Key Points
Disease summary:
Hypoglycemia is defined as a decrease in the blood glucose level or its tissue utilization accompanied by typical signs and symptoms. Based on rate of decline (rapid or slow) in glucose blood levels, symptoms of hypoglycemia are classified mainly in two major categories: adrenergic and neuroglycopenic. Inadequate supply of glucose to the brain and other tissues may have a negative impact on their energy requirements and function.
Whipple triad defines a combination of three criteria used to diagnose hypoglycemia:
The presence of characteristic hypoglycemia symptoms
Low glucose levels and typical symptoms
The resolution of symptoms after the normalization of blood glucose
Hereditary basis:
Hypoglycemia can be inherited as an isolated finding or as one component of a multisystem syndrome. Observed pattern of inheritance includes autosomal dominant, autosomal recessive, and X-linked recessive. See mur_ch57cap1.
Differential diagnosis:
Various disorders of excessive or underproduction of glucose have a genetic component. The most common forms of genetic hyperinsulinemia are represented by familial hyperinsulinemia hypoglycemia (FHH) (Table 57-1). Autosomal dominant and recessive forms are identified based on SUR1/Kir6.2 receptor mutations in the different genes that encoded it: ABCC8, KCNJ11. Other rarer genetic causes of hyperinsulinism have been linked to mutations that coded for different enzymes or receptors identified with other subtypes of FHH: GCK, HADH, INSR, GLUD1, SLC16A1.
In 50% of patients with hyperinsulinism, there are no identifiable genetic markers but single-nucleotide polymorphisms (SNPs) were reported in some infants with hypoglycemia.
Beckwith-Wiedemann syndrome is an autosomal dominant condition with variable penetrance and genomic imprinting should be a part of the differential diagnosis of hyperinsulinemia.
Glucose-processing defects (glycogen synthase deficiency, glycogen-storage disease, respiratory chain defects) are mostly manifested during infancy and early childhood. Defects in alternative fuel production (carnitine acyl transferase deficiency, hepatic HMG CoA lyase deficiency, long-chain or medium-chain or variably short-chain acyl-coenzyme A dehydrogenase deficiency) can destabilize the energy balance in the body making it difficult to accommodate a prolonged starvation or acute stress period.
Disorders of glucose underproduction are caused by inadequate glucose stores (prematurity, small for gestational age), glycogen synthase deficiency, glycogen-storage disease, or hormonal abnormalities.
Glycogen synthase deficiency is manifested as fasting hypoglycemia because of the liver’s inability to store glucose, whereas in glycogen-storage disease there are problems with glucose release and gluconeogenesis.
Hormonal deficiencies (partial or complete) are expressed as autosomal recessive or X-linked recessive condition. Some of these hormonal deficiencies may be associated with transient or persistent hypoglycemia.
| Syndrome | Gene Symbol | Associated Findings | |
|---|---|---|---|
| Hyperinsulinemia | Hyperinsulinemic hypoglycemia Familial (HHF) 1 HHF 2 HHF 3 HHF 4 HHF 5 HHF 6 HHF 7 | ABCC8 KCNJ11 GCK HADH INSR GLUD1 SLC16A1 | Hypoglycemia in the newborn or infant, elevated serum insulin, low serum ketone bodies, hypotonia, poor feeding, apnea, increased glucose response to glucagon administration Children—hypoglycemia, diaphoresis, behavior changes Adults—altered mental status, headaches, lethargy, loss of consciousness |
| Beckwith-Wiedemann syndrome (BWS) | CDKN1C H19 IGF2 KCNQ1 KCNQ1OT1 | About 85% cases of BWS are sporadic but some (<15%) cases of BWS are familial Classic form: hemihypertrophy, macroglossia, ear creases, ear pits, hypoglycemia (50% of babies), visceromegaly (liver, spleen, kidneys, or adrenals) midline abdominal wall defects (omphalocele, umbilical hernia, diastasis recti), associated embryonal malignancies: Wilms tumor, hepatoblastoma | |
| Islet cell adenoma or tumor-associated with MEN1 | MEN1 | Multiple endocrine neoplasia type 1 is caused by mutation in the MEN1 gene while MEN2A or MEN2B, is caused by mutations in the RET gene and MEN4 by a mutation in the CDKN1B gene. MEN1 characteristics:
| |
| Defects in alternative fuel production | Carnitine acyltransferase deficiency | CPT1A CPT2 | Neonatal form—respiratory failure, hypoglycemia, seizures, hepatomegaly, liver failure, cardiomegaly Infantile form—hypoketotic hypoglycemia, seizures Adult form—rhabdomyolysis, myoglobinuria, recurrent myalgia |
| Hepatic hydroxymethylglutaryl coenzyme A [HMG CoA] lyase deficiency | HMGCL | Presenting in the first year of life with vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia | |
| Long-chain and medium-chain acyl-coenzyme A dehydrogenase deficiency | ACADL ACADM | Vomiting, feeding problems, lowered consciousness fatty acid accumulation, hyperammonemia Hypoglycemia, early-onset cardiomyopathy, neuropathy, pigmentary retinopathy, sudden death | |
| Variably in short-chain acyl-coenzyme A dehydrogenase deficiency | ACADS | Neonatal form—poor appetite, developmental delay, seizures, myopathy, and nonketotic hypoglycemia Infant form (generalized)—acute acidosis, low muscle tone Adult form (localized)—chronic myopathy | |
| Disorders of glycogenolysis | Glycogen synthase deficiency | GYS2 | Fasting hypoglycemia, increased ketones, free fatty acids, low levels of alanine and lactate, and in severe cases recurrent hypoglycemic seizures Decreased glycogen stores in the liver and inadequate gluconeogenesis Primarily manifested during infancy and early childhood |
| Glycogen-storage disease type Ia/b | G6PC | Hypoglycemia, lactic acidosis, hypertriglyceridemia, hyperuricemia, doll-like faces with fat cheeks, growth failure, hepatomegaly | |
| Glycogen-storage disease type III | AGL | Hypoglycemia, growth retardation, hypotonia cardiomyopathy (later), hepatomegaly | |
| Glycogen-storage disease type VI | PYGL | Hypoglycemia, hyperlipidemia, hyperketosis, hepatomegaly, and growth retardation in early childhood | |
| Fructose 1,6 diphosphatase deficiency | FBP1 | Hypoglycemia, metabolic acidosis, seizures, hypertension, miosis, fatty liver, ketone bodies | |
| Phosphoenol pyruvate deficiency I,II | PCK1 PCK2 | Hypoglycemia, metabolic acidosis, cerebral atrophy, liver failure, generalised muscle weakness, early death | |
| Pyruvate carboxylase deficiency | PC | Type A (infantile form)—fatigue, abdominal pain, muscle hypotonia, lactic acidosis Type B (severe neonatal form)—hyperammonemia, liver failure, abnormal movements, death within the first 3 months of life Type C (intermittent or benign form)—mildly delayed neurologic development, transient metabolic acidosis | |
| Hereditary fructose intolerance | ALDOB | Vomiting, abdominal pain, enlarged liver, hypoglycemia, jaundice, hemorrhage, kidney failure, or seizures | |
| Galactosemia | GALT GALK1 GALE | Hepatomegaly, cirrhosis, renal failure, brain damage, ovarian failure | |
| Hormonal disorders | X-linked panhypopituitarism | SOX3 | Neonatal hypoglycemia, growth hormone deficiency, variable deficiencies of other pituitary hormones, hypoplasia of the anterior pituitary with hypoplasia or absence of the lower half of the infundibulum, normal psychomotor development |
| X-linked adrenal hypoplasia congenita | NR0B1 | Hypogonadotropic hypogonadism (males), skeletal immaturity, adrenal insufficiency (dehydration, shock, hypoglycemia) | |
| Combined pituitary hormone deficiency 1 | PROP1 | Growth failure, developmental deficiency starting early in life, mild hypothyroidism, deficient secondary sexual development, infertility, ACTH deficiency (late onset) | |
| Glucocorticoid deficiency-1 | MC2R | Cutaneous hyperpigmentation, tall stature, craniofacial abnormalities, hypoglycemia, muscles weakness | |
| Disorders of amino acid metabolism | Maple syrup urine disease Ia, b, II | BCKDHA BCKDHB DBT DLD | Mental or physical retardation, feeding difficulties and a maple syrup odor to the urine. MSUD patients are included into five phenotypes: classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase (E3)-deficient |
| Other | Neurofibromatosis 1 | NF1 | Six or more café-au-lait macules >5 mm in diameter in prepubertal and >15 mm in diameter in adult individuals, two or more neurofibromas of any type, two or more Lisch nodules freckles of the axillae, optic gliomas |
Diagnostic Criteria and Clinical Characteristics
An essential energetic source for central nervous system (CNS) function is represented by glucose. About 90% of cerebral metabolism is based on this substrate and a rapid or slow decline in availability of glucose in the body will produce associated signs and symptoms. The main clinical manifestations of hypoglycemia can be comprised in two major clinical pathways:
Symptoms caused by activation of the autonomic nervous system (ANS) and its counter-regulatory hormones: sweating, nausea, anxiety, tachycardia, palpitations, shaking, hunger
Neuroglycopenic symptoms due to deficiency of glucose: headache, visual disturbances, slurred speech, restlessness, bizarre behavior, somnolence, confusion, seizures, ataxia, coma
The symptoms related to activation of the ANS generally appear before neuroglycopenic symptoms which occur when glucose levels are below 40 to 50 mg/dL.
Neonatal hypoglycemic clinical presentation is sometimes difficult to diagnose. Diseases manifesting in the neonatal period have a more severe presentation. Some of the following symptoms may raise the suspicion of low blood glucose: cyanotic episodes, apnea, poor feeding, brief myoclonic jerks, lethargy, somnolence, and seizures.
In neonates, common causes of hypoglycemia are considered the following:
Transient: prematurity, sepsis, perinatal asphyxia, uncontrolled diabetes (mother)
Permanent
Hyperinsulinemic hypoglycemia of infancy (HHI)
Carbohydrate metabolism disorders
Disorders of fatty acid oxidation
Glycogen storage diseases
Galactosemia
Amino acid and acid organic disorders
Causes of hypoglycemia in older infants, children, and teenagers
Overtreatment with insulin in type 1 diabetes, sepsis, glycogen storage disease (GSD) type I or III or VI, phosphoenolpyruvate carboxykinase deficiency, disorders of fatty acid oxidation, amino acid and acid organic disorders (maple syrup urine disease, propionic acidemia), poisoning (drugs)
In young and older adults, the most frequent forms of hypoglycemia are
Overdosing of diabetes mellitus with insulin or oral hypoglycemic agents, Addison disease, alcohol-induced hypoglycemia, insulin-secreting pancreatic tumor, postgastric bypass surgery
A pertinent diagnosis of hypoglycemia has to be based on history, clinical examination, and various laboratory data.
It is important to know the age of debut of hypoglycemia, information about the birth history, previous seizures, food intolerance, behavioral changes, fasting hypoglycemia, visceromegaly, family history of diabetes, and if various medications with potential of inducing hypoglycemia have been administrated. Other information may be necessary based on individual approach of the patients with possible hypoglycemia.
A thorough physical examination can help us to sort out various conditions related to hypoglycemia. Specific physical findings have been linked to certain conditions where the low blood sugar is a component of the diagnosis. Because of a great number of conditions what can be accompanied by hypoglycemia a systematic approach relying on major clinical syndromes involved is desirable.
The following clinical signs are most common in patients with hypoglycemia:
Tachycardia, inappropriate mood, seizure, coma
Diplopia, papilledema, visual field defects (bilateral hemianopsia)
Large body size—hyperinsulinism
Failure to thrive, dysmorphic features, skeleton malformation, organomegaly
Midline facial, cranial abnormalities (cleft lip or palate), microphallus, growth failure with decreased growth rate for age, hypotension, hyperpigmentation
Jaundice concomitant with an enlarged liver, eye changes (cataracts)
A major step toward a refined diagnosis and urgent treatment of hypoglycemia is represented by obtaining accurate laboratory data. It is important to measure serum glucose concentration with a laboratory-based glucose analyzer prior to the administration of glucose.
Most of the authors define hypoglycemia based on the following serum glucose levels:
Less than 60 mg/dL in men
Less than 50 mg/dL in women
Less than 40 to 45 mg/dL in infants and children
However, these levels are still disputed among physicians particularly in neonates. Typically once hypoglycemia is confirmed (by serum glucose levels and/or adequate symptoms), it is important to obtain what was defined in the classical literature as, “critical sample” of blood. As a part of initial diagnosis an initial blood sample should measure various metabolic precursors and hormones involved in glucose counter-regulation helping us to have a more systematic approach of the metabolic and hormonal imbalances of the patient.
Blood Sample
Serum—glucose, electrolytes, bicarbonate, anion gap, insulin, C-peptide, growth hormone, cortisol, lactate, ammonia, pyruvate, beta-hydroxybutyrate, free fatty acid (FFA), total and free carnitine, branched-chain amino acid, toxicology screen for adults (ethanol, salicylates, sulphonylureas)
Urine—ketones, C-peptide
Any abnormal titers of FFA should hint to a defect in fatty acid metabolism, while high plasma lactate levels point to a defect in gluconeogenesis, glycolysis, or respiratory-chain defects. Low cortisol, growth hormone, sex hormone levels should guide us to a possible diagnosis of hypopituitarism or adrenal insufficiency.
Other Studies
Glucagon challenge
Intra-arterial calcium stimulation with hepatic venous sampling
Liver function tests, thyroid tests
Blood cultures, chest radiograph, urinalysis
Genetic analysis for genetic disorders associated with hyperinsulinism (FHH, BWS, etc)
Abdominal ultrasonography, computed tomography (CT) scanning, magnetic resonance imaging (MRI) (head, pancreas)
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