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Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience.The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease.Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients havingor = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type.Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.

We evaluated the possible genetic contribution to hyperinsulinism in a series of patients seen during the past 15 years. Of 26 families, 5 (19%) had more than one child affected (multiplex family). There were no apparent differences between patients in the 5 multiplex and 21 simplex families, clinically, biochemically, or on histologic examination of the pancreatic specimens. The families studied had a total of 63 offspring; the 26 index patients had 37 siblings, 6 of whom were affected. After four patients with hyperinsulinism caused by adenoma were excluded from the study, segregation analysis was carrled out to test the data for agreement with results expected if familial and isolated hyperinsulinism represented a single disease with recessive mode of inheritance and a segregation ratio of 0.25. Excellent agreement was found between the observed number of affected siblings (20) and the expected number (19.65), with a segregation ratio of 0.254. The results were consistent with the hypothesis that in most or all cases, hyperinsulinism is inherited as an autosomal recessive disease. There was no evidence of distinct familial and sporadic types.

Islet cell adenomas are an important consideration in infants and children with hypoglycemia due to hyperinsulinism. Between 1965 and 1977, 32 patients with hyperinsulinism were seen at the Children's Hospital of Philadelphia. Sixteen of these patients underwent surgery. Eight patients had single pancreatic adenomas, 5 of whom were infants under 1 yr of age. In 3 infants an adenoma was recognized and removed at the time of surgery. In 4 patients a subtotal pancreatectomy was successful in removing the adenoma. One infant is whom the adenoma was not included in the subtotal pancreatectomy died postoperatively with intractable hypoglycemia. Of the 7 patients cured by surgery, 6 are normal and 1 has brain damage due to delay in treatment of hypoglycemia. One child has mild diabetes. A combined medical and surgical protocol has been developed that permits rapid diagnosis of hyperinsulinism and selection of candidates for surgery. Infants under 1 yr of age who fail to respond to diazoxide should be explored. In children whose hyperinsulinism appears beyond 1 yr of age, surgery is indicated, since an adenoma is likely.

Nineteen children with impaired glucose tolerance were studied. Ten of these patients fulfilled the Fajans and Conn criteria for chemical diabetes; nine did not. The GTT patterns of the latter group are categorized. There was a high incidence of reactive hypoglycemia in both groups. There was no correlation between insulin level or insulin: glucose ratio abnormalities and the degree or trend of the patient's glucose intolerance.

Diazoxide has been used in the treatment of eight infants and children with severe idiopathic hypoglycemia. During periods of treatment ranging from 4 to 18 months, patients responded well to administration of Diazoxide even though control had previously been inadequate on corticosteroid therapy. The most frequent side effect has been hypertrichosis lanuginosa. Suppression of insulin response appears to be an important part of the mechanism of action of Diazoxide.

Pediatric patients with impaired glucose tolerance were categorized and studied. Some were treated with tolbutamide, while others received no drug therapy. Evaluation of blood glucose response during intermittent glucose tolerance tests showed the courses of untreated patients to be more satisfactory than that of subjects who received tolbutamide. Furthermore, there was no correlation between improved glucose handling and the normalization of insulin release or insulin: glucose ratios in either treated or untreated subjects.

Summary A case of extensive ileitis is reported with fistulas and polyp formation which made massive entero-colic resection advisable. An opportunity for a 22 month period of observation of fluid, electrolyte, nutritional balance was afforded, terminated by the intervention of an acute jejunitis. The significant metabolic complications which occurred were: chronic dehydration, malnutrition due to intractable diarrhea, alkalosis, hypocalcemic tetany, mild hypoprothrombinemia. The complications which were strikingly mild or absent: hypochloremia, hypopotassemia, acidosis, hypoproteinemia, anemia, nutritional edema, a fatty liver.

A histochemical technique (pinacyanole metachromasia), specific for insulin in vitro and in beta cells of pancreatic tissue sections, was used to study surgically resected pancreases of 12 patients with documented idiopathic hypoglycemia of infancy. Hematoxylin and eosin—stained sections from 3 patients revealed overt hypertrophy and hyperplasia of all insular units. In the pancreases of the other 9 patients, hematoxylin and eosin sections showed histologically unremarkable islets, whereas the histochemically stained sections revealed the presence of many additional beta cells scattered either singly or in small packets of 2 to 6 cells. These were separate from the islets and most often seen about the walls of small ducts or in the glandular acini proper. The term beta cell nesidioblastosis most appropriately describes this cellular variant. These results, including electron microscopic findings of membrane-bound insulin inclusions in many cells, provide histomorphologic correlation with other evidence in support of the concept that excess production of insulin is an important feature of idiopathic hypoglycemia of infancy.

Ten children with juvenile diabetes mellitus were studied with oral glucose tolerancetests at the onset of their disease and during the period of partial remission. No significant improvement in carbohydrate tolerance was observed. Free fatty-acid responses improved, but abnormalities were still demonstrable. Fasting growth hormone levels were normal, and no changes were noted in the growth-hormone responses before therapy and during remission. Plasma insulin concentrations were very low at the time of the clinical onset, and no significant improvement in insulin secretion was observed during the phase of partial remission. These data suggest that increased insulin production or changes in growth hormone do not play roles in the early partial remission of juvenile diabetes.

A striking deficiency of hepatic fructose-1,6-diphosphatase activity has been demonstrated in a child who has hypoglycaemia and metabolic acidosis on fasting. Liver glycogen was normal, and normal activities of all of the hepatic enzymes concerned with glycogen synthesis and degradation were noted; severe ballooning of hepatic cells by large lipid-containing vacuoles was the only histological abnormality. Oral glucose and galactose tolerance tests were normal, but oral fructose and glycerol provoked hypoglycaemia. The presence of normal levels of hepatic fructose-1-phosphate aldolase activity clearly distinguishes this disease from hereditary fructose intolerance. A sibling who died with many similar features suggests that this is an inherited defect. This new syndrome of fasting hypoglycaemia and metabolic acidosis seems to represent the clinical expression of impaired gluconeogenesis due to an inherited deficiency of hepatic fructose-1,6-diphosphatase.

The case histories of 2 Negro brothers are presented. Neither child hasgalactose-1-phosphate uridyl transferase activity in his circulating red cells, and thus each fulfills the laboratory criterion for the diagnosis of congenital galactosemia. One sibling demonstrated a classic galactosemic picture in infancy, while the other brother has never exhibited any signs or symptoms which could be attributed to galactosemia. Metabolic studies on the asymptomatic brother appear to place him in a subgroup of atypical “galactosemic patients,” as previously delineated by Segal and co-workers.5

Intravenous arginine provocative tests were performed in 23 children with juvenile onset diabetes mellitus and the results compared with those obtained in a control group of 19 normal children. Fasting growth hormone concentrations were similar in the two groups, and the mean peak response following the arginine stimulation was almost identical. Although the blood glucose levels rose higher in the diabetic group following arginine stimulation, the percent change of glucose was found to be the same in diabetics as in normals. Plasma FFA changes were consistent with the diabetic child's state of insulin deficiency. These data indicate that the child with diabetes mellitus responds in a normal fashion to an arginine provocation. No evidence of abnormal secretion or of an exaggerated responsiveness to the endogenous growth hormone was detected.

In comparison with normal children, the diabetic child has a significantly more rapid increase of blood ketones following injection of epinephrine. Beta adrenergic blockade with MJ 1999 removes this ketone responsiveness, presumably by interfering with free fatty acid release from adipose tissue triglyceride, and perhaps from hepatic, stores. Two diabetic preadolescent girls, who were virtually incapacitated because of repeated hospitalizations for severe diabetic ketoacidosis, were studied. A specific stress interview with one child produced marked changes in blood glucose and plasma free fatty acid concentrations, associated with significant increases in plasma concentrations of corticoids and growth hormone as well as in urinary excretion of epinephrine. Beta adrenergic blockade prior to a repeat stress interview blocked the metabolic changes without interfering with the hormonal response to stress. During a therapeutic trial with MJ 1999 for the past 12 months, the need for hospitalization for each of these children has been markedly decreased.