time of initial presentation, the patient was prescribed glucagon for use as needed for refractory hypoglycemia, and no other specific therapy was provided as the episodes were mostly diurnal and responded readily to glucose ingestion. Subsequently, the patient initiated use of continuous glucose monitoring for greater convenience and closer self-monitoring. Approximately 10 years after initial presentation, the patient experienced worsening of the frequency and severity of hypoglycemia. On re-evaluation, he was found to have anemia, and subsequent work-up led to a diagnosis of multiple myeloma. He was treated with daratumumab, and, following treatment initiation, his hypoglycemic symptoms improved, and the insulin antibody titer fell to 2.5 nmol/L.

Comment — Daratumumab is an immunoglobulin G1 (IgG1)-kappa human monoclonal antibody that binds to the CD38 transmembrane glycoprotein on the surface of tumor cells and induces apoptosis. Immune cells that express CD38 also are susceptible to cell lysis by daratumumab.

Daratumumab treatment likely attenuated hypoglycemia through these immunosuppressive effects. Similarly, evidence supports rituximab (a monoclonal antibody directed against CD20-expressing B cells) as an effective therapy for type B insulin resistance, which is mediated by antibodies to the insulin receptor, as well as for insulin-antibody mediated hypoglycemia [19-21]. (See "Insulin resistance: Definition and clinical spectrum".)

CASE 8 — A 28-year-old female was referred for evaluation after she was found unresponsive at her desk. She was taken to the emergency room, and a venous glucose was low at 36 mg/dL (2 mmol/L). She responded to treatment with intravenous dextrose. A hypoglycemic agent screen was negative.

The patient felt generally well thereafter, although she noted fatigue and occasional nausea. She had not experienced a recurrence of her symptoms, although she had begun eating more frequently as a preventive measure. Examination is remarkable for a body mass index (BMI) of 19 kg/m² and a blood pressure of 110/65 mmHg. Her systolic blood pressure dropped by 15 mmHg on standing. After discussion with the patient, an outpatient fast was initiated and then continued as an inpatient. The fast was stopped after 32 hours when the patient developed symptoms of hypoglycemia. Laboratory values are shown below:

●Glucose – 38mg/dL (2.1 mmol/L)

●Insulin – 0.1 microU/mL (0.6 pmol/L)

●Proinsulin – 0.9pmol/L

●C-peptide – <0.1 ng/mL (<33 pmol/L)

●Hypoglycemic agent screen – Negative

Administration of glucagon resulted in the glycemic response shown in the table (table 4).

Symptoms resolved after an intravenous bolus of 50 percent dextrose.

Comment — These data demonstrate that beta cell polypeptides are appropriately suppressed, and no response to glucagon is evident at the end of the fast. Therefore, hypoglycemia is not mediated by insulin or an insulin-like factor. Non-insulin-mediated hypoglycemia is uncommon in adults but can develop in the setting of primary or central adrenal insufficiency. Indeed, the patient had an elevated corticotropin (ACTH) and an 8 AM cortisol level of 2 mcg/dL. Further, the cortisol level did not increase in response to 250 mcg of exogenous ACTH. A urine screen for synthetic steroids was negative. Subsequently, anti-21-hydroxylase antibodies were positive, supporting a diagnosis of Addison disease due to autoimmune adrenalitis. The patient responded well to corticosteroid (and mineralocorticoid) therapy and did not have any subsequent episodes of hypoglycemia. (See "Determining the etiology of adrenal insufficiency in adults".)

CASE 9 — A 35-year-old female nurse presented with a swollen painful left thigh, low-grade fever, dyspnea, and chest pain in a radicular distribution. Imaging and subsequent biopsy of the leg revealed an osteosarcoma that was widely metastatic to the lungs, liver, and the thoracic spine. A week after the diagnosis, she developed dysarthria and confusion. This resolved after consumption of orange juice. After several such episodes, a reflectance glucose meter showed a fasting glucose value of 40 mg/dL (2.2 mmol/L). She received treatment with intravenous dextrose, which resolved her symptoms, and she was referred for evaluation of her hypoglycemia. The examination was remarkable only for the swollen left leg and abnormal gait. The patient agreed to undergo a supervised 72-hour fast. The fast was initiated but stopped after three hours when the patient developed symptoms of hypoglycemia. Laboratory values are shown below:

●Glucose – 42 mg/dL (2.3 mmol/L)

●Insulin – <0.1 microU/mL (<0.6 pmol/L)

●Proinsulin – 5 pmol/L

●C-peptide – <0.1 ng/mL (<33 pmol/L)

●Beta-hydroxybutyrate – 0.1 mmol/L (<0.4 mmol/L)

Administration of glucagon resulted in the glycemic response shown in the table (table 5).

Comment — Since the criteria for Whipple triad (neuroglycopenic symptoms occur with a low venous glucose and are corrected by reversal of hypoglycemia) were already fulfilled, the supervised fast was undertaken solely to elucidate the mechanism of hypoglycemia. Under these circumstances, the fast could have been stopped once venous glucose decreased below 55 mg/dL even in the absence of neuroglycopenic symptoms. Beta cell polypeptides were appropriately suppressed. This process is therefore not insulin mediated, and studies to localize an insulinoma are not indicated.

These data are consistent with the presence of an insulin-like factor causing hypoglycemia. Despite suppressed insulin concentrations at the time of hypoglycemia, hepatic glycogen reserves were sufficient to generate a >25 mg/dL rise in glucose concentrations after glucagon administration. This strongly suggests the presence of a circulating insulin-like hormone that mediates tumor-associated hypoglycemia and also restrains ketone production, as evidenced by the suppressed beta-hydroxybutyrate concentration [22].

There has been debate as to the specific mediator that causes tumor-induced hypoglycemia, but the diagnosis nonetheless can be made based on the test results and the presence of malignancy. Tumor-associated hypoglycemia usually occurs in the setting of known malignancy and is rarely the presenting feature [23].

Treatment options are relatively limited and largely directed at the primary tumor. Sometimes metastatic tumor load to the liver is amenable to hepatic embolization, which may ameliorate symptoms. In this patient's case, chemotherapy initially decreased tumor load, but the tumor then became refractory to therapy. Embolization of the bulkier hepatic metastases provided some relief, but eventually the patient succumbed to her disease. Somatostatin analogues are usually ineffective in this setting. (See "Nonislet cell tumor hypoglycemia".)

CASE 10 — A 25-year-old male working in the financial sector presented with an approximately eight-month history of spells that typically occurred when he skipped meals. These episodes were characterized by dysarthria and confusion. He had two seizures, one of which occurred while he was driving and resulted in a car accident. Eventually a glucose was measured during an episode and found to be 55 mg/dL (3 mmol/L). Insulin was 38.7 microU/mL (232 pmol/L), C-peptide was 3.8 ng/mL (1258 pmol/L), and proinsulin was 128 pmol/L. A triphasic CT scan of the abdomen documented a 1 cm vascular tumor in the tail of the pancreas compatible with an insulinoma. He underwent a laparoscopic distal pancreatectomy and splenectomy. The tumor had clear margins (0.8 x 0.9 x 0.7 cm). Seven lymph nodes were negative for metastatic disease and the Ki-67 index was 8 percent.

Three years later, the patient presented with recurrent symptoms and, while waiting in the lobby, had another hypoglycemic episode. A blood draw obtained at the time showed a glucose of 29 mg/dL (1.6 mmol/L) accompanied by an insulin of 132 microU/mL (792 pmol/L), a C-peptide of 5.6 ng/mL (1854 pmol/L), and a proinsulin of 149 pmol/L. A CT revealed no lesions in the pancreas or in the original surgical site. However, two new vascular lesions were seen in the liver. Results from a subsequent selective arterial calcium stimulation test are shown in the table (table 6).

Comment — These data were compatible with hepatic metastatic disease. Medical therapy with long-acting somatostatin was contemplated, but the patient was considered a candidate for ultrasound-guided transcutaneous thermal ablation. Six months post-procedure, the patient remained asymptomatic with stable hepatic imaging (other than a decreased vascular signature of the treated sites). (See "Insulinoma", section on 'Liver-directed therapy for metastatic disease'.)

SUMMARY

●Approach to the evaluation of insulinoma – The evaluation of patients suspected of having an insulinoma traditionally involves a two-step approach that requires biochemical confirmation of a low serum glucose in the presence of endogenous hyperinsulinemia (high serum insulin and C-peptide concentrations) in the absence of any evidence of hypoglycemic drug ingestion, followed by an attempt to localize the tumor preoperatively. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

●Verifying hyperinsulinemic hypoglycemia – The first of these objectives can be best achieved by studying the patient during a spontaneous episode of hypoglycemia. Failing that, have the patient with food-deprived symptoms fast for up to 72 hours and the rare patient with postprandial symptoms undergo a mixed-meal test. The results are unequivocal in most patients with insulinoma. Some patients, however, have serum insulin and C-peptide concentrations that are borderline or normal and, therefore, indirect assessment of hyperinsulinemia by measuring serum beta-hydroxybutyrate and the serum glucose response to glucagon at the end of the fast may be helpful. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)

●Insulinoma localization – Ultrasonography and spiral CT of the abdomen should be performed once biochemical evidence of insulinoma is established. When these imaging techniques do not disclose the site of the tumor, endoscopic ultrasonography or arteriography and selective arterial calcium stimulation should be considered. (See "Insulinoma", section on 'Tumor localization'.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Neena Natt, MD, who contributed to an earlier version of this topic review.

The UpToDate editorial staff also acknowledges F John Service, MD, PhD, now deceased, who contributed to an earlier version of this topic.