Basics
Description
- Metabolic acidosis is a common acute presentation of an inborn error of metabolism (IEM), particularly in the presence of elevated anion gap. Acidosis can also be seen as a result of hypoperfusion, congenital heart disease, sepsis, liver failure, toxic ingestion, and diabetic ketoacidosis (DKA).
- IEMs are generally defects of protein, fat, or carbohydrate metabolism or of the mitochondrial respiratory chain that result in either accumulation or deficiency of a metabolite.
- IEMs should be considered early in the workup of a child with metabolic acidosis in order to detect those conditions that are treatable prior to development of permanent neurologic sequelae. Sequelae can be related to duration and severity of exposure. Basic evaluation for IEMs should be undertaken concurrently with other diagnostic evaluations.
Alert
Infants with IEMs are at increased risk for decompensation and acute presentation in cases of infection, fever, fasting, or other causes of catabolism.
Risk Factors
Genetics
Autosomal recessive with exception of pyruvate dehydrogenase deficiency (X-linked dominant), ornithine transcarbamylase (X-linked), and some diseases of the mitochondrial genome(maternally inherited).
General Prevention
- Avoid propofol if possible (anecdotal increase in pancreatitis).
- Avoid prolonged fasting or nutritional deprivation.
- Avoid use of systemic steroids whenever possible.
Pathophysiology
Metabolic acidosis is often a downstream effect of the primary metabolic abnormality. A block in normal metabolism can result in dysfunction of the mitochondrial respiratory chain, buildup of toxic intermediates, disordered or reduced energy production, buildup of waste nitrogen in the form of ammonia and specific amino acids, and through conjugation of the acids with carnitine, lead to carnitine depletion. These events can lead to multi-organ dysfunction including the following:
- CNS toxicity: edema, neurologic effects of hypoglycemia, toxic encephalopathy
- Cardiac: arrhythmias, left ventricular noncompaction, cardiomyopathy
- Liver: hepatosplenomegaly, elevation of liver function tests, prolonged hyperbilirubinemia
- Hematologic: bone marrow suppression
- Renal: proximal tubule dysfunction, kidney failure (later onset)
Etiology
Multifactorial. Primary metabolic disease is typically due to a genetic defect that causes a block in metabolism resulting in buildup of toxic intermediates or absence/reduction of necessary downstream products.
Commonly Associated Conditions
- Maternal HELLP, fatty liver of pregnancy, preeclampsia: associated with specific fetal disorders of fatty acid oxidation
- Metabolic stroke: stroke affecting the basal ganglia (not ischemic or hemorrhagic in character)
Diagnosis
History
- Pregnancy history: maternal hypertension, elevated liver enzymes, low platelets (HELLP) syndrome; acute fatty liver of pregnancy; preeclampsia; reduced fetal movements; IUGR; fetal bradycardia
- Family history of consanguinity, siblings with unexplained severe childhood illness, sudden infant death syndrome (SIDS), developmental delay, Reye syndrome, or death
- Deterioration after a symptom-free interval (typically at least several days required for toxic metabolic buildup)
- Classic presentation is of poor feeding, vomiting, and alterations in neurologic status (irritability, hypotonia, encephalopathy).
- Without treatment, this will progress to lethargy, temperature instability, seizure, coma, and death.
- Diet history including frequency of feeds, vigor, whether breast milk or formula and, if formula, the type of formula (low protein may delay onset of symptoms)
- Fits, cycling movements
- Associations with IEMs
- Gram-negative sepsis (galactosemia)
- Cerebral or pulmonary hemorrhage (urea cycle disorder)
- Severe, prolonged, unexplained hypoglycemia in term neonate (suggests organic acidemia or defect of gluconeogenesis)
- Mild respiratory alkalosis (hyperammonemia)
- Ketosis (organic acidemia, congenital lactic acidosis)
- Coagulopathy, jaundice (mitochondrial, hemochromatosis, fatty acid oxidation disorders, hereditary fructose intolerance, tyrosinemia, galactosemia)
Physical Exam
- Vital signs: tachypnea, hypotension. Look for Cushing triad.
- General
- Dysmorphic features (may be present in mitochondrial and peroxisomal disorders and some fatty acid oxidation disorders)
- HEENT: bulging fontanelle (cerebral edema), maple syrup urine disease (MSUD)
- Eye: cataracts, dislocated lens, corneal clouding, retinal changes
- Skin: jaundice, rashes
- Cardiac
- Cardiomyopathy (fatty acid oxidation, propionic acidemia), pericardial effusion (congenital disorder of glycosylation), cardiomegaly
- Respiratory: tachypnea, Kussmaul breathing, apnea
- Hepatosplenomegaly (disorders of gluconeogenesis, storage disorders, galactosemia)
- Neurologic: reflexes, tone, seizure
- Odor
- Sweet: MSUD (urine and ear cerumen)
- Sweaty feet: isovaleric acidemia
- Fruity: methylmalonic acidemia, propionic acidemia
- "Tom Cat " urine odor: multiple carboxylase deficiency
- Growth parameters
- Typically normal in newborn period but may have IUGR or delayed return to birth weight (BW)
Diagnostic Tests & Interpretation
Lab
- Initial evaluation (concurrently with sepsis evaluation)
- Complete blood count with differential
- Blood gas including pH and lactate
- Serum urea, creatinine, glucose, electrolytes (anion gap),AST, ALT
- Ammonia (place on watery ice, run immediately)
- Creatine kinase
- CRP
- Urinalysis, urine-reducing substance
- Obtain copy of newborn screen report.
- CSF: if obtained in course of complete sepsis evaluation
- Consider freezing a tube for later use.
- May send lactate, lactate-to-pyruvate ratio
- Should be sent for definitive diagnosis:
- Plasma amino acids (PAA), acylcarnitines, urine organic acids, urine orotic acid (if ammonia is elevated), urine ketones
- Treatment should not be delayed in the case of presumptive IEM.
- In case of death, obtain the following:
- Urine: deep frozen
- Blood: EDTA for DNA analysis
- Skin: sterile, for fibroblast culture; store at 4 " 8 ฐC
- Liver, muscle: snap frozen
- CSF if possible (for amino acids and neurotransmitters)
- Plasma: heparinized
- Blood spot: for acylcarnitine profile
Imaging
- Echocardiogram to evaluate for structural heart disease and cardiac function
- Consider head ultrasound (ventriculomegaly seen in pyruvate dehydrogenase complex deficiency)
Diagnostic Procedures/Other
- Ammonia (>200 ผmol/L) very strongly implies metabolic disease. Up to 65 " 100 ผmol/L is normal in a healthy neonate.
- Calculate anion gap: High anion gap implies excessive acid production or retention.
- If not previously performed, secondary testing should include acylcarnitine profile, free fatty acids and 3-hydroxybutyrate, osmolality, plasma amino acids, lactate and pyruvate ratio, and urine organic acids.
- Ophthalmology exam
- Confirmatory testing is by specific enzyme analysis or genetic testing.
Differential Diagnosis
In neonates, inborn errors of metabolism present with similar symptoms and can easily be confused with other serious diseases.
- Sepsis
- Birth asphyxia
- Ductal-dependent congenital heart disease
- Neonatal withdrawal syndrome
- Endocrine abnormalities (adrenal insufficiency)
- IEM resulting in metabolic acidosis can be divided into the lactic acidoses, those that cause a ketoacidosis, and the organic acid disorders.
- Lactic acidosis
- Pyruvate dehydrogenase deficiency
- Pyruvate carboxylase deficiency
- Phosphoenolpyruvate carboxykinase deficiency
- Defects in tricarboxylic acid cycle enzymes
- Mitochondrial diseases or other conditions affecting oxidative phosphorylation
- Severe disorders of gluconeogenesis (e.g., glucose-6-phosphatase deficiency)
- Multiple carboxylase deficiency, biotinidase deficiency
- Disorders of fatty acid oxidation
- Ketoacidosis
- Disorders of ketone use (e.g., ฒ-ketothiolase deficiency)
- Ketosis can also occur in lactic acidosis syndromes (above) and organic acidemias (below).
- Other organic acid disorders
- MSUD
- Branched-chain organic acidurias (methylmalonic acidemia, propionic acidemia, isovaleric acidemia)
- Others: In some cases, other abnormalities (e.g., lethargy, hyperammonemia) may occur prior to severe acidosis.
Treatment
General Measures
- Stop feeding.
- Provide 6 " 10 mg/kg/min dextrose (typically as D10 at twice maintenance).
- If considering pyruvate dehydrogenase deficiency, use lower dextrose infusion rate, typically D5.
- Admit to intensive care unit.
- Consult biochemical genetics team.
- Consider early continuous venovenous hemodialysis to remove toxin and decrease ammonia. Peritoneal dialysis is less effective but can be used.
- Correct hypothermia, dehydration, electrolyte disturbance, etc.
- Consider sodium bicarbonate.
- Start at 1 mEq/kg.
- Often, the patient will require large doses due to ongoing acid production.
- Insulin as needed for iatrogenic hyperglycemia.
- Resume nutritionally complete feeding as soon as possible under guidance of biochemical genetics team. This may include specialized iTPN or formula.
Additional Therapies
- Nitrogen scavenger such as sodium benzoate and sodium phenylacetate if urea cycle overwhelmed or primary urea cycle disorder
- Carnitine promotes excretion of organic acids. Administer 50 mg/kg/dose IV every 6 hours. Use is controversial in disorders of fatty acid oxidation; not to be used in LCHAD (theoretical arrhythmia risk)
- Specific supplementation
- Biotin (holocarboxylase deficiency) 10 mg PO/NG
- Hydroxocobalamin (cobalamin-responsive methylmalonic academia) 1 mg IM
- Pyridoxine (pyridoxine-dependent seizure)
- Pyridoxal phosphate (pyridoxine-5 '-phosphate oxidase deficiency)
- Glycine (isovaleric acidemia)
- Nitisinone (tyrosinemia)
- Arginine (urea cycle)
- Thiamine (MSUD, some forms of congenital lactic acidosis) 50 mg PO/NG daily to b.i.d.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Refer to a biochemical genetics team for ongoing evaluation and management.
- Generally, patients will require frequent monitoring in the newborn period and throughout life; however, this varies with the diagnosis.
- Specific treatment based on correct diagnosis of IEM
Complications
- Prognosis varies based on disease.
- For some disorders, appropriate treatment dramatically improves morbidity and mortality (especially the fatty acid oxidation disorders and vitamin responsive disorders); for others, there is improved survival but still significant morbidity.
- Long-term complications are becoming better understood with improved survival (e.g., risk of pancreatitis and renal failure in the branch chain acidurias). As in other chronic pediatric illnesses, such as diabetes, recurrent episodes are often triggered by stress, noncompliance, or illness and may increase in frequency during the teen years.
- Severity of neurologic complications increases with frequency and duration of episodes of metabolic decompensation and/or frequency and duration of elevated ammonia. Neurologic complications can include metabolic stroke (basal ganglia), herniation, seizure disorder, and intellectual impairment.
- There may be progressive impairment of the heart, liver, or kidney; chronic bone marrow suppression; as well as effects of malnutrition and hyperglycemia (due to frequent D10 infusions).
Additional Reading
- Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998;102(6):E69 " E77. [View Abstract]
- Cook P, Walker V. Investigation of the child with an acute metabolic disorder. J Clin Pathol. 2011;64(3):181 " 191. [View Abstract]
- Leonard J, Morris A. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr. 2006;95(1):6 " 14. [View Abstract]
Codes
ICD09
- 775.7 Late metabolic acidosis of newborn
- 277.89 Other specified disorders of metabolism
- 270.6 Disorders of urea cycle metabolism
- 271.8 Other specified disorders of carbohydrate transport and metabolism
- 277.87 Disorders of mitochondrial metabolism
- 270.3 Disturbances of branched-chain amino-acid metabolism
ICD10
- P74.0 Late metabolic acidosis of newborn
- E88.89 Other specified metabolic disorders
- E72.29 Other disorders of urea cycle metabolism
- E74.4 Disorders of pyruvate metabolism and gluconeogenesis
SNOMED
- 9635004 Late metabolic acidosis of newborn
- 86095007 Inborn error of metabolism (disorder)
- 36444000 Disorder of the urea cycle metabolism (disorder)
- 46683007 Pyruvate dehydrogenase complex deficiency (disorder)
- 276567007 Antepartum fetal acidosis (disorder)
FAQ
- Q: What factors determine developmental outcome in children with inborn errors of metabolism?
- A: The specific diagnosis and patient mutation, how rapidly appropriate therapy is initiated, frequency of decompensating, and compliance with chronic management all contribute to developmental outcome.
- Q: If the newborn screen (NBS) was normal, can the infant still be affected by an IEM?
- A: Many IEMs are not included on the NBS, and there can also be false negatives.
- Q: Do IEMs only affect infants?
- A: No. An individual can present with an IEM at any point in his or her life, depending on the level of enzyme deficiency/threshold for catabolic stress.