neoreview metabolic dis hypoglycemia 2004

DOI: 10.1542/neo.5-9-e3772004;5;e377Neoreviews

Stephen G. KahlerMetabolic Disorders Associated With Neonatal Hypoglycemia

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Metabolic Disorders AssociatedWith Neonatal HypoglycemiaStephen G. Kahler, MD* Objectives After completing this article, readers should be able to:

1. Describe four sources of glucose available to the neonate in the first 24 postnatalhours.

2. Select the best routine diagnostic test to recognize fatty acid oxidation defects.3. List three or more metabolic disorders that can be identified by newborn screening

performed using tandem mass spectrometry.

IntroductionHypoglycemia is a common problem in neonates that has many causes. This reviewfocuses on metabolic disorders that may be associated with hypoglycemia in theneonatal period.

Metabolic Requirements for Glucose Homeostasis in NewbornsDuring intrauterine life, the fetus derives fuel, as glucose, from the mother via theplacenta. After birth, the energy demands on the former fetus increase dramatically.The baby now must maintain its own body temperature and must undertake the workof breathing and other activities. Further, the maintenance of blood glucose levelsrequires glycogenolysis and gluconeogenesis. Postnatally, there are four sources ofglucose: dietary glucose; glucose derived from the cleavage of more complex sugars inthe gut (eg, lactose to glucose and galactose); glucose released from glycogen stores(primarily in the liver); and gluconeogenesis, in which glucose is synthesized fromcarbon skeletons derived from certain amino acids using energy derived from catabo-lism of fatty acids.

Most term infants have sufficient glycogen stores to maintain blood glucose levels forseveral hours before gluconeogenesis is required. Infants who are breastfed in theUnited States typically are offered only water as a supplement to human milk duringthe first few postnatal days, a period when the mothers milk supply is not yetestablished. In contrast, formula-fed babies receive calories by mouth by the end of thefirst postnatal day. Consequently, the metabolic stress of prolonged fasting occursmore frequently in breastfed than in formula-fed babies. Although breastfed babieshave higher levels of ketone bodies that appear to provide adequate energy during thishigh metabolic stress period, they may be more vulnerable to metabolic disorders thatlimit ketone production.

HypoglycemiaHypoglycemia is defined on the basis of symptoms and blood glucose levels. Mostauthorities regard a blood glucose level below 40 mg/dL (2.3 mmol/L) as low, regardlessof the presence of clinical signs. (Blood glucose concentrations may be transiently lower inthe first hours after birth.) Some infants exhibit clinical findings (eg, jitteriness, lethargy) athigher levels that respond immediately to glucose, suggesting that their blood glucoseconcentrations were too low for adequate function. Some of the symptoms of hypoglyce-mia (eg, lethargy) are due to lack of glucose; others (eg, jitteriness) are due to thehormonal response to hypoglycemia (especially increased catecholamine release). Apnea orseizures may occur, and there may be cardiac dysfunction.

*Visiting Professor of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School ofMedicine, Baltimore, Md.

Article endocrinology

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Metabolic Disorders Presenting WithHypoglycemiaThe disorders discussed in this article are presented inorder based on the glucose source affected (ie, digestionand absorption, glycogenolysis, and gluconeogenesis).

Disorders of Absorption and DigestionDisorders of absorption or digestion rarely are encoun-tered in newborns; if they are present (as in lactoseintolerance), they rarely are sufficiently severe to result inhypoglycemia. However, they typically cause significantdiarrhea.

Hepatocellular dysfunction from any cause may leadto hypoglycemia; the liver dysfunction should be obviousif there is jaundice. Infection and galactosemia are com-mon causes. Galactosemia due to galactose-1-uridylphosphate uridyltransferase deficiency commonly causeshepatic dysfunction, but may not cause marked hypogly-cemia. Its diagnosis in the newborn period is criticalbecause 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. Thediagnosis can be suspected on the basis of positive reduc-ing substances in the urine and confirmed by metaboliteor enzyme assay. Urine obtained more than 1 day aftercessation of galactose intake may be negative for reduc-ing substances. Tyrosinemia may cause a similar pictureof hepatocellular and renal dysfunction. Fructose intol-erance appears similarly, but infants usually are not ex-posed to fructose or sucrose.

Disorders of GlycogenolysisThe first glycogen storage disease discovered, von Gierkedisease (GSD 1) is a defect of glucose release fromhepatic cells due to abnormalities of glucose-6-phosphatase. Several subcategories exist. GSD 1 actuallyis a mixed disorder because glucose-6-phosphate, thesubstrate for the abnormal enzyme, is derived from bothglycogen breakdown and gluconeogenesis. The result ofthe enzymatic defect is hypoglycemia as soon as intestinalsources of glucose are exhausted (typically 2 h after afeeding) and production of alternate fuelslactate andketone bodiesbegins. It is not uncommon for an infantwho has GSD 1 to have a blood glucose level of20 mg/dL (1.1 mmol/L) and minimal symptoms due tothe presence of alternate substrates.

The other major defects of glycogenolysis are defi-ciencies of glycogen debrancher enzyme, liver phosphor-ylase, and the phosphorylase kinase system. These con-ditions usually are silent in the newborn period because

prolonged fasting is rare. Fasting hypoglycemia withoutacidosis occurs after several hours. Hepatomegaly occurswithin a few months and consists of both increasedglycogen and fat. (Splenomegaly rarely is found in gly-cogen storage disorders, which is an important differen-tial point.) Disorders due to impaired glycogen synthesisinclude brancher deficiency, which causes cirrhosis andmay cause cardiomyopathy, and the very rare glycogensynthase deficiency (GSD type 0).

Disorders of GluconeogenesisThe fasting that accompanies the first few days of breast-feeding is a major test of gluconeogenesis. Accordingly,defects that impair gluconeogenesis may result in signif-icant and catastrophic decompensation. Disorders due toimpaired fatty acid oxidation can result in hypoglycemia,with the added problem of the accumulation of toxicintermediates. The most common disorder of fatty acidoxidation is medium-chain acyl CoA dehydrogenase(MCAD) deficiency, which occurs in perhaps 1 in10,000 people of northern European descent. A fewpercent of MCAD-deficient infants, especially breastfedones, experience an episode of hypoglycemia in the firstfew postnatal days. However, most affected infants donot have symptoms until a few months of age or evenlater. Decompensations often are provoked by infectionin conjunction with fasting and may be exacerbated bycarnitine depletion. The response to intravenous ad-ministration of glucose may be slow, with the bloodglucose concentration rising but the lethargy persisting,which reflects the toxicity of accumulated metabolicintermediates.

Other disorders of fatty acid oxidation that maypresent in the newborn period are the defects of long-chain fatty acid oxidation. Cardiomyopathy, encephalop-athy, and hepatic dysfunction may be prominent in defi-ciencies of very-long-chain acyl CoA dehydrogenase,long-chain hydroxyacyl CoA dehydrogenase (LCHAD),carnitine-acylcarnitine translocase, and carnitine palmi-toyltransferases I and II. LCHAD deficiency in the fetuscan provoke significant liver dysfunction (HELLP syn-drome, acute fatty liver of pregnancy) in the heterozy-gous mother, although most cases of these maternalconditions are unrelated to LCHAD deficiency.

Mild hypoglycemia certainly can occur in various or-ganic acidurias (eg, propionic and methylmalonic aci-demia, maple syrup urine disease), but the presentingurgent problems in these disorders most commonly areketoacidosis, lactic acidosis, and hyperammonemia, withassociated encephalopathy. Other causes of hepatocellu-lar dysfunction also can lead to hypoglycemia, but the

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diagnosis in such cases generally is evident because of thepresence of laboratory values suggestive of liver failure.

Hyperinsulinism is a metabolic disorder that affectsboth glycogenolysis and gluconeogenesis and most com-monly reflects the presence of maternal hyperglycemia.Other causes are fetal overgrowth syndromes, especiallyBeckwith-Wiedemann syndrome, and overgrowth of thepancreas, previously referred to as nesidioblastosis. (SeeGenetic and Nongenetic Forms of Hyperinsulinism inNeonates in this issue.)

Other hormones involved in glucose regulation in-clude glucagon, cortisol, growth hormone, thyroid hor-mone, and catecholamines. Deficiencies of any of thesehormones from structural or functional defects may beassociated with neonatal hypoglycemia. Growth hor-mone deficiency may be silent in the newborn periodbecause insulin is a more important growth hormone inthe fetus. Cortisol deficiency (as occurs in congenitaladrenal hyperplasia) also may be cryptic initially, butit may present with subsequent complete metaboliccollapse later in the first 2 postnatal weeks, with ac-companying salt-wasting, hypoglycemia, and circulatorycollapse.

The congenital disorders of glycosylation (CDGs)(formerly carbohydrate-deficient glycoprotein disorders)form a new category of disorders that lead to impairedsynthesis of many molecules, including hormone andlipid carriers. Hypoglycemia often occurs, and plasmacholesterol also may be very low in these conditions.Deficient steroid-binding protein leads to functional cor-tisol deficiency, while (pseudo)hypothyroidism may bedetected by newborn screening because of low thyroid-binding globulin. CDG 1a, which is due to phospho-mannomutase 2 deficiency, has accompanying malfor-mations, including cerebellar hypoplasia. CDG 1b, withan associated defect in phosphomannose isomerase, maypresent with hypoglycemia followed by protein-losingenteropathy and hepatic fibrosis. This condition istreated successfully with oral mannose. Many otherCDGs are known. All are recognized by isoelectric focus-ing of transferrin.

Identification of the Infant Who Has aMetabolic DisorderThe pregnancy and history of feeding and fasting canpoint to likely causes of hypoglycemia. Investigation ofhypoglycemia includes the family history, pregnancy his-tory (with particular reference to weight gain and glucosetolerance), peculiarities regarding labor and delivery,examination of the placenta (not always done), and ex-amination of the infant. Common causes of neonatal

hypoglycemia, such as sepsis, intrauterine growth restric-tion, and transient hyperinsulinism, must be ruled outbefore more unusual diagnoses are entertained. Thefeeding history and risk factors for infection are especiallyimportant. Overgrowth or intrauterine starvation is ob-vious. Prenatal infection can cause placental insuffi-ciency, leading to intrauterine starvation with subse-quent hypoglycemia and hepatic dysfunction, which canexacerbate abnormalities of glucose homeostasis.

Essentially all of the metabolic disorders discussed inthis article are inherited in an autosomal recessive pat-tern. The family history may be positive for similarlyaffected siblings or unexplained infant deaths. Consan-guinity usually is not present, but can suggest the pres-ence of a metabolic disorder that has a recessive inheri-tance when it is. Genital abnormalities (eg, virilization,hyperpigmentation) can point to adrenal hyperplasia.Midline facial defects may suggest abnormalities of pitu-itary function. MCAD deficiency is characterized byacute illness, not chronic problems. In contrast, infantswho have organic acidurias may experience chronic feed-ing difficulties, but may not have complete metaboliccollapse until after the first several days to a few weeksafter birth. An increasing number of metabolic disorders,including some discussed here, can be identified on theinitial routine newborn screen.

Diagnostic TestsA blood sample obtained just before glucose is adminis-tered can provide invaluable information later, so itshould be obtained if at all possible. This sample offersconvincing information regarding insulin and other hor-mones, which changes rapidly after glucose is adminis-tered. The blood glucose test strip, based on glucoseoxidase, is a rapid but not always reliable test at low levels,so abnormalities must be confirmed with a proper bloodglucose determination. Samples for insulin, cortisol,growth and thyroid hormones, electrolytes, ammonia,amino acids, carnitine and acylcarnitines, blood culture,blood counts, and liver function/transaminases addressmost of the potential causes, but not all of these tests areneeded in a given situation.

Measurement of blood electrolytes, with calculationof the anion gap, can suggest acidosis and the presence ofa missing anion (usually lactate or ketone bodies). Thearterial pH may be normal, even in the presence ofsignificant acidosis, because of respiratory compensation.If acidosis is suspected, lactate should be measured di-rectly. Other blood tests should include measurement ofinsulin and other hormones (growth hormone, thyroidhormone, cortisol) and plasma amino acid analysis. Spe-





cial attention should be paid to alanine (which reflectselevation of pyruvate and lactate) and the gluconeogenicamino acids. Analysis of blood spot acylcarnitines canreveal MCAD deficiency or other disorders of fatty acidoxidation rapidly.

Urinalysis should be performed in all cases of sus-pected metabolic disorders, although the clinicianshould remember that the dipstick does not discriminatebetween the various reducing sugars. The dipstick alsodoes not detect beta-hydroxybutyrate, a ketone body.Measurement of urine organic acids can reveal excessivelactate, ketone bodies, and the metabolites of organicacidurias and fatty acid oxidation defects. The acylcarni-tine profile generally is abnormal in the presence of fattyacid oxidation defects, but infants who have organicacidurias may have normal organic acid levels betweenepisodes of acute decompensation. A fasting stress testmay be necessary to reveal a deficient hormonal responseto hypoglycemia. Because such a test can be dangerous inMCAD deficiency and fatty acid oxidation defects, itshould be undertaken only after these disorders havebeen ruled out by acylcarnitine analysis.

Newborn ScreeningThe introduction of tandem mass spectrometry for new-born screening is leading to early diagnosis of manylife-threatening disorders. At least 30 state newbornscreening programs in the United States have adopted orare evaluating this technique, and two private laborato-ries also are offering it. The technology allows the sepa-ration of complex mixtures (extracts of dried bloodspots) and identification of components of interest inabout 2 minutes. (In comparison, urine organic acidanalysis by gas chromatography-mass spectrometry cantake 40 min per sample after sample preparation; quan-titative amino acid analysis by column chromatographycan take a few hours per sample.) The technique isconceptually simple: mass spectrometers weigh mole-cules (ie, determine their mass). Two mass spectrometerscoupled in series, therefore, can determine the mass of aparent molecule and fragments derived from the parent.

The addition of acylcarnitine profiling to newbornscreening panels allows the identification of nearly allchildren who have the various fatty acid oxidation de-fects. Acylcarnitines share a common core and differ intheir side chains, which have different masses. More thana dozen different disorders of fatty acid and organic acidmetabolism can be distinguished rapidly by the differentacylcarnitines that accumulate because of impaired en-zyme activity (eg, various acyl-CoA dehydrogenase defi-

ciencies). Many different amino acids also can be deter-mined in the same instrument at the same time, leadingto rapid diagnosis of more than a dozen aminoacidopa-thies, such as phenylketonuria, tyrosinemia, and maplesyrup urine disease. The technique also can be used toidentify infants who have many disorders of organic acidand urea cycle metabolism.

Batched, semiautomated preparation of samplesmakes it possible to analyze several hundred samples perday on a single instrument. Testing usually is performedon a sample obtained between 48 and 72 hours of age.The sample must be dried, shipped to the screeninglaboratory, and analyzed. Thus, the infant may be nearly1 week old before the results are known. During thisinterval, the disorders that are provoked by fasting in thenewborn period, especially MCAD deficiency, alreadymay have presented clinically.

In some cases, the newborn screening test provides adefinitive diagnosis; in others, the abnormality may besubtle, requiring repeat testing or different tests. A nor-mal newborn screening result cannot rule out a particulardisorder completely, so sick infants or children in whommetabolic disease is suspected should be evaluated as ifnewborn screening had not been performed.

ConclusionAlthough rare, metabolic disorders can lead to significantmorbidity and mortality due to severe hypoglycemia andmetabolic collapse. Breastfed infants may be at increasedrisk, particularly from disorders of ketogenesis, duringthe first 48 hours of postnatal life. Fortunately, improvedtechniques for newborn screening can help to identifymany affected infants before they present clinically.

Suggested ReadingBurton BK. Inborn errors of metabolism in infancy: a guide to

diagnosis. Pediatrics. 1998;102:e6977. Available at: http://pediatrics.aappublicationsorg/cgi/content/full/102/6/e69

Hoffman GF, Nyhan WL, Zschocke J, Kahler SG, Mayatepek E.Inherited Metabolic Diseases. Philadelphia, Pa: Lippincott, Wil-liams & Wilkins; 2001

Ogier de Baulny H. Management and emergency treatments ofneonates with a suspicion of inborn errors of metabolism. SeminNeonatol. 2002;7:1726

Ozand PT. Hypoglycemia in association with various organic andamino acid disorders. Semin Perinatol. 2000;24:172193

Pitt JJ, Eggington M, Kahler SG. Comprehensive screening of urinesamples for inborn errors of metabolism by electrospray tandemmass spectrometry. Clin Chem. 2002;48:19701980

Roe CR. Inherited disorders of mitochondrial fatty acid oxidation:a new responsibility for the neonatologist. Semin Neonatol.2002;7:3747


e380 NeoReviews Vol.5 No.9 September 2004



NeoReviews Quiz

5. The occurrence of hypoglycemia as a manifestation of a metabolic disorder varies in relation to thepostnatal age of the infant. Of the following, symptomatic hypoglycemia occurring soon after birth is mostlikely to be the presenting feature of:

A. Galactosemia.B. Glycogen debrancher enzyme deficiency.C. Maple syrup urine disease.D. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.E. Methylmalonic acidemia.





DOI: 10.1542/neo.5-9-e3772004;5;e377Neoreviews

Stephen G. KahlerMetabolic Disorders Associated With Neonatal Hypoglycemia

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