Nocturnal Hypoglycemia in ACTH and GH Deficient Children
Nocturnal Hypoglycemia in ACTH and GH Deficient Children
Objectives To evaluate the usefulness of continuous glucose monitoring (CGM) to identify nocturnal hypoglycaemia in children affected by combined ACTH and GH deficiency and to optimize the hydrocortisone replacement therapy in these patients.
Study design Eleven patients with ACTH and GH deficiency (five boys and six girls, age 1·6–16·8 years) underwent CGM for 36 h, including two nights. At least two consecutive glucose levels <2·78 mm were considered hypoglycaemic episodes. The differences in age and doses of hydrocortisone and recombinant human growth hormone (rhGH) between children with and without hypoglycaemia were analysed. The percentage of the glucose values <3·33 mm and the mean glucose levels were also evaluated.
Results Continuous glucose monitoring demonstrated nocturnal hypoglycaemia lasting from 30 to 155 min (1·5% of the total monitoring time) in three cases (27%). No statistically significant differences in age and rhGH dose were observed between children with or without hypoglycaemia. Conversely, the difference in the hydrocortisone doses between the patients with and without hypoglycaemia resulted statistically significant (5·9 vs 8·5 mg/m/day; P = 0·04). Eight patients presented glucose values less than 3·33 mm during 5% of the total monitoring time. Hydrocortisone dose showed significant positive linear relation with mean glucose level (r = 0·79, P = 0·0035) and inverse relation with time lags of glucose levels under 3·33 mm (r = −0·65, P = 0·03).
Conclusions Our study shows that CGM may represent a valuable tool to detect nocturnal asymptomatic hypoglycaemic episodes and optimize the hydrocortisone therapeutic regimen in children with ACTH and GH deficiency.
Congenital central adrenal insufficiency (CAI), presenting alone or, more frequently, associated with GH deficiency (GHD), is a rare condition. It is characterized either by impaired synthesis and release of ACTH from the pituitary gland, or by impaired release or action of hypothalamic corticotropin-releasing factor, eventually leading to blunted cortisol secretion. It can be associated with abnormalities in hypothalamus-pituitary development, isolated or part of more complex cerebral malformations, such as septo-optic dysplasia (SOD).
In children affected by CAI, isolated or associated with GHD, the optimal regimen of glucocorticoid replacement therapy is still controversial. The most important reason is the inability to reproduce the physiological cortisol circadian rhythm, characterized by very low or undetectable circulating levels at midnight, increasing between 2:00 AM and 4:00 AM, peaking early in the morning, and then declining over the day. Hydrocortisone, at a dose of 6–8 mg/m/day, subdivided into three oral doses, is now considered the optimal regimen of replacement therapy in adults and children with CAI. However, this currently recommended regimen reduces, but does not eliminate, nocturnal hypocortisolaemia. Consequently, children with CAI may have nocturnal hypoglycaemia. This is especially true in children with associated GHD, which represents an additional risk factor for hypoglycaemia.
Continuous glucose monitoring (CGM) is a sophisticated method, which measures interstitial glucose concentrations. Recently, a Consensus Statement about the use of CGM in children and adolescents with diabetes was published. The usefulness of this method was also evaluated in very low birth weight infants, in newborn babies at risk of hypoglycaemia and in children with other hypoglycemic disorders, such as hyperinsulinism or glycogen storage diseases. Only one study recently described the use of CGM in adults affected by Addison's Disease. So far, no experience with CGM in children with CAI and GHD has been described.
The first aim of our study was to verify if children with combined ACTH and GH deficiency on replacement therapy present hypoglycaemic episodes detected using CGM. The second aim was to investigate the potential risk factors for hypoglycaemia, assessing the relationships with the doses of hydrocortisone and recombinant human GH (rhGH), to establish the more appropriate replacement therapy in these patients.
Abstract and Introduction
Abstract
Objectives To evaluate the usefulness of continuous glucose monitoring (CGM) to identify nocturnal hypoglycaemia in children affected by combined ACTH and GH deficiency and to optimize the hydrocortisone replacement therapy in these patients.
Study design Eleven patients with ACTH and GH deficiency (five boys and six girls, age 1·6–16·8 years) underwent CGM for 36 h, including two nights. At least two consecutive glucose levels <2·78 mm were considered hypoglycaemic episodes. The differences in age and doses of hydrocortisone and recombinant human growth hormone (rhGH) between children with and without hypoglycaemia were analysed. The percentage of the glucose values <3·33 mm and the mean glucose levels were also evaluated.
Results Continuous glucose monitoring demonstrated nocturnal hypoglycaemia lasting from 30 to 155 min (1·5% of the total monitoring time) in three cases (27%). No statistically significant differences in age and rhGH dose were observed between children with or without hypoglycaemia. Conversely, the difference in the hydrocortisone doses between the patients with and without hypoglycaemia resulted statistically significant (5·9 vs 8·5 mg/m/day; P = 0·04). Eight patients presented glucose values less than 3·33 mm during 5% of the total monitoring time. Hydrocortisone dose showed significant positive linear relation with mean glucose level (r = 0·79, P = 0·0035) and inverse relation with time lags of glucose levels under 3·33 mm (r = −0·65, P = 0·03).
Conclusions Our study shows that CGM may represent a valuable tool to detect nocturnal asymptomatic hypoglycaemic episodes and optimize the hydrocortisone therapeutic regimen in children with ACTH and GH deficiency.
Introduction
Congenital central adrenal insufficiency (CAI), presenting alone or, more frequently, associated with GH deficiency (GHD), is a rare condition. It is characterized either by impaired synthesis and release of ACTH from the pituitary gland, or by impaired release or action of hypothalamic corticotropin-releasing factor, eventually leading to blunted cortisol secretion. It can be associated with abnormalities in hypothalamus-pituitary development, isolated or part of more complex cerebral malformations, such as septo-optic dysplasia (SOD).
In children affected by CAI, isolated or associated with GHD, the optimal regimen of glucocorticoid replacement therapy is still controversial. The most important reason is the inability to reproduce the physiological cortisol circadian rhythm, characterized by very low or undetectable circulating levels at midnight, increasing between 2:00 AM and 4:00 AM, peaking early in the morning, and then declining over the day. Hydrocortisone, at a dose of 6–8 mg/m/day, subdivided into three oral doses, is now considered the optimal regimen of replacement therapy in adults and children with CAI. However, this currently recommended regimen reduces, but does not eliminate, nocturnal hypocortisolaemia. Consequently, children with CAI may have nocturnal hypoglycaemia. This is especially true in children with associated GHD, which represents an additional risk factor for hypoglycaemia.
Continuous glucose monitoring (CGM) is a sophisticated method, which measures interstitial glucose concentrations. Recently, a Consensus Statement about the use of CGM in children and adolescents with diabetes was published. The usefulness of this method was also evaluated in very low birth weight infants, in newborn babies at risk of hypoglycaemia and in children with other hypoglycemic disorders, such as hyperinsulinism or glycogen storage diseases. Only one study recently described the use of CGM in adults affected by Addison's Disease. So far, no experience with CGM in children with CAI and GHD has been described.
The first aim of our study was to verify if children with combined ACTH and GH deficiency on replacement therapy present hypoglycaemic episodes detected using CGM. The second aim was to investigate the potential risk factors for hypoglycaemia, assessing the relationships with the doses of hydrocortisone and recombinant human GH (rhGH), to establish the more appropriate replacement therapy in these patients.