Recognition of hypoglycemia

 

First of all, we must clearly distinguish hypoglycemia, as a point, from the non-specific neuroglycopenic symptoms it can cause, as the latter may be present without hypoglycemia, if for any reason the supply of glucose to the brain is limited.
Neuroglycopenic manifestations, in previously healthy individuals, are almost always the result of hypoglycemia and are the main, if not the only cause that leads to seeking medical help. Acute neuroglycopenia occurs when blood sugar levels fall relatively quickly below a critical threshold, which in healthy individuals is approximately 45 mg / dl (2.5 mmol / l). Sweating, anxiety, tachycardia and paleness are the main manifestations and are due to the activation of the sympathetic system in response to hypoglycemia. In prolonged hypoglycemia, however, the symptoms are mainly characterized by malnutrition, lethargy, confusion and convulsions. In patients with diabetes, this threshold may be well above 45 mg / dl, while in patients with chronic hypoglycaemia it may be much lower, to such an extent that loss of consciousness is possible before symptoms appear. The latter case often occurs in diabetic patients undergoing insulin therapy and is called unrecognizable hypoglycemia (hypoglycemia).
Subacute neuroglycopenia, on the other hand, is more common in the setting of metabolic disorders or chronic hyperinsulinism and causes intermittent brain dysfunction that can be mistaken for a psychiatric disorder.
 

 

Diagnosis

 

The diagnosis of hypoglycemia will be delayed if we do not think about it for any patient who presents repeatedly or even an episode of disturbance of consciousness or behavior. If hypoglycaemia is suspected, we must prove it, either by causing the hypoglycaemic episode with special tests (eg fasting test), or by waiting for the automatic onset of the episode in a hospital setting, or by providing the patient with a special meter to enable documentation of hypoglycemia during an autoimmune episode and immediately arrive at an organized center for laboratory confirmation and further investigation.

 

Fasting test

In 90% of patients with recurrent episodes of hypoglycaemia, a blood draw after 18 hours of overnight fasting in three different cases will reveal hypoglycaemia <45 mg / dl.

Prolonged fasting testing is seldom applied as it lacks specialty and is practically difficult to apply to pediatric patients.

 

Intense exercise test

This is a useful diagnostic test in patients with hyperinsulinism, who can tolerate long periods of fasting. Measure glucose, insulin and in some cases growth hormone and cortisol, before and every 10 minutes during strenuous exercise on a treadmill or stationary bike lasting 30΄. Normally, blood sugar levels rise or fall, while insulin levels fall. Patients with hyperinsulinism usually do not complete the exercise test due to exhaustion, developing hypoglycaemia with unstressed insulin. The above test is practically inapplicable in young pediatric patients.

 

Meal delivery test

It is used to investigate reactive hypoglycemia, a very rare disorder that may also be due to metabolic causes (eg fructose metabolism disorders). The test is positive if clinical symptoms of hypoglycaemia occur after a scheduled meal and hypoglycaemia <45 mg / dl is documented. In the differential diagnosis of reactive hypoglycemia, the case of hypoglycemia after alcohol consumption should always be ruled out.

 

Glucagon test

After an overnight fast of at least 6 hours, 0.1 mg / Kg glucagon IM (with a maximum dose of 1 mg) is administered after blood sampling at time 0 ', followed by blood sampling at times 60', 90 ', 120', 150 ', 180 '. In addition to sugar, levels of cortisol, growth hormone and insulin are determined, as well as β-hydroxybutyric and lactic acid in suspected metabolic disease. The increase in sugar up to 90 ', confirms the adequacy of the mechanisms of mobilization of hepatic glycogen, while its subsequent decrease should normally be accompanied by a drop in insulin to practically measurable levels when hypoglycemia is achieved, accompanied by an increased response of corticosteroids. growth hormone.

 

Laboratory measurements

Measuring insulin also needs special attention as its molecule breaks down easily. Insulin measuring vials should always be placed immediately on ice and centrifuged in a refrigerated centrifuge. Modern c-peptide determination may reveal exogenous insulin administration, a case that should be ruled out in unexplained severe hypoglycaemia in diabetic patients or close family members, and is also useful in both insulin-like peptide hypoglycaemia. (eg secretion of IGF-2 from malignancies) as well as in autoimmune hypoglycemia (caused by anti-insulin antibodies or antibodies against insulin receptors resulting in reduced insulin clearance and characterized by high insulin levels but low c insulin levels -peptide).

The measurement of ketones is now easy as it can be done with a portable capillary blood meter. In particular, the Abbott PrecisionXceed meter is the only glucose meter that can measure using a different tape and β-hydroxybutyric acid, thus being a useful tool both in the case of diabetic ketoacidosis and in the investigation of metabolic diseases and of course hypoglycemia. Values> 0.5 mmol / l are considered positive and under certain conditions lead to the investigation of metabolic disease, while the confirmation of the non-ketotic nature of the hypoglycemic episode will turn the investigation to endocrine causes, which will be discussed in detail.
 

Differential diagnosis

 

The main diagnostic distinction in hypoglycemia is whether it is ketotic or non-ketotic. Non-ketotic is almost always due to elevated insulin levels or the activity of "insulin-like" molecules, mainly IGF-2, produced by tumors or in the context of Beckwith-Wiedemann syndrome.

Very rarely, hepatic impairment, cachexia and neurogenic anorexia can cause hypoglycemic hypoglycaemia. In most cases of spontaneous hypoglycaemia only mild ketoneemia coexists.

 

Hyperinsulinemic hypoglycemia

 

Hyperinsulinism can rarely be due to childhood insulinoma, with the most common diagnosis being persistent childhood hyperinsulinemic hypoglycaemia (PHHI) or hyperinsulinemia (hypoglycemia). The diagnosis is most commonly made in infancy and even a few hours or days after birth in the face of seizures or loss of consciousness, severe lethargy and prolonged drowsiness, while several cases are diagnosed later up to the age of 4 years due to seizures and / or loss. consciousness and / or behavioral disorders. Very low blood sugar (<40 mg / dl) with concomitant inappropriate insulin levels (which normally should have been non-measurable) and increased response to cortisol and (although not always) growth hormone, in combination with persistence of hypoglycaemia after the 1st week of life (in contrast to transient hypoglycaemia of SGA or LGA or diabetic neonatal mother) confirm the diagnosis.

It is a genetically heterogeneous disease with a frequency of 1: 50,000 births. In 40-45% of cases, mutations in the ABCC8 and KCNJ11 genes are responsible, which encode the SUR1 and Kir6.2 subunits of the ATP-dependent potassium channel of the β-cell. The CATR channel plays a major role in regulating insulin secretion, effectively acting as a bridge between glucose metabolism and cell membrane electrical activity. In the remaining 5-10% of cases mutations of the genes GLUD1, GCK, HNF4A, HADH and SLC16A1 are found, while in 40-45% the genetic damage and the pathogenetic mechanism are still unknown.

The GLUD1 gene encodes glutamic dehydrogenase (GDH), a mitochondrial enzyme that regulates leucine-controlled secretion of insulin. Heterozygous activating mutations of GLUD1 cause protein-releasing YY, which is usually diagnosed outside the neonatal period and is characterized by hyperammonemia (x 3-8 times normal levels) and a good response to diazoxide.

Glucokinase (GCK) controls the first and most important step in glucose metabolism. Heterozygous activating mutations in the gene lead to increased glycolysis rate and consequent insulin hypersecretion by the β-cell, usually with a good response to diazoxide. In contrast, inactivating mutations in the GCK gene cause the most common monogenic form of diabetes, MODY 2 (MaturityOnsetDiabetesoftheYoung).

Respectively, activating mutations of hepatocellular nuclear factor 4A (HNF4A) cause MODY 1, while inactivators lead to varying clinical severity and duration of YY, in macrosomic infants, and a good response to diazoxide. The mechanism of induction of hyperinsulinism is unknown, as in the case of residual transferable mutations of hydroxy-acyl-coenzyme A (HADH) dehydrogenase, which catalyzes the final stage of β-oxidation in the mitochondria and shows markedly increased β- cell. Only 5 patients have been reported to date, with a disease of varying severity, however sensitive to diazoxide and starting in the 1st week to the 4th month of life.

Finally, activating mutations in the SLC16A1 gene cause exercise-dependent PC. Said gene, which is not normally expressed in the β-cell, encodes the monocarboxylic transporter 1, which carries pyruvate and lactic acid. The last precursors of energy molecules increase much after hard work, leading to an increase in ATP and insulin overexpression by the β-cell. Although hyperinsulinemia is severe, it can only be treated by avoiding strenuous exercise.

It is obvious from the above, that the knowledge of the molecular-genetic mechanism of YY is necessary both for the better prognosis and clinical treatment as well as for the appropriate genetic advice. For example, most patients with mutations in the GLUD1, HNF4A, HADH genes respond well to diazoxide, while patients with ABCC8 and KCNJ11 mutations usually have the most severe symptoms, often with a poor response to diazoxide, especially homozygous mutations that are expressed in a residual manner and usually cause diffuse islet hyperplasia. In contrast, heterozygous mutations that behave as predominant can cause focal islet hyperplasia, which can be detected with 18FDOPA-PETscan. This examination is performed in specialized centers abroad and can lead to the final surgical treatment of the problem without the disability of diabetes, a complication of stomatal pancreatectomy. The latter operation may need to be resorted to if all available drugs, and even their combined administration, fail to adequately control the PC. Glucagon, continuous subcutaneous infusion, nifedipine and somatostatin analogues are the other drugs available to treat diazoxide-resistant hyperinsulinism. Since the response to each drug individually can not predict the response to their combined administration, one should exhaust all possibilities before recommending stroke pancreatectomy, an operation that will sooner or later lead to insulin-dependent diabetes mellitus.

Focal lesions of islet hyperplasia may also result from paternal single-parent diosome of chromosome 11p15.5-11p15.1 within a single β-cell. The single-parent diisome results in the predominant behavior of the paternal mutation of the KATP channel at 11p15.1, which in combination with the reduced expression of the maternal HR and CDKN1C gene suppressants and the increased expression of the paternal IGF-2 causes 11.p.5, cell cycle disorder, monoclonal proliferation of that cell and the consequent focal lesion in the pancreas, responsible for insulin hypersecretion.

 

Beckwith-Wiedemann syndrome

 

It is a phenotypically and genetically heterogeneous syndrome of physical overgrowth with the main characteristics of the lingual and the abnormalities of the abdominal wall. Body hemiplasia, fetal tumors, adrenal cytomegalovirus, visceral encephalopathy, ear and kidney abnormalities, vaulted palate and polydactyly are also common. Symptomatic hypoglycemia is common and quite severe in the first days of life, but usually transient as it resolves after the 10th day, unlike PC that shows no improvement after the 1st week of life. In 90% of cases, abnormalities in the expression of one or more genes in the 11p15.5 region are responsible, the expression of which depends on the parental impression, ie their maternal or paternal origin. The largest category of molecular disorders in BWS (10-20%) concerns paternal duplication of chromosome 11p15 resulting in decreased expression of the maternal tumor suppressor gene CDKN1C and overexpression of IGF-2, whose elevated levels cause neonatal, congenital, with the insulin receptor. Insulin levels at the time of hypoglycemia are inappropriate for sugar levels and BWS, but clearly lower than those found in PC. With IGF-2 measurement not widely available, the diagnosis is first made clinically, and then genetically confirmed in a large proportion of patients. These children are placed in a special protocol of long-term follow-up as there is a risk of visceral tumors mainly in infancy and 1st childhood.