Persistent neonatal hypoglycemia in nesidioblastosis of the pancreas

A now 10 month old female infant suffered from persistent non ketotic neonatal hypoglycemia despite continuous intravenous application of glucose (greater than 10 mg/kg/min). There was only a transient response of blood glucose after intravenous administration of glucagon and prednisolon. Biochemical findings indicated hyperinsulinismus (insulin level of 26 mE/ml during hypoglycemia). Oral diazoxid treatment in high doses (22 mg/kg) stopped hypoglycemia episodes for several days but the newborn remained glucose infusion depended. Finally the treatment had to be interrupted because of vomiting. At the age of 4 1/2 weeks a subtotal pancreatectomy was performed. The histological examination of the pancreas confirmed the clinically suspected diagnosis of nesidioblastosis. After pancreatectomy the infant required insulin therapy. Since six months the girl is without insulin in a good condition. Despite periods of arrested head growth before pancreatectomy the psychomotoric development is normal.     

Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy

The appropriate management of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) still remains controversial. Some patients show a response to treatment with diazoxide or somatostatin, but a number of children require total or near-total pancreatectomy to control hyperinsulinism. Recent studies suggest a dysfunction in the adenosine triphosphate-sensitive potassium channel present in the plasma membrane of pancreatic beta-cells in PHHI. The closure of these channels initiating the depolarization of the beta-cell membrane and opening of calcium channels results in an increase in intracellular calcium which triggers insulin secretion. A calcium channel blocking agent has been shown to block this process and decrease insulin secretion of the nesidioblastotic beta-cells in vitro and to control the hyperinsulinemic hypoglycemia of the patient in vivo. To examine the efficacy of calcium channel blocker therapy, three patients with PHHI were treated with nifedipine. PHHI was diagnosed by inappropriately high insulin levels for low blood glucose levels at 8-10 days of age. Normoglycemia was maintained by a high dose of glucose infusion at a rate of 14-16 mg/kg/min. Therapy using diazoxide and/or somatostatin analogue failed to restore euglycemia in these three patients. The first patient underwent near-total pancreatectomy; however, hyperinsulinism recurred 30 days after surgery. All patients were started on short acting nifedipine at a dose of 0.3 mg/kg/day per os in four doses. To maintain blood glucose levels in normal ranges, the dose of nifedipine was progressively increased to 0.7-0.8 mg/kg/day. Glucose infusion rate to restore euglycemia decreased and was discontinued on the 4th to 10th day of nifedipine treatment. The patients, who have now been followed on nifedipine therapy for over 12 months, are normoglycemic with normal insulin levels. The growth and neuromotor development of the patients are unremarkable except for mild developmental delay of the patient who underwent near-total pancreatectomy. No side effects were encountered at the doses used. In conclusion, calcium channel blocking agents can be used with efficacy and safety in PHHI to control the hyperinsulinemia.     

PLASMA INSULIN AND BLOOD GLUCOSE DURING LONG-TERM TREATMENT WITH DIAZOXIDE FOR INFANT HYPOGLYCEMIA

Abstract. Victorin, L. H. and Thorell, J. (Department of Paediatrics, University of Göteborg, Göteborg, and the Isotope Laboratory, Lund University at the General Hospital, Malmö, Sweden). Plasma insulin and blood glucose during long-term treatment with diazoxide for infant hypoglycemia. Acta Paediat Scand, 63: 302, 1974.–Hypoglycemia of varying etiology is a mayor therapeutic problem in infancy and childhood. It has been shown that diazoxide may increase blood glucose, presumably mainly by prevention of excess insulin release from the pancreas. A case is reported where diazoxide has been used for more than three years in a boy with neurological symptoms due to severe idiopathic hypoglycemia with leucine intolerance where dietary treatment had proved insufficient. A profound improvement in blood glucose level and suppression of pathologic insulin response to both glucose and leucine loads was noted with a diazoxide dose of 15 mg/kg/day which, however, had to be abandoned due to side effects. Over a period of months without diazoxide, insulin responses to glucose and leucine loads progressively increased with recurrence of clinical symtoms. Over the last three years a dose of 5 mg/kg/day has proved effective in keeping clinical symptoms down without side effects. During these years a marked improvement has taken place in neurological, mental and physical development. It is concluded that when due consideration is given to known side effects diazoxide is a valuable adjuvant for long-term treatment of infantile hypoglycemia.     

Compound heterozygosity for the common sulfonylurea receptor mutations can cause mild diazoxide-sensitive hyperinsulinism

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder characterized by dysregulation of insulin secretion and prolonged hypoglycemia. Mutations in the genes of both subunits of the beta-cell KATP channel, Kir 6.2 (potassium channel) and SUR1 (sulfonylurea receptor) have been associated with the autosomal recessive form of this disorder. It was previously demonstrated that patients harboring SUR1 mutations often do not respond well to diazoxide. A patient is reported of compound heterozygosity for the 2 most common mutations previously reported to be associated with PHHI in Ashkenazi Jews; splice mutation of intron 32 (3993-9G-->A) and deletion of phenylalanine at position 1388. Relatively low glucose utilization (<10 mg/kg/min) was needed to maintain blood gllucose concentrations. In addition, treatment with diazoxide was highly effective. We suggest that diazoxide unresponsiveness is not always present in patients with SUR1 mutations and that the probable cause of the milder phenotype in this compund heterozygote state     

Nesidioblastosis. Apropos of 12 new cases

Two new cases of diffuse hyperplasia of the pancreas are reported. This infrequent condition is caused by intermittent and variable insulin hypersecretion. The hyperinsulinism is responsible for severe, lasting and intractable hypoglycemia that causes seizures and mental retardation. Onset usually occurs in the neonatal period. The diagnosis of hyperinsulinism rests on four criteria: the presence of increased insulin levels in the face of hypoglycemia, the low urinary excretion of ketone bodies during hypoglycemic episodes, the need for more than 15/mg/kg/min glucose to maintain the serum glucose level above 2 mmol/l, and a positive response to glucagon. The topographic diagnosis is often disappointing. Medical treatment of the hypoglycemia with diazoxide is a transient measure. Subtotal pancreatectomy is indispensable. Postoperative results are variable. Insulin deficiency diabetes mellitus is common and unusual in that insulin induces an exaggerated response. Recovery can be observed. If hypoglycemia recurs, diazoxide is often effective.     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade.

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological ''nesidioblastosis'' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child''s tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.     

When it is more than transient neonatal hypoglycemia: hyperinsulinemia--a case study challenge

Persistent uncontrolled neonatal hypoglycemia may cause irreversible brain damage. Hyperinsulinemia is a rare cause of persistent hypoglycemia, diagnosed by excluding other etiologies. Inappropriately high fasting serum insulin levels with concurrent hypoglycemia confirm the diagnosis. Initial interventions for hyperinsulinemia are conservative. The first line of therapy is administration of adequate intravenous (i.v.) glucose to maintain serum or whole blood glucose levels at or greater than 40 mg/dl. When enteral feedings are tolerated, schedules and caloric concentration are adjusted. Pharmacologic therapy is added to facilitate weaning from i.v. glucose. The drug of first choice is diazoxide. Octreotide is added if diazoxide therapy fails. Partial or complete pancreatectomy is the final treatment option. Nursing care for infants with hyperinsulinemia must also focus on the support and education of families. Family education must be individualized and should cover feeding regimes, administration of medication, proper use of equipment, and care during illness.     

Somatostatin in the emergency treatment of persistent hypoglycemias caused by hyperinsulinism (nesidioblastosis of the pancreas)

11 infants with persisting hypoglycemia due to hyperinsulinism (nesidioblastosis of the pancreas) were treated with somatostatin. Somatostatin administration in a relatively high dosage (initially 145 micrograms/m2 body surface as bolus followed by a continuous infusion of the same dose per hour) resulted in a suppression of the circulating insulin concentration leading to a less abrupt fall of the postprandial plasma glucose level. By somatostatin infusion we were able to keep two patients with intractable neonatal hypoglycemia in a normoglycemic state until subtotal pancreatectomy. Infants suffering from nesidioblastosis require 1.0-4.5 micrograms/kg/h somatostatin and a concomitant carbohydrate supply of 0.3-0.48 g/kg/h in order to maintain normoglycemia. An initial somatostatin bolus can be omitted. Somatostatin is very reliable in the treatment of neonatal hypoglycemia due to hyperinsulinism for a limited period of time until subtotal pancreatectomy is performed. In most cases of nesidioblastosis this operative measure seems to be inevitable for the control of hyperinsulinism.     

Non-islet-cell tumor hypoglycemia and lactic acidosis in a child with congenital HIV and Burkitt's lymphoma

BACKGROUND: Non-islet-cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia associated with tumors of mesenchymal, epithelial, or hematopoietic origin. Lactic acidosis is likewise an uncommon complication of hematological malignancy associated mainly with leukemia and lymphoma. Most cases of NICTH and lactic acidosis have been described in the adult population. We report a child with congenital HIV and AIDS who developed Burkitt's lymphoma, lactic acidosis and NICTH. PATIENT: An 11 year-old boy with AIDS, cerebral palsy and seizure disorder presented with intractable hypoglycemia 12 days after diagnosis of Burkitt's lymphoma. He had persistent hypoglycemia (serum glucose 20-40 mg/dl; 1.1-2.2 mmo/l) despite glucose infusion rate of 6 mg/kg/minute and trial of diazoxide treatment. Critical sample obtained at time of hypoglycemia showed insulin at 1.78 microU/ml (normal <5 microU/ml), pro-insulin 5.6 pmol/l (<18.8 pmol/l), IGF-I <25 ng/ml (80-723 ng/ml), IGF-II 422 ng/ml (610-1,217 ng/ml), lactate 15.6 mmol/l (normal: 0.5-2.2 mmol/l), cortisol 21 microg/dl (580 nmol/l; normal >10 microg/dl; 276 nmol/l), and negative insulin antibodies. He remained alert and seizure free despite profound hypoglycemia. A 1 mg glucagon stimulation test showed a rise in serum glucose of 29 mg/dl (>1.6 mmol/l). Continuous glucagon infusion at 0.15-0.3 mg/h maintained euglycemia until the time of his demise (1 month after admission) due to complications of his underlying illness. CONCLUSION: We present a case of lactic acidosis and NICTH in an 11 year-old boy with AIDS and Burkitts's lymphoma. We review the mechanism of hyperlacticacidemia in supporting cerebral function during profound hypoglycemia. NICTH and lactic acidosis in association with malignancy carries a poor prognosis. In this patient, continuous glucagon infusion was a successful alternative to corticosteroid treatment in maintaining euglycemia.     

Prolonged hyperinsulinism and hypoglycemia. In an asphyxiated, small for gestation infant. Case management and literature review

The authors describe a term female, asphyxiated, small for gestational age (SGA) infant with documented hyperinsulinism and hypoglycemia occurring at approximately 45 hours of age. The hypoglycemia was refractory to a high rate glucose infusion and steroid administration but responded to diazoxide. The subsequent hospital course was complicated by right-sided heart failure and sepsis. With the onset of sepsis, a transient hyperglycemia was noted that required intermittent insulin therapy for 10 days. Hypoglycemia and hyperinsulinism reemerged and responded to diazoxide therapy. An attempt to discontinue diazoxide at age 6 months was aborted at 2 weeks when hyperinsulinism and hypoglycemia recurred. The infant required diazoxide for 7 more months, then she recovered without having any sequelae. The review of this uncommon hypoglycemia etiology in an SGA and asphyxiated infant and the merits of long-term diazoxide treatment are discussed.     

先天性高胰岛素血症

报道1例先天性持续性高胰岛素性低血糖症患儿的临床诊治情况。患儿,男,孕36周,因“胎儿宫内窘迫”剖宫产出生,出生体重4200g,生后即表现为反复低血糖,加用糖皮质激素治疗后患儿的血糖仍一直波动于1.2~2.8mmol/L之间,需静脉输注10%葡萄糖溶液,糖速为10~17mg/(kg·min),才能维持血糖的稳定。生后30d测定血胰岛素浓度为24.13U/L,同份标本的血糖为1.5mmol/L,血浆胰岛素(U/L)/血浆葡萄糖(mg/dL)比值为0.89,表明体内存在器质性胰岛素不适当分泌过多,诊断为先天性高胰岛素血症。     

Congenital nesidioblastosis. Successful treatment with total pancreatectomy

A 6,410 g newborn baby suffered from severe hypoglycemia despite therapy with high doses of diazoxide and glucagon as well as intravenous application of glucose. There was no persistent response of blood glucose to continuous infusion of somatostatin. A 85% pancreatectomy was performed at the age of 6 weeks, after biochemical findings had indicated hyperinsulinism. As the hypoglycemia reappeared postoperatively, the child underwent total pancreatectomy. Now, at the age of 9 months, the baby's growth and development is normal under substitution therapy with Pankreon and depot-insulin 0.2 U/kg/day.     

Severe hypoglycemia secondary to methimazole‐induced insulin autoimmune syndrome in a 16 year old African‐American male

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African‐American adolescent. A 16‐yr‐old healthy African‐American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio‐ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia.     

Nesidioblastosis in infants: report of two cases and review of the literature

In the last 2 years, two newborns were found to have persistent hypoglycaemia due to nesidioblastosis. Both required more than 15 mg/kg/min IV glucose and had inappropriately high plasma insulin levels. Near-total pancreatectomy (NTP) with splenic conservation was curative in both, with negligible morbidity and no mortality. Prompt diagnosis and stringent control of plasma glucose with hourly monitoring in an intensive care unit, use of a central venous line, and oral diazoxide prevented subsequent neurological handicaps. A high index of suspicion for this rare disorder should be kept in mind in a chubby infant who is jittery, apathetic, and has seizures with hypoglycaemia. Medical management is required to confirm the nonketotic, hyperinsulinaemic hypoglycaemia, whereas NTP provides a long-term cure. Offprint requests to: M. Roohatgi     

The hyperinsulinaemic hypoglycaemias in infancy: a study of six cases

The aim of the present study was to evaluate various functional tests for the differentiation of hyperinsulinaemic hypoglycaemia. The pathophysiological and histological findings in six infants, aged 2–7 months, with persistent hyperinsulinaemic hypoglycaemia are described. Islet cell adenoma was found in four infants and pancreatic nesidioblastosis in two others. Circulating levels of blood glucose (BG), immunoreactive insulin and C-peptide immunoreactivity were measured under basal conditions and during both stimulation and suppression. The diagnosis of hyperinsulinaemia was made by estimation of the BG/serum insulin ratio, which was the most important diagnostic criterion of hyperinsulinism. Control subjects of comparable age showed a ratio of 8.3±4.4 (range 4.1–13.3), whereas the six patients had values between 0.3 and 5.1. At least four determinations with ratios lower than 2.6 were necessary for confirming the diagnosis. Preoperatively we performed oral glucose tolerance, diazoxide infusion, somatostatin infusion and C-peptide suppression tests. It is suggested that the various function tests, especially the suppression tests, do not differentiate hyperinsulinism caused by an adenoma from that caused by diffuse pancreatic nesidioblastosis.Abbreviations IRI Immunoreactive insulin - BG blood glucose - CPR C-peptide immunoreactivity - HCP human C-peptide - BW body weight     

Hyperinsulinism in infancy

Abstract Five infants with persistent hypoglycaemia due to hyperinsulinism were reported. Provocative tests for insulin release were unhelpful. Diazoxide was useful in the treatment of three patients but many side-effects were observed. These included petechial rash, hypertrichosis, acute renal failure, fluid retention and cardiac failure. Two patients underwent spontaneous remission. Three patients had nesidioblastosis, two of whom were subjected to 95% pancreatectomy. Postoperatively, recurrence of hypoglycaemia was due to hyperinsulinism in one patient and to presumed glucagon deficiency in the other. Phenytoin effectively corrected the hypoglycaemia in the patient who had postoperative hyperinsulinism. It is recommended that medical therapy with diazoxide (10–15 mg/kg per day) together with a diuretic be commenced once hyperinsulinism is diagnosed. Subtotal pancreatectomy should be performed early in these patients if hypoglycaemia cannot be controlled with medical therapy or if side-effects of treatment are documented.     

Complications of diazoxide treatment in persistent neonatal hyperinsulinism.

Seven infants with persistent neonatal hyperinsulinism were treated in Dhahran Health Centre from 1983 to 1986. The insulin:glucose ratio (serum insulin concentration pmol/l) divided by the blood glucose concentration (mmol/l) ranged from 12 to 636, mean (SD) 177 (201). To control hypoglycaemia, diazoxide (12-24 mg/kg/day) was given in a continuous intravenous glucose infusion (12-22 mg/kg/min) on 11 separate occasions, four infants twice each and three infants once each. An increase of more than one standard deviation in the heart and respiratory rates, together with other symptoms of heart failure, was considered to be evidence of diazoxide toxicity. Cardiorespiratory failure (toxicity) occurred on eight of the 11 occasions (73%) in seven infants. The average daily fluid intake, weight change, respiratory rate and heart rate before treatment were similar whether or not the infant developed toxicity. A diazoxide toxicity index was obtained by multiplying the dose of diazoxide by the insulin:glucose ratio to relate the diazoxide dose to the severity of the disease. In all instances when the toxicity index was more than 1533 (mean (SD) 3732 (2741) cardiac toxicity developed. In contrast, infants with a toxicity index of less than 675 (mean (SD) 364 (270), had no symptoms of toxicity. Symptoms were significantly related to the severity of the disease and the diazoxide dose. It is possible to use the toxicity index to predict the risk of toxicity and to calculate a safe dose of diazoxide in infants with persistent neonatal hyperinsulinism.     

Hyperinsulinism in infancy

Five infants with persistent hypoglycaemia due to hyperinsulinism were reported. Provocative tests for insulin release were unhelpful. Diazoxide was useful in the treatment of three patients but many side-effects were observed. These included petechial rash, hypertrichosis, acute renal failure, fluid retention and cardiac failure. Two patients underwent spontaneous remission. Three patients had nesidioblastosis, two of whom were subjected to 95% pancreatectomy. Postoperatively, recurrence of hypoglycaemia was due to hyperinsulinism in one patient and to presumed glucagon deficiency in the other. Phenytoin effectively corrected the hypoglycaemia in the patient who had postoperative hyperinsulinism. It is recommended that medical therapy with diazoxide (10-15 mg/kg per day) together with a diuretic be commenced once hyperinsulinism is diagnosed. Subtotal pancreatectomy should be performed early in these patients if hypoglycaemia cannot be controlled with medical therapy or if side-effects of treatment are documented.     

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patient was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m ² per minute). Results from the 120 mU/m ² per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 ± 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 ± 1.1, patients with CF = 10.2 ± 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance ( r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes. (J Pediatr 1997;130:948-56)