Diazoxide-responsive hyperinsulinaemic hypoglycaemia in tyrosinaemia type 1

Abstract

Summary Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1. Learning points Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia. If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected. Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects. The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Case report: Two unexpected cases of DGUOK-related mitochondrial DNA depletion syndrome presenting with hyperinsulinemic hypoglycemia

“…Regardless, if there is evidence of HI, treatment with diazoxide may be of benefit because recurrent hypoketotic hypoglycemia may be contributing to the progressive neurologic dysfunction observed in these patients. Diazoxide-responsiveness has already been demonstrated in patients with tyrosinemia type 1 and HI, further supporting this treatment strategy for DGUOK deficiency (19).…”

Physical Growth of Patients with Hereditary Tyrosinaemia Type I: A Single-Centre Retrospective Study

“…In our cohort, 3 children presented with hyperinsulinemic hypoglycemia, one was treated with diazoxide and 2 with additional glucose polymers in early infancy. Hypoglycemia in young infants with HTI is not uncommon [ 37 , 38 , 39 , 40 , 41 ]. The exact cause is undetermined, some describing histological abnormalities of the pancreas with an increased number of islets of Langerhans and hypertrophy [ 40 , 42 ], while others suggest impaired gluconeogenesis due to poor hepatic function and/or reduced hepatic clearance or insufficient glycogen stores [ 43 , 44 ].…”