Acidosis The differential diagnosis of metabolic acidosis is broad (see Chapter 100 Renal and Electrolyte Emergencies ) but IEMs must be considered in patients with unexplained or greater-thanexpected metabolic acidosis Clinical manifestations of acidosis are nonspecific and include vomiting and tachypnea Primary metabolic acidosis is diagnosed by low pH, low PCO , and low bicarbonate An elevated anion gap (>16 mmol/L), which is characteristic of acute metabolic crisis with many IEMs, helps distinguish among causes of metabolic acidosis An elevated anion gap with a normal chloride usually reflects excess acid production, most often of lactate, ketone bodies, and/or other organic acids Organic acidemias are characterized by metabolic acidosis, usually severe, with marked ketonuria, with or without hyperammonemia or hypoglycemia In neonates believed to have pyloric stenosis, the diagnosis of IEM, particularly an organic acidemia, should be considered if the patient has metabolic acidosis rather than metabolic alkalosis Fatty acid oxidation disorders may also present with metabolic acidosis, but usually with hypoglycemia and absent ketones or hypoketosis The IEMs in which a primary lactic acidosis is the cause of the metabolic acidosis include disorders of gluconeogenesis and mitochondrial disorders of oxidation In patients with metabolic acidosis, concentration of serum ammonia and glucose, and presence or absence of urine ketones and reducing substances will also help direct further metabolic workup Plasma amino acids, acylcarnitines and urine organic acids, and acylglycines should be measured Measurement of serum lactate, pyruvate, ketones, and organic acids may also be helpful TABLE 95.5 SECONDARY TESTS Test Laboratory abnormality metabolic diseases a Indications, comments Aminoacidopathies Organic acidemias Tandem mass spectrometry, requires minimum mL blood, mL ideal b , heparin, or EDTA tube Obtain if metabolic catastrophe, neurologic, cardiac, GI/hepatic, musculoskeletal, psychiatric symptoms suggestive of possible IEM, metabolic acidosis, elevated anion gap, hypoglycemia, inappropriate ketonuria, hyperammonemia Blood Amino acids— quantitative (plasma or serum) Urea cycle defects Mitochondrial disorders Acylcarnitine profile (plasma or serum) Organic acidemias Fatty acid oxidation defects Mitochondrial disorders Primary carnitine deficiency Lactate, pyruvate Disorders of carbohydrate (deproteinized blood) utilization Mitochondrial disorders Carnitine deficiency may be due to primary defect in carnitine or carnitine transporter, or secondary due to organic acidemia or fatty acid oxidation defect; can also occur in normal children during dehydration Free and total carnitine may also be helpful if carnitine deficiency is suspected Samples must be free flow, deproteinized at bedside—1 mL into tubes with 2-mL perchloric or trichloroacetic acid, transport on ice Evaluate lactate, pyruvate, and ratio Lactate also increased in patient with hypoxia, poor perfusion, sepsis Urine Organic acids Aminoacidopathies Organic acidemias Fatty acid oxidation defects Mitochondrial disorders Peroxisomal disorders Acylglycines Organic acidemias Fatty acid oxidation defects Orotic acid Urea cycle defects (ornithine transcarbamylase deficiency) Urine best source for organic acids, minimum 2–5 mL, 10–20 mL ideal without preservative c Obtain if metabolic catastrophe, neurologic, cardiac, GI/hepatic, musculoskeletal, psychiatric, symptoms suggestive of possible IEM, metabolic acidosis, elevated anion gap, hypoglycemia, inappropriate ketonuria, hyperammonemia Should be performed only in conjunction with serum or plasma carnitines, minimum 2–5 mL without preservative c Send if hyperammonemia, minimum mL without preservative Cerebrospinal fluid Glucose, protein, lactate, Aminoacidopathies pyruvate, glycine, Organic acidemias serine, alanine, 1–4 mL, freeze −20°C or −70°C organic acids, neurotransmitters, folate, pterins, other disease-specific metabolites Mitochondrial disorders Nonketotic hyperglycinemia Neurotransmitter disorders a Within disease categories, not all diseases have the laboratory abnormality In disorders of protein metabolism, carbohydrate metabolism, and fatty acid oxidation defects and abnormality may be present only during acute crisis b Samples, quantities required, collection method, preparation, and storage are institution dependent Tandem mass spectrometry measures amino acids and acylcarnitines, derived from carnitine, which combines with acyl-CoA derived from fatty acids and organic acids (which may have been derived from amino acids) Tandem mass spectrometry may be used as a screen for aminoacidopathies, organic acidemias, and fatty acid oxidation defects Confirmation of diagnosis usually requires further testing, including plasma amino acids, urinary organic acids, histologic examination, DNA analysis, and enzyme and/or biochemical assays c Total minimum is mL for organic acids and acylglycines EDTA, ethylenediaminetetraacetic acid; GI, gastrointestinal; IEM, inborn error of metabolism Hyperammonemia Ammonia is an intermediary in the catabolism of nitrogen-containing compounds, particularly amino acids Normal ammonia levels are less than 100 μg/dL in neonates and less than 80 μg/dL beyond the neonatal period Elevated ammonia is neurotoxic and immediate treatment should begin pending confirmation of a specific diagnosis Early manifestations of hyperammonemia are anorexia and irritability, followed by rapid progression to vomiting, lethargy, seizures, coma, and death in hours Marked hyperammonemia causes brainstem dysfunction leading to deep rapid breathing and resulting in respiratory alkalosis, a hallmark of urea cycle disorders Cerebral edema and intracranial hemorrhage are also common Children and adolescents may report headache, abdominal pain, and fatigue Some patients with chronic hyperammonemia adapt to their elevated ammonia level and may appear to have no overt symptoms despite elevated ammonia