BASICS
DESCRIPTION
- Nesidioblastosis (NB) is a disease characterized by hyperfunctioning pancreatic Ž ² cells, usually associated with hypoglycemia in the presence of high endogenous insulin levels. It is necessary to exclude insulinoma or exogenous insulin of sulfonylurea administration when making the diagnosis.
- Most commonly described in neonates and children, but recent studies have shown an increased number of cases in adults
- Focal NB: confined to one discrete area of the pancreas
- Diffuse NB: All or most islet cells are affected.
- Most common cause of persistent hyperinsulinemic hypoglycemia in neonates
- Synonym(s): noninsulinoma pancreatogenous hypoglycemia (NIPHS); persistent hyperinsulinemic hypoglycemia of infancy (PHHI); congenital hyperinsulinism; islet cell hyperplasia
EPIDEMIOLOGY
Few data available on the incidence of disease ‚
Incidence
- Infants/children
- Sporadic: 1/30,000 to 1/50,000 live births
- Familial: 1/2,500 births have been seen.
- Adults: 0.5 " “15% of organic hyperinsulinemias
- Annual incidence is 0.09/100,000.
- Peaks in 5th decade of life
ETIOLOGY AND PATHOPHYSIOLOGY
NB involves hyperplastic pancreatic Ž ² cells that hyperfunction and cause excessive insulin secretion. KATP channel activity results with a constant insulin release: ‚
- Focal NB: accounts for up to 40% of cases and consists of a discrete area of the pancreas with adenomatous hyperplasia of the islet cells
- Diffuse NB: Most or all Ž ² cells in the pancreas show hyperplasia.
- Most cases have a genetic predisposition; in adults, may involve dysregulation
- Increase in expression of IGF-2, IGF-1 receptor-α and TGF- Ž ² in islet cells from NB patients compared with controls
- Associated with gastric bypass surgery; has been associated with other upper gastrointestinal surgeries; elevated levels of GLP-1 in response to rapid presentation of nutrients to the distal jejunum (1, 2, 3, 4).
Genetics
- Complex AR/AD mutations on ABCC8 and KCJN11 genes on chromosome 11 have been found in focal and diffuse NB (5).
- More recent discoveries:
- HADH1: Studies have shown good response with diazoxide (AR).
- GK: poor response with diazoxide (AD)
- GLUD1: associated with high ammonia levels, also called HI/HA syndrome (AD)
- SLC16A1
- HNF4A: has shown spontaneous resolution in a few cases (6,7)
RISK FACTORS
- Infants/children: likely a genetic predisposition to this disorder
- Adults: NB may also be genetically linked. However, there has been an association with gastric bypass surgery (1,2).
GENERAL PREVENTION
- Genetic counseling may be of benefit to families affected by this disease. No clear guidelines exist for preconception genetic counseling.
- Adults who are considering gastric bypass surgery should be cautioned.
COMMONLY ASSOCIATED CONDITIONS
- Insulinoma (most common)
- Teratomas
- MEN1 syndrome
- Glucagonoma
- VIPoma
- Neuroblastoma
DIAGNOSIS
HISTORY
- Infants/children: irritability, lethargy, convulsions, coma, hunger, mental retardation
- Adults: lethargy, confusion, sweating, chills, palpitations, dizziness, loss of consciousness, syncope, headaches
- Symptoms may occur with fasting or postprandially.
PHYSICAL EXAM
- Infants: hypotonia, absent or decreased reflexes, macrosomia
- Adults: obesity, tachycardia, tachypnea
DIFFERENTIAL DIAGNOSIS
- Insulinoma
- Insulin autoimmunity
- Exogenous sulfonylurea, insulin
- MEN1 syndrome
- Beckwith-Wiedemann syndrome
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
General labs including comprehensive metabolic panel, CBC, thyroid-stimulating hormone (TSH), cortisol, and ammonia levels should be checked to rule out other endocrine causes for hypoglycemia: ‚
- Glucose: <40 mg/dL
- Insulin level: >6 Ž ¼L/Ml
- Dramatically high levels of insulin suggest insulin antibodies may be present.
- Insulin antibodies: not present
- C-peptide: >0.6 ng/mL
- Urine/plasma for sulfonylurea derivatives: not present
- Urine/plasma ketones: not present
- Free fatty acid (FFA): <1 mmol/L
- Growth hormone (GH) and cortisol levels are increased.
- Endoscopic US (8)[C]
- CT scan
- MRI
- 11C-5-HTP, 18F-DOPA, and 67Ga-DOTA-DPhe1-Tyr3-octreotide (67Ga-DOTATOC) PET scan (9,10)[C]
Follow-Up Tests & Special Considerations
- Very difficult to determine whether disease is focal or diffuse preoperatively
- The 18F-DOPA PET and arterial calcium stimulation tests have yielded the best results to date (9,10)[C].
Diagnostic Procedures/Other
- Selective pancreatic arterial calcium injection test can identify areas of Ž ² cell hyperfunction (4,11,12)[C].
- Splenic artery " ”body and tail; gastroduodenal artery " ”head, uncinate process; superior mesenteric artery " ”uncinate process, head
- Percutaneous transhepatic pancreatic venous sampling
- Intraoperative localization (US, bimanual)
Test Interpretation
- Hypertrophic Ž ² cells with pleomorphic nuclei, ductuloinsular complexes, and neoformation of islet cells
- A biopsy is the only way to diagnose NB.
TREATMENT
GENERAL MEASURES
Frequent consistent meals throughout the day to maintain normal glucose levels ‚
MEDICATION
First Line
- Diazoxide: blocks receptors on pancreatic Ž ² cells, keeping the K channel open and decreasing insulin release (2)[C]
- Children: 5 mg/kg/day divided TID. Max dose is 15 mg/kg/day.
- Adults: 50 to 300 mg/day. Max dose is 600 mg/day (9)[C].
- Adverse effects: water retention; hirsutism; hypertrichosis; weight gain; decreased linear growth; ketoacidosis (12)[C]
Second Line
- Octreotide: a somatostatin analogue that can decrease insulin secretion (2)[C]
- Adverse effects include diarrhea, vomiting, and decreased linear growth.
- Dose: 2 to 20 Ž ¼g/kg/day divided BID or TID; max dose 500 Ž ¼g/dose or 1,500 Ž ¼g/day
- Nifedipine: a calcium channel blocker that blocks insulin release
- Adverse effects include edema, flushing, constipation, and hypotension.
- Dose: 1 to 2 mg/kg/day divided QID; max dose 30 mg/day
- Verapamil: A calcium channel blocker that blocks insulin release (13)[C]:
- Adverse effects include headache, gingival hyperplasia, constipation, fatigue, edema, and hypotension
- Dose: initial 80 mg TID; max dose 480 mg/day
ISSUES FOR REFERRAL
- Pediatric/adult endocrinology specialists should be consulted.
- Nutrition: to provide ongoing resources for appropriate dietary intake
- Surgery: in cases that are refractory to medications
SURGERY/OTHER PROCEDURES
- Focal: Partial pancreatectomy " ”enucleation or distal resections if anatomically suited; blind distal pancreatectomy no longer recommended
- Diffuse: subtotal (95%) or near-total (99%) pancreatectomy
- Reversal of Roux-en-Y gastric bypass to modified sleeve gastrectomy or normal anatomy (14)[B]
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
All patients with suspected NB should be admitted until glucose is stabilized and an appropriate follow-up is arranged. ‚
- Secure the airway, breathing, and circulation (ABCs).
- Provide IM 0.2 to 0.3 mg/kg/dose glucagon (max 1 mg).
- Place a central line and infuse IV glucose at 10 to 40 mg/min until euglycemia is advised.
- Check blood sugars q20 " “60 min until stable.
Discharge Criteria
- Glucose level has been stable for 24 to 48 hours. Patient tolerates the PO diet, and medical therapy has started.
- Nutrition consultation has been done.
- Appropriate patient and parental education has been provided.
- Appropriate glucose monitoring kits have been provided with intensive education. Continuous glucose monitors systems now available.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Endocrinology
- Nutrition
- Surgery: if patient failed conservative therapy
- Genetics
Patient Monitoring
- For infants and children, watch for signs of neurohypoglycemia because it can cause irreversible damage.
- Patients need to check multiple blood sugars daily.
DIET
- High-protein, high-carbohydrate diet
- Frequent meals with frequent snacks
PATIENT EDUCATION
- Patients always need to have a glucose source close to them at all times.
- IM glucagon should be available, with appropriate education on use for family members.
- Caution during exercise
- Medical ID bracelets
PROGNOSIS
- Focal disease: After a partial resection, symptoms generally resolve completely.
- Diffuse disease: ~50% are cured without needing medications after a 95 " “99% pancreatectomy.
COMPLICATIONS
- Continuous hypoglycemia after surgery: Subsequent medical management is typically effective.
- Diabetes mellitus: more likely to occur with larger pancreatic resections (3,15).
- Malabsorption: more likely to occur with larger pancreatic resections (13).
REFERENCES
11 Service ‚ GJ, Thompson ‚ GB, Service ‚ FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249 " “254.22 Bernard ‚ B, Kline ‚ GA, Service ‚ FJ. Hypoglycaemia following upper gastrointestinal surgery: case report and review of the literature. BMC Gastroenterol. 2010;10:77.33 Dravecka ‚ I, Lazurova ‚ I. Nesidioblastosis in adults. Neoplasma. 2014;61(3):252 " “256.44 Martens ‚ P, Tits ‚ J. Approach to the patient with spontaneous hypoglycemia. Eur J Intern Med. 2014;25(5):415 " “421.55 Sempoux ‚ C, Guiot ‚ Y, Dahan ‚ K, et al. The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. Diabetes. 2003;52(3):784 " “794.66 Palladino ‚ AA, Stanley ‚ CA. Nesidioblastosis no longer! It 's all about genetics. J Clin Endocrinol Metab. 2011;96(3):617 " “619.77 Pearson ‚ ER, Boj ‚ SF, Steele ‚ AM, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118.88 Limongelli ‚ P, Belli ‚ A, Cioffi ‚ L, et al. Hepatobiliary and pancreatic: nesidioblastosis. J Gastroenterol Hepatol. 2012;27(9):1538.99 de Herder ‚ WW, Niederle ‚ B, Scoazec ‚ JY, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84(3):183 " “188.1010 Gupta ‚ RA, Patel ‚ RP, Nagral ‚ S. Adult onset nesidioblastosis treated by subtotal pancreatectomy. JOP. 2013;14(3):286 " “288.1111 Raffel ‚ A, Krausch ‚ MM, Anlauf ‚ M, et al. Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: a diagnostic and therapeutic challenge. Surgery. 2007;141(2):179 " “184.1212 Witteles ‚ RM, Straus ‚ FHII, Sugg ‚ SL, et al. Adult-onset nesidioblastosis causing hypoglycemia: an important clinical entity and continuing treatment dilemma. Arch Surg. 2001;136(6):656 " “663.1313 Kaczirek ‚ K, Niederle ‚ B. Nesidioblastosis: an old term and a new understanding. World J Surg. 2004;28(12):1227 " “1230.1414 Campos ‚ GM, Ziemelis ‚ M, Paparodis ‚ R, et al. Laparoscopic reversal of Roux-en-Y gastric bypass: technique and utility for treatment of endocrine complications. Surg Obes Relat Dis. 2014;10(1):36 " “43.1515 Ferrario ‚ C, Stoll ‚ D, Boubaker ‚ A, et al. Diffuse nesidioblastosis with hypoglycemia mimicking an insulinoma: a case report. J Med Case Rep. 2012;6(1):332.
CODES
ICD10
E16.9 Disorder of pancreatic internal secretion, unspecified ‚
ICD9
251.9 Unspecified disorder of pancreatic internal secretion ‚
SNOMED
- Islet cell hyperplasia (disorder)
- Hyperplasia of pancreatic islet beta cell (disorder)
CLINICAL PEARLS
- NB is a genetically linked disorder, typically seen in infancy. However, there has been an association with gastric bypass surgery.
- Insulinoma symptoms generally occur in the fasting state.
- NIPHS symptoms can occur postprandially.
- Late-onset disease typically has a better prognosis.