Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), formally known as nesidioblastosis, is a glucose metabolic disorder characterized by hypoglycemia and inappropriate secretion of insulin 1. The disease includes focal and diffuse forms, both of which have a similar clinical presentation. Its incidence in the general population is one of 50 000 live births 2, but in areas with high-consanguineous unions the incidence may be as high as one of 2500 live births 3. The familial form may be caused by autosomal recessive or dominant defects in the sulfonylurea receptor gene 4, the potassium inward-rectifying receptor (Kir6.2) gene 5, the glutamate dehydrogenase gene 6, or the glucokinase gene 7. The chromosome involved is 11p14-15.1. Babies with PHHI run a high risk of severe neurologic damage secondary to severe hypoglycemia unless immediate and adequate steps are taken 8. These steps should include high-glucose infusion and medical treatment with diazoxide, octreotide (somatostatin analog), and nifedipine. However, surgery should be considered if medical treatment is not successful 9.
Patients and methods
We have retrospectively analyzed the charts of six children at Riyadh Military Hospital, Riyadh. They were diagnosed with PHHI in 1990. Four children (three girls and one boy) belonged to the familial group and two were in the sporadic group. The disease was diagnosed on the basis of high-insulin levels, low-glucose levels, and a high insulin-to-glucose ratio. All patients underwent assessment of lactate, pyruvate, and ammonia levels, as well as growth hormone, cortisol, and thyroid hormones. Urinary organic acid screening and tandem mass spectrometry were also performed. Radiological assessment was made by MRI of the brain and by ultrasound examination of the abdomen. Our management policy was to maintain blood sugar level at more than 70 mg/dl (3.88 mmol/l). Medical therapy included diazoxide (maximum dose: 25 mg/kg/day) and octreotide (maximum dose: 40 mg/kg/day), glucagon injection (as required) and intravenous glucose infusion (15 mg/kg/min). If medical therapy as initial management failed (lack of response), the patient was subjected to near-total (90–95%) pancreatectomy. Surgery was performed by an open technique. Blood sugar was monitored frequently postoperatively. If the patient remained hypoglycemic (blood glucose<2 mmol/l), medical therapy was started. Glucose infusion was continued and adjusted according to blood sugar levels.
All babies were born after full-term pregnancies. The birth weights ranged from 3.3 to 3.8 kg (median: 3.6 kg). There were six patients (four girls and two boys). One family had four affected children. At the time of this study, patient age ranged from 6 months to 17 years (median age: 8 years). Age at diagnosis ranged from a few hours after birth to 2½ months. Age at surgery ranged from 1 to 6 months (median: 3 months) (Table 1).
Hypoglycemic convulsion was the most common presenting complaint. All patients had inappropriately elevated levels of insulin during episodes of hypoglycemia ranging from 12 to 125 mU/ml. The insulin-to-glucose ratio was high for all patients, and all patients required glucose infusion rate greater than 15 mg/kg/min. All patients had normal growth hormone, cortisol, and thyroid hormone levels. Lactate, pyruvate, and ammonia levels were also normal. Urinary organic acid screening and tandem mass spectrometry screening were negative for all patients. MRI of the brain was significant for two patients who later developed epilepsy. Ultrasound examination of the abdomen was unremarkable. All patients were started on diazoxide, octreotide, and glucose infusion. In addition, glucagon was given (as required) PRN. The medical treatment was considered a failure when patients, despite undergoing maximum treatment, had hypoglycemic episodes. All patients required surgery after failure of medical treatment. Three patients underwent 95% pancreatectomy, two patients underwent 90% pancreatectomy, and one patient underwent 70% pancreatectomy. Two patients (one who underwent 90% pancreatectomy and another who underwent 95% pancreatectomy) had repeated hypoglycemic episodes that required medical treatment after surgery, which later required a second surgery. Obvious overgrowth of the remaining pancreas was observed during the second surgery of the patient who underwent 95% pancreatectomy, which was performed 4 months after the first surgery.
Three patients developed diabetes: two at 10 years of age, including one who had 70% pancreatectomy, and one at 1 year of age. None of the patients had exocrine insufficiency or developmental delay. Two patients developed epilepsy later (Table 2). There was no mortality. All patients continue to be followed at the clinic. Histology for all patients revealed diffuse nesidioblastosis.
We have presented the clinical outcome of six patients with PHHI who underwent surgery after failure of medical treatment with a mean follow-up of 8.25 years. Most of the cases are sporadic. However, in our series we had four patients from the familial group (66.6%) and two from the sporadic group (33.2%). Insulin-dependent diabetes developed in three out of six (50%) treated children (two at the age of 10 years and one at the age of 1 year). Other investigators have found that diabetes develops in 56% of children having near-total pancreatectomy 9. We found that older age at surgery leads to greater risk of diabetes, in agreement with previous studies 10. This finding relating age at surgery and development of diabetes needs confirmation with larger case series before they can be generalized. Two children were hypoglycemic after surgery, requiring medical treatment, which later required second surgery. One patient underwent 90% pancreatectomy during the first surgery and the other underwent 95% pancreatectomy. Overgrowth of the remaining pancreas was observed in one patient who underwent 95% resection. Postpancreatectomy pancreatic regrowth in four infants with PHHI has also been documented in other studies 9,11. Postpancreatectomy regrowth is well documented in experimental models 12. The patient who underwent 70% pancreatectomy (the first case in our series) was operated upon by a general surgeon who was covering the service of pediatric surgery at that time. This might explain the underestimation of the actual percentage of the pancreatectomy in this case, which did well postoperatively.
All patients were developmentally normal and two patients (33.3%) were diagnosed with epilepsy after a few years as compared with 64% of patients with developmental delay in another series 13, possibly associated with delayed treatment.
In our cases, age at diagnosis ranged from a few hours after birth to 2½ months (median age, few hours). This is because most of our patients were from the same family and had been admitted soon after birth to the Neonatal Intensive Care Unit for workup.
The earlier the age at diagnosis, the better the neurological outcome. Delayed surgery might be associated with higher risk of development of diabetes. Pancreatectomy 90–95% is the treatment of choice for PHHI not responsive to medical treatment.
Conflicts of interest
There are no conflicts of interest.
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