Subjects

All children referred to the Leeds General Infirmary during the past 18 years for surgical management of PHHI were contacted. In total there were 12 children: one died in the postoperative period from sepsis (1984); one has since moved out of the region; and four did not give consent for investigation; the remaining six patients were involved in this study. We also traced one child (patient 7) who was managed medically without recourse to surgery and who was willing to participate. Median gestational age was 41 weeks (range 35–41), and median birth weight 4600 g (range 2020–5200), which placed four of the seven children above the 97th centile for weight at birth. There were five girls and two boys. Median age at pancreatic resection was 91 days (range 26 days to 2.2 years). Median age at the time of the pancreatic function study was 4.3 years (range 1.0–14.9) (table1).

Results

Of the 13 children who have had PHHI over the past 18 years, 12 were managed surgically, with one death in the postoperative period. A 95% pancreatectomy was undertaken in all children with PHHI after 1990. Before this date, lesser resections were done as this was considered to be the best procedure at that time. No child required a further pancreatic resection because of postoperative hypoglycaemia. Six of the children were available for detailed study of pancreatic function together with an additional child who had not undergone surgery (table 1). Of these seven children (table 2), two continue to require diazoxide to prevent hypoglycaemia; one is nearly 12 months on from a 95% pancreatectomy (patient 5) and the other is 13 years old and has not had a pancreatic resection (patient 7). One child has developed insulin dependent diabetes requiring Mixtard 20/80—18 units in the morning and 8 units in the evening (weight 57 kg). Two children still require gastrostomy/jejunostomy supplementary feeds to maintain blood glucose concentrations. One child takes 1 capsule of Creon (pancreatin; Duphar, Southampton, UK) with meals because of steatorrhoea and another has intolerance of fatty foods, causing diarrhoea, but is not on enzyme supplementation. Two children have severe developmental delay and fits—one underwent 95% pancreatectomy at 26 days of life (patient 2) because of intractable hypoglycaemia and the other child did not undergo pancreatic resection (patient 7).

Pancreozymin-secretin stimulation tests (table 3) showed slightly decreased amylase activity in one child (patient 2); slightly decreased lipase activity in one (patient 7); decreased lipase and amylase in one (patient 5); and frankly abnormal test results in the four other children,13 including the child on pancreatic supplements and a girl with fatty food intolerance. The other two children did not have steatorrhoea or evidence of malabsorption. We also measured duodenal juice elastase activity although there are as yet no available normal values for children.

Fat soluble vitamin concentrations were generally within the lower limit of the normal reference range although four children had subnormal vitamin A concentrations (table 4). Clotting studies were all normal. Despite the fact that faecal chymotrypsin has been considered the best non-invasive test of pancreatic insufficiency,15only one child had a value below the normal reference range in agreement with her very abnormal pancreozymin secretin test. Interestingly, patient 7 who did not have pancreatic resection showed the highest faecal chymotrypsin value and duodenal juice amylase, chymotrypsin, and elastase values.

Three of the children (patients 1, 2, and 4) had glucose tolerance tests done according to WHO criteria.16 Fasting and 120 minute serum glucose values (mmol/l) after a standard 1.75 g/kg body weight glucose load were 4.2, 3.0; 5.2, 6.0; and 4.2, 4.0 respectively.

MRI and ultrasound imaging of the pancreas visualised only small remnants of pancreatic tissue in the region of the head of the pancreas around the common bile duct consistent with an 85–95% pancreatectomy (fig 1), apart from patient 7 who had not had pancreatectomy. Significant pancreatic regeneration could not be shown in any of the children, although immediate postoperative scans were not available for comparison. Ultrasonography of the pancreatic remnant yielded less detailed images of the pancreatic remnant than MRI.

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Figure 1

MRI showing the remnant of the pancreatic head (T2 weighted image at the level of the renal hila).

Discussion

The diagnosis of PHHI must be considered in any infant with refractory hypoglycaemia. Early diagnosis and appropriate treatment is imperative to prevent hypoglycaemic injury to the neonatal brain.17 Some infants, especially those presenting after the first few months of life, may be more receptive to medical interventions alone and successful medical treatment in up to 75% of cases has been reported.1 2 A significant proportion of children will, however, require surgical resection of the pancreas to control the hyperinsulinaemia. Two extensive reviews of the literature on surgical resection for PHHI spanning the years 1934–76 and 1977–87 have addressed the controversy about the extent of pancreatectomy. The first review showed an overall mortality rate of 10% and an incidence of 54% mental retardation in survivors. Eighteen per cent of patients undergoing < 90% pancreatic resection required further pancreatic resection.18 In the second series of 165 neonates, one quarter underwent 95–98% pancreatectomy with a mortality of 2.4% (one death) and an overall mental retardation rate of 12.5%; only 4.8% (two patients) required a further pancreatic resection. This compared with a 28% reoperation rate in the other three quarters having less than a 95% pancreatectomy.19 From this and other studies, a so-called 95% pancreatectomy is generally accepted as the surgical treatment of choice. Postmortem examinations of the pancreas indicate that in practice this resection, in which only a small remnant of pancreas is left between the common bile duct and the duodenum,5 is less prone to anatomical variability.20

Pancreatic regrowth has been implicated as a possible cause for postoperative failure of glycaemic control in children with PHHI undergoing pancreatic resection. Postoperative regeneration has been shown using imaging techniques and confirmed at reoperation.21 22 The degree of pancreatic regeneration is unpredictable but can apparently be extensive, although long term pancreatic imaging has not been previously reported. We were unable to show any evidence of significant pancreatic regrowth after pancreatic resection in any of our children using ultrasound and MRI imaging, although residual pancreatic head tissue was clearly shown. Pancreatic regrowth may therefore be a compensatory response to surgical resection and may represent only a temporary phenomenon that disappears over time.

Since 1987 there have been several other studies concerning the extent of pancreatic resection and addressing the long term follow up of these patients (table 5).10 11 22-28 In all treatment groups, mental retardation continues to be a significant complication of this condition with an overall incidence of 15%. Our rate of 29% is unduly high but may simply reflect our small sample size.

The incidence of insulin dependent diabetes appears to relate not only to the extent of primary pancreatic resection but also to length of follow up. Leibowitz et al found that all six children reaching puberty who had undergone “subtotal” pancreatectomy for neonatal PHHI developed diabetes mellitus.10 Similarly, Shilyansky et al showed a 69% incidence of diabetes mellitus in children with PHHI followed up for more than four years,11 and all patients older than 14 years had diabetes. These findings support the β cell maturation hypothesis discussed previously. Patient 6 in our study was in early puberty and had developed insulin dependent diabetes mellitus at 9 years of age. Patient 7 was pubertal but did not have diabetes and had not had a pancreatic resection, again supporting the hypothesis that surgical resection may advance the end stage of the condition with β cell failure.4 10 Glucose tolerance tests taken in our three young children not on diazoxide (patients 1, 2, and 4) are currently in the normal range and one could surmise that their β cells are at the stage of maturation rather than failure.

Pancreatic exocrine function has not been previously studied in detail in children who have had a pancreatic resection for PHHI. The studies that table 5 summarises have generally defined pancreatic exocrine failure in terms of clinical requirement for pancreatic enzyme supplementation. Overall, only 5% of children were taking pancreatic enzyme supplements—10% of those after 95% pancreatectomy and 6% of those after 75–90% resection. We have shown from the pancreozymin secretin tests that all of our children have subclinical exocrine insufficiency and it is likely that they will all ultimately develop exocrine failure. Whether the extent of the pancreatic resection or simply the age of the child is the dominant factor in ultimate exocrine failure is unknown, but it is interesting to note that our 13 year old pubertal girl, who had not had surgery, recorded the highest enzyme activity, other than lipase, of all the children.

The aetiology of PHHI has still not been fully determined and more than one cause is possible. In 1994 a “PHHI gene” was localised to chromosome 11,29 and later that same year mutations in the sulphonylurea receptor (SUR) gene were implicated.30 31The SUR, a subunit of the β cell membrane’s ATP dependent potassium channel, is involved in regulation of insulin secretion. Gene mutations leading to a defective SUR protein may disrupt the activity of the potassium channel causing excessive insulin secretion. If it were possible to modulate activity of the SUR medically it may offer an alternative to surgical intervention. Not only would this negate the need for complex pancreatic surgery but it may also postpone or prevent the progression to end stage β cell failure. In vitro studies indicate that calcium channel blockers may be able to reversibly block insulin secretion from the β cells of patients with PHHI,32 and this may allow the development of new therapeutic strategies in this disabling condition. However, the transgenic mouse model of hyperinsulinaemia suggests that β cell maturation and premature death may be inevitable in PHHI,12 and our study supports this. It is important to be aware of the possible development of pancreatic failure in children with PHHI and investigate pancreatic function regularly.