Persistent Hyperinsulinemic Hypoglycemia of Infancy: An Overview

Introduction

Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI), also known as congenital hyperinsulinism, is a complex and rare condition that requires thorough understanding and careful management. First described by MacQuarrie in 1954, PHHI has been the subject of considerable research to understand its causes, manifestations, and treatment methods. This article is intended to shed light on the critical aspects of PHHI, including its risk factors, symptoms, diagnostic tests, available medications, relevant medical procedures, and home-care measures that can help manage the symptoms of PHHI.

Description of Persistent Hyperinsulinemic Hypoglycemia of Infancy

PHHI is a rare metabolic disorder, characterized by the inappropriate secretion of insulin by the pancreas in newborns and infants. This excessive insulin production leads to persistently low blood sugar levels (hypoglycemia), causing a range of symptoms and health risks. The condition’s progression varies considerably, depending on the severity and the individual’s response to treatment.

PHHI can be transient, resolving itself within days or weeks after birth, or it can be persistent, requiring ongoing medical intervention. Though transient cases are more common, persistent PHHI can lead to significant complications such as seizures, developmental delays, and learning disabilities due to prolonged low blood sugar.

The prevalence of PHHI is estimated to be approximately 1 in 25,000 to 50,000 live births, making it a relatively rare condition. However, its impact on the affected infants and their families can be profound, underscoring the importance of understanding and managing this condition.

Risk Factors for Developing Persistent Hyperinsulinemic Hypoglycemia of Infancy

Lifestyle Risk Factors

While PHHI is largely linked to genetic causes, certain lifestyle factors during pregnancy might indirectly influence the condition’s occurrence. These include maternal diabetes, obesity, and intake of certain medications that affect insulin secretion or glucose metabolism. However, more research is needed to establish these links definitively.

Medical Risk Factors

Medical conditions such as gestational diabetes, birth asphyxia, or intrauterine growth restriction can predispose an infant to PHHI. Additionally, infants born with certain syndromes like Beckwith-Wiedemann Syndrome or Sotos Syndrome, which are associated with abnormalities in the insulin and insulin-like growth factor pathways, may also have an increased risk of PHHI.

Genetic and Age-Related Risk Factors

PHHI often has a strong genetic component, with certain mutations in genes involved in insulin regulation (such as ABCC8 and KCNJ11) significantly increasing the risk. Moreover, PHHI primarily affects newborns and infants, making age a critical risk factor. This condition rarely occurs in older children or adults. It’s important to note that genetic counseling can provide valuable insights into the risk of PHHI in families where the condition has previously occurred.

Clinical Manifestations

Neonatal Diabetes Mellitus

While not as prevalent as other clinical manifestations, Neonatal Diabetes Mellitus (NDM) is reported in approximately 1 in 500,000 infants. PHHI can cause NDM due to persistent low blood glucose levels that stimulate excessive insulin secretion. The persistent over-secretion of insulin can exhaust the insulin-producing beta cells in the pancreas, leading to diabetes in the newborn period. This results in high blood glucose levels, frequent urination, and dehydration. Understanding this manifestation is crucial as it requires different management strategies than typical PHHI.

Inborn Errors of Metabolism

Inborn Errors of Metabolism (IEM) are genetic disorders that disrupt metabolism, reported in a minority of PHHI cases. They result from defects in specific enzymes involved in the biochemical pathways of carbohydrate, protein, or fat metabolism. In the case of PHHI, specific metabolic errors can lead to a buildup of certain metabolites or a deficit of energy-producing substrates, resulting in hypoglycemia. These errors, however, usually present with additional symptoms and abnormal lab findings beyond hypoglycemia.

Sepsis

Sepsis, a severe reaction to infection that can cause body-wide inflammation, may be a manifestation in PHHI, particularly if low blood sugar levels persist. Hypoglycemia can impair the immune response, potentially leading to severe infections like sepsis. Infants with sepsis often present with fever, lethargy, and poor feeding. It is crucial to identify and treat sepsis promptly due to its potential severity.

Hypopituitarism

Hypopituitarism, a condition characterized by decreased secretion of one or more pituitary hormones, occurs rarely in PHHI. The pituitary gland plays a role in regulating blood glucose, and disorders of this gland can cause hypoglycemia. Symptoms can vary based on the specific hormones that are deficient and may include growth failure, hypothyroidism, and adrenal insufficiency.

Dumping Syndrome

Dumping Syndrome is a group of symptoms that can occur after eating, especially after gastric surgery. While not common in PHHI, it can occur when hypoglycemia triggers rapid gastric emptying, leading to symptoms like weakness, abdominal cramps, rapid heart rate, and even fainting. Careful meal planning and nutrition management can help mitigate these symptoms.

Diagnostic Evaluation

Diagnosing PHHI requires a comprehensive evaluation to confirm persistent hypoglycemia, identify the cause, and rule out other possible conditions. The diagnosis is often made based on a combination of clinical findings, lab results, and sometimes genetic testing.

Blood Glucose Level Test

A Blood Glucose Level Test is a fundamental diagnostic tool in assessing hypoglycemia. It measures the concentration of glucose in the blood, typically after a period of fasting. In PHHI, blood glucose levels are persistently low. The test is non-invasive, usually involving a simple finger-prick. It provides immediate results and is important for diagnosing and managing PHHI.

In a PHHI diagnosis, blood glucose levels are typically less than 70 mg/dL in newborns and less than 50 mg/dL in older infants. If the test results are negative for hypoglycemia, but symptoms persist, further testing may be required to identify other potential causes.

Serum Insulin Level Test

The Serum Insulin Level Test measures the amount of insulin in the blood. This test is performed because, in PHHI, insulin levels remain high despite low blood glucose levels. The test involves drawing blood from a vein, typically in the arm.

In PHHI, a diagnosis may be suggested by a serum insulin level that is inappropriately high given the blood glucose level. If the insulin level is not elevated, further evaluation is necessary, particularly if the symptoms persist.

C-Peptide Test

The C-Peptide Test measures the level of C-peptide, a byproduct produced when insulin is made by the pancreas. It’s used to determine how much insulin the body is producing. The test requires a blood sample drawn from a vein.

In PHHI, C-peptide levels may be elevated, suggesting an overproduction of insulin. If C-peptide levels are normal or low with ongoing symptoms of hypoglycemia, it may indicate other causes of hypoglycemia, and further investigation is required.

Proinsulin Level Test

The Proinsulin Level Test measures the amount of proinsulin, the precursor molecule to insulin, in the blood. This test also requires a blood sample. Higher proinsulin levels can suggest hyperinsulinemia.

In PHHI, elevated proinsulin levels may support the diagnosis. If proinsulin levels are normal despite symptoms of hypoglycemia, additional testing may be needed.

Ketone Bodies Test

The Ketone Bodies Test measures the amount of ketones, chemicals produced when the body burns fat for energy, in the blood or urine. This test is critical because, in states of low insulin (such as prolonged fasting or diabetes), ketone bodies should be present. But in PHHI, despite hypoglycemia, ketone bodies are low or absent due to the high insulin levels.

If this test is negative, it may further support a diagnosis of PHHI. However, a negative result in the presence of ongoing symptoms necessitates further diagnostic evaluation.

Genetic Testing

Genetic Testing involves examining the patient’s DNA for specific mutations known to cause PHHI. This is typically done with a blood sample or a swab from the inside of the cheek.

Positive results can confirm a diagnosis of PHHI and may also provide information about the best treatment approach. If genetic testing is negative, but symptoms persist, other diagnostic evaluations are needed.

If all Tests are Negative but Symptoms Persist

It’s important to remember that medical tests are not perfect. If all tests are negative, yet symptoms of hypoglycemia continue, it’s crucial to seek further medical evaluation. There could be other, less common causes of hypoglycemia or different medical conditions presenting with similar symptoms. Persistent symptoms should always be thoroughly investigated, and second opinions should be considered. Your health care provider is there to support you and help manage your child’s health effectively.

Health Conditions with Similar Symptoms to Persistent Hyperinsulinemic Hypoglycemia of Infancy

Neonatal Diabetes Mellitus

Neonatal Diabetes Mellitus (NDM) is a rare condition where high blood sugar levels are detected in the first months of a baby’s life, usually before 6 months of age. It is caused by a problem with the insulin-secreting cells in the pancreas.

The main symptom of NDM that mirrors PHHI is the presence of high levels of insulin. Unlike PHHI, though, NDM results in high blood glucose levels rather than low. Another distinguishing feature is that NDM patients often present with failure to thrive, dehydration, and frequent urination, which are not typical in PHHI. NDM can be diagnosed through genetic testing or by measuring blood glucose levels. A high blood glucose level along with an inappropriately normal or elevated insulin level can suggest NDM rather than PHHI.

Inborn Errors of Metabolism

Inborn Errors of Metabolism (IEM) are a group of inherited disorders that impact metabolism. They can cause a wide range of symptoms, depending on the specific type of metabolic error.

Both IEM and PHHI can cause low blood glucose levels. However, infants with IEM may also exhibit other signs and symptoms like lethargy, poor feeding, vomiting, and failure to gain weight. Specific lab findings, such as abnormal organic acids, amino acids, or fatty acid metabolites in blood or urine, can distinguish IEM from PHHI. A positive result on newborn screening or detection of specific metabolites in blood or urine samples may suggest an IEM rather than PHHI.

Sepsis

Sepsis is a serious condition resulting from the body’s response to an infection, leading to widespread inflammation and organ dysfunction.

Like PHHI, sepsis can lead to hypoglycemia. However, sepsis is typically accompanied by other symptoms such as fever, rapid heartbeat, rapid breathing, and changes in skin color. In addition, blood cultures and other lab tests showing infection can distinguish sepsis from PHHI. A positive blood culture or other evidence of infection would suggest sepsis rather than PHHI.

Hypopituitarism

Hypopituitarism is a condition where the pituitary gland does not produce enough of certain hormones. This can impact growth, blood pressure, and other bodily functions.

While both hypopituitarism and PHHI can result in hypoglycemia, infants with hypopituitarism may also show slow growth, cold sensitivity, constipation, and low blood pressure. A low level of pituitary hormones in the blood can distinguish hypopituitarism from PHHI. Low levels of these hormones in the presence of hypoglycemia could suggest hypopituitarism rather than PHHI.

Dumping Syndrome

Dumping Syndrome occurs when food moves too quickly from the stomach into the small intestine, often following stomach surgery. It can cause a range of gastrointestinal symptoms.

While both dumping syndrome and PHHI can cause hypoglycemia, dumping syndrome often presents with symptoms such as abdominal cramping, nausea, diarrhea, and dizziness after eating. Timing of hypoglycemia is crucial in distinguishing between the two conditions. In dumping syndrome, hypoglycemia occurs shortly after meals, which is not the case with PHHI. Additionally, a detailed history of recent stomach surgeries can aid in diagnosis.

Treatment Options

Medications

Diazoxide

Diazoxide is a medication primarily used to treat hypoglycemia by reducing insulin release, thus raising blood glucose levels.

It’s often the first-line treatment in managing PHHI. It’s administered orally, and its effects can be seen rapidly, often within a few days. However, not all patients respond to Diazoxide, and it can cause side effects like fluid retention and rapid heartbeat.

With successful treatment, patients can expect a significant reduction in hypoglycemic episodes.

Chlorothiazide

Chlorothiazide is a diuretic medication that helps to remove excess fluid from the body.

It’s often used in conjunction with Diazoxide to help mitigate its fluid-retaining effects. It’s not a first-line treatment for PHHI itself, but plays an essential supportive role in its management.

The primary goal of Chlorothiazide administration is to prevent or manage Diazoxide-induced side effects.

Octreotide

Octreotide is a medication that mimics natural somatostatin hormone, which inhibits the secretion of several other hormones, including insulin.

It’s used when other treatments, such as Diazoxide, are ineffective. It’s administered through injection and can be used for both temporary and long-term treatment.

Octreotide can significantly reduce hypoglycemia, but it’s less predictable than Diazoxide and may cause side effects like slow growth and gastrointestinal problems.

Nifedipine

Nifedipine is a calcium channel blocker, typically used to treat high blood pressure.

Although it’s not commonly used for PHHI, it can be an option when other treatments are ineffective or not tolerated, as it helps inhibit insulin secretion. Nifedipine is used cautiously, as it can cause side effects like low blood pressure and rapid heartbeat.

Like other treatments, it aims to reduce hypoglycemia but its use in PHHI requires further research.

Lanreotide

Lanreotide is a long-acting version of Octreotide, another somatostatin analog.

It’s used when other treatments are ineffective or cause too many side effects. Lanreotide is administered via injection every four weeks, which can be advantageous for long-term management of PHHI.

It can reduce hypoglycemic episodes, but like Octreotide, it’s less predictable and can cause side effects like slow growth and gastrointestinal problems.

Procedures

Pancreatic Surgery (Partial Pancreatectomy)

Pancreatic surgery, or partial pancreatectomy, involves removing part of the pancreas.

This procedure is usually considered when medications fail to control hypoglycemia, or if the disease is focal and limited to a specific part of the pancreas. The amount of pancreas removed depends on the specific patient’s needs.

This surgery can effectively treat PHHI, but it comes with risks such as diabetes and pancreatic insufficiency.

Insulin Pump Therapy

Insulin pump therapy involves the use of a device that continuously delivers insulin in order to regulate blood glucose levels.

This treatment is typically used for patients with severe PHHI who are unresponsive to other treatments, or for those who have developed diabetes after pancreatic surgery. The insulin pump provides precise control over insulin delivery, helping to maintain stable blood glucose levels.

Insulin pump therapy can effectively manage blood glucose levels, but it requires careful monitoring and management.

Improving Persistent Hyperinsulinemic Hypoglycemia of Infancy and Seeking Medical Help

Living with PHHI is challenging, but there are strategies that can help manage the condition:

• Regular Blood Glucose Monitoring: Regular monitoring helps to keep blood glucose levels within the target range and prevent hypoglycemic episodes.
• Frequent Feeding Schedule: Eating small, frequent meals can help maintain steady blood glucose levels.
• Emergency Glucose or Glucagon Administration Plan: In case of severe hypoglycemia, having an emergency plan in place is crucial.
• Special Diet Plan (Monitored by a Dietitian): A dietitian can help devise a nutritional plan to maintain stable blood glucose levels.
• Regular Pediatric Endocrinologist Check-ups: Regular appointments allow for the monitoring of disease progression and adjustment of treatment plans as necessary.

With telemedicine, you can consult with your healthcare providers from the comfort of your home. This convenience allows for more frequent check-ins and easier access to medical advice.

Living with Persistent Hyperinsulinemic Hypoglycemia of Infancy: Tips for Better Quality of Life

Living with PHHI can be challenging, but there are ways to enhance the quality of life. Effective management of the condition through medication, dietary changes, and routine medical check-ups, combined with the support of healthcare professionals and loved ones, can make a significant difference.

Conclusion

Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) is a serious condition that requires prompt diagnosis and treatment. By understanding the disease and knowing the treatment options, you can make informed decisions about managing the disease.

Early diagnosis and treatment can significantly improve the prognosis and quality of life for patients with PHHI. If you suspect you or a loved one may have this condition, don’t hesitate to reach out to our primary care practice through our telemedicine service. We’re here to help you navigate this journey, offering expert medical advice and compassionate support every step of the way.

Brief Legal Disclaimer: This article is for informational purposes only and not intended as medical advice. Always consult a healthcare professional for diagnosis and treatment. Reliance on the information provided here is at your own risk.