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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.





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.

Corticosteroid insufficiency (ACTH-cortisol)


The exclusion of both adrenal and pituitary insufficiency is of primary importance in the etiological investigation of hypoglycaemia.


Adrenal insufficiency


Adrenal insufficiency is due to either A 'adrenal insufficiency or pituitary insufficiency and is either congenital or acquired. The progressive establishment of anorexia and vomiting with concomitant hypoglycemia, easy fatigue and muscle weakness with concomitant hyponatremia-hyperkalemia, hypotension and generalized hyperpigmentation of the skin, indicates adrenal insufficiency. Congenital adrenal hyperplasia (as well as rare forms of congenital adrenal hypoplasia) is a major cause of adrenal insufficiency in the neonatal period, and Addison's disease is the most common cause in children and adolescents. The latter is usually of autoimmune etiology and may not be isolated but may be a manifestation of autoimmune polyendocrinopathy type 1 (hypoparathyroidism, Addison and mucosal candidiasis) or type 2 (Hashimoto's thyroiditis, Addison, type 1 diabetes). The diagnosis is made very easily on hypoglycemia as the cortisol response is insufficient and the ACTH value is disproportionately high. The search for anti-adrenal antibodies (against 21-hydroxylase) is now available in our country in large diagnostic centers and specialized immunological laboratories.

Secondary adrenal insufficiency is not uncommon in childhood after abrupt discontinuation of steroid-administered PO therapy or slow-release injections (eg for the treatment of eyelid hemangiomas). These children require hydrocortisone replacement for several months, in the lowest possible doses and with gradual reduction, until the balance is restored to the corticosteroid axis.

If it is a boy with adrenal insufficiency and a history of seizures or signs of neurological impairment, one should consider sex-linked adrenoleukodystrophy (ALD), which is due to the accumulation of long-chain fatty acids, and perform an MRI scan of the brain. disease.


Congenital growth hormone deficiency - pituitary insufficiency


Severe symptomatic hypoglycaemia, even life-threatening, can occur in infancy - early infancy in the context of congenital growth hormone deficiency. It is a rare disease as it affects about 1. Of cases of pituitary insufficiency and is usually accompanied by cholestatic jaundice, which is perhaps the most important diagnostic guide. Simultaneous monitoring of the integrity of the somatotrophic (growth hormone) and corticotrophic axis (ACTH-cortisol) is possible through the glucagon test, which is applicable even to infants. For the diagnosis in infancy, however, a measurement of cortisol, growth hormone and insulin (to exclude PC) at the time of hypoglycemia is sufficient.


Insufficiency of the cortical axis


In the case of corticotrophic insufficiency (resistance to ACTH, or ACTH insufficiency) that is progressively established in childhood, in the context of syndrome 3-A (Esophageal achalasia, Addison, Allergy, autonomic nervous system dysfunction and progressive neurodegenerative Recently described and very life-threatening DAVID (Deficiency AdrenocotricotropinandVariableImmuneDeficiency) syndrome, characterized by ACTH deficiency and combined immunodeficiency, hypoglycaemia and its symptoms may be subacute, at least in the early stages, but acute and life-threatening.


Syndrome 3-A, resistance to ACTH


Syndrome 3-A is inherited with the autosomal recessive character. About half of patients have mutations in the AAAS gene, which is located on chromosome 12p13 and encodes the protein ALADIN, a key component of nuclear membrane pores. Although alkalinity is not the manifestation leading to the diagnosis, it seems to be the most stable and early component of the disease and is easily detected by the Schirmer test. Esophageal achalasia is also usually slow-progressing, leading to difficulty swallowing even after ingestion. The diagnosis of adrenal insufficiency in children with 3-A requires special care, as it is possible that the provoked tests, even the low-dose ACTH test (1 μg), do not give clearly pathological results. Recently, 2 sudden deaths of children with 3-A syndrome have been reported, who did not receive hydrocortisone replacement because they had a normal ACTH challenge test.


ACTH Insufficiency, DAVID Syndrome


The reason for the realization of this new - life threatening - disease entity were 3 brothers (2 boys and 1 girl), a family of French healthy parents without kinship. The two boys suffered from a common variable immune deficiency, suffered from recurrent dangerous infections, and received regular human immunoglobulins. The first boy was admitted to the ICU during a severe shock infection, when the second boy arrived at the emergency room with a status picture, during which hypoglycemia of 18 mg / dl was found. HACTH and cortisol were non-measurable. After hydrocortisone replacement, the boy did not have to take immunoglobulins again as he never had a serious infection again, which proves the strong link between the immune system and pituitary and corticosteroid function in particular. In fact, the older sister, who had exactly the same type of immunodeficiency, but without ACTH deficiency, had never been seriously ill and never had to be hospitalized for an infection. The recognition of the syndrome led to the identification of 2 other young patients with the same combination, in other hospitals in France. The attempt to identify the genetic cause has not yet paid off, as mutations of the transcription factor TPIT (mutations of which cause individual ACTH deficiency) as well as the LIF, IKAROS and EOS genes have been ruled out.


Treatment of hypoglycemia


Early detection and correction of hypoglycaemia is critical, as we may have permanent brain damage soon after the onset of symptoms, especially in newborns and infants. For this reason, every child with a serious illness and affected general condition should have their blood sugar levels checked. Hypoglycemia during resuscitation is associated with increased mortality.

Urgent treatment of symptomatic hypoglycaemia in a patient with loss of consciousness includes administration of glucagon, preferably intramuscularly (or subcutaneously) at a dose of 0.1-0.2 mg / kg and intravenous administration of 0.2-1 gr / kg with a mean dose 0.4-0.5 gr / kg body weight of glucose in the form of dextrose solution 10% (4 ml / kg in infants and young children) or 35% (about 1 ml / kg in older children). Less concentrated glucose solutions are used at younger ages to avoid vascular irritation and injury from the use of hypertonic solutions such as Dx 35%. Some even recommend smaller doses, just 0.2 g / kg glucose, to correct hypoglycemia to avoid a hyperinsulinemic response and reactive hypoglycaemia. In urgent treatment, hydrocortisone (Solucortef) can be given parenterally at a dose of 5 mg / Kg (50 mg / m2).

After the correction of hypoglycemia, normal glucose homeostasis should be ensured, especially in newborns, with continuous iv glucose administration. The normal needs of newborns are met by continuous administration of glucose at a rate of 6-10 mg / kg / min. At this rate, of course, po feeding should be taken into account, based on the carbohydrate content of the milk given. Non-maintenance of glycemia with a glucose rate of up to 10 mg / Kg / min is also a diagnostic criterion for hyperinsulinemic hypoglycemia.

Next, of course, is the investigation and treatment of the primary cause.

The causes of hypoglycemia are summarized in the table below.


Causes of hypoglycemia

Decreased glucose production / availability (type 1 glycogenase)
Exhausted glucose stores
SGA, prematurity
Poor nutrition / fasting
Malabsorption / diarrhea
Increased use of glucose
LGA, Child of a diabetic mother
Hyperinsulinemic hypoglycemia
Beckwith-Wiedemann syndrome
Infection / Sepsis
Congenital metabolic disorders
Hormonal deficiency
Adrenal insufficiency (A'pathetic or B'pathetic)
Growth hormone deficiency
Glucagon deficiency
Insulin / antidiabetic tablets
Poisoning (alcohol, propanolol, salicylates)
Reye's syndrome




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