Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS).
OBJECTIVE
Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease.


METHODS
Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests.


RESULTS
All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation.


CONCLUSIONS
Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.
Won
Justin G S
JG
Department of Medicine, Veterans General Hospital - Taipei, Taiwan, Republic of China. gswon@vghtpe.gov.tw
Tseng
Hsiao-Shan
HS
Yang
An-Hang
AH
Tang
Kam-Tsun
KT
Jap
Tjin-Shing
TS
Lee
Chen Hsen
CH
Lin
Hong-Da
HD
Burcus
Niculina
N
Pittenger
Gary
G
Vinik
Aaron
A
D000328:Adult; D000368:Aged; D000682:Amyloid / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D049109:Cell Proliferation; D003981:Diazoxide / Q000627:therapeutic use; D005215:Fasting; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D006946:Hyperinsulinism / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D007003:Hypoglycemia / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D037181:Lectins, C-Type / Q000032:analysis; D008297:Male; D008875:Middle Aged; D046768:Nesidioblastosis / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D010180:Pancreatectomy; D000073718:Pancreatitis-Associated Proteins; D019518:Postprandial Period; D011384:Proinsulin / Q000032:analysis / Q000097:blood; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D013577:Syndrome; D015534:Trans-Activators / Q000032:analysis
D000682:Amyloid; D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002096:C-Peptide; D018398:Homeodomain Proteins; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D044169:Receptors, Calcium-Sensing; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D011384:Proinsulin; D003981:Diazoxide