Selective Arterial Calcium Stimulation with Hepatic Venous Sampling in Patients with Recurrent Endogenous Hyperinsulinemic Hypoglycemia and Metastatic Insulinoma: Evaluation in Five Patients.

Selective arterial calcium stimulation (SACST) with hepatic venous sampling was performed in 5 patients (3 female, 2 male; age range, 53-73 y) with recurrent endogenous hyperinsulinemic hypoglycemia caused by metastatic insulinoma between January 2004 and December 2014. The biochemical results of SACST confirmed functional hepatic metastases alone (n = 3), peripancreatic lymph-node and hepatic metastases (n = 1), and occult insulinoma in the pancreatic bed (n = 1), thereby helping to guide management. SACST may be useful to determine the extent of functional metastatic insulinoma, particularly within the liver, and may provide clinicians with additional information to help guide the multidisciplinary management of patients with recurrent endogenous hyperinsulinemic hypoglycemia.

Selective Arterial Calcium Stimulation With Hepatic Venous Sampling Differentiates Insulinoma From Nesidioblastosis.

CONTEXT: In adult patients with endogenous hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging, insulinoma and non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS) resulting from diffuse nesidioblastosis must be considered in the differential diagnosis. It is not known whether the biochemical results of selective arterial calcium stimulation (SACST) with hepatic venous sampling can differentiate insulinoma from diffuse nesidioblastosis. OBJECTIVE: To determine the specificity of SACST with hepatic venous sampling in differentiating insulinoma from diffuse nesidioblastosis. DESIGN: Retrospective review (January 1996 to March 2014). SETTING: Tertiary referral center. PATIENTS OR OTHER PARTICIPANTS: A total of 116 patients with biochemical evidence of endogenous hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging who were subsequently shown at surgery to have insulinoma (n = 42) or nesidioblastosis (n = 74) after undergoing SACST with hepatic venous sampling. INTERVENTION(S): SACST with hepatic venous sampling before pancreatic exploration. MAIN OUTCOME MEASURE(S): Receiver operating characteristic curves were generated from the biochemical results of SACST to determine the specificity of the maximum hepatic venous insulin concentration (mHVI) and the relative-fold increase in hepatic venous insulin concentration (rHVI) over baseline after calcium injection from the dominant artery in differentiating insulinoma from nesidioblastosis. RESULTS: The mHVI (21.5-fold; P < .001) and rHVI (3.9-fold; P < .001) were significantly higher in the insulinoma group compared to the nesidioblastosis group. The areas under the receiver operating characteristic curve for mHVI and rHVI were excellent (0.94; P < .0001) and good (0.83; P < .0001), respectively, for differentiating insulinoma from nesidioblastosis. mHVI cutoffs of > 91.5 and > 263.5 µIU/mL were 95 and 100% specific for insulinoma, respectively. A 19-fold increase in rHVI over baseline was 99% specific for insulinoma. CONCLUSIONS: These data suggest that the mHVI and rHVI at SACST may be useful in differentiating insulinoma from nesidioblastosis with high specificity in patients with hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging.

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.

BACKGROUND: To determine the impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selective arterial calcium stimulation (SACST) with hepatic venous sampling for preoperative localization of occult insulinoma. METHODS: An institutional review board-approved retrospective review was undertaken of 42 patients with surgically confirmed, occult insulinoma who underwent SACST from January 1996 to March 2014. Location of the insulinoma was predicted initially based on the biochemical results of SACST alone according to Doppman's criteria. Pancreatic arteriograms were reviewed blinded to the biochemical results and the regional perfusion of each artery assessed. The anatomic and perfusion data were combined with the biochemical results to make a second prediction and compared with the surgical findings. RESULTS: The biochemical results were positive in 1, 2, and 3 arterial distributions in 73.8%, 21.4%, and 4.8% of patients, respectively. The celiac trunk and superior mesenteric artery (SMA) anatomy were aberrant in 38.1% and 35.7% of patients, respectively. Clinically significant variations included dorsal pancreatic artery replaced to SMA (21.4%) and celiac stenosis (4.8%). Significant variation and overlap in regional pancreatic perfusion was observed, particularly for the SMA. Sensitivity for insulinoma localization was 54.8% (diagnostic arteriography), 73.8% (biochemical data), 88.1% (biochemical, anatomic, perfusion data), and 92.8% (arteriographic, biochemical, anatomic, perfusion data). CONCLUSION: Careful review of the pancreatic arterial anatomy and regional perfusion is critical for correct interpretation of the biochemical results of SACST and improves the sensitivity of localization for occult insulinoma, particularly in the presence of pancreatic arterial variants or overlap in regional perfusion.

Outcomes and quality of life after partial pancreatectomy for noninsulinoma pancreatogenous hypoglycemia from diffuse islet cell disease.

BACKGROUND: Noninsulinoma pancreatogenous hypoglycemia (NIPH) is a rare cause of hypoglycemia, especially affecting postbariatric surgery patients, related to excessive insulin secretion. Partial pancreatectomy controls hypoglycemia in the early postoperative period; however, multiple patients have experienced symptomatic relapse. The study goal was to assess frequency and severity of recurrent symptoms in operated patients. METHODS: All patients who underwent pancreatic resection for NIPH at Mayo Clinic from January 1996 through December 2008 were reviewed for demographics, preoperative testing, operative and postoperative details. Data from patient records, mail survey, European Quality of Life Survey (EQ-5D), and Fear of Hypoglycemia Scale (FOHS) were used to assess outcome. RESULTS: Seventy-five patients underwent pancreatic resection for NIPH (5 dead, 1 incarcerated). 48 patients (70%) completed the survey; mean follow-up, 53 months. Median time to recurrent symptoms was 16 months in 41 patients (87%). Despite symptom recurrence, 36 patients (75%) reported overall improvement in symptoms and quality of life (QOL); median EQ-5D health scores increased from 40 to 75 out of 100 (P < .001). Moreover, they reported marked reduction in psychologic stress and hypoglycemic symptoms with greater than 50% decrease in FOHS overall, worry, and behavioral median scores (P < .001). Overall, half of the patients were classified as highly/moderately surgically successful, whereas the other half was minimally successful or surgical failures. CONCLUSION: Although nearly 90% of NIPH patients reported recurrent symptoms suggestive of hypoglycemia, a majority reported improvements in QOL and marked reduction in other symptoms after pancreatic resection. Nevertheless, 25% of patients experienced no benefit from partial pancreatectomy.

Hypoglycaemia following upper gastrointestinal surgery: case report and review of the literature.

BACKGROUND: Hyperinsulinemic hypoglycemia is relatively recently recognized in persons undergoing bariatric surgery although knowledge and experience with this condition may not be commensurate with the number of such procedures being performed globally. This paper presents a novel case as an example of how such patients may present and how they may be investigated. CASE PRESENTATION: A 69-year-old man was assessed 3 months post-fundoplication surgery for postprandial hypoglycaemia with neuroglycopenia that became progressively severe. A 72-h fast failed to show hypoglycaemia. During a clinic visit, the patient became confused and had a low plasma glucose, high plasma insulin, and high plasma C-peptide; symptoms were relieved with glucose. No tumours were visualized on CT, MRI, or endoscopic ultrasound. A total body Indium111-octreotide scan was negative. Selective arterial calcium stimulation showed a high insulin gradient in the splenic and superior mesenteric arteries, suggesting diffuse pancreatic beta cell hyperplasia. The patient declined pancreatic resection and recurrent symptomatic hypoglycaemia was successfully prevented with low dose octreotide. CONCLUSIONS: Although increasingly recognized following bariatric surgery, this is the first reported development of NIPHS (non-insulinoma pancreatogenous hypoglycemia syndrome) following fundoplication surgery, as well as the first documented use of octreotide in post-operative NIPHS. Medical management may be an alternative to surgery for patients with this rare condition.

Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007.

OBJECTIVE: The objective of the study was to assess changes in the presentation and diagnostic and radiological evaluation of patients with surgically confirmed insulinoma at the Mayo Clinic 1987-2007. METHODS: A retrospective analysis of patients with insulinoma was conducted. Patients with prior gastric bypass were excluded. RESULTS: A total of 237 patients [135 women (57%)] were identified. Hypoglycemia was reported solely in the fasting state in 73%, the fasting and postprandial state in 21%, and exclusively postprandially in 6%. There was a predominance of men in the postprandial symptom group. Considering the period of study by quartile, outpatient evaluation increased from 35 to 83% and successful preoperative localization improved from 74 to 100% comparing the first to the fourth quartiles. Although the rates of localization by noninvasive techniques remained static at approximately 75%, the addition of invasive modalities has resulted in successful preoperative localization in all patients in the past 10 yr. The sensitivity and specificity of the established diagnostic criteria using insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose response to iv glucagon were greater than 90% and greater than 70%, respectively. CONCLUSIONS: Although fasting hypoglycemia is characteristic of patients with insulinoma, postprandial symptoms have been reported with increasing, albeit low, frequency. Trends in the evaluation and preoperative management include a shift to outpatient diagnostic testing, an emphasis on successful preoperative localization to avoid blind pancreatic exploration, and a validation of the diagnostic criteria for hyperinsulinemic hypoglycemia.

Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.

OBJECTIVE: The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus. EVIDENCE: Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (plus sign in circle ooo), low (plus sign in circle plus sign in circle oo), moderate (plus sign in circle plus sign in circle plus sign in circle o), or high (plus sign in circle plus sign in circle plus sign in circle plus sign in circle). CONCLUSIONS: We recommend evaluation and management of hypoglycemia only in patients in whom Whipple's triad--symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised--is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies--drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction--addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations--in persons with diabetes.

Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression.

Hypoglycemia secondary to nesidioblastosis is rare in adults, and the pathogenesis of this condition is unknown. To determine factors leading to nesidioblastosis in adults, we analyzed 36 cases of nesidioblastosis including 27 cases of postgastric bypass nesidioblastosis and 9 cases of idiopathic nesidioblastosis in adults by immunohistochemistry using antibodies to insulin-like growth factor 1, insulin-like growth factor 2 (IGF2), insulin-like growth factor one receptor-alpha epidermal growth factor receptor, transforming growth factor-beta1 and 2, and transforming growth factor-beta receptor type 3. Fifty-two surgically excised pancreatic specimens from patients with benign exocrine tumors and no evidence of hypoglycemia were used as controls. There was increased IGF2, insulin-like growth factor receptor 1 receptor-alpha and transforming growth factor-beta receptor 3 expression in islets from nesidioblastosis patients compared to controls. Peliosis-type vascular ectasia was more common in nesidioblastosis patients compared to controls. These findings suggest that increased production of growth factors and growth factor receptors may contribute to the development of nesidioblastosis in adults.

Clinical management after bariatric surgery: value of a multidisciplinary approach.

Comprehensive and collaborative longitudinal care is essential for optimal outcomes after bariatric surgery. This approach is important to manage the many potential surgical and medical comorbidities in patients who undergo bariatric surgery. Medical management programs require prompt and often frequent adjustment as the nutritional program changes and as weight loss occurs. Familiarity with the recommended nutritional program, monitoring and treatment of potential vitamin and mineral deficiencies, effects of weight loss on medical comorbid conditions, and common postoperative surgical issues should allow clinicians to provide excellent care. Patients must understand the importance of regularly scheduled medical follow-up to minimize potentially serious medical and surgical complications. Because the long-term success of bariatric surgery relies on patients' ability to make sustained lifestyle changes in nutrition and physical activity, we highlight the role of these 2 modalities in their overall care. Our guidelines are based on clinical studies, when available, combined with our extensive clinical experience. We present our multidisciplinary approach to postoperative care that is provided after bariatric surgery and that builds on our presurgical evaluation.

Recurrent hyperinsulinemic hypoglycemia caused by an insulin-secreting insulinoma.

BACKGROUND: A 37-year-old woman presented to her local physician in 1995 for evaluation of episodes of neuroglycopenia, which manifested as visual distortion and withdrawal without response to verbal commands in the food-deprived state. A 72 h fast was positive for hypoglycemia and the patient was given diazoxide and prednisone, but hypoglycemia was not controlled. The patient underwent pancreatic exploration in 1997, but no insulinoma was found. She was referred to the Mayo Clinic in 1998 for further evaluation and treatment. Abdominal CT and transabdominal ultrasound revealed a 1 cm insulinoma in the uncinate process of the pancreas. The patient again underwent pancreatic exploration. The insulinoma was removed, but during enucleation the tumor fractured. Hypoglycemia recurred 6 months later. INVESTIGATIONS: Laboratory tests, transabdominal ultrasound CT of the pancreas, endoscopic ultrasonography, fine-needle aspiration, and pancreatic exploration. DIAGNOSIS: Recurrence of hyperinsulinemic hypoglycemia caused by fracture of an insulin-secreting insulinoma. MANAGEMENT: Surgical excision of the recurrent tumor.

Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery.

We describe six patients (five women and one man; median age, 47 years; range, 39 to 54) with postprandial symptoms of neuroglycopenia owing to endogenous hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass surgery. Except for equivocal evidence in one patient, there was no radiologic evidence of insulinoma. Selective arterial calcium-stimulation tests, positive in each patient, were used to guide partial pancreatectomy. Nesidioblastosis was identified in resected specimens from each patient, and multiple insulinomas were identified in one. Hypoglycemic symptoms diminished postoperatively. We speculate that hyperfunction of pancreatic islets did not lead to obesity but that beta-cell trophic factors may have increased as a result of gastric bypass.

Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia.

OBJECTIVE: We have determined whether the behavior of betahydroxybutyrate (BOHB) during the 72-h fast of persons without evidence of hyperinsulinemic or any form of organic hypoglycemia might provide indicators of a negative fast. DESIGN: Twenty-one patients with surgically confirmed insulinoma and 34 patients with negative 72-h fasts had BOHB measured every 6 h until Whipple's triad in the former and until 72-h in the latter. RESULTS: Quadratic regression curves of BOHB from the negative fasts showed the typical curve to be flat initially, then increase in a manner that was roughly linear. Using time-specific medians, the changes were: 12-18 h, 0% increase; 18-36 h, 333% increase; 36-54 h, 210% increase, and 54-72 h, 167% increase. In contrast, patients with insulinoma had suppressed BOHB concentrations. Two successive BOHB values in excess of the 18-h level seemed to portend a negative fast. By using the previously published criterion of BOHB more than 2.7 mmol/liter (a surrogate for hypoinsulinemia and thereby an indicator of a negative fast), 74% of persons with a negative fast reached this level before the 72-h point. CONCLUSIONS: Serial measurements of BOHB during the 72-h fast have the potential to provide not only clues during the fast that it will ultimately be negative, but also the opportunity to truncate the fast if the endpoint BOHB criterion for a negative fast is met before 72 h.

Glucose counterregulatory hormones in the 72-hour fast.

OBJECTIVE: To attempt to establish a reference range of glucagon concentrations during hypoglycemia. METHODS: We measured glucagon, cortisol, and growth hormone responses in 65 patients with insulinoma and 29 normal control subjects who underwent a 72-hour fast. For comparison, we also assessed these responses in eight patients with noninsulinoma pancreatogenous hypoglycemia syndrome. RESULTS: At the end of the fasts, median serum cortisol (19.0 mg/dL [range, 3.7 to 44.0] versus 11.0 mg/dL [range, 5.0 to 28.0], respectively; P<0.001) and growth hormone levels (3.5 ng/mL [range, 0.1 to 46.0] versus 1.2 ng/mL [range, 0.1 to 34.0], respectively; P = 0.021) were higher, whereas plasma glucagon (54.5 pg/mL [range, 11.0 to 170.0] versus 75.0 pg/mL [range, 17.0 to 940.0], respectively; P = 0.012) was lower in patients with insulinoma (serum glucose level, 39 mg/dL [range, 14 to 58]) than in control subjects (serum glucose level, 63 mg/dL [range, 47 to 89]). In contrast, the 8 patients with noninsulinoma pancreatogenous hypoglycemia syndrome, a disorder of postprandial hyperinsulinemic hypoglycemia with normal findings on a 72-hour fast (serum glucose level, 71.5 mg/dL [range, 48 to 82]), had concentrations of glucagon (81.0 pg/mL [range, 47.0 to 150.0]), cortisol (10.5 mg/dL [range, 2.7 to 17.0]), and growth hormone (1.5 ng/mL [range, 0.8 to 6.9]) similar to those in the control subjects. On multivariate analysis, the duration of the fast, baseline glucagon concentration, and male gender (but not age, body mass index, or concentrations of glucose and insulin) were correlated with end-of-fast glucagon concentration. CONCLUSION: Defective glucagon secretion in hypoglycemic disorders applies to the stimulus of hypoglycemia but not to food deprivation. A conservative estimate for glucagon deficiency based on the minimal observed glucagon response could be a level of 10 pg/mL during hypoglycemia.