Hypoglycemia

In general, hypoglycemia can be induced by lack of adequate glucose intake, poor homeostatic controls, iatrogenic causes, infection, and inborn errors of glucose metabolism. The brain is particularly dependent on glucose for energy but can alternatively use ketone bodies. Symptoms of hypoglycemia include lethargy, sweating, pallor, seizures, and mental status changes. Central to determining a metabolic cause of hypoglycemia is its onset after a carbohydrate load. For example, whereas early postprandial symptoms are more likely to be related to hyperinsulinism and glycogenoses, defects in fatty acid oxidation, ketone body synthesis, gluconeogenesis, and other IEM tend to take longer to present with hypoglycemia (Figure 121-2). Diagnostic pathways to approach the metabolic differential diagnosis for hypoglycemia are useful (Figure 121-3). A focused evaluation for an IEM may include electrolytes, glucose level, urine ketones, urine-reducing substances, ammonia, lactate, urine organic acids, and plasma acylcarnitines. One should also consider evaluation for non-IEM causes of hypoglycemia such as infection, drugs or toxins, and abnormal counterregulatory hormone mechanisms.

Figure 121-2 Contributions to and factors influencing fasting glucose levels.

Figure 121-3 Diagnostic pathway for hypoglycemia.

Metabolic Acidosis

Acid-base status is affected by several buffering systems. Whereas fast-acting buffering is accomplished by proteins and the bicarbonate-carbonic acid system, slower acting mechanisms include renal bicarbonate resorption. Metabolic acidosis generally results from bicarbonate losses or an increased presence of acid. These can be distinguished by bicarbonate losses leading to a non-anion gap metabolic acidosis in which chloride levels increase in compensation. Renal tubular acidosis and diarrhea are common causes of non-anion gap metabolic acidosis. A non-anion gap acidosis does not exclude IEM, such as in metabolic disorders with renal tubular acidosis, but many IEM are associated with anion gaps because of buildup of acid metabolites, particularly during periods of illness or stress. Determining which acid is accumulating is important for diagnosis. Lactic acid is commonly elevated in many metabolic diseases. In contrast, acidoses of other organic acids should be suspected in anion gap metabolic acidoses with ketosis, a normal response to lack of adequate glucose and utilization of fatty acid stores. Ketosis may also contribute to acidosis, as classically seen in diabetes mellitus.

Ketosis

Ketone production is a common physiologic response to fasting. Infants, however, rarely produce urine ketones even in a fasting state, making the finding highly suggestive of an IEM in this population. In children and adults, ketosis may indicate a biochemical disorder when present with metabolic acidosis or in a nonfasted state, but a lack of sufficient ketones with hypoglycemia suggests a fatty acid oxidation disorder (FAOD) or ketogenesis disorder.

Hyperammonemia

Ammonia is a product of protein metabolism that, in elevated levels, is toxic to the central nervous system (CNS), resulting in cerebral edema. Normally, ammonia is converted to urea in the liver via the urea cycle and is excreted in the urine. When the nitrogen load exceeds the clearance capacity of the liver, ammonia accumulates. The nitrogen load increases with dietary protein intake and endogenous protein breakdown, both of which can cause hyperammonemia in patients with primary or secondary urea cycle defects. Symptoms of hyperammonemia include vomiting, seizures, lethargy, coma, and hyperventilation associated with respiratory alkalosis. Nonspecific episodes of headache, vomiting, and mental status changes may be the only signs in later-onset cases. For extremely high ammonia levels, such as during neonatal presentations of urea cycle disorders (UCDs), dialysis to rapidly reduce the toxic levels may be necessary in addition to less invasive therapies. Nonmetabolic causes of hyperammonemia include sepsis; liver failure; use of medications such as valproate; and transient hyperammonemia of the newborn, a disorder associated with severe neonatal hyperammonemia that resolves perinatally, although residual neurologic sequelae may result. Classic metabolic causes of hyperammonemia include UCDs, organic acidurias, FAODs, hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, pyruvate carboxylase deficiency, and hyperammonemia-hyperinsulinemia syndrome. Several of these disorders, including organic acidurias and FAODs, cause secondary urea cycle inhibition. Whereas hyperammonemia without metabolic acidosis and hypoglycemia is suggestive of UCD, an anion gap metabolic acidosis should arouse suspicion for an organic aciduria. Diagnostic pathways for biochemical causes of hyperammonemia are depicted in Figure 121-4.

Figure 121-4 Diagnostic pathway for hyperammonemia.

Galactosemia

Classic galactosemia is an autosomal recessive disorder caused by defects in the pathway for hepatic conversion of galactose to glucose. Three enzymes, galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and UDP galactose-4-epimerase, are involved and cause variable disease in deficient states. Classic galactosemia (GALT deficiency) is the most common and the most severe. It leads to galactose-1-phosphate buildup in liver, brain, and renal tubules with resulting hepatic parenchymal disease, intellectual impairment, and renal tubular dysfunction. Upon exposure to lactose in milk, neonates present with vomiting, jaundice, and hepatomegaly within a few weeks of birth and may be predisposed to Escherichia coli sepsis. Cataracts may result from galactitol accumulation in the lens. Positive urine-reducing substances, particularly during the prediagnosis period, are a classic finding but may not always be present. Treatment simply involves a lactose-free diet, which dramatically improves and prevents many manifestations. However, even in presymptomatically treated patients, speech delay, learning difficulties, and ovarian failure have been noted. Most U.S. NBS panels detect galactosemia and confirmatory testing is used to verify deficient GALT enzyme activity and elevated galactose-1-phosphate in red blood cells and elevated urine galactitol, with possible proteinuria or aminoaciduria.

Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) is caused by a deficiency of fructose-1,6-bisphosphate aldolase. Infants typically present with poor growth, vomiting, loose stools, jaundice, hepatomegaly, and renal tubular acidosis as sucrose or fructose is introduced in the diet. Laboratory findings include hypoglycemia, elevated transaminases, positive urine-reducing substances, proteinuria, and generalized aminoaciduria. Fructose tolerance tests are not advised without appropriate supervision in a hospital setting because enzyme assays and molecular testing are available. Good outcomes are associated with strict exclusion of dietary fructose and sucrose.

Glycogen Storage Disorders

Glycogen is a branched polymer of glucose monomers used for storage in the liver and muscle. Several enzyme defects in the biosynthesis and breakdown of glycogen make up the collective group of autosomal recessive glycogen storage disorders (GSDs). Type I (von Gierke disease; glucose-6-phosphatase deficiency), type III (debrancher enzyme deficiency), and type VI (hepatic phosphorylase deficiency) are the most well-known hepatic forms. Type I is the most common and presents with varied features, including failure to thrive, hepatomegaly, and fasting hypoglycemia. Type Ib has been associated with neutropenia and inflammatory bowel disease. Treatment involves regular feedings, restricted intake of lactose and sucrose, and ingesting safe amounts of uncooked cornstarch to balance prevention of hypoglycemia with the risk of additional glycogen storage. Type III is often accompanied by significant muscle disease. Type V (muscle phosphorylase deficiency) and VII (phosphofructokinase deficiency) are classic muscle forms associated with later-onset exercise intolerance and myopathy. Type II (Pompe’s disease; acid maltase deficiency) is unique as a lysosomal enzyme deficiency that tends to present with cardiomegaly during infancy. Enzyme replacement therapy has had variable effects on patients with type II disease. Laboratory findings of GSDs may include fasting hypoglycemia, ketosis, lactic acidosis, creatine kinase, hyperlipidemia, and hyperuricemia. Glucagon tolerance tests, specific enzyme assays from affected tissues, and molecular testing narrow the diagnosis.

Urea Cycle Disorders

The urea cycle converts ammonia, a product of protein breakdown, to water-soluble urea, which is excreted in urine. If deficient, ammonia elevations result in toxicity to the CNS. Several enzymes are involved in the hepatic mitochondrial urea cycle, each of which causes disease if deficient (Figure 121-6). Other than arginase deficiency, which has a chronic progressive neurologic presentation, the UCDs present during infancy with poor feeding, vomiting, and lethargy. Neonates classically manifest symptoms after 12 to 24 hours of life, presumably because of the toxic accumulation of ammonia. In addition, the effect of ammonia on brainstem respiratory control typically results in hyperventilation and respiratory alkalosis. However, patients with more residual enzyme activity may not be diagnosed until childhood or adulthood. All UCDs are autosomal recessive except for ornithine transcarbamoylase (OTC) deficiency, which is X-linked and the most common. Accordingly, a family history of male newborn deaths suggestive of X-linked disease is suggestive of OTC deficiency. The hair condition trichorrhexis nodosa is unique in argininosuccinate lyase deficiency.

Figure 121-6 The urea cycle.

Classic patterns of biochemical findings assist with diagnosis. A low citrulline level (see Figure 121-6) is suggestive of enzymatic defects upstream in the urea cycle, of which only OTC deficiency has elevated urinary orotic acid, a product of accumulated carbamylphosphate. In contrast, citrulline levels are high in patients with downstream defects of the urea cycle. Molecular DNA analysis is available for many of the disorders.

Acute management of hyperammonemia includes nitrogen scavengers such as sodium benzoate and sodium phenylacetate that convert ammonia sources into renally cleared metabolites. In severe cases, dialysis is used to rapidly remove ammonia. Long-term management focuses on the prevention of hyperammonemia. This is accomplished by balancing protein restriction with provision of essential amino acids to allow normal growth. Arginine, which becomes an essential amino acid in UCD, is often supplemented. Of note, heterozygous affected female carriers of OTC deficiency often require therapy. Liver transplantation is another therapeutic option. Most patients with UCD have varying degrees of neurologic impairment, but prognoses are generally better with aggressive early treatment.

Phenylketonuria

Classic PKU results from deficient phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Rare cases may be caused by deficiency of the cofactor tetrahydrobiopterin or by defects in biopterin synthesis that require additional treatment with various neurotransmitters. Untreated patients present with progressive brain disease that manifests as acquired microcephaly, developmental delays, seizures, behavioral problems, and intellectual disabilities. A fair complexion, eczema, and a mousy or musty odor (caused by increased levels of phenylacetic acid) have also been noted. Classic PKU is associated with persistently elevated phenylalanine levels above 20 mg/dL with normal or low tyrosine and characteristic urinary derivatives. In variants with persistent hyperphenylalaninemia, phenylalanine levels range from 4 to 10 mg/dL.

Patients with classic PKU and other variants with elevated phenylalanine require phenylalanine-restricted diets to maintain goal levels of 2 to 6 mg/dL. Patients diagnosed via NBS who start restrictions within the first month and achieve appropriate control of levels have normal intellectual and neurologic development. NBS performed before 24 hours of age has a risk of false-negative results and should always be repeated. Of note, women with PKU are fertile, and maternal PKU is a teratogenic condition requiring strict metabolic control before and during pregnancy.

Maple Syrup Urine Disease

Maple syrup urine disease is caused by a deficiency of branched-chain 2-keto dehydrogenase complex involved in the early steps of branched-chain amino acid (BCAA; e.g., leucine, isoleucine, and valine) metabolism in mitochondria. Most cases are the classic form in which neonates present with nonspecific symptoms of poor feeding, changes in tone, and lethargy after several days of cumulative milk ingestion. Accumulating ketoacids result in a sweet odor resembling burnt sugar in urine and other body substances. The ketoacid of leucine is neurotoxic and causes seizures, encephalopathy, and coma. Laboratory findings include metabolic acidosis; ketosis; and significantly elevated plasma BCAAs, particularly leucine. Alloisoleucine, an isoleucine pathway metabolite, is a pathognomonic finding. Treatment includes dietary restriction of BCAA to reduce disease toxicity but allow normal growth and BCAA deficiency, which results in rash and anemia. Prompt management of acute episodes is important to prevent neurologic sequelae.

Hereditary Tyrosinemia Type 1

Defects of the tyrosine metabolism pathway cause several types of tyrosinemia. Transient tyrosinemia is a commonly diagnosed type in premature and newborn infants and results from delayed hepatic maturation that improves with age. Hereditary tyrosinemia type 1, in contrast, leads to severe liver disease. It is prevalent in French Canadians and presents with hepatomegaly, coagulation defects, failure to thrive, or jaundice during infancy or with gradual hepatic parenchymal disease. It is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), which catalyzes a reaction late in the phenylalanine and tyrosine pathway. Despite the name, tyrosine levels are not always very elevated. Patients often develop hepatocellular carcinoma. In addition to liver disease, patients have renal tubular acidosis that may lead to hypophosphatemic rickets.

Laboratory findings reveal severe liver disease, generalized aminoaciduria, hypermethioninemia, and tyrosine metabolites. Increased urine succinylacetone is pathognomonic. Dietary management includes phenylalanine and tyrosine restriction. Nitisinone therapy has significantly reduced liver and renal morbidity. It inhibits the step before FAH to decrease toxic fumarylacetoacetate and succinylacetone accumulation. Liver transplantation remains the only truly curative therapy.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is an autosomal recessive defect of glycine metabolism. Secondary inhibition results from ketotic hyperglycinemia and valproate. Excessive glycine accumulation in the brain is associated with encephalopathy. The most severe forms present acutely in infants with hypotonia, intractable seizures, and hiccups caused by diaphragmatic spasms. Laboratory findings include CSF glycine elevation out of proportion to the blood level, low serine levels (the product the enzyme), and an increase in the ratio of glycine to serine in body fluids. The disease is not associated with acidosis or ketosis. Efforts to find effective therapy are ongoing.

The Ketotic Hyperglycinemias: Propionic and Methylmalonic Acidemia

Propionic acidemia (PA) and methylmalonic acidemia (MMA) were initially termed ketotic hyperglycinemias to distinguish them from nonketotic hyperglycinemias. The deficient enzymes act sequentially downstream in threonine, valine, methionine, and isoleucine metabolism. MMA may also result from defects in the synthesis of its cofactor, adenosyl-cobalamin. Although variable phenotypes exist, the classic presentation occurs within the first week of life with poor feeding, vomiting, lethargy, and liver enlargement. Patients with PA are predisposed to cardiomyopathy, and those with MMA are predisposed to renal tubulopathy. Both can develop pancreatitis and brain lesions, particularly in the basal ganglia. Acute laboratory findings for both disorders include anion gap metabolic acidosis, ketosis, hyperammonemia (from secondary urea cycle inhibition), and hyperglycinemia or hyperglycinuria. Thrombocytopenia, leukopenia, or anemia may occur secondary to bone marrow suppression. Urinary propionylglycine and methylcitrate (metabolites of propionate) are seen in patients with PA. Urinary methylmalonic acid is seen in classic MMA. Enzyme assays can be performed for PA, MMA, or cobalamin defects. Long-term management requires dietary restriction of precursor amino acids and adequate calories to optimize growth but prevent toxicity. Some patients with MMA respond well to cobalamin supplementation. Periodic administration of antimicrobials may help reduce gut bacteria, a source of propionate production. Patients need urgent management for acute presentations of disease often precipitated by intercurrent viral illness.

Isovaleric Acidemia

Isovaleric acidemia is caused by a deficiency of isovaleryl-CoA dehydrogenase in the leucine oxidative pathway. Infants often present in the first week of life with poor feeding, vomiting, lethargy, and seizures. A pungent odor resembling sweaty feet may result from accumulated isovaleric acid. A later-onset chronic intermittent form consists of periodic metabolic crises induced by protein intake or illness. Similar to ketotic hyperglycinemias, laboratory findings include anion gap metabolic acidosis, ketosis, hyperammonemia (from secondary urea cycle inhibition), and evidence of bone marrow suppression. Biochemical findings include urinary isovalerylglycine and 3-hydroxyisovaleric acid. Long-term management requires dietary restriction with adequate supplies to optimize growth but prevent toxicity. Glycine therapy may promote production of the nontoxic compound isovalerylglycine and reduce levels of isovaleric acid in body fluids. Patients need urgent management for acute presentations of disease.

Multiple Carboxylase Deficiency

Multiple carboxylase deficiency is a disorder of biotin metabolism resulting from one of two possible enzyme deficiencies—holocarboxylase synthetase, which couples biotin to four different carboxylase enzymes, or biotinidase, which recycles biotin after degradation of the enzymes. Whereas holocarboxylase synthetase deficiency may present in neonates with hypotonia, patients with biotinidase deficiency tend to present later during infancy with ataxia, neurologic symptoms, and seborrhea. The diagnosis is made by measurement of the carboxylase enzyme activities. Other laboratory findings include an anion gap metabolic acidosis, with elevated lactate, 3-methyl-crotonylglycine, and propionate metabolites. Treatment involves biotin, often in supratherapeutic doses, to overcome lower affinity enzyme-deficient states.

Glutaric Acidemia Type 1

Glutaric acidemia type 1, prevalent in some Canadian and Amish populations, is caused by deficiency of glutaryl-CoA dehydrogenase in the lysine, hydroxylysine, and tryptophan metabolism pathways. Although macrocephaly is often present at birth, patients tend to present acutely with encephalopathy during infancy and develop progressive extrapyramidal symptoms, including dystonia and athetosis. Imaging may reveal bilateral brain damage in the basal ganglia, subdural hygromas or hemorrhages, and widening of the sylvian fissures. The course is highly variable. Laboratory findings include urinary glutaric acid and 3-hydroxyglutaric acid and decreased enzyme activity. Treatment involves dietary restriction of precursor amino acids and management of movement disorders. Aggressive management of acute episodes to reduce catabolism may help reduce long-term neurologic morbidity.

Primary Lactic Acidosis

Lactate is formed from pyruvate during anaerobic glucose metabolism. Lactate and pyruvate exist in equilibrium and are affected by the redox state of cells and the generation of electron donors such as NADH (nicotinamide adenine dinucleotide), which contribute to oxidative phosphorylation. Oxidative phosphorylation occurs along the mitochondrial respiratory or electron transport chain (ETC). It couples the donation of electrons to acceptors (e.g., oxygen) with the transport of protons across a membrane, which then forms a proton gradient whose release is associated with adenosine triphosphate generation (Figure 121-7). Lactate accumulates because of blocks in pathways leading up to the ETC or defects along the ETC itself (which may result from circulatory collapse or hypoxia in addition to IEM). Primary lactic acidemias include defects in the mitochondrial respiratory chain, Krebs cycle, pyruvate metabolism, and several disorders of gluconeogenesis, and secondary lactic acidemias result from organic acidurias, FAODs, and UCDs that affect cellular redox potential or conversion of pyruvate to lactate. Several of these disorders can be inherited via maternal mitochondrial inheritance, as discussed in Chapter 115.

Figure 121-7 Regeneration of adenosine triphosphate for source of energy in muscle contraction.

Primary disorders, particularly those involving pyruvate and ETC metabolism, are associated with neurodevelopmental and multiorgan disease, but the extent of systemic involvement, severity, age of onset, and prognosis can vary greatly, even between patients with the same disease. Laboratory testing for the various defects includes lactate and pyruvate levels in various body fluids, muscle biopsy for histopathology and electron microscopy, and molecular DNA analysis or enzyme assays (often using blood, muscle, liver, or skin). Treatment options often have limited effectiveness, but patients may receive various cofactors that promote flux through pathways and symptomatic therapies.

Disorders of Fatty Acid Oxidation

Disorders of fatty acid oxidation (FAOD) are caused by deficiencies in enzymes that participate in mitochondrial β-oxidation of fatty acids. General signs and symptoms include hypoketotic hypoglycemia, vomiting, lethargy, and liver disease. Medium-chain acyl-CoA dehydrogenase deficiency is the most common FAOD and tends to present during infancy after a precipitating event such as fasting or illness. In the past, fatal cases have been diagnosed as sudden infant death syndrome, but with NBS, the mortality associated with the disease, particularly in the first presentation, has decreased significantly. Long-chain FAODs are associated with cardiomyopathy and rhabdomyolysis.

The finding of low ketones with fasting is an inappropriate response and a classic finding suggestive of FAOD. Characteristic patterns of accumulated plasma acylcarnitines and urinary acylglycines are useful in the diagnosis; however, abnormal laboratory findings may be intermittent or absent during well states. Enzyme assays are available, and common mutations for several of the disorders have been described. Treatment focuses on dietary fat restriction, frequent carbohydrate feedings, avoidance of fasting, and prompt management during catabolic states. Medium-chain fatty acid supplementation may be beneficial for long-chain defects.

Defects in Ketone Metabolism

Ketone bodies are products of fatty acid metabolism that are used as an energy source for the heart and brain, particularly during fasting. Defects in ketone metabolism lead to variable clinical presentations, including vomiting, lethargy, and seizures. Whereas defects in ketone catabolism are associated with persistent ketosis and acidosis, defects in ketone synthesis present with hypoketotic hypoglycemia and acidosis. Metabolites of isoleucine and leucine metabolism are often found in certain enzyme deficiencies caused by defects along the corresponding catabolic pathways. Thus, treatment efforts for these disorders include avoidance of fasting and may include protein restriction. Urgent management to reduce catabolism should be instituted during acute episodes.

Lysosomal Disorders

Lysosomes are cellular organelles that are important in the degradation of complex molecules. Various acid hydrolases within the lysosome may be deficient, leading to accumulation of enzyme substrates in various tissues. The particular storage material that accumulates defines the type of lysosomal storage disorder (LSDs), such as mucopolysaccharidoses, sphingolipidoses, and mucolipidoses. Lysosomal protein transport out of the lysosome may also be defective. Most but not all LSDs are autosomal recessive (i.e., Hunter and Fabry syndromes are X-linked). The clinical presentation and age of onset vary by disease. LSDs, particularly the mucopolysaccharidoses, are often associated with characteristic physical examination findings, including corneal clouding, coarse facies, organomegaly with liver disease, and skeletal abnormalities (Figure 121-8). Urine screening tests and enzyme assays are commonly used for diagnosis. Treatment is generally supportive in nature, but enzyme replacement and bone marrow transplantation have been effective in several disorders.

Figure 121-8 Characteristics of mucopolysaccharidoses.

Peroxisomal Disorders

Peroxisomes are cellular organelles with various functions, including β-oxidation of very-long-chain fatty acids (VLCFAs), α-oxidation of branched fatty acids, bile acid synthesis, glyoxylate metabolism, and plasmalogen synthesis. Most disorders are autosomal recessive except X-linked adrenoleukodystrophy. Zellweger-spectrum disorders and rhizomelic chondrodysplasia punctata type 1 are defects of peroxisomal biogenesis and result from multiple enzymatic defects. Zellweger syndrome is the most severe, with seizures, hepatomegaly, and dysmorphic features in infancy. Primary hyperoxaluria, X-linked adrenoleukodystrophy, and adult Refsum disease are examples of peroxisomal disorders with single enzyme deficiencies. X-linked adrenoleukodystrophy classically presents in young boys with developmental regression, seizures, and adrenal insufficiency but also has a later-onset form. Dietary management and bone marrow transplantation are in investigative phases. Classic biochemical findings associated with each disorder assist with diagnosis. For example, serum VLCFAs are elevated in peroxisomal β-oxidation disorders. Enzyme assays and molecular testing are available for most.