Pediatrics International | 2021
Propranolol for infantile hemangiomas with hyperinsulinemic hypoglycemia
Abstract
A congenital portosystemic shunt (CPSS) is a rare congenital malformation (1 in 30 000 newborns), but is detected in approximately 50% of infants with hypergalactosemia in neonatal mass screening. Because portal blood flows directly into the systemic circulation, CPSS is associated with hypergalactosemia, hyperammonemia, hyperbileacidemia, hypermanganesemia, hepatopulmonary syndrome, portal pulmonary hypertension, and hyperinsulinemic hypoglycemia (HH). HH with CPSS is also rare, and surgical treatment of the shunt is required in uncontrolled HH, especially in cases with a congenital extrahepatic portosystemic shunt (CEPS). The b-blocker propranolol was recently reported to be effective for treating infantile hemangiomas (IHs). However, hypoglycemia is an infrequent (0.4 0.6%) but serious side effect of propranolol treatment. Herein, we present a case of an infant with a CEPS, HH, and multiple IHs who was successfully treated with propranolol without hypoglycemia. Written informed consent for publication of this report was obtained from the patient’s parents. An 18-day-old girl was referred to a local hospital because of hypergalactosemia detected at a neonatal mass screening. Multiple IHs distributed throughout her body appeared from birth, and then gradually increased (Fig. 1a, b). Abdominal ultrasonography showed no intrahepatic hemangioma. Although her galactose level was normalized after lactose-free milk intake, a CEPS was detected and she was admitted to our hospital (Fig. 1c). Treatment with low-dose propranolol (1.0 mg/kg/day) was started for multiple IHs and then asymptomatic hypoglycemia (<40 mg/dL) was observed. However, there were no serious symptoms, such as convulsions or consciousness disturbance, and her blood glucose level recovered rapidly after feeding. A high immunoreactive insulin level (11.4 μU/mL) was observed in the hypoglycemic state and the glucose infusion rate required to maintain blood glucose levels was also high (10.0 mg/kg/min). Therefore, she was diagnosed with HH. Propranolol was discontinued and frequent feeding, oral diazoxide, medium chain triglyceride oil, and special milk for glycogen storage disease were administered to alleviate the side effects of propranolol and HH. Her hypoglycemia improved considerably with these treatments. The patient was transferred to a specialized hospital for definitive treatment of the CEPS, which involved a successful shunt occlusion with endovascular therapy. Her HH and other symptoms related to the CEPS (e.g., hypergalactosemia, hyperammonemia, and hyperbileacidemia) improved. Low-dose propranolol (0.5 mg/kg/day) was carefully re-administered with frequent blood glucose monitoring and the dose was gradually increased to 3.0 mg/kg/day. No hypoglycemia was observed during propranolol treatment and her multiple IHs reduced in size (Fig. 1d). Hypoglycemia is a serious side effect of propranolol treatment. Propranolol impairs the counter-regulatory response to hypoglycemia and blocks the adrenergic warning signs of hypoglycemia. Although this is a rare event, there may be an increased risk in patients with preexisting conditions that cause hypoglycemia. Additionally, there may be individuals with a latent high risk of hypoglycemia, including those with congenital hyperinsulinism, glycogen storage disease, defects in gluconeogenesis, and fatty acid oxidation disorders. For early detection of hypoglycemia, clinicians should always consider the contribution of metabolic diseases, and blood glucose levels should be closely monitored after propranolol administration, including following induction and dose increases. Most episodes of hypoglycemia occur after an overnight to 24-hour fast, and occasionally occur in the setting of poor oral intake in the preceding days. Infants appear to be at higher risk for hypoglycemia than adults because their glucose utilization rates are higher in the fasting state and their glycogen stores are low. Therefore, caregivers need to be educated on how to prevent hypoglycemia (e.g., administer propranolol after feeding, avoid fasting, and stop when the patient has an illness). The present case had multiple IHs throughout her body, with a severe risk of disfigurement, ulceration, and bleeding. Thus, early propranolol treatment was required. However, in addition to hypoglycemia owing to the CEPS before treatment, asymptomatic hypoglycemia occurred with low-dose propranolol, which made continuation of treatment difficult. We considered that propranolol exacerbated her HH. Thus, propranolol was stopped and the patient was treated with nutritional therapy, diazoxide, and endovascular therapy. After treatment for CEPS, propranolol was safely administered without hypoglycemia and all the hemangiomas improved. This is Correspondence: Michio Ozeki, MD PhD, Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu 501-1194, Japan. Email: [email protected] Received 9 July 2020; revised 27 August 2020; accepted 7 September 2020. doi: 10.1111/ped.14471