Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia

Abstract

Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the K_ATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.

Figure 1

Relationship between plasma glucose and risk of neuronal injury in normal children: as glucose levels decrease, the risk of hypogycaemia‐induced neuronal damage increases. While there is no numerical definition of hypoglycaemia in children, the inverse correlation between glucose and risk supports a pragmatic clinical approach to keep glucose levels near the normal range to prevent long‐term brain damage.

Figure 2

Typical histopathological appearance of diffuse and focal congenital hyperinsulinism (CHI) pancreata representing histological diversity of CHI. Panels A and B show insulin positive cells (INS+) in tissue from children with diffuse and focal disease, respectively. In diffuse disease all islet cells are similarly affected, but in focal CHI the condition is associated with expansion of INS+ cells within a defined focal lesion. Scale bar, 1 mm; magnification × 1.5.

Figure 3

Necrolytic migratory erythema is a rare side effect of glucagon therapy. Typically the rash spreads with a red irregular border and starts to disappear within 1–2 days of stopping treatment. CHI, congenital hyperinsulinism; CT, computed tomography; SSRA, somatostatin receptor analogue; PET, positron‐emission tomography.

Figure 4

An infant on diazoxide at 10 mg/kg/day developing excess body hair, a common occurrence with diazoxide dose >5 mg/kg/day.

Figure 5

Surgical view of subtotal pancreatectomy performed using an open laparotomy approach. The tail of the pancreas has been mobilized and held vertically upwards. It is important to safeguard important structures such as the splenic artery, portal vein and bile duct during the process of dissection.

Figure 6

Treatment algorithm of congenital hyperinsulinism (CHI) with key components of diazoxide responsiveness and gene mutation analysis guiding clinical decisions. CT, computed tomography; SSRA, somatostatin receptor analogue; PET, positron‐emission tomography.

Figure 7

Brain MRI showing consequences of severe perinatal hypoglycaemia, with extensive bilateral areas of cystic encephalomalacia in the occipito‐parietal area and posterior temporal lobes.