Hyperlactatemia

A plasma lactate above the age-appropriate upper limit, often with or without metabolic acidosis. Lactate is normally cleared rapidly by the liver via gluconeogenesis and by tissues via oxidation; persistent elevation indicates either excess production (hypoxia, shock, mitochondrial dysfunction, gluconeogenic block) or impaired clearance. The single most common cause across all ages is tissue hypoperfusion (shock, sepsis, hypoxia). The genetic differential is reached only after secondary causes and sampling artifacts are excluded.

Three sorting questions before opening the genetic differential:

1. Is it real? Tourniquet artifact, prolonged transit, hemolysis, and capillary heel-stick draws can falsely elevate lactate. Confirm with a free-flowing arterial or venous sample on ice, processed STAT.
2. Is it secondary? Shock, sepsis, severe hypoxia, post-seizure, severe dehydration, thiamine deficiency, drug effects (metformin, propofol infusion syndrome, NRTIs, linezolid). Correct the secondary cause and re-check.
3. If primary, what is the lactate-to-pyruvate (L:P) ratio and the clinical phenotype?

The L:P ratio is the most useful single discriminator inside the genetic differential:

• L:P > 25 (often > 30): respiratory chain / mitochondrial defect. Lactate accumulates faster than pyruvate.
• L:P normal or low: pyruvate dehydrogenase (PDH) deficiency, gluconeogenic defects, or biotin / thiamine deficiency. Pyruvate accumulates alongside lactate.

Mitochondrial respiratory chain disorders (high L:P)

• Leigh syndrome: subacute necrotizing encephalomyelopathy. Symmetric T2 hyperintensities of basal ganglia, brainstem, and thalami on MRI. Caused by both nuclear and mtDNA variants (SURF1, NDUFS1, NDUFS4, SCO2, mtDNA ATP6 m.8993T>G / m.8993T>C, many others). Lactate elevated in blood and CSF; CSF lactate sometimes higher than serum.
• MELAS (m.3243A>G in MT-TL1): stroke-like episodes (often not in a vascular territory), seizures, lactic acidosis, sensorineural hearing loss, diabetes, short stature, cardiomyopathy. Heteroplasmy determines phenotype.
• MERRF (m.8344A>G in MT-TK): myoclonic epilepsy, ataxia, ragged-red fibers, lactic acidosis.
• Kearns-Sayre syndrome (single large mtDNA deletion): chronic progressive external ophthalmoplegia + pigmentary retinopathy + onset before age 20 + at least one of cardiac conduction block, cerebellar ataxia, or CSF protein > 100. Lactic acidosis common.
• Pearson syndrome (single large mtDNA deletion): sideroblastic anemia + exocrine pancreatic dysfunction + lactic acidosis in infancy. Survivors evolve into Kearns-Sayre over years.
• POLG-related disorders: broad phenotype (Alpers, ataxia-neuropathy, PEO). Liver failure with valproate use is a defining iatrogenic disaster.
• mtDNA depletion syndromes (DGUOK, MPV17, TK2, SUCLA2, SUCLG1): hepatocerebral, myopathic, or encephalomyopathic forms. MPV17 presents with infantile liver failure + neurological involvement.

Pyruvate metabolism (often normal-to-low L:P)

• Pyruvate dehydrogenase deficiency (PDHA1, X-linked; PDHB, DLAT, DLD also): elevated lactate at rest and after carbohydrate load, normal-low L:P ratio, structural brain malformations (corpus callosum dysgenesis), seizures, ID. Ketogenic diet bypasses the block and is the disease-modifying intervention. Male predominance because of X-linkage of PDHA1, but heterozygous females can be symptomatic via X-inactivation skewing.
• Pyruvate carboxylase deficiency (PC): lactic acidosis + low alanine + low glucose + hyperammonemia + ketonuria. Three clinical forms (A, B, C) with varying severity.
• Note: pyruvate kinase deficiency is a glycolytic enzyme defect causing hemolytic anemia, not lactic acidosis. Easy point to confuse on the surface.

Gluconeogenesis defects (lactate rises with fasting)

• Glycogen storage disease type I (von Gierke) (G6PC, SLC37A4): fasting hypoglycemia + hepatomegaly + lactic acidosis + hyperuricemia + hyperlipidemia. "Doll-like" facies. Diagnostic: fasting lactate rises while glucose falls (opposite of normal). Treatment: frequent feeds + uncooked cornstarch.
• Fructose-1,6-bisphosphatase deficiency: episodic hypoglycemia + lactic acidosis + ketosis triggered by fasting or fructose. Between episodes, often well.
• PEPCK deficiency, glucose-6-phosphatase variants: rarer.

Other contributors

• Organic acidemias (propionic, methylmalonic, isovaleric): lactic acidosis is a secondary feature of the larger high anion-gap acidosis.
• Biotin deficiency / biotinidase deficiency / holocarboxylase synthetase deficiency: lactic acidosis + dermatitis + alopecia. Biotin-responsive.
• Thiamine deficiency / thiamine-responsive megaloblastic anemia: lactic acidosis with neurologic features.

1. Confirm with a clean free-flowing arterial or venous sample on ice, processed STAT. Repeat before chasing genetics.
2. Arterial blood gas, electrolytes (anion gap), glucose, ammonia, ketones (beta-hydroxybutyrate), free fatty acids, insulin, cortisol for the metabolic phenotype.
3. Plasma lactate AND pyruvate drawn simultaneously: calculate L:P ratio.
4. Plasma amino acids, urine organic acids, plasma acylcarnitine profile to screen for organic acidemias, fatty acid oxidation defects, and gluconeogenesis defects.
5. Brain MRI for Leigh pattern, stroke-like lesions (MELAS), structural malformations (PDH), white matter changes (Kearns-Sayre, POLG).
6. CSF lactate when CNS involvement is dominant and serum lactate is normal-to-mildly elevated (mitochondrial encephalopathies can have isolated CSF elevation).
7. Mitochondrial genetic testing: mtDNA sequencing + deletion analysis on blood (skeletal muscle if blood negative and clinical suspicion remains) + nuclear mitochondrial gene panel / exome. Heteroplasmy load varies by tissue; sometimes only muscle or urine sediment is informative.
8. Muscle biopsy (ragged-red fibers, COX-negative fibers, respiratory chain enzyme activity) when noninvasive testing is unrevealing.