Islet Cell Hyperplasia Research Articles

Effects of chronic ethanol consumption in atherosclerosis-prone JCR:LA-corpulent rat.

Rats of the atherosclerosis-prone JCR:LA-corpulent strain were subjected to long-term low (0.5% wt/vol) or high (4% wt/vol) consumption of ethanol from 1 to 12 months of age. The corpulent rats are hyperphagic, obese, and insulin-resistant; exhibit a marked very low density lipoprotein hyperlipidemia; and develop both vascular and myocardial lesions while eating a normal rat chow. The total lipid profile of the rat sera showed only limited changes with ethanol consumption. There were also no significant effects on high density lipoprotein lipids. Ethanol consumption was associated with elevated fasting glucose concentrations in both lean and corpulent rats and a strong decrease in fasting insulin levels and pancreatic B-cell volume density in the hyperinsulinemic corpulent rats. The relative frequency of myocardial nodules of chronic inflammatory cells was increased in the ethanol-consuming rats, both lean and corpulent. In contrast, old organized lesions (scars) were absent in the ethanol-consuming corpulent rats. Thus, ethanol consumption had no major effect on serum lipids or lipoproteins in the corpulent rat but was associated with a reduction in insulin resistance and islet cell hyperplasia, with an associated decreased incidence of myocardial lesions.

Surgical disorders of the pancreas in infancy and childhood

Pancreatic disorders in infants and children encountered over a 20 year period are reviewed. A total of 79 children were treated. Forty-eight had pancreatitis or its complications, 17 had congenital malformations, 12 had hypoglycemia and hyperinsulinism, and 2 had carcinoma. The mortality rate for the children with pancreatitis was 17 percent and was limited to patients treated nonoperatively. Idiopathic and drug-induced pancreatitis (the latter, particularly from corticosteroids) were the predominant types. Only rarely should such patients undergo operative treatment. Operations performed for various obstructive or traumatic lesions of the pancreas, as well as for complications of pancreatitis, obtained uniformly good results. The most common congenital malformation of the pancreas was an annular pancreas in association with duodenal atresia; all children with this abnormality were successfully treated with bypass procedures. Four patients with an ectopic pancreas underwent successful wedge resection. Nine infants with nesidioblastosis or islet cell hyperplasia and three children with islet cell adenomas underwent successful resection without any deaths, although neurologic sequelae due to prolonged preoperative hypoglycemia were common. Two patients underwent radical resection for pancreatic carcinoma, one of whom had survived 20 years postoperatively at last follow-up. Pancreatic disorders requiring operation in childhood are uncommon, but are likely to be complex and challenging when they do occur.

A New Hepato‐pancreato‐renal Disorder Resembling Tyrosinemia Involving Neuropathy and Abnormal Metabolism of Polyunsaturated Acids

SummaryThis report describes a new disorder resembling hereditary tyrosinemia (HT) but differing from it in several respects. Similarities include failure to thrive with hypoproteinemia, micronodular cirrhosis, α‐fetoprotein positive hepatocellular carcinoma, renal Fanconi syndrome with renal tubular ectasia, hypermethioninemia, and hypoglycemia associated with islet cell hyperplasia. However, the tyrosine metabolic pathway was intact. Unique findings include optic atrophy, cerebellar degeneration, and exocrine pancreatic hypoplasia. Polyunsaturated fatty acid (PUFA) status was evaluated in the serum and liver. Initial PUFA profile to serum phospholipids revealed grossly elevated linoleic acid and subnormal linolenic acid. All PUFAs derived from these precursors were absent suggesting gross abnormalities in the utilization of these two essential fatty acids for synthesis of longer chain highly unsaturated structural PUFA. Analysis of liver phospholipids indicated that linoleic acid was lower and w3 and monenoic acids were higher than in the liver specimens from two cases of HT. The gross abnormalities in PUFA pattern, although perhaps secondary to another cause, represent serious structural and functional abnormalities of essential membrane lipids and potentially of eicosanoids derived from them.

Malakoplakia associated with adrenal and islet cell hyperplasia and glucagonoma

Summary Extensive involvement of the urinary tract and related structures by malakoplakia presented difficult diagnostic problems in two elderly individuals. At post-mortem examination there was bilateral adrenal cortical hyperplasia in both patients and, in one, there was also a pancreatic glucagonoma and diffuse hyperplasia of the pancreatic islet tissues. There is now an increasing body of evidence that malakoplakia is associated with hypercorticosteroidism possibly due to an effect on macrophage exocytotic mechanisms. The coexistence of malakoplakia and glucagonoma has not been previously described.

BECKWITH WIEDEMANN SYNDROME PRESENTING IN PREMATURE INFANTS

Beckwith-Wiedemann syndrome (BWS) is characterized in most reported cases by the triad of Exomphalous, Macroglossia and Gigantism (EMG syndrome). However, these major manifestations probably represent the extremes of this syndrome while cases with minor or time-dependent manifestations are usually not published. We present the variable expressions of BWS syndrome in 3 preterm infants. The first had 75th percentile measurements at her birth (32 weeks) with macroglossia, large fontanel, ear creases and omphalocele. At corrected age of 7 months she was diagnosed to have hepatoblastoma. The second had 60-75th percentile measurements at her 28 week birth. Dysmorphia was not noted at birth or during life. At corrected age of 2-1/2 months, she developed signs of puberty, and at 4 months, hepatomegaly. The liver histologically showed extensive hepatoblastoma. At autopsy adrenal cytomegaly, pancreatic islet cell hyperplasia and umbilical hernia were also noted to be present. The third had 97% weight, 75% height and 30% OFC at his 32 week birth. No anomalies were present at birth. Four weeks after birth he developed an umbilical hernia, facial coarsening and macroglossia (causing difficulty in breathing and feeding) but no visceromegaly. By the age of 3 months, the clinical presentation was highly suggestive of BWS. Extensive investigation failed to show any metabolic or endocrine abnormality.

Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality.

In 1964, Smith et al described a syndrome of microcephaly, growth and mental retardation, unusual facial appearance, syndactyly of toes 2 and 3, and genital abnormalities. Major structural malformations and early death have been uncommon in the many subsequent literature reports. We report on 19 infants with a phenotype we propose to call Smith-Lemli-Opitz syndrome (SLOS)-Type II, in which major structural abnormalities, male pseudohermaphroditism, and early lethality are common. Of these 19 patients, 18 had postaxial hexadactyly, 16 had congenital heart defect, 13 had cleft palate, and 10 had cataracts. Unusual findings seen in these patients at autopsy included Hirschsprung "disease" in five patients, unilobated lungs in six, large adrenals in four, and pancreatic islet cell hyperplasia in three. Comparison of our cases to 19 similar literature cases suggests the existence of a distinct phenotype that may be separate from SLOS as originally described. It is also inherited as an autosomal recessive, as documented by occurrence in one pair of sibs in this study and recurrence in three reported families.

Production of pituitary protein 7B2 immunoreactivity by endocrine tumors and its possible diagnostic value.

7B2 is a protein originally isolated from pituitary, which has been shown to be present in the central nervous system and in certain peripheral tissues, with very high concentrations in pancreatic islets. Endocrine and nonendocrine tumors from 185 patients were investigated by RIA for the presence of immunoreactive pituitary protein 7B2. The highest mean concentration of 7B2 immunoreactivity was found in insulinomas [452 +/- 174 (+/- SEM) pmol/g wet wt tissue; n = 16], which was significantly higher than the concentration in normal adult pancreatic tissue (28.3 +/- 4.4 pmol/g; n = 7). High concentrations of 7B2 immunoreactivity also were found in other endocrine tumors. The cellular localization of 7B2 was studied in normal pancreas, pancreas with hyperplastic islets, and endocrine tumors. 7B2 immunoreactivity was localized to B-cells in the normal pancreas and to variable proportions of cells in islet cell hyperplasias, B-cell tumors, and pheochromocytomas. Plasma concentrations of 7B2 immunoreactivity also were determined in 255 patients with established diagnoses of endocrine or nonendocrine tumors. The proportion of patients with elevated plasma concentrations (arbitrarily set at more than 4 SD above the mean) were 42 of 72 with pancreatic islet cell tumors, 7 of 11 with midgut carcinoid tumors, and 5 of 13 with medullary carcinomas of the thyroid. Especially high values were found in patients with glucagonomas (14 of 20), vipomas (12 of 13), and pancreatic polypeptide-producing tumors (5 of 6). Thus, 7B2 immunoreactivity is produced by a variety of different tumors and may serve as a tumor marker, especially in patients with certain pancreatic islet tumors.

Islet-cell hyperplasia in genetic deficiency of alpha-1-proteinase inhibitor.

By light microscopy and immunoperoxidase methods, morphology and distribution of alpha-1-proteinase inhibitor (Api) cells in the pancreatic islets were studied in seven patients with and in 17 patients without periodic acid-Schiff-positive, diastase-resistant globules in the liver. Five of the seven patients with liver globules had cirrhosis and emphysema, suggesting genetic deficiency of Api, which was confirmed in four by pi phenotyping (blood from one patient was not available). The two remaining patients had only a mild degree of liver fibrosis and mild emphysema and showed a normal MM phenotype. Islet cell hyperplasia and an increased population of Api cells were observed in all five patients with genetic deficiency, compared with the 17 patients without Api deficiency. These morphologic changes were more pronounced in the one homozygous patient than in the heterozygous patients. Nesidioblastosis, ductular proliferation, and atypia of insular cells were seen only in patients with an abnormal phenotype. The increased amount of Api in the islets in the genetic deficiency state may be due to hyperplasia and hypertrophy of Api cells or due to storage of abnormal Api in the preexisting Api cells. The exact stimulus for islet cell hyperplasia and proliferation of Api cells is still unknown.

Development of Pancreatic Hyperplasia in Female SHN Mice Receiving Ectopic Pituitary Isografts<xref ref-type="fn" rid="FN2">2</xref>

The long-term effects on pancreas of ectopic pituitary grafting at various sites were studied in female SHN mice. Hyperprolactinemia induced by pituitary grafting resulted in an increase in the pancreatic weights, mainly due to hyperplastic proliferation of the pancreatic acinar glands. In addition, islet-cell hyperplasia and adenoma were found in the pituitary-grafted mice. Hyperplastic nodules resembling adenoma of the pancreatic acinar cells were also induced by pituitary grafting. The pancreata of mice with pituitary grafts frequently adhered to the uterus, ovary, and other organs; some of the pancreata further invaded these organs. Control mice bearing no pituitary grafts showed no pancreatic lesions. These results indicate the participation of prolactin in pancreatic tumorigenesis.

Nonimmune Hydrops Fetalis

Autopsies were performed in 40 cases of nonimmune hydrops fetalis during the period from 1975 to 1983. In 25 cases specific anatomic diagnoses, including hematologic disorders, infections, chromosomal abnormalities, congenital anomalies, and tumors, were made. In the majority the diagnosis of hydrops fetalis was made prenatally by ultrasonography. The mean gestational age at delivery was 30 weeks; 23 infants were stillborn, and 17 died during the neonatal period. Body weights were consistently increased; peripheral edema and ascites were present in all cases and pleural effusions in all but two cases. Hepatosplenomegaly, cardiomegaly, and pulmonary hypoplasia were frequent findings. The most consistent microscopic changes involved endocrine organs. Islet cell hyperplasia and Leydig cell hyperplasia were common, and thyroid hyperplasia was found occasionally. The fetal zone of the adrenal cortex was often thick and composed of swollen, vacuolated cells. Enhanced extramedullary erythropoiesis was observed in all cases. Thirty-nine placentas were examined; 34 were edematous (mean weight, 547 g), with villous edema, excess erythroblastemia and normoblastemia, and occasional intravillous hematopoiesis. Nonimmune hydrops fetalis has a range of known causes. Thorough autopsy, including placental examination, is the most useful approach for determining the etiology. In 23 cases the probable or possible cause was established in this manner. Antibody studies should also be performed in all cases to exclude an immunologic etiology. Synthesis of clinical, serologic, and pathologic data offers prospects for rational management and prediction of recurrence.

Islet cell hyperplasia: An unusual cause of hypoglycemia in an adult

This is a case presentation of a 32-year-old man with a one year history of symptomatic hypoglycemia and documented elevations of his fasting plasma insulin to glucose ratio, caused by islet cell hyperplasia. Islet cell hyperplasia is a common cause of hypoglycemia in the pediatric population, but is very rare in adults. As in the pediatric group, adults should be treated with subtotal (75–85%) resection of the pancreas and with diazoxide for symptomatic recurrence of hypoglycemia. We suggest that the term islet cell hyperplasia is preferred to designate a diffuse proliferation of endocrine cells that may express itself with different morphologic patterns, varying from case to case. Islet cell hyperplasia, therefore, comprises nesidioblastosis, endocrine cell budding from ductal structures, as well as islet and islet cell hypertrophy, septal islets, islet dysplasia, and adenomatosis. Immunohistochemistry is a valuable method for the demonstration of the polymorphic hormonal content of the proliferated islet cells. We propose that the term nesidioblastosis, previously used to describe some similar cases, should be avoided because of confusion about its definition.

Adrenal and Islet Cell Hyperplasia in Malakoplakia

Adrenal and Islet Cell Hyperplasia in Malakoplakia

Nesidioblastosis and endocrine hyperplasia of the pancreas: A secondary phenomenon

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.

Pancreatic polypeptide in islet cell tumors. Morphologic and functional correlations.

Twelve islet cell tumors and one islet cell hyperplasia were studied with immunocytochemical and radioimmunoassay methods. With immunocytochemical staining, all six insulinomas, one mixed insulinoma-glucagonoma, and four gastrinomas were positive for insulin, insulin and glucagon, and gastrin, respectively. Pancreatic polypeptide (PP) was positive in three insulinomas and one mixed insulinoma-glucagonoma. All of the tumors were positive for neuron-specific enolase (NSE). Radioimmunoassays of tissue extracts further disclosed that all functioning tumors contained more than one pancreatic hormone. PP concentrations of two insulinomas and one mixed insulinoma-glucagonoma were higher than that of normal control pancreases. A study of protein meal-stimulated PP secretion revealed that three of the insulinoma cases and two gastrinoma cases exhibited higher plasma PP levels than the age-matched controls. The findings suggest that: both functioning and nonfunctioning islet cell tumors derive from neuroendocrine cells positive for NSE; all functioning islet cell tumors appear to contain PP in the tumor tissue as a minor component; as many as 70% of the patients with islet cell tumors present with abnormally higher plasma PP levels after protein meals; and a study of meal-stimulated PP secretion may well be used as a marker for the presence of functional islet cell tumors.

Nonimmune hydrops fetalis: A challenge in perinatal pathology

Autopsies were performed in 40 cases of nonimmune hydrops fetalis during the period from 1975 to 1983. In 25 cases specific anatomic diagnoses, including hematologic disorders, infections, chromosomal abnormalities, congenital anomalies, and tumors, were made. In the majority the diagnosis of hydrops fetalis was made prenatally by ultrasonography. The mean gestational age at delivery was 30 weeks; 23 infants were stillborn, and 17 died during the neonatal period. Body weights were consistently increased; peripheral edema and ascites were present in all cases and pleural effusions in all but two cases. Hepatosplenomegaly, cardiomegaly, and pulmonary hypoplasia were frequent findings. The most consistent microscopic changes involved endocrine organs. Islet cell hyperplasia and Leydig cell hyperplasia were common, and thyroid hyperplasia was found occasionally. The fetal zone of the adrenal cortex was often thick and composed of swollen, vacuolated cells. Enhanced extramedullary erythropoiesis was observed in all cases. Thirty-nine placentas were examined; 34 were edematous (mean weight, 547 g), with villous edema, excess erythroblastemia and normoblastemia, and occasional intravillous hematopoiesis. Nonimmune hydrops fetalis has a range of known causes. Thorough autopsy, including placental examination, is the most useful approach for determining the etiology. In 23 cases the probable or possible cause was established in this manner. Antibody studies should also be performed in all cases to exclude an immunologic etiology. Synthesis of clinical, serologic, and pathologic data offers prospects for rational management and prediction of recurrence.

Glucose-stimulated DNA replication of the pancreatic islets during the development of the rat fetus. Effects of nutrients, growth hormone, and triiodothyronine.

DNA replication and insulin release have been studied in islets isolated, using a tissue culture technique, from rat fetuses of different gestational ages. The islets were cultured for 3 days in media with high and low concentrations of glucose or amino acids. The DNA replication was determined by autoradiography and the insulin secreted into the medium was measured by radioimmunoassay. In islets of 22-day-old fetuses, DNA replication was stimulated by both glucose and amino acids. At gestational days 18 and 20, only amino acids increased DNA replication. However, both high glucose and high amino acid concentrations increased the islet insulin secretion into the culture medium at all ages studied. In an attempt to induce glucose-sensitive DNA replication in vitro, islets obtained from 18- and 20-day-old fetal pancreata were cultured in the presence of either triiodothyronine or human growth hormone. Triiodothyronine failed to influence either DNA replication or insulin release. Growth hormone, however, increased DNA replication and insulin release in both the experimental groups but did not induce a growth response to glucose. It is concluded that the appearance of glucose-stimulated B-cell growth is a late event in the fetal development of the rat, parallelling the late maturation of both insulin biosynthesis and release. This finding may explain the difficulties in producing islet cell hyperplasia and diabetic fetopathy previously shown in rat models of diabetes in pregnancy.

Hyperinsulinemia and decreased surfactant in fetal rabbits.

To isolate and demonstrate the effect of insulin on pulmonary surfactant in vivo, islet cell hyperplasia and hyperinsulinemia were produced in fetal rabbits by the litter reduction technique without concomitant hormonal or metabolic changes in mother or fetus. This produced fetuses which were heavier than controls (37.1 vs. 31.5 g), with two-fold higher insulin levels (48.1 vs. 24.3 microU/ml). The fetal weight correlated directly with the insulin level, while the L/S ratio was found to correlate inversely with the insulin level. This inhibitory effect may be mediated by any of several mechanisms which await further investigation.

Men I syndrome and islet cell lesions of the pancreas.

S INCE Dr Edward Ellison’s reign as Chairman of Surgery at the Medical College of Wisconsin from 1958 to 1970, a deep interest has existed at our institution in hyperfunctioning islet cell lesions of the pancreas, Our charge in this report is to discuss the salient features of multiple endocrine neoplasia, Type 1 (MEN I) syndrome, which includes islet cell pancreatic lesions as a major component, and to review the different types of isolated sporadic islet cell pancreatic tumors. Although the MEN I syndrome and isolated pancreatic islet cell tumor are relatively rare, patients with these conditions are being recognized with increasing frequency due to the current general availability of hormone radioimmunoassays. Most radiologists who practice at major hospitals will likely encounter one or more patients with the clinical features of the MEN I syndrome or of a sporadic islet cell tumor. A high index of suspicion is essential to make an accurate diagnosis of the condition, leading to appropriate management of the patient and screening of his family. Since 1960, we have evaluated 66 individuals from among 200 kindred of two families with the MEN I syndrome. Data from the larger of the two families spans five generations.’ Evidence collected to date indicates that 21 individuals in this family have the syndrome (Fig 1). Of these individuals, 12 exhibited biochemical or morphologic evidence, or both, of islet cell neoplasm or hyperplasia. During the past two decades, we have also evaluated 50 isolated patients with sporadic nonfamilial islet cell lesions. Of these, 48 had a functioning neoplasm or hyperplasia while two had a nonfunctioning tumor.

Prevalence of diffuse pancreatic beta islet cell disease with hyperinsulinism: Problems in recognition and management

AbstractAmong 77 patients with endogenous hyperinsulinism seen in 2 medical centers, diffuse islet cell disease accounted for 17 (22%) patients. Since diffuse islet cell disease poses special problems in management, its prevalence is emphasized in this report.Among these patients with diffuse islet cell disease, there were 11 patients with adenomatosis, 4 with nesidioblastosis, and 2 with islet cell hyperplasia. Six of the 77 patients were found in multiple endocrine neoplasia, type I kindreds; diffuse islet cell disease was documented in 4 of these patients.We outline principles of management in patients with diffuse islet cell disease. Frozen section microscopy failed to identify nesidioblastosis or islet cell hyperplasia.

Cortisone-induced islet cell hyperplasia in hamsters.

Pancreatic islet cell hyperplasia was studied in hamsters during one to eight weeks of cortisone treatment. Measurement of serum glucose and insulin; pancreatic insulin, glucagon, somatostatin, pancreatic polypeptide as well as islet tissue morphometry were performed. Serum glucose was highest at week 2, followed by mild to moderate hyperglycemia. Serum insulin was increasingly higher from week 1 to week 8. Pancreatic insulin was maximal at week 5 then declined through week 8 in the presence of beta cell neurosis in markedly hyperplastic islets. Pancreatic concentration of somatostatin and pancreatic polypeptide moderately increased more than the control levels; however, compared with the controls, glucagon was reduced by cortisone treatment. Effect of cortisone in the four types of islet cells is discussed, particularly on beta cell hyperplasia, which appears to be a response to decreased insulin binding to the target organs with no changes in receptor concentration.