What are the possible causes of recurrent lactic acidosis?

Recurrent Lactic Acidosis: Causes and Diagnostic Approach

Recurrent lactic acidosis should prompt immediate investigation for mitochondrial disorders—particularly MNGIE (mitochondrial neurogastrointestinal encephalomyopathy)—which presents with recurrent episodes of lactic acidosis alongside gastrointestinal dysmotility, bacterial overgrowth, and progressive neurological decline. 1

Primary Causes of Recurrent Lactic Acidosis

Mitochondrial Disorders (Most Important for Recurrent Episodes)

Mitochondrial cytopathies are relatively common when specifically sought, accounting for 19% of 80 adult patients labeled as chronic intestinal pseudo-obstruction. 1 These disorders cause recurrent lactic acidosis through impaired oxidative phosphorylation at the cellular level. 2

MNGIE (Mitochondrial Neurogastrointestinal Encephalomyopathy):

• Presents between first and third decade (mean age 18 years) with recurrent diarrhea, symptoms of obstruction, and recurrent lactic acidosis 1
• Characterized by severe gastrointestinal dysmotility (including bacterial overgrowth and lactic acidosis), cachexia, leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia with ptosis (91%), and hearing loss (55%) 1
• Caused by mutations in the thymidine phosphorylase (TP) gene 1
• Very reduced life expectancy with mean survival 37.6 years (range 26-58 years) 1
• Diagnostic testing: plasma and urine thymidine/deoxyuridine, white cell thymine phosphorylase, Tymp gene sequencing, MR brain scanning, and muscle biopsy 1

MELAS Syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes):

• Cardinal features include exercise intolerance, onset before 40 years, seizures, ragged-red fibers on muscle biopsy, lactic acidosis, and stroke-like manifestations 1
• Many individuals have migraine-like headaches 1
• Blood leukocyte DNA reveals A3243G mutation in 80% of MELAS patients 1
• Ischemic lesions preferentially involve posterior cerebral hemispheres but don't conform to specific arterial territories 1

Glycogen Storage Disease Type I

Recurrent hypoglycemia causes lactic acidosis, hepatomegaly, hypertriglyceridemia, hyperuricemia, and failure to thrive in young children with GSD I. 1 This represents a chronic cause of Type B lactic acidosis due to deficient glucose-6-phosphatase activity and impaired gluconeogenesis. 2

Laboratory findings consistent with GSD I:

• Blood/plasma hypoglycemia, lactic acidosis, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia 1
• Neutropenia suggests GSD Ib (though can occur in GSD Ia) 1
• Diagnosis confirmed by full gene sequencing of G6PC (GSD Ia) and SLC37A4 (GSD Ib) genes 1

Medication-Induced Recurrent Episodes

Metformin-associated lactic acidosis (MALA):

• Incidence of 2-9 per 100,000 patients/year, dramatically increasing with renal impairment 2
• Risk factors: eGFR <30 mL/min/1.73 m², elderly patients (>65 years), liver disease, sepsis, acute kidney injury, dehydration, hypoxic states 2
• Recurrent episodes occur when patients repeatedly develop intercurrent illnesses (sepsis, dehydration, acute kidney injury) while continuing metformin 2

Nucleoside Reverse Transcriptase Inhibitors (NRTIs):

• Particularly stavudine and didanosine cause mitochondrial toxicity with incidence of 1.3 cases/1,000 person-years of NRTI exposure 2
• Risk factors: obesity, female sex, prolonged NRTI use (>6 months), pregnancy 2
• Prodrome lasts 1-6 weeks with nausea, vomiting, abdominal pain, dyspnea, and weakness before severe acidosis develops 2

Linezolid:

• Inhibits mitochondrial ribosomes, diminishing respiratory chain enzyme content and limiting aerobic energy production 3
• Results in accelerated anaerobic glycolysis and lactate generation independent of tissue hypoxia 3
• During prolonged linezolid therapy, blood drug and lactate levels should be regularly monitored 3

Organic Acidemias (Inborn Errors of Metabolism)

Methylmalonic acidemia, propionic acidemia, and maple syrup urine disease disrupt normal oxidative metabolism and precipitate Type B lactic acidosis. 2 These typically present in infancy or childhood with recurrent metabolic crises.

Malignancy-Associated Lactic Acidosis (Warburg Effect)

B-cell lymphoma and other malignancies can cause Type B lactic acidosis through metabolic reprogramming (Warburg effect), where cancer cells preferentially use anaerobic glycolysis even in the presence of adequate oxygen. 4 This presents with persistently elevated lactate despite stable hemodynamics. 4

Diagnostic Algorithm for Recurrent Lactic Acidosis

Initial Laboratory Assessment

Measure arterial pH, serum lactate, anion gap, and base deficit:

• Lactic acidosis defined as lactate >5 mmol/L and pH <7.35 5
• Anion gap (Na - [Cl+CO2]) >16 indicates lactic acidosis 2
• Base deficit provides independent information about global tissue acidosis 2

Differentiate Type A (tissue hypoxia) from Type B (no tissue hypoxia):

• Type A: Check for shock states, sepsis, hemorrhage, cardiac failure, respiratory failure 2, 6
• Type B: Normal-to-high oxygen delivery, high venous oxygen saturation, lack of response to interventions that increase tissue oxygen provision 3

Specific Testing for Recurrent Episodes

When Type A causes are excluded, pursue:

1. Mitochondrial disorder screening:

   • Plasma and urine thymidine/deoxyuridine levels 1
   • White cell thymine phosphorylase activity 1
   • Tymp gene sequencing 1
   • MR brain scanning (looking for leukoencephalopathy) 1
   • Muscle biopsy for ragged-red fibers and mitochondrial DNA mutations 1

2. Glycogen storage disease testing:

   • Full gene sequencing of G6PC and SLC37A4 genes 1
   • Fasting glucose, triglycerides, cholesterol, uric acid 1
   • Liver biopsy showing fat and glycogen in hepatocytes (if performed) 1

3. Medication review:

   • Check eGFR in metformin users (contraindicated if <30 mL/min/1.73 m²) 2
   • Review for NRTIs (stavudine, didanosine) in HIV patients 2
   • Assess duration of linezolid therapy and monitor drug levels 3

4. Malignancy screening:

   • Consider CT imaging for lymphoma if persistently elevated lactate with stable hemodynamics 4
   • Check LDH, peripheral smear, flow cytometry 4

Critical Pitfalls to Avoid

Do not dismiss nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) in patients with recurrent lactic acidosis—these may be the sole early warning of mitochondrial disorders like MNGIE. 1, 2

Do not assume all lactic acidosis is Type A (tissue hypoxia)—normal or high venous oxygen saturation with elevated lactate suggests Type B lactic acidosis from mitochondrial dysfunction, malignancy, or medications. 3, 4

Do not continue metformin in patients with recurrent episodes of acute illness—explicitly counsel patients to discontinue metformin during any serious intercurrent illness (sepsis, dehydration, vomiting). 2

Do not wait for overt severe acidosis before investigating mitochondrial disorders—the 1-6 week prodrome in NRTI-associated cases offers a crucial window for intervention. 2

Management Principles

Treat the underlying cause:

• Discontinue offending medications immediately (metformin, NRTIs, linezolid) 2, 3
• For mitochondrial disorders: supportive care, avoid fasting, consider coenzyme Q10, L-carnitine, riboflavins (though none clearly effective for MELAS) 1
• For GSD I: avoid fasting with frequent feedings high in complex carbohydrates, restrict fructose and galactose 1

Do NOT use sodium bicarbonate for pH ≥7.15—it does not improve hemodynamics or survival and may increase lactate production. 2, 6

Hemodialysis is the definitive treatment for metformin-associated lactic acidosis and often reverses symptoms. 2