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Diffuse nesidioblastosis as a cause of hyperinsulinemic
hypoglycemia in adults: a diagnostic and therapeutic challenge.Surgery.
2007 Feb; 141 (2):179-84; discussion 185-6.
Hyperinsulinemic hypoglycemia is caused by uncontrolled insulin
release either from neoplastic pancreatic beta-cells or from
functionally defective beta-cells. The latter disorder, which is
usually seen in newborns, has been called nesidioblastosis and is
divided histopathologically into a focal and diffuse type. In
adults, nesidioblastosis is rare, and therefore its
histopathologic and clinical features are not well known. In our
institution, 4 of 128 adult patients (>3%) suffering from
hyperinsulinemic hypoglycemia were found to have diffuse
nesidioblastosis. The remaining patients had an insulinoma
resected successfully in all but one patient. The diagnosis of
diffuse nesidioblastosis was established histopathologically after
removing a segment of the distal pancreas. Resection of up to 90%
of the pancreas relieved 2 of the 4 patients of their symptoms. We
conclude that diffuse nesidioblastosis is rare in adults but may
account for more than 3% of patients with hyperinsulinemic
hypoglycemia. The histopathologic diagnosis relies predominantly
on demonstration of beta-cell hypertrophy. The cause of the
disease is not known but may be related to defects in the glucose
recognition system of the beta-cell. Treatment consists of
operative reduction of the beta-cell mass, but the extent of
pancreatic resection required is hard to judge, and there is a
thin line between successful treatment, persistence of the
disease, and pancreatic endocrine insufficiency.
Nesidioblastosis--a rare cause of hypoglycaemia in adults.Exp
Clin Endocrinol Diabetes. 2005 Jun;113(6):350-3.
A case of
suspected clinically hormonally active insulinoma in a 48-year-old
woman is presented. Despite the lack of features, which might
correspond to the insulinoma in radiological examinations, the
patient was qualified for a distal subtotal pancreatectomy and
then, due to persistent hyperinsulinism, for total pancreatectomy.
The insulinoma was found neither in a palpable examination of the
pancreas nor in the intraoperative ultrasonic examination. In a
histopathological examination supplemented with
immunohistochemical tests, nesidioblastosis - a rare cause of
hypoglycaemia in adults - was diagnosed.
Nesidioblastosis: an old term and a new understanding.World J Surg. 2004 Dec;28(12):1227-30. Epub 2004 Nov 4.
Nesidioblastosis is a clinically, pathologically, and genetically
heterogeneous disease. Differences between well described forms in
neonates with persistent hyperinsulinemic hypoglycemia of infancy
(PHHI) and rare forms in adults are described. Histopathologic
criteria include hypertrophic islets occasionally showing beta
cells with pleomorphic nuclei, ductuloinsular complexes, and
neoformation of islets from ducts. These changes can be found as
diffuse or focal forms of nesidioblastosis. Although most cases
occur sporadically, several genetic defects ( SUR1, Kir6.2, GCK,
and GLUD1 genes) have been described in neonates. In adults a
higher rate of nesidioblastosis is observed in conjunction with
multiple endocrine neoplasia type 1. The disease is diagnosed
biochemically by a supervised fasting test in adults and in
neonates by determining the glucose requirements to maintain
normoglycemia, inappropriately high insulin and c-peptide levels,
low free fatty acid and ketone body concentrations, glycemic
response to glucagons, and the absence of ketonuria. If all highly
selective noninvasive imaging techniques fail to identify a tumor,
selective arterial calcium stimulation testing for gradient-guided
surgery in adults and percutaneous transhepatic pancreatic venous
sampling in neonates should be performed. a 95% pancreatectomy is
necessary in neonates with a diffuse form of nesidioblastosis,
whereas focal forms can be treated by partial pancreatectomy.
Adult-onset
nesidioblastosis causing hypoglycemia: an important clinical
entity and continuing treatment dilemma.Arch
Surg. 2001;136(6):656-63.
HYPOTHESIS:
Nesidioblastosis is an important cause of adult hyperinsulinemic
hypoglycemia, and control of this disorder can often be obtained
with a 70% distal pancreatectomy. DESIGN: The records of all adult
patients operated on for hypoglycemia between 1974 and 1999 were
reviewed retrospectively. Patients with the pathologic diagnosis
of nesidioblastosis were contacted for follow-up (1.5-21 years)
and are presented. Patients' results were compared with those of
36 other individuals with this disorder who were previously
reported in the literature. SETTING: The University of Chicago
Medical Center (Chicago, Ill), a tertiary care facility. PATIENTS:
A consecutive sample of all patients operated on for hypoglycemia.
INTERVENTIONS: Seventy percent distal pancreatectomy for all
patients with nesidioblastosis, and maintenance therapy with
verapamil hydrochloride for 2 patients. MAIN OUTCOME MEASURES:
Achievement of normoglycemia with and without medication,
development of insulin-dependent diabetes mellitus, pancreatic
exocrine insufficiency, and need for reoperation. RESULTS: Of 32
adult patients who underwent surgical exploration for
hyperinsulinemic hypoglycemia at our institution, 27 (84%) were
found to have 1 or more insulinomas, and 5 (16%) were diagnosed
with nesidioblastosis. Each patient with nesidioblastosis
underwent a 70% distal pancreatectomy. Follow-up duration for the
5 patients ranged from 1.5 to 21 years, with 3 patients (60%)
asymptomatic and taking no medications, and 2 patients (40%)
experiencing some recurrences of hypoglycemia. The 2 patients with
recurrences are now successfully treated with a calcium channel
blocker, an approach, to our knowledge, never before reported for
adult-onset nesidioblastosis. CONCLUSIONS: Nesidioblastosis is an
uncommon but clinically important cause of hypoglycemia in the
adult population, and must always be considered in a patient with
a presumptive preoperative diagnosis of insulinoma. This study
indicates that a 70% distal pancreatectomy is often successful in
controlling hypoglycemia, and rarely results in diabetes mellitus.
However, the optimal treatment of this disorder remains to be
determined.
Adult
nesidioblastosis. An unusual cause of fasting hypoglycemia.Am
Surg. 1989 Jun;55(6):366-9.
Laidlaw
coined the term nesidioblastosis in 1938 to characterize the
neodifferentiation of the islet cells of Langerhans from
pancreatic duct epithelium. It is well recognized in the pediatric
population as a frequent cause of persistent neonatal
hypoglycemia. However, its occurrence in adults is presumed to be
rare and, therefore, it is not appreciated as a cause of
hyperinsulinism. Three women, aged 29, 42, and 63, with adult
onset hyperinsulinism secondary to nesidioblastosis are reported.
All three patients required near-total pancreatectomy. The
preoperative findings were consistent with hyperinsulinemic
hypoglycemia as with insulinomas. Results of pancreatic imaging
studies were normal in two patients and one patient had a
pancreatic examination by computerized tomography and magnetic
resonance imaging, with false-positive results. Two of the three
patients had previously undergone a 50 per cent distal
pancreatectomy in which the resected specimens were interpreted as
normal in one patient and consistent with nesidioblastosis in the
second. Both patients subsequently developed recurrent symptomatic
hyperinsulinemic hypoglycemia that persisted despite dosage
adjustments in diazoxide therapy. The oldest patient underwent a
95 per cent pancreatectomy at the initial surgical exploration
because an insulinoma could not be identified. The other patients
underwent a completion 95 per cent pancreatectomy. In both,
histochemical examination of each specimen disclosed
nesidioblastosis, characterized by clusters of islet cells
interspersed throughout the exocrine tissue.
Nesidioblastosis and endocrine hyperplasia of the pancreas: a
secondary phenomenon.Hum
Pathol. 1986 Jan;17(1):46-54.
Diffuse
endocrine cell proliferation (nesidioblastosis) and islet cell
hyperplasia are considered causes of organic hyperinsulinism but
have not been distinguished (by histometric or immunohistologic
methods) from the normally variable pancreatic islet cell
population during development and in adults. Therefore, in this
study morphologic, immunohistologic (to detect insulin, glucagon,
somatostatin, and pancreatic polypeptide), and morphometric
features were evaluated in 1) normal pancreases (from fetal to
adult; n = 49); 2) pancreases from patients with nesidioblastosis
(n = 5); and 3) tumor-associated pancreases (TAP) from patients
with insulin-producing islet cell tumors (n = 8). The study of
normal postnatal development revealed that all features of fetal
development remain present after birth and that the diagnosis of
any diffuse endocrine disorder should therefore be based
essentially on quantitative histometric parameters (total
endocrine area, islet size distribution, distribution of each
endocrine cell type). With these parameters endocrine cell
hyperplasia was demonstrated in TAP from adults due to increased
numbers of A and D cells. However, in the cases previously
diagnosed as pathologic nesidioblastosis, all parameters were
within the normal range. Thus, nesidioblastosis does not appear to
be a pathologic entity. Careful re-examination of the pancreases,
prompted by these data, revealed small islet cell tumors in three
of these five cases. It is concluded that the endocrine pancreas
can react rapidly, both morphologically and functionally, to
changes in hormonal feedback, e.g., islet cell tumors. Therefore,
the observation of a diffuse islet cell disorder in a patient with
hyperinsulinism should not be considered an indication that an
islet cell tumor is not present.
Nesidioblastosis and islet cell changes related to endogenous
hypergastrinemia.Virchows
Arch B Cell Pathol Incl Mol Pathol.
1985; 48 (3):261-76.
The endocrine
pancreas from four hypergastrinemic patients with recurrent peptic
ulceration has been studied by light and electron microscopy.
Greatly increased numbers of ducts and centroacinar cells have
been observed associated with a striking increase in the number of
islets and endocrine cells scattered in the acinar tissue (nesidioblastosis).
The islet cells scattered throughout the exocrine parenchyma are
of all the known islet cell types, with a prevalence of B and
especially A cells. Many islets, probably formed de novo, are of a
considerable size, have irregular contours and are in close
apposition to centroacinar cells and ducts. The degree of
nesidioblastosis and islet hyperplasia does not seem to be related
to the plasma gastrin levels. Cytological changes have also been
found in the islet cells of the hypergastrinemic patients compared
with controls. These changes mainly affect the B cells and consist
of a striking decrease in the number of mature secretory granules
associated with a fairly extended ergastoplasm and Golgi apparatus
and with a relevant increase in the number of immature granules.
In two of the four patients examined, who had more severe
hypergastrinemia, cytological signs of enhanced secretion are also
recognized in A cells. The features indicating hypersecretion of B
and A cells seem to be related to the plasma gastrin levels. The
above findings indicate that chronic endogenous hypergastrinemia
promotes proliferation and differentiation of islet cells and
stimulates the secretory function of B cells and, to a lesser
extent, of A cells, thus providing evidence for a trophic and
secretagogue action of gastrin on the endocrine pancreas.
Nesidioblastosis and multifocal pancreatic islet cell hyperplasia
in an adult. Clinicopathologic features and in vitro pancreatic
studies.Am
J Clin Pathol. 1985 Oct;84(4):534-41.
The
clinicopathologic features of an adult with insulinoma and
pancreatic islet cell hyperplasia, who presented with
hyperinsulinemic hypoglycemia are reported, together with in vitro
studies on the patient's pancreatic islets. Islet cell hyperplasia
with ductal proliferation and budding and beta cell degranulation
was demonstrated by immunochemical means. The in vitro studies of
cultured hyperplastic islet cells support the clinicopathologic
features. Thus, in comparison with control islets maintained in
culture for up to 14 days, hyperplastic islets could be cultured
for up to 60 days, during which time cell overgrowth required
subculture on three occasions. Furthermore, in contrast to control
islets the release of both insulin and somatostatin from cultured
hyperplastic islets was refractory to glucose, glucagon, and
tolbutamide; theophylline was the only secretagogue to stimulate
insulin and somatostatin release from hyperplastic islets in
vitro. Indirect immunofluorescence revealed the presence of islet
cell surface autoantibodies in the plasma of this patient reactive
with both normal human islets and a rat insulinoma line (RIN-m5F).
These studies demonstrate the proliferative capacity and
relatively undifferentiated functional state of hyperplastic
islets in vitro. They provide further evidence that islet cell
division is capable of being stimulated in adult life. The
pathogenic significance of islet cell surface autoantibodies in
hyperplastic islet cell disease and insulinoma warrants further
investigation.
Clinical and
histologic indications for extensive pancreatic resection in
nesidioblastosis.
Am J Surg. 1982 Jan;143(1):116-9.
Nine
children with nesidioblastosis underwent pancreatic resection at
St. Louis Children's Hospital. Four of these underwent 99 percent
of near-total resection. Only one child required permanent insulin
therapy postoperatively. Pathologic examination of the resected
pancreases revealed a diffuse disturbance of the pancreatic
architecture. Prolonged hypoglycemia can have devastating
neurologic sequelae. Based on clinical experience and the
pathologic demonstration of a diffuse process in the affected
pancreas, it is advocated that near-total (99 percent)
pancreatectomy is the primary procedure of choice for this
disease.
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