A term male infant was born to non-consanguineous Asian parents by caesarean section. Maternal antenatal screen was unremarkable. His birth weight was 3230 g (50th–90th percentile) and length and head circumference were gestational age-appropriate. Apgar scores at birth were 9 at 1 min and 10 at 5 min. He was non-dysmorphic and systemic examination was unremarkable. At 3 h of life, he was noted to be lethargic and on checking his blood glucose level it was unrecordable. He was treated with i.v. glucose infusion and s.c. glucagon but remained hypoglycaemic even on a GIR of 12.6 mg/kg per min.
Q What is the definition of hypoglycemia in a neonate ?
Two consecutive readings of blood sugar <40 mg/dl or 1 reading <25 mg/dl
Q When does nadir of blood sugar occur after birth and when does it normalize ?
- Nadir is seen 2-4 hrs after birth
- Normalizes by 6 hrs
Q Broadly speaking , what are the causes of hypoglycemia in neonates ?
- Congenital hormone deficiency
- Cortisol deficiency
- Inborn errors of metabolism
- Glycogen storage disorders
- Disorders of gluconeogenesis
During an episode of hypoglycaemia (20 mg/dl), his insulin level was 11.7 mU/l (Fig. 1). The serum growth hormone, lactate, ammonia and acylcarnitine levels were normal. His blood glucose levels normalised with a GIR of 16.4 mg/kg per min.
Q What insulin level during hypoglycemia suggests hyperinsulinemia ?
When blood glucose is <50 mg/dl, Insulin levels >5 mIU/ml is considered inappropriate and we should consider evaluation for hyperinsulinemia
Q What are causes of hyperinsulinemic hypoglycemia in children ?
- Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)
- Beckwith Weidman syndrome
- Insulinoma (rare)
- Insulin administration (accidental / malicious intent)
- Oral hypoglycemia agent administration
Q What is the most likely diagnosis in this case ?
Most likely diagnosis would be PHHI. However rarely insulinoma can present in infancy and must be ruled out. Beckwith Weidman can be ruled out because it has characteristic clinical features.
Q What are features of Beckwith Weidman syndrome ?
- Hyperinsulinemic hypoglycemia
- Abdominal wall defects and umbilical hernia
- Renal abnormalities
Q What are other names of Persistent hyperinsulinemic hypoglycemia of infancy ?
- Congenital hyperinsulinism
- Primary islet cell hypertrophy (nesidioblastosis)
- Familial hyperinsulinemic hypoglycemia
Q What are clinical features of PHHI ?
- Severity of Hypoglycemia varies depending on the mutation
- In many cases it presents at birth and in many presentation may be delayed by 1-2 years
- Because of specificity spill over of Insulin acting on IGF1 receptor
- It is similar to macrosomia seen in infants of diabetic mothers
When feeds were commenced, hypoglycaemia recurred. The patient was started on diazoxide (with hydrochlorothiazide) at 10 mg/kg per day on day 3 and then increased to 20 mg/kg per day but continued to have persistent hypoglycaemia. As the patient failed to respond to diazoxide, s.c. octreotide was started at the dose of 10 μg/kg per day. His blood glucose profile remained labile and hence the dose of octreotide was increased to 20 μg/kg per day. As the patient was medically unresponsive to diazoxide, genetic studies were undertaken for the cause of HH.
Q Which are two most common genetic mutation tested for in patients with PHHI ?
- ABCC8 gene- encodes SUR1 subunit of K-ATP channel
- KCNJ11 gene- encodes for Kir6.2 subunit of K-ATP channel
Q Can the disease spontaneously resolve ?
Yes. Spontaneous resolution after period of diazoxide therapy has been reported. The exact reason for this phenomenon is not known.
Genetic studies were done in the molecular genetics laboratory in Exeter, UK. Sequence analysis for the ABCC8 gene showed a paternally inherited heterozygous missense mutation (p.D1472N; c.4414G>A) and failed to detect a change from the normal sequence in the KCNJ11 gene. A second ABCC8 mutation of maternal origin was not found by sequence or dosage analysis multiplex ligation-dependent probe amplification (MLPA). The sequence analysis included the coding regions, conserved splice sites and a recently reported deep intronic splicing mutation. This paternally inherited ABCC8 (p.D1472N) mutation was previously reported in a patient with a focal (tail) pancreatic lesion.
As 18F-DOPA-PET/CT was unavailable locally in our country, 68G–DOTATATE-PET nuclear scan was done but the results were non-conclusive. A pre-operative high-resolution ultrasound scanning was attempted and a questionable small nodular focus, which distorted the anterior contour at the junction of the pancreatic body and medial tail region, was identified.
The patient failed to respond to diazoxide (up to 20 mg/kg per day) and his blood glucose levels could only be kept stable on a high dose of s.c. octreotide infusion. He therefore underwent partial pancreatectomy (50%) on day 103 of life, leaving the head and part of the body of pancreas. Post-operatively, he continued to have persistent HH and the GIR remained high at 17 mg/kg per min to maintain normoglycaemia despite being on 20 μg/kg per day octreotide. Histopathological examination of the resected pancreas showed absence of any focal lesions. The pancreas had normally sized to large islets. The islets showed scattered endocrine cells with large and hyperchromatic nuclei. These changes are consistent with typical diffuse disease. Owing to the persistent hypoglycaemia, he subsequently underwent a subtotal pancreatectomy (95%) on day 183 of life. In the immediate post-operative period, he required a GIR of 10 mg/kg per min to maintain normal blood glucose levels, but over the next 2 weeks, his blood glucose levels stabilised.
Q Why is it important to differentiate between focal vs diffuse disease ?
The surgical management differs in focal vs diffuse disease. There is very little that you can do to preoperatively differentiate between focal and diffuse disease. Focal disease does well with partial pancreatectomy. Diffuse disease requires more extensive surgery in form of near total pancreatectomy.
The patient required nasogastric tube feeding due to poor oro-pharyngeal coordination and he achieved full enteral feeds by the 30th post-operative day. Gastro-oesophageal reflux disease was treated with anti-reflux medication. He was discharged on day 244 of life with pre-feed home blood glucose monitoring and once-daily injections of octreotide (10 μg/kg per day), which was later discontinued on day 301 of life. His growth and neuro-developmental assessment at the age of 1 year was normal.
- Genetic testing for hyperinsulinemia should be done in which patients ?
- Persistent hypoglycemia with hyperinsulinemia and hypoketonemia
- Requiring Glucose insfusion > 8 mg/kg/min to maintain Euglycemia
Q What is the indication to do a F18-DOPA-PET CT in PHHI patients ?
If genetic mutation had been previously associated with focal disease, F18 DOPA PET scan can help locate focal disease. Presence of focal disease helps in surgical management of the patient.
Q Why is hyperinsulinemic hypoglycemia in infants particularly dangerous ?
It is dangerous because the brain receives no fuel. Primary source of fuel is glucose which is cut off while insulin inhibits ketogenesis and secondary fuels (ketones) are also cut off.
Q What is the characteristic biochemical picture of hyperinsulinemic hypoglycemia ?
- Low blood sugar
- Insulin level >5 mIU/ml during low blood sugar
- Low Serum Ketones
- Low Serum fatty acid level
- Preserved response to glucagon in prolonged fast
Q What is the importance of paternally inherited mutation in PHHI ?
Paternally inherited mutations tend to have more focal form then diffuse form.
Q What is the difference between recessive and dominantly inherited mutation in PHHI ?
Recessive mutations tend to be more severe and often Diazoxide resistant. Dominant forms are generally responsive to diazoxide.
Q What are two common side effect of Diazoxide use ?
- Fluid retention
Learning points from this case
- Persistent Hyperinsulinemic hypoglycemia of infancy (PHHI) is an important cause of neonatal hypoglycemia
- Hyperinsulinemic hypoglycemia is diagnosed by insulin level >5 mIU/ml when the blood sugar is <50 mg/dl
- ABCC8 and KCNJ11 are two common sites for mutation in PHHI
- F18 DOPA PET can help localize focal disease in PHHI which can help surgical excision.