Congenital hyperinsulinaemic hypoglycaemia is a rare but serious condition where the pancreas produces too much insulin, leading to dangerously low blood sugar levels in infants and children. Effective treatment depends on early diagnosis and careful selection of medicines or surgery to prevent brain damage and support normal development.

How Treatment Can Help Children with Congenital Hyperinsulinaemic Hypoglycaemia

Congenital hyperinsulinaemic hypoglycaemia, often shortened to CHI or HH, is the most common cause of severe, persistent low blood sugar in newborns and children. The condition affects approximately 1 in 50,000 babies born, though it can be more common in certain populations^[1]. The main goal of treatment is to keep blood sugar levels stable and high enough to protect the brain from damage. Without proper treatment, children can experience seizures, developmental delays, vision problems, or even more severe complications^[2].

Treatment for CHI varies greatly depending on the form of the disease, how severe it is, and how each child responds to medicines. Some children have a diffuse form, where all the insulin-producing cells in the pancreas are affected, while others have a focal form, where only a small area of the pancreas is producing too much insulin. There is also a transient form that may resolve as the child grows^[12]. Because of this complexity, treatment must be tailored to each child’s specific situation.

Medical societies have developed clinical guidelines to help doctors diagnose and treat CHI more effectively. These guidelines recommend that treatment should begin as soon as the diagnosis is confirmed, with medicines being the first approach in most cases. When medicines don’t work or when a focal lesion is found, surgery may be recommended^[13]. In addition to these established treatments, researchers are actively testing new therapies in clinical trials, offering hope for better options in the future.

Standard Medical Treatment for Congenital Hyperinsulinaemic Hypoglycaemia

The cornerstone of CHI treatment is the medicine diazoxide, which is considered the first-line therapy recommended by international guidelines. Diazoxide works by opening specific channels in the insulin-producing cells of the pancreas, which helps to reduce the amount of insulin released into the bloodstream. This medicine is considered an essential medicine by the World Health Organization and is the only treatment for CHI approved by the United States Food and Drug Administration^[13].

Diazoxide is particularly effective for children with certain genetic forms of CHI and can successfully control blood sugar levels in many patients. The medicine is given by mouth, usually several times a day. When diazoxide works well, children can maintain safe blood sugar levels and may develop the ability to fast for age-appropriate periods without experiencing dangerous drops in blood sugar^[1]. However, not all children respond to diazoxide. Those with specific genetic mutations, particularly those affecting potassium channels in a diffuse pattern throughout the pancreas, are often resistant to this medicine^[1].

Common side effects of diazoxide include fluid retention, which is why doctors often prescribe a diuretic medicine called chlorothiazide alongside it. Chlorothiazide not only helps reduce fluid buildup but may also have a synergistic effect that enhances diazoxide’s ability to raise blood sugar levels^[10]. Other possible side effects of diazoxide include increased hair growth on the body, loss of appetite, and rarely, more serious effects on blood cells or the heart.

When diazoxide fails to control blood sugar levels adequately, the second-line treatment is octreotide, a synthetic version of a natural hormone called somatostatin. Octreotide works differently than diazoxide: it suppresses insulin secretion through a different pathway in the pancreatic cells. This medicine must be given by injection under the skin, usually multiple times throughout the day, which can be challenging for families and uncomfortable for children^[9].

Octreotide is particularly useful as a bridge therapy when planning for surgery or when diazoxide has failed but surgery isn’t immediately possible. The medicine can cause various side effects, including digestive problems like diarrhea, abdominal discomfort, and changes in how the gallbladder functions. Some children may develop gallstones with long-term use. The dosage needs careful adjustment, and children on octreotide require close monitoring to ensure blood sugar remains stable^[1].

Another medicine sometimes used is lanreotide, which is similar to octreotide but is a longer-acting somatostatin analogue. Lanreotide offers the advantage of less frequent injections, which may improve quality of life for children and families^[14].

Nifedipine, a calcium channel blocker typically used for high blood pressure, has also been employed in CHI treatment. It works by affecting calcium channels in the pancreatic cells, which play a role in insulin secretion. While nifedipine is used in some centers, its effectiveness can vary, and it is typically considered when other options have been tried^[10].

Additional therapeutic options include glucagon, which can be given by continuous infusion to help maintain blood sugar levels by promoting the release of stored glucose from the liver. This is often used in emergency situations or as a temporary measure. Some doctors have also used acarbose, a medicine that slows the breakdown of complex carbohydrates in the intestines, though its role in CHI management is more limited^[14].

The duration of medical therapy varies greatly. Some children with milder or transient forms may only need treatment for weeks to months, while those with persistent genetic forms may require lifelong medication. Regular monitoring through blood sugar checks, growth measurements, and developmental assessments is essential throughout treatment^[11].

Surgery as a Treatment Option

When medicines cannot adequately control blood sugar levels, surgery becomes necessary to prevent ongoing episodes of hypoglycemia that could damage the brain. The type of surgery performed depends on whether the child has focal or diffuse disease. This distinction is critical and is made using specialized imaging techniques and genetic testing^[3].

The gold standard for determining whether CHI is focal or diffuse is a specialized scan called fluorine-18-dihydroxyphenyloalanine PET scan, or 18F-DOPA PET. This imaging test can identify small focal lesions in the pancreas where abnormal insulin-producing cells are concentrated. When a focal lesion is found, it can be surgically removed in a procedure called focal lesionectomy. This surgery removes only the problematic area of the pancreas, leaving the rest of the organ intact and functioning normally. Many children who undergo successful focal lesionectomy are cured of CHI and no longer need medication^[1].

For children with diffuse disease who don’t respond to medicines, a much more extensive surgery called near-total pancreatectomy is performed. In this procedure, surgeons remove most of the pancreas, typically 95% or more. This dramatically reduces insulin production and can help control blood sugar levels. However, this surgery comes with significant long-term consequences. Many children who undergo near-total pancreatectomy eventually develop diabetes mellitus because they no longer have enough pancreas left to produce adequate insulin. They may also develop problems digesting food because the pancreas produces enzymes needed for digestion^[10].

Both laparoscopic (minimally invasive) and open surgical approaches can be used, depending on the child’s anatomy and the surgeon’s expertise. Surgery for CHI requires a highly specialized team, including pediatric surgeons experienced in pancreatic surgery, pediatric endocrinologists, and intensive care specialists^[1].

Promising New Treatments Being Tested in Clinical Trials

Researchers are actively investigating new medicines that could offer better control of blood sugar in CHI or provide options for children who don’t respond to current treatments. One of the most promising areas of research involves medicines called mTOR inhibitors, specifically sirolimus and everolimus. These drugs were originally developed to prevent organ rejection in transplant patients, but they have shown potential in treating CHI^[14].

Sirolimus and everolimus work through a completely different mechanism than existing CHI treatments. They affect a cellular pathway called the mTOR pathway, which plays a role in cell growth and metabolism. By inhibiting this pathway, these medicines can help reduce insulin secretion from pancreatic cells. Early reports from clinical use have shown that some children with CHI who were previously unresponsive to diazoxide and octreotide have achieved better blood sugar control with these mTOR inhibitors^[9].

Clinical trials testing sirolimus and everolimus in CHI are being conducted in various countries, including the United States and Europe. These studies are examining both the safety and effectiveness of these medicines in children with different forms of CHI. The trials typically follow a phased approach: early phase studies (Phase I and Phase II) focus on determining the right dose and whether the medicine shows promising effects, while later phase studies (Phase III) compare the new treatment more rigorously against standard care or placebo^[13].

Preliminary results from some clinical studies have been encouraging. Children treated with mTOR inhibitors have shown improvements in their ability to maintain normal blood sugar levels and some have been able to reduce or stop other medications. However, these medicines also come with their own set of potential side effects, including effects on the immune system, mouth sores, increased cholesterol levels, and potential impacts on growth. Long-term safety data is still being collected^[9].

Another area of research involves better understanding the genetic causes of CHI. Scientists have identified mutations in at least nine different genes that can cause the condition, including ABCC8 and KCNJ11, which are the most commonly affected genes. Understanding these genetic mechanisms is helping researchers develop more targeted therapies. Some clinical trials are focusing on specific genetic subtypes of CHI, testing whether certain treatments work better for particular genetic forms of the disease^[2].

Researchers are also investigating innovative ways to deliver existing medicines more effectively. For example, studies are exploring longer-acting formulations of somatostatin analogues that would require less frequent injections, improving quality of life for children and their families. Some centers are testing combinations of medicines that might work synergistically to provide better blood sugar control than any single drug alone^[5].

Gene therapy approaches are being explored in early-stage research, though these are still far from clinical use. The idea is to correct the underlying genetic defect in the pancreatic cells, potentially offering a cure for genetic forms of CHI. Similarly, research into cell-based therapies and tissue engineering may one day provide alternative approaches to treating or curing CHI^[5].

Eligibility for clinical trials varies depending on the specific study. Generally, trials may include children with CHI who have failed standard treatments, those with specific genetic mutations, or newly diagnosed patients where researchers want to compare new approaches to established therapies. Trials are being conducted at specialized centers in North America, Europe, and other regions. Families interested in clinical trials should discuss options with their child’s endocrinologist and may need to travel to participate^[13].

Most common treatment methods

• Pharmacologic therapy with diazoxide
  • First-line medication recommended by international guidelines for newly diagnosed CHI
  • Works by opening potassium channels in pancreatic beta cells to reduce insulin secretion
  • Taken orally multiple times daily
  • Often combined with chlorothiazide to manage fluid retention and enhance effectiveness
  • Effective in many patients but not in those with certain genetic mutations affecting potassium channels
• Somatostatin analogue therapy
  • Second-line treatment when diazoxide fails or is not tolerated
  • Includes octreotide (short-acting, given by multiple daily injections)
  • Includes lanreotide (longer-acting formulation with less frequent dosing)
  • Suppresses insulin secretion through a different mechanism than diazoxide
  • Used as bridge therapy before surgery or as long-term treatment when surgery is not possible
• Calcium channel blockers
  • Nifedipine used in some centers as an alternative or adjunct therapy
  • Affects calcium channels involved in insulin secretion
  • Effectiveness varies among patients
• Emergency glucose therapy
  • Intravenous glucose infusions at high rates during acute hypoglycemia
  • Continuous glucagon infusion to promote glucose release from liver stores
  • Used to stabilize blood sugar before definitive treatment begins
• Surgical intervention
  • Focal lesionectomy for children with localized focal disease identified by 18F-DOPA PET scan
  • Near-total pancreatectomy (removing 95% or more of the pancreas) for diffuse disease unresponsive to medications
  • Can be curative for focal disease but carries significant risks for diffuse disease
  • Performed by specialized pediatric surgeons at expert centers
• Experimental therapies in clinical trials
  • mTOR inhibitors (sirolimus and everolimus) showing promise in medication-resistant cases
  • Work through novel mechanism affecting cellular growth and metabolism pathways
  • Being tested in Phase I, II, and III trials in specialized centers
  • May offer alternative for children who cannot undergo surgery or don’t respond to standard medicines
• Supportive therapies
  • Acarbose to slow carbohydrate absorption in specific situations
  • Frequent feeding schedules and specialized diets to maintain blood sugar stability
  • Continuous glucose monitoring systems to track blood sugar patterns