Assessment of Nifedipine Therapy in Hyperinsulinemic Hypoglycemia due to Mutations in the ABCC8 Gene.

CONTEXT: Previous case reports have documented the effectiveness of l-type calcium channel blockers (such as nifedipine and verapamil) for treating different forms of hyperinsulinemic hypoglycemia (HH). OBJECTIVE: To systematically assess the glycemic response to nifedipine therapy in 11 patients with HH due to mutations in the ABCC8 gene. DESIGN: Dose escalation of nifedipine therapy. SETTINGS AND PATIENTS: Eleven children who were inpatients at a tertiary hospital and had diazoxide unresponsive HH due to mutations in the ABCC8 gene. INTERVENTION(S): Nifedipine was administered orally at an escalating dose up to a maximum of 2.5 mg/kg/d. MAIN OUTCOME MEASURES: Improvement in glycemic control, avoidance of hypoglycemic episodes, reduction of intravenous glucose infusion, and reduction in the requirements of other medical therapies. RESULTS: The median age of the patients was 0.44 years (range 0.14 to 3.77). The ABCC8 gene mutations were homozygous in 3 cases, paternally inherited heterozygous in 4, and compound heterozygous in 4. 18F-DOPA PET/CT scan demonstrated a focal lesion in 2 cases and the rest were diffuse HH disease. One subject had nifedipine as monotherapy, whereas the rest had it in combination with octreotide/glucagon/diazoxide or cornstarch. After a median of 6.5 (3 to 23) days of maximal (2.5 mg/kg/d) dose of nifedipine therapy, none of the patients showed any improvement in glycemic control and patients continued to have hypoglycemic episodes. CONCLUSIONS: HH due to mutations in the ABCC8 gene does not respond to nifedipine therapy. Mutations in the KATP channel genes might render the l-type calcium channel ineffective to therapy with nifedipine.

Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact.

Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic ß cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life.

Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy.

CONTEXT: Octreotide, a somatostatin analog, is commonly used in diazoxide unresponsive congenital hyperinsulinism (CHI) patients as a second-line therapy. OBJECTIVE: The aims of this study were to evaluate the dose range, side effects, and long-term follow-up of octreotide therapy in a large cohort of CHI patients. SETTING: The study was conducted at an international referral center for the management of CHI. PATIENTS: Twenty-eight (17 males) diazoxide unresponsive CHI patients (15 biallelic and 10 monoallelic ATP sensitive potassium channel mutation) managed with daily multidose octreotide therapy between 2001 and 2013 participated in the study. MAIN OUTCOME MEASURES: Regular follow-up of auxology, growth factors (serum IGF-1 and IGF binding protein 3 levels), thyroid functions, liver function tests, and hepatobiliary ultrasonography were measured. RESULTS: The median age of CHI diagnosis was 1 week (range 1-80 wk). The mean (±SD) dose of octreotide required was 17.8 (±7.5) µg/kg · d (range 7.5-30 µg/kg · d). The mean (±SD) duration of follow-up on octreotide therapy was 52.4 (±33.8) months (range 6 mo to 9.5 y). Elevation of liver enzymes was the most prevalent side effect (n = 13; 46.4%), which resolved spontaneously. Gallbladder pathology was detected in nine patients (32%). Mean (±SD) duration of octreotide therapy before the development of gallbladder pathology was 4.3 (±4.6 mo), whereas 19 patients were free of gallstones after a follow-up of 53.6 ± 32.9 months on octreotide therapy. There was no relationship between the dose or the duration of octreotide therapy and development of gallbladder pathology or liver dysfunction. CONCLUSIONS: Transient elevation of liver enzymes and asymptomatic gallbladder pathology were the most prevalent long-term side effects of octreotide therapy. There was no correlation between the dose or the duration of octreotide therapy and development of liver dysfunction and gallbladder pathology.