Noninsulinoma Pancreatogenous Hypoglycemia Syndrome Research Articles

NANETS Consensus Guidelines for the Diagnosis of Neuroendocrine Tumor

Neuroendocrine tumors (NETs) are rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines. 1 Some of these substances cause specific clinical syndromes, 2 whereas other may have elevated plasma or urine levels that are not associated with specific syndromes or symptom complexes Unfortunately, there is no Bideal neuroendocrine tumor marker,[ 3 but according to the presentation, the sensitivity and specificity of each marker vary, and it is generally possible to choose those of greatest value for each clinical syndrome. The biochemical markers are those hormones or amines secreted by the neuroendocrine cells from which these tumors are derived. Some of these are not specific to any tumor, but are produced and secreted by most NETs, whereas other biochemical markers are more specific to the type of tumor and where their quantification can lead to the suspicion or confirmation of the presence of such a tumor. The annual incidence of NETs has risen to 40 to 50 cases per million, perhaps because of better diagnosis and the availability of highly specific and sensitive ways to measure these tumors’ products, improved immunohistochemistry, and enhanced techniques for tumor detection. Thus, the perceived increase in incidence may not be a real change in the incidence of the disease. There are a number of impediments to the diagnosis of these tumors. They are rare, comprising less than 2% of gastrointestinal (GI) malignancies, and are therefore not high on the list of causes of specific symptom complexes. Symptoms themselves are often nonspecific and do not lend themselves readily to identifying the specific underlying tumor. In addition, the manifestations are protean and mimic a variety of disorders. Tumors may be found incidentally on laparoscopy for abdominal pain or during the surgical removal of an appendix or even during a computerized tomographic scan of the abdomen for unexplained symptoms. Lung carcinoids may present with hemoptysis or asthma-like symptoms, and midgut carcinoids may be confused with irritable bowel syndrome (IBS). The natural history of this disease is invariably attended by a long history of vague abdominal symptoms, a series of visits to a primary care practitioner, and referral to a gastroenterologist, often with a misdiagnosis of IBS. These symptoms persist with a median latency to correct diagnosis of 9.2 years by which time the tumor has metastasized, causing symptoms such as flushing and diarrhea and progressing on its slow but relentless course until the patient dies. Clearly, a greater index of suspicion and a carcinoid tumor profile screen are warranted for all patients presenting with Btraditional IBS symptoms.[ Midgut carcinoids are associated with mesenteric fibrosis, which can compress mesenteric vessels and cause bowel ischemia and malabsorption, which may be found in the absence of an abdominal mass. The diagnosis of metastases to the liver is generally more obvious but often still takes place only after a delay of many years. Even then, an incorrect diagnosis is not uncommon. Unless biopsy material is examined for the secretory peptides chromogranin, synaptophysin, or neuron-specific enolase (NSE), tumors may be labeled erroneously as adenocarcinoma, with a negative impact on physician’s attitudes regarding management and underestimation of prospects for survival. 4 The common symptomatic manifestations of patients with carcinoid tumors are illustrated in Tables 1 and 2. Flushing

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

BackgroundHyperinsulinemic 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 PresentationA 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.ConclusionsAlthough 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.

Advances in the diagnosis and management of hyperinsulinemic hypoglycemia

Hyperinsulinemic hypoglycemia (HH) is a consequence of unregulated insulin secretion by pancreatic beta-cells and is a major cause of hypoglycemic brain injury and mental retardation. Congenital HH is caused by mutations in genes involved in regulation of insulin secretion, seven of which have been identified (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A). Severe forms of congenital HH are caused by mutations in ABCC8 and KCNJ11, which encode the two components of the pancreatic beta-cell ATP-sensitive potassium channel. Mutations in HNF4A, GLUD1, CGK, and HADH lead to transient or persistent HH, whereas mutations in SLC16A1 cause exercise-induced HH. Rapid genetic analysis combined with an understanding of the histological features (focal or diffuse disease) of congenital HH and the introduction of (18)F-L-3,4-dihydroxyphenylalanine PET-CT to guide laparoscopic surgery have totally transformed the clinical approach to this complex disease. Adult-onset HH is mostly caused by an insulinoma; however, it has also been reported to present as postprandial HH in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, in those who have undergone gastric-bypass surgery for morbid obesity, and in those with mutations in the insulin-receptor gene.

Insulinoma

Although rare, insulinomas are the most common functioning islet cell tumour of the pancreas. Recognition of the key neuroglycopenic symptoms should trigger the initial investigation. Biochemical proof of endogenous hyperinsulinemic hypoglycemia establishes the diagnosis. Several options are available for imaging and localizing these tumours including ultrasonography, computed tomography, and intra-arterial calcium stimulation with venous sampling. The tumours are usually small, single, benign, well-circumscribed, and evenly distributed throughout the pancreas. This tumour may be a part of the multiple endocrine neoplasia type 1 (MEN-1) syndrome, in which case the tumours are almost always multiple. Surgical treatment is the only curative method, traditionally accomplished with enucleation or partial pancreatic resection. Patients are almost invariably cured lifelong with complete excision of a benign insulinoma. The most recent developments in this area are the recognition of noninsulinoma pancreatogenous hypoglycemia syndrome as a cause of organic hypoglycemia, and the development of laparoscopic techniques to excise these tumours.

Glucose Counterregulatory Hormones in the 72-Hour Fast

To attempt to establish a reference range of glucagon concentrations during hypoglycemia. 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. 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. 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.

Noninsulinoma pancreatogenous hypoglycemia syndrome: An update in 10 surgically treated patients

Background. Neuroglycopenia from endogenous hyperinsulinism usually is caused by insulinomas in adults. We recently reported a novel hypoglycemic disorder in 5 patients (patients 1 to 5) with postprandial neuroglycopenia, negative 72-hour fasts, negative perioperative imaging studies, but positive calcium stimulation tests and islet hypertrophy and nesidioblastosis in the gradient-guided resected pancreata. Methods. In this report we compare our experience with 5 additional patients (patients 6 to 10) with this syndrome to that in the original report. Results. The clinical features of patients 6 to 10 were similar to those of patients 1 to 5. Each had positive calcium stimulation testing that guided the extent of the distal pancreatectomy and histologic evidence of islet cell hypertrophy or nesidioblastosis. All 10 patients are alive from 9 to 50 months after operation, 1 of whom had no amelioration of neuroglycopenia. Minor perioperative complications occurred in 3 patients. One patient has experienced repeated bouts of acute pancreatitis, pseudocyst formation, and exocrine insufficiency. Conclusions. We have identified adult patients with severe, postprandial hyperinsulinemic hypoglycemia from diffuse islet cell disease, 80% of whom have been well palliated with surgery. The results in 7 men have been better than those in the 3 women for reasons that are not obvious. (Surgery 2000;128:937-45.)