ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Clin Endocrinol (Oxf). 2019 Dec;91(6):770–775. PMID: 31520536

Diazoxide is the first line treatment for patients with hyperinsulinaemic hypoglycaemia (HH). The vast majority of patients tolerate diazoxide well without any major complications. However, diazoxide is known to cause several side effects including hypertrichosis, neutropaenia, thrombocytopaenia, hyperuricaemia and fluid retention. Pulmonary hypertension (PH) is a rare side effect of diazoxide and has been documented in several previous studies in addition to this study. The US Food and Drug Administration (FDA) issued a safety alert in September 2015 cautioning that diazoxide could lead to PH, which is characterized by an elevation of the pulmonary arterial pressure that consequently increases right ventricular afterload and results in right heart failure. Interestingly there are genetic causes of primary pulmonary hypertension due to defects in one of the genes (ABCC8 ) which also leads to congenital hyperinsulinism (1). The underlying risk factors and mechanisms which trigger PH in patients who are treated with diazoxide are not known. Potential risk factors based on a previous study include being born premature, respiratory failure and congenital heart disease (2).

This current study from four HH Centers in the UK supports the fact that having underlying congenital heart disease (ventricular and atrial septal defects in particular) seems to be an important risk factor for developing PH and therefore recommends that patients should have a baseline echocardiogram prior to commencing treatment with diazoxide. In addition, this study suggests that the total fluid volume before commencing diazoxide therapy might also be a potential risk factor. Although PH has been reported in association with diazoxide treatment, it is difficult to directly link diazoxide with PH. Diazoxide is a known vasodilator of vascular smooth muscle and has been used to treat hypertension in adults, in whom there are no reports of PH on diazoxide. This suggests that the mechanism/s of PH in HH patients treated with diazoxide are probably multifactorial and not just due to diazoxide per se. As diazoxide is known to cause fluid retention, as a general recommendation any newborn started on diazoxide must have careful monitoring of fluid balance. The mechanisms that lead to PH due to diazoxide need further investigations.

References:

1. Bohnen MS, Ma L, Zhu N, et al. Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circ Genom Precis Med. 2018;11(10):e002087.

2. Herrera A, Vajravelu ME, Givler S, et al. Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. J Clin Endocrinol Metab. 2018;103(12):4365–4372.