Metabolic Disorders Associated With Neonatal Hypoglycemia

Abstract

After completing this article, readers should be able to: Hypoglycemia is a common problem in neonates that has many causes. This review focuses on metabolic disorders that may be associated with hypoglycemia in the neonatal period.During intrauterine life, the fetus derives fuel, as glucose, from the mother via the placenta. After birth, the energy demands on the former fetus increase dramatically. The baby now must maintain its own body temperature and must undertake the work of breathing and other activities. Further, the maintenance of blood glucose levels requires glycogenolysis and gluconeogenesis. Postnatally, there are four sources of glucose: dietary glucose; glucose derived from the cleavage of more complex sugars in the gut (eg, lactose to glucose and galactose); glucose released from glycogen stores (primarily in the liver); and gluconeogenesis, in which glucose is synthesized from carbon skeletons derived from certain amino acids using energy derived from catabolism of fatty acids.Most term infants have sufficient glycogen stores to maintain blood glucose levels for several hours before gluconeogenesis is required. Infants who are breastfed in the United States typically are offered only water as a supplement to human milk during the first few postnatal days, a period when the mother’s milk supply is not yet established. In contrast, formula-fed babies receive calories by mouth by the end of the first postnatal day. Consequently, the metabolic stress of prolonged fasting occurs more frequently in breastfed than in formula-fed babies. Although breastfed babies have higher levels of ketone bodies that appear to provide adequate energy during this high metabolic stress period, they may be more vulnerable to metabolic disorders that limit ketone production.Hypoglycemia is defined on the basis of symptoms and blood glucose levels. Most authorities regard a blood glucose level below 40 mg/dL (2.3 mmol/L) as low, regardless of the presence of clinical signs. (Blood glucose concentrations may be transiently lower in the first hours after birth.) Some infants exhibit clinical findings (eg, jitteriness, lethargy) at higher levels that respond immediately to glucose, suggesting that their blood glucose concentrations were too low for adequate function. Some of the symptoms of hypoglycemia (eg, lethargy) are due to lack of glucose; others (eg, jitteriness) are due to the hormonal response to hypoglycemia (especially increased catecholamine release). Apnea or seizures may occur, and there may be cardiac dysfunction.The disorders discussed in this article are presented in order based on the glucose source affected (ie, digestion and absorption, glycogenolysis, and gluconeogenesis).Disorders of absorption or digestion rarely are encountered in newborns; if they are present (as in lactose intolerance), they rarely are sufficiently severe to result in hypoglycemia. However, they typically cause significant diarrhea.Hepatocellular dysfunction from any cause may lead to hypoglycemia; the liver dysfunction should be obvious if there is jaundice. Infection and galactosemia are common causes. Galactosemia due to galactose-1-uridyl phosphate uridyltransferase deficiency commonly causes hepatic dysfunction, but may not cause marked hypoglycemia. Its diagnosis in the newborn period is critical because of the associated liver and renal dysfunction, cerebral edema, and cataracts and the risk of gram-negative sepsis. When suspected, all intake of galactose (human milk and cow milk formulas) must cease. The diagnosis can be suspected on the basis of positive reducing substances in the urine and confirmed by metabolite or enzyme assay. Urine obtained more than 1 day after cessation of galactose intake may be negative for reducing substances. Tyrosinemia may cause a similar picture of hepatocellular and renal dysfunction. Fructose intolerance appears similarly, but infants usually are not exposed to fructose or sucrose.The first glycogen storage disease discovered, von Gierke disease (GSD 1) is a defect of glucose release from hepatic cells due to abnormalities of glucose-6-phosphatase. Several subcategories exist. GSD 1 actually is a mixed disorder because glucose-6-phosphate, the substrate for the abnormal enzyme, is derived from both glycogen breakdown and gluconeogenesis. The result of the enzymatic defect is hypoglycemia as soon as intestinal sources of glucose are exhausted (typically 2 h after a feeding) and production of alternate fuels—lactate and ketone bodies—begins. It is not uncommon for an infant who has GSD 1 to have a blood glucose level of 20 mg/dL (1.1 mmol/L) and minimal symptoms due to the presence of alternate substrates.The other major defects of glycogenolysis are deficiencies of glycogen debrancher enzyme, liver phosphorylase, and the phosphorylase kinase system. These conditions usually are silent in the newborn period because prolonged fasting is rare. Fasting hypoglycemia without acidosis occurs after several hours. Hepatomegaly occurs within a few months and consists of both increased glycogen and fat. (Splenomegaly rarely is found in glycogen storage disorders, which is an important differential point.) Disorders due to impaired glycogen synthesis include brancher deficiency, which causes cirrhosis and may cause cardiomyopathy, and the very rare glycogen synthase deficiency (GSD type 0).The fasting that accompanies the first few days of breastfeeding is a major test of gluconeogenesis. Accordingly, defects that impair gluconeogenesis may result in significant and catastrophic decompensation. Disorders due to impaired fatty acid oxidation can result in hypoglycemia, with the added problem of the accumulation of toxic intermediates. The most common disorder of fatty acid oxidation is medium-chain acyl CoA dehydrogenase (MCAD) deficiency, which occurs in perhaps 1 in 10,000 people of northern European descent. A few percent of MCAD-deficient infants, especially breastfed ones, experience an episode of hypoglycemia in the first few postnatal days. However, most affected infants do not have symptoms until a few months of age or even later. Decompensations often are provoked by infection in conjunction with fasting and may be exacerbated by carnitine depletion. The response to intravenous administration of glucose may be slow, with the blood glucose concentration rising but the lethargy persisting, which reflects the toxicity of accumulated metabolic intermediates.Other disorders of fatty acid oxidation that may present in the newborn period are the defects of long-chain fatty acid oxidation. Cardiomyopathy, encephalopathy, and hepatic dysfunction may be prominent in deficiencies of very-long-chain acyl CoA dehydrogenase, long-chain hydroxyacyl CoA dehydrogenase (LCHAD), carnitine-acylcarnitine translocase, and carnitine palmitoyltransferases I and II. LCHAD deficiency in the fetus can provoke significant liver dysfunction (HELLP syndrome, acute fatty liver of pregnancy) in the heterozygous mother, although most cases of these maternal conditions are unrelated to LCHAD deficiency.Mild hypoglycemia certainly can occur in various organic acidurias (eg, propionic and methylmalonic acidemia, maple syrup urine disease), but the presenting urgent problems in these disorders most commonly are ketoacidosis, lactic acidosis, and hyperammonemia, with associated encephalopathy. Other causes of hepatocellular dysfunction also can lead to hypoglycemia, but the diagnosis in such cases generally is evident because of the presence of laboratory values suggestive of liver failure.Hyperinsulinism is a metabolic disorder that affects both glycogenolysis and gluconeogenesis and most commonly reflects the presence of maternal hyperglycemia. Other causes are fetal overgrowth syndromes, especially Beckwith-Wiedemann syndrome, and overgrowth of the pancreas, previously referred to as nesidioblastosis. (See Genetic and Nongenetic Forms of Hyperinsulinism in Neonates in this issue.)Other hormones involved in glucose regulation include glucagon, cortisol, growth hormone, thyroid hormone, and catecholamines. Deficiencies of any of these hormones from structural or functional defects may be associated with neonatal hypoglycemia. Growth hormone deficiency may be silent in the newborn period because insulin is a more important growth hormone in the fetus. Cortisol deficiency (as occurs in congenital adrenal hyperplasia) also may be cryptic initially, but it may present with subsequent complete metabolic collapse later in the first 2 postnatal weeks, with accompanying salt-wasting, hypoglycemia, and circulatory collapse.The congenital disorders of glycosylation (CDGs) (formerly carbohydrate-deficient glycoprotein disorders) form a new category of disorders that lead to impaired synthesis of many molecules, including hormone and lipid carriers. Hypoglycemia often occurs, and plasma cholesterol also may be very low in these conditions. Deficient steroid-binding protein leads to functional cortisol deficiency, while (pseudo)hypothyroidism may be detected by newborn screening because of low thyroid-binding globulin. CDG 1a, which is due to phosphomannomutase 2 deficiency, has accompanying malformations, including cerebellar hypoplasia. CDG 1b, with an associated defect in phosphomannose isomerase, may present with hypoglycemia followed by protein-losing enteropathy and hepatic fibrosis. This condition is treated successfully with oral mannose. Many other CDGs are known. All are recognized by isoelectric focusing of transferrin.The pregnancy and history of feeding and fasting can point to likely causes of hypoglycemia. Investigation of hypoglycemia includes the family history, pregnancy history (with particular reference to weight gain and glucose tolerance), peculiarities regarding labor and delivery, examination of the placenta (not always done), and examination of the infant. Common causes of neonatal hypoglycemia, such as sepsis, intrauterine growth restriction, and transient hyperinsulinism, must be ruled out before more unusual diagnoses are entertained. The feeding history and risk factors for infection are especially important. Overgrowth or intrauterine starvation is obvious. Prenatal infection can cause placental insufficiency, leading to intrauterine starvation with subsequent hypoglycemia and hepatic dysfunction, which can exacerbate abnormalities of glucose homeostasis.Essentially all of the metabolic disorders discussed in this article are inherited in an autosomal recessive pattern. The family history may be positive for similarly affected siblings or unexplained infant deaths. Consanguinity usually is not present, but can suggest the presence of a metabolic disorder that has a recessive inheritance when it is. Genital abnormalities (eg, virilization, hyperpigmentation) can point to adrenal hyperplasia. Midline facial defects may suggest abnormalities of pituitary function. MCAD deficiency is characterized by acute illness, not chronic problems. In contrast, infants who have organic acidurias may experience chronic feeding difficulties, but may not have complete metabolic collapse until after the first several days to a few weeks after birth. An increasing number of metabolic disorders, including some discussed here, can be identified on the initial routine newborn screen.A blood sample obtained just before glucose is administered can provide invaluable information later, so it should be obtained if at all possible. This sample offers convincing information regarding insulin and other hormones, which changes rapidly after glucose is administered. The blood glucose test strip, based on glucose oxidase, is a rapid but not always reliable test at low levels, so abnormalities must be confirmed with a proper blood glucose determination. Samples for insulin, cortisol, growth and thyroid hormones, electrolytes, ammonia, amino acids, carnitine and acylcarnitines, blood culture, blood counts, and liver function/transaminases address most of the potential causes, but not all of these tests are needed in a given situation.Measurement of blood electrolytes, with calculation of the anion gap, can suggest acidosis and the presence of a missing anion (usually lactate or ketone bodies). The arterial pH may be normal, even in the presence of significant acidosis, because of respiratory compensation. If acidosis is suspected, lactate should be measured directly. Other blood tests should include measurement of insulin and other hormones (growth hormone, thyroid hormone, cortisol) and plasma amino acid analysis. Special attention should be paid to alanine (which reflects elevation of pyruvate and lactate) and the gluconeogenic amino acids. Analysis of blood spot acylcarnitines can reveal MCAD deficiency or other disorders of fatty acid oxidation rapidly.Urinalysis should be performed in all cases of suspected metabolic disorders, although the clinician should remember that the dipstick does not discriminate between the various reducing sugars. The dipstick also does not detect beta-hydroxybutyrate, a ketone body. Measurement of urine organic acids can reveal excessive lactate, ketone bodies, and the metabolites of organic acidurias and fatty acid oxidation defects. The acylcarnitine profile generally is abnormal in the presence of fatty acid oxidation defects, but infants who have organic acidurias may have normal organic acid levels between episodes of acute decompensation. A fasting stress test may be necessary to reveal a deficient hormonal response to hypoglycemia. Because such a test can be dangerous in MCAD deficiency and fatty acid oxidation defects, it should be undertaken only after these disorders have been ruled out by acylcarnitine analysis.The introduction of tandem mass spectrometry for newborn screening is leading to early diagnosis of many life-threatening disorders. At least 30 state newborn screening programs in the United States have adopted or are evaluating this technique, and two private laboratories also are offering it. The technology allows the separation of complex mixtures (extracts of dried blood spots) and identification of components of interest in about 2 minutes. (In comparison, urine organic acid analysis by gas chromatography-mass spectrometry can take 40 min per sample after sample preparation; quantitative amino acid analysis by column chromatography can take a few hours per sample.) The technique is conceptually simple: mass spectrometers “weigh” molecules (ie, determine their mass). Two mass spectrometers coupled in series, therefore, can determine the mass of a parent molecule and fragments derived from the parent.The addition of acylcarnitine profiling to newborn screening panels allows the identification of nearly all children who have the various fatty acid oxidation defects. Acylcarnitines share a common core and differ in their side chains, which have different masses. More than a dozen different disorders of fatty acid and organic acid metabolism can be distinguished rapidly by the different acylcarnitines that accumulate because of impaired enzyme activity (eg, various acyl-CoA dehydrogenase deficiencies). Many different amino acids also can be determined in the same instrument at the same time, leading to rapid diagnosis of more than a dozen aminoacidopathies, such as phenylketonuria, tyrosinemia, and maple syrup urine disease. The technique also can be used to identify infants who have many disorders of organic acid and urea cycle metabolism.Batched, semiautomated preparation of samples makes it possible to analyze several hundred samples per day on a single instrument. Testing usually is performed on a sample obtained between 48 and 72 hours of age. The sample must be dried, shipped to the screening laboratory, and analyzed. Thus, the infant may be nearly 1 week old before the results are known. During this interval, the disorders that are provoked by fasting in the newborn period, especially MCAD deficiency, already may have presented clinically.In some cases, the newborn screening test provides a definitive diagnosis; in others, the abnormality may be subtle, requiring repeat testing or different tests. A normal newborn screening result cannot rule out a particular disorder completely, so sick infants or children in whom metabolic disease is suspected should be evaluated as if newborn screening had not been performed.Although rare, metabolic disorders can lead to significant morbidity and mortality due to severe hypoglycemia and metabolic collapse. Breastfed infants may be at increased risk, particularly from disorders of ketogenesis, during the first 48 hours of postnatal life. Fortunately, improved techniques for newborn screening can help to identify many affected infants before they present clinically.