Neonatal, Infantile, or Childhood-Persistent Hypoglycemias

These can arise from hormonal disorders or alternate fuel breakdown disorders such as:

• • Hyperinsulinism
  • Counter-regulatory hormone deficiency
  • Glycogenolysis disorders
  • Gluconeogenesis disorders
  • Lipolysis disorders
  • Fatty acid oxidation disorders

Clinical clues that suggest HI include:

• • Hypoglycemia at less than 1 month of age
  • IV glucose support needed to maintain blood glucose >70 mg/dl as measured by a Glucose Infusion Rate (GIR) > 5-8 mg dextrose/kg/minute
  • Large birth weight for gestational age (LGA)

Finding the cause

Congenital HI is only one of several causes of hypoglycemia. While there are certain clinical cues that suggest this diagnosis, biochemical testing is necessary to distinguish congenital HI from other etiologies.

Biochemical diagnosis

Distinguishing congenital HI from other hypoglycemic disorders requires a very standardized approach which measures biomarkers specifically at the time of hypoglycemia (low blood sugar ≤50 mg/dl). This may require a “fasting study” conducted in a highly supervised setting with trained staff. In these fasting studies, food is withheld and frequent blood glucose measurements are done to track the fall in blood glucose, ensuring that the fast goes no longer than is absolutely necessary for a safe diagnosis.

At the time of hypoglycemia, and only at the time of hypoglycemia (blood glucose ≤50 mg/dL), a battery of biomarkers are measured to distinguish hyperinsulinism from other causes of hypoglycemia. This is often referred to as “the critical draw.” Given that it is done precisely during the time of hypoglycemia, it provides a wealth of information relevant for many diseases considered in the differential diagnosis. Biomarkers include:

• • Insulin, C-peptide, beta-hydroxybutyrate (B-OHB), non-esterified free fatty acids (NEFFA), Insulin-like Growth Factor Binding Protein 1 (IGFBP-1)
  • Lactate, ammonia, growth hormone, cortisol, chemistry panel, free and total acyl-carnitine profile
  • Glucagon stimulatory test

A detectable insulin level at the time of hypoglycemia  is diagnostic, but a lack of a detectable insulin level does not rule out the diagnosis. Insulin secretion is sporadic and does not follow any recognizable or predictable pattern. It also varies from person to person. Additionally, insulin is rapidly cleared and degraded so a detectable/measurable insulin level is not always present at the time of hypoglycemia. Thus, relying on insulin as the sole biomarker may miss the diagnosis of congenital HI.

Biochemical evidence of excessive insulin action is a more sensitive way to establish the diagnosis.¹ Excess insulin action suppresses the of breakdown of alternate sources of fuel (e.g., suppressed beta-hydroxy butyrate and suppressed non-esterified free fatty acids), and results in an inappropriate rise in plasma glucose >30 mg/dl within 30 minutes following the administration of 1mg of IV or IM glucagon at the time of plasma glucose ≤50 mg/dl. Elevated C-peptide levels at the time of hypoglycemia are also more sensitive than insulin levels.

Genetic etiology

There are now more than 10 identified genetic loci underlying congenital HI. The most common mutations (approximately 50% to 60%) occur at the ABCC8 and KCNJ11 genes that encode the SUR-1 and Kir6.² subunits of the K_ATP channel. These mutations lead to reduced expression, trafficking, or function of the K_ATP channel, all resulting in excess insulin secretion independent of blood glucose levels. The next most common forms of hyperinsulinism arise from activating mutations in genes encoding glutamate dehydrogenase (GLUD1) and glucokinase (GCK), each accounting for less than 4% to 5% of the overall hyperinsulinism population with congenital HI, while more rare causes exist in smaller numbers of patients.¹⁶

For the majority of these mutations, the entire pancreas is affected (i.e., diffuse HI), resulting in dysregulated, excess secretion of insulin from beta cells. However, of those patients with HI due to mutations in the K_ATP channel, nearly half have a paternally inherited mutation, resulting in a focal region of abnormal beta cells while the remainder of the pancreas is normal (i.e., focal HI).

For approximately 50% of individuals with congenital HI, a genetic etiology may not be identified. Genetic analysis is not required for the diagnosis of congenital HI, but knowledge of the genetic etiology may inform further diagnostic steps and the treatment for patients who are not responsive to initial medical management with diazoxide (see below)¹².

Other possible causes of HI

Perinatal stress-induced or transient HI can develop from placental insufficiency, birth asphyxia, or fetal hypoxia. There is significant overlap between this transient HI and congenital HI, and the treatment and approach are very similar. In addition, HI is associated with several syndromes, including, but not limited to, Beckwith-Wiedemann syndrome and Kabuki syndrome.

Back>

Medical management

The following medications are currently prescribed by doctors to treat congenital HI. Of these, only diazoxide is approved by the FDA specifically for the treatment of hyperinsulinemic hypoglycemia.

Diazoxide

Diazoxide is the only FDA-approved medication for hyperinsulinemic-hypoglycemia. This twice-daily oral medication is a K_ATP channel agonist, which opens the channel, decreasing insulin secretion. It is the first-line pharmacological therapy in HI patients, but it is ineffective in about half of patients.

Even in patients responsive to diazoxide who are able to attain euglycemia, side effects such as fluid retention, hypertrichosis, and feeding aversion may be intolerable. Fluid retention is an extremely common side effect and diuretics are co-administered; however, severe sodium and fluid retention can lead to cardiovascular complications, and in 2015, the FDA issued a drug safety communication and included a new warning and precaution in diazoxide labelling after identifying pulmonary hypertension in infants and newborns treated with diazoxide.¹⁸ Patients who are “diazoxide non-responsive⁴” are likely to have a K_ATP channel mutation.¹ For these cases, genetic testing is indicated to inform surgical management (see below).

Octreotide

Octreotide is used off-label as the second-line medical therapy for infants unresponsive to diazoxide. This short-acting injectable somatostatin analog inhibits insulin secretion distal to, or “downstream” of, the K_ATP channel. It is administered subcutaneously or, in rare cases, via continuous infusion. An initial glucose response may be achieved, but tachyphylaxis, or “wearing off,” may develop after a few doses, making therapy inadequate for long-term use¹ in all but 10-15% of patients.⁷ For this reason, it is often necessary to provide enteral dextrose delivered through a G-tube for part or all of the day. Other side effects can include gastrointestinal problems, gallstones, and growth hormone/thyroid suppression.⁷ There has also been an association between octreotide and necrotizing enterocolitis (NEC) in very young infants. While the causal relationship remains unknown, this risk limits the use of this medication in very young patients who are often those who need it most.

Long-acting somatostatin receptor type 2 (SST2) agonists

The off-label use of monthly injections of lanreotide or octreotide longacting release (LAR) has replaced short-acting octreotide in some patients. However, patients may show variable blood glucose levels across the month, with hyperglycemia sometimes lasting for days after the dose, and hypoglycemia often occurring prior to the next scheduled injection¹³. While there is some use in infants, these long-acting therapies cannot be withdrawn in the event of unwanted side effects and are challenging to dose, limiting widespread use in the youngest patients. Moreover, these deep subcutaneous injections must be given with large-bore needles and are commonly associated with painful injection site reactions and deep tissue nodule formation. This poses administration challenges in young infants and children, and generates significant psychosocial stress for patients and families¹⁴.

Glucagon

Excess insulin in congenital HI suppresses gluconeogenesis and glycogenolysis. Administering glucagon can overcome the effects of excess insulin and can raise blood sugar; as such, an inappropriate rise in glucose following administration is sensitive in diagnosing congenital HI.¹⁵ Glucagon as a therapy has been limited to date due to the long-term instability in solution. Patients are provided glucagon through an IV in a hospital setting, but a high degree of maintenance is required to ensure fibrillation does not occur. Outpatient glucagon has been limited to emergency “rescue” injections in which glucagon powder is reconstituted before intramuscular administration. Recently there has been the development of glucagon analogs or forms that can be administered through an insulin pump, but the short-acting nature of glucagon means the risk of hypoglycemia is present if constant delivery can’t be ensured, and in many children subcutaneous administration presents its own challenges.

Supplemental dextrose

Intragastric continuous dextrose may be useful in severely affected infants to help support blood glucose alone or in combination with other therapies. This is highly relevant for patients who have undergone a sub-total pancreatectomy given the risk of persistent hypoglycemia in 50-60% of patients post operatively (see below). A gastrostomy tube (G-tube) is often placed at the time of pancreatic surgery in anticipation of a need for long-term dextrose support.⁵ However, there is a limit to the amount of glucose that can be delivered, and too great a rate may be associated with poor absorption and intolerance.⁶  Other side effects include vomiting, diarrhea, and the potential for obesity due to excess caloric intake. Adding to these challenges are the difficulties patients face with restriction in their activity while connected to the feeding apparatus, pump malfunctions/disconnections that lead to dramatic episodes of hypoglycemia, and adhering to the necessary oral feeding behaviors.⁷

Surgical therapy¹

Patients with congenital HI who are unable to maintain normal glucose values with aggressive medical treatment may require surgical removal of a portion or the entire pancreas. Surgical therapy is reserved only for patients who fail aggressive medical therapy. While genetic testing is becoming more widespread, it is quite often done after diazoxide therapy has failed.

For patients specifically with K_ATP channel mutations, there are two forms: Approximately 50% will have focal disease, in which only a portion of the pancreas is affected; and 50% will have a diffuse form, in which the entire organ has disease. The mode of inheritance can inform the extent of disease, so with patients who have K_ATP mutations, parental genetics is often obtained. Paternally inherited K_ATP mutations suggest focal disease is more likely, with the assumption that there is maternal loss of the normal allele in specific areas of the pancreas. This can be supported by specialized pancreatic imaging with 18F-DOPA-PET scans, where focal uptake of radioactivity may allow visualization of diseased pancreas and inform the surgical approach.^5,10,11

Focal and diffuse disease are clinically indistinguishable. While preoperative testing, including genetics and imaging, may suggest focal versus diffuse disease, the gold standard for diagnosis is through histological examination of intra-operative biopsies. This requires a collaboration between pathologists and surgeons, with involvement from geneticists, nuclear medicine, and endocrinologists to determine the best surgical approach.¹

Focal hyperinsulinism can usually be cured with resection of the diseased portion of the pancreas. Infants with diffuse disease often undergo more extensive surgeries, termed “near-total pancreatectomies” (95%–98%) to control the hypoglycemia. Unfortunately, 50-60% of patients who undergo a near-total pancreatectomy still have hypoglycemia. Many require aggressive, post-surgical therapy with diazoxide, octreotide and/or frequent feedings to maintain a normal blood glucose level. Of these, 25% develop diabetes and 25% are “cured.” In the long term, nearly all patients who have had a near total pancreatectomy progress to hyperglycemia by mid-adolescence, with over 90% requiring insulin therapy.^4,8

Back>

A sense of isolation

Treatments like glucose packs, which administer a constant drip of glucose to the patients via a G-tube, prevent patients from participating in a lot of typical social activities. Swimming, climbing, overnights; they all become a logistical nightmare. This is especially hard for young children who are still developing socially, learning how to make friends, and wanting to belong, to be included in peer activities. Contributing to these feelings is a frequent side effect of the commonly prescribed therapy, diazoxide: Hypertrichosis. This is excessive hair growth and is quite often significant and noticeable over the entire body, which make the patient a target of teasing and bullying.

The onus of raising awareness is often on them

Because HI is so rare, families often find themselves being referred to one of the few treatment centers where comprehensive HI awareness and knowledge exist and where they can receive the appropriate treatment the disease demands. Many times, after establishing a diagnosis with a specialist at one of these centers, families return home and must then educate their own primary care physician on signs, symptoms, and treatments of congenital HI.

Painful treatments

Some medical therapies are administered by injections given with large-bore needles. These are quite painful for the patient, an unavoidable hurdle made all the more taxing because we’re talking about neonates, infants, and children. Adding to the stress is the fact that because these injections are monthly it becomes more feasible to have the parents administer them at home, requiring they subject their own children to an ordeal of physical and emotional pain on a regular basis.

Administration of meds

Administering crucial medication and checking blood sugars while children are in daycare or school can be difficult. Many schools don’t staff a nurse, and those that do are not familiar with congenital HI or the administration of medications used to treat this disease. It’s not unusual for parents to have to take time off work and go to the school themselves to ensure their child gets their medicine, or to train the nursing staff in how to monitor and treat their child. These logistical challenges contribute to highly stressful situations each day.

Back>