Diagnosis of CHI
Early diagnosis and treatment of CHI are very important in preventing any brain injury caused by hypoglycemia. Therefore, CHI should be suspected in any patient with repeated and persistent hypoglycemia. The following parameters play a major role in establishing the diagnosis of CHI:
Serum Insulin
Though the fundamental sign in diagnosis of CHI is detectable/high levels of insulin concentration in the blood at the time of hypoglycemia, the levels of insulin fluctuate widely over the time, as it is being used up for the breakdown of glucose and hence low or undetectable insulin do not always exclude the diagnosis of CHI. Therefore, it becomes difficult to establish the diagnosis of CHI if one relies only on demonstrating an elevated blood insulin concentration at the time of hypoglycemia. Other signs and chemical markers must be tested to provide clues of excess insulin action. Moreover, there is no correlation between measured serum insulin concentration and the severity of the hypoglcemia.
Serum C-peptide
A Connecting-peptide is a substance that is created when the hormone insulin is produced and released into the body. It is secreted by islet β-cells of pancreas and has a same precursor proinsulin with insulin. A proinsulin can be decomposed into one molecule of insulin and one molecule of C-peptide. This makes the molar weight of C-peptide the same as that of individual’s secreted insulin. Moreover, it is not easy for C-peptide to be degraded by the liver. Hence, C-peptide levels in the blood can also reflect the content of insulin in the body as well as the function of islet cells. In CHI, an inappropriate C-peptide concentration can be detected at the time of hypoglycemia and in some cases, serum C-peptide levels (≥0.5 ng/mL) may help confirm the diagnosis.
Blood Glucose
Hypoglycemia that occurs while the newborn is on glucose infusion is strongly suggestive of CHI and an intravenous glucose infusion rate requirement of >8 mg/kg/min is diagnostic of CHI. In milder forms of CHI, it is also important to establish the duration of fasting and whether if the hypoglycemia is precipitated by meals or by exercise. Plasma glucose (always take capillary sample or free flow venous sample and not from intravenous line that is used for glucose infusion) should be taken at the time of hypoglycemia screen.
Serum Ketones and free fatty acids
The metabolic effects of high insulin concentration in the blood can also be depicted by low serum ketones and free fatty acid concentrations in the blood at the time of hypoglycemia. It is advisable to measure of point of care ketones or take these blood samples at the time of hypoglycemia screen.
Glucagon infusion
In cases where the diagnosis of CHI is difficult, glucagon stimulation test can also be used to demonstrate the excess of insulin. Glucagon, a peptide hormone secreted by the alpha-cells of the pancreas, opposes insulin action and stimulates the release of glucose from glycogen stores of liver. A rise in blood glucose concentration by >1.5mmol/L (27mg/dl) after intramuscular or intravenous glucagon at the time of hypoglycemia is considered as positive glycemic response and is a sensitive marker of hyperinsulinism. A similar positive glycemic response can also be found after subcutaneous octreotide administration.
It is important to note that such biochemical results are generally informative only if taken at the time of hypoglycemia called the critical sample. It is very important to discuss with the specialist before undertaking the glucagon test and diagnostic fasting test carried out in a safe setting in an experienced hospital is sometimes required to provoke hypoglycemia to collect a critical sample.
Inheritance of CHI
The human body is made up of billions of building blocks called cells. Genetic material is located in the form of nuclear-DNA in the cell nucleus. This genetic material carries hereditary information from one generation to the next and contains instructions for cells to make proteins for growth and development. The genetic material is actually condensed in the form of structures called as chromosomes that are like threads of DNA. Each cell contains 46 chromosomes (23 pairs consisting of 22 autosomes and 1 sex chromosome) and each chromosome carries thousands of genes arranged one after another on the chromosomes. An individual gets one chromosome from each of his/her parent and passes them to the next generation. Any alteration in the basic structure of the genes or its arrangement / sequence can lead to a mutation of the gene which can present itself in either autosomal recessive or autosomal dominant pattern.
An autosomal recessive pattern means both copies of genes passed on from each parent in the cell has mutations. Whereas in autosomal dominant pattern one copy of the altered gene in passed on from either of the parent.
Congenital Hyperinsulinism is a genetic disorder with different inheritance patters, usually depending on the form of the condition.
The diffuse form of CHI is most often inherited in autosomal recessive pattern, meaning both copies of the gene in each cell has mutations. Both parents of an individual with autosomal recessive condition carry a copy of the mutated gene, but they do not show any signs or symptoms of the conditions and are termed as carriers. However, diffuse form can also be inherited as an autosomal dominant pattern, albeit less frequently, meaning one copy of the altered gene from either of the parent in each cell is mutated.
The inheritance of focal form of CHI is more complex and in for most genes, both copies, one from either of the parent, are active in all cells. But for a small number of genes, one of the two copies is inactive. In most cases, for the focal form individuals inherit one copy of the mutated, inactive gene from the unaffected father. And during development inside the womb of the mother, a second mutation occurs in the active copy of the gene within the pancreas. This second mutation occurs only in some cells in the pancreas and as a result, only some pancreatic β-cells show abnormal insulin secretion, while the other β-cells function normally.
Hence, urgent genetic testing is extremely important in children who are either partial responsive or unresponsive to diazoxide as this will help to differentiate between focal and diffuse forms. Clinicians should arrange to send DNA samples on the child as well as mum and dad. Please discuss with Dr. Jaikumar Contractor to arrange for DNA samples to be sent off and for prompt genetic results.
Focal form of CHI
The focal form of congenital hyperinsulinism (CHI) is characterized by abnormal pancreatic β-cells localized in a specific region of the pancreas. These lesions are generally about 2-10 mm in size and appear as small region of islet cell like clusters with abnormal nuclei of irregular shape. Patients with focal CHI are usually unresponsive to medical therapy and require a surgical lesionectomy for complete cure.
Diffuse form of CHI
Diffuse form of CHI means a disease involving all the β-cells throughout the islet of pancreas, although with a variable involvement. These account for about 60% of all CHI cases and severe forms are unresponsive to standard medical therapy, requiring a near-total pancreatectomy. However, over the last several years, newer medications have been used to manage this complex severe form of CHI to avoid near-total pancreatectomy.
In some cases, the pancreatic histology does not fit the typical focal or diffuse appearance and are described as Atypical forms of CHI.
At this stage based on the genetic results, imaging may be required to differentiate between the focal and diffuse form. Currently, imaging with 18F-DOPA-PET/CT scan is undertaken to identify the location of focal lesion in the pancreas. The scan involves use of a special radioactive drug 18F-DOPA which is taken up by the pancreatic islet cells and converted into dopamine using an enzyme DOPA decarboxylase. Focal and diffuse forms of the disease show an increased activity of this enzyme and diffuse disease show a uniform uptake of 18F-DOPA throughout the whole of the pancreas, while in focal lesion the uptake of 18F-DOPA is markedly increased in a part of the pancreas as compared to the surrounding tissue around it.
Recently, there has been several studies published showing PET/CT imaging with Ga-Exendin isotope has been more effective to locate pancreatic lesion.
The need to differentiate between focal and diffuse lesion lies in the fact that the surgical approach differs markedly between the two lesions. Accurate localization and limited removal of the focal lesion can result in complete cure whereas medically unresponsive diffuse disease still require a near-total pancreatectomy, greatly increasing the risk of post-pancreatectomy diabetes mellitus. Moreover, the results from these non-invasive and high accuracy imaging techniques are much better than the traditional imaging methods such as CT and MRI which are not very useful to localize these lesions. But its limitation lies in the limited availability at only a few centers and the expertise required in the interpretation of the images.
