What are the causes of lactic acidosis in patients, particularly those with diabetes, kidney disease, or taking metformin?

Causes of Lactic Acidosis

Lactic acidosis develops from two fundamental mechanisms: Type A (tissue hypoxia/hypoperfusion) and Type B (metabolic disturbances without hypoxia), with the most critical causes being circulatory shock, sepsis, metformin accumulation in renal impairment, and mitochondrial dysfunction from certain medications. 1

Type A Lactic Acidosis: Tissue Hypoxia and Hypoperfusion

Type A results from inadequate oxygen delivery to tissues, causing cells to shift to anaerobic metabolism and produce excess lactate. 1

Circulatory and Cardiac Causes

• Shock states (cardiogenic, distributive, hypovolemic) represent the most common cause, where inadequate tissue perfusion forces anaerobic metabolism 1
• Cardiac failure with reduced cardiac output leads to systemic hypoperfusion 1
• Mesenteric ischemia should be strongly suspected when lactic acidosis (lactate >2 mmol/L) occurs with elevated urea and abdominal pain—88% of these patients have metabolic acidosis, and lactate >2 mmol/L carries a hazard ratio of 4.1 for irreversible intestinal ischemia 1

Severe Infections

• Sepsis and septic shock cause lactic acidosis through both tissue hypoperfusion and mitochondrial dysfunction, particularly in patients with underlying diabetes mellitus 1
• The combination of infection with hemodynamic instability dramatically increases risk 1

Rhabdomyolysis

• Damaged muscle tissue undergoes anaerobic metabolism during rhabdomyolysis, producing lactate and contributing to acidosis 1
• Particularly dangerous in sickle cell trait patients with exertional rhabdomyolysis, who develop the triad of lactic acidosis, hyperkalemia, and impaired cardiac function that can progress to pulseless electrical activity 1
• Malignant hyperthermia causes increased metabolic rate and muscle contractile activity, resulting in lactic acidosis 1

Type B Lactic Acidosis: Metabolic and Drug-Induced

Type B occurs without tissue hypoxia due to metabolic disturbances, drug toxicity, or impaired lactate clearance. 1

Metformin-Associated Lactic Acidosis (MALA)

Metformin is the most clinically significant drug cause of lactic acidosis, with incidence of 2-9 per 100,000 patients/year, but risk increases dramatically with renal impairment. 1, 2

Mechanism and Risk Factors

• Metformin decreases liver uptake of lactate, increasing blood lactate levels, and is substantially excreted by the kidney 3
• Renal impairment is the critical risk factor: metformin clearance decreases by approximately 75% when eGFR drops to 60 mL/min/1.73 m², and serum concentrations become 2-fold higher 1
• Metformin is contraindicated when eGFR <30 mL/min/1.73 m² 3, 2
• Initiation is not recommended with eGFR 30-45 mL/min/1.73 m², and dose reduction to 1000 mg daily is required in this range 3, 1

High-Risk Clinical Scenarios for MALA

• Acute kidney injury from any cause—metformin should be stopped immediately 1
• Sepsis or systemic infection with hemodynamic instability 1
• Cardiogenic or distributive shock 1
• Hypoxic states including respiratory failure or severe hypoxemia 1
• Liver dysfunction or failure, which impairs lactate clearance since the liver is the major site of lactate removal 1
• COVID-19 infection is associated with higher risk (adjusted hazard ratio 4.46) 1
• Elderly patients (>65 years) have greater likelihood of hepatic, renal, or cardiac impairment 1, 3

Sick-Day Rules

Patients should be advised to discontinue metformin temporarily during serious intercurrent illness that increases AKI risk, including around surgery, angiography, and when unwell at home. 4

• Stop metformin at the time of or prior to iodinated contrast imaging in patients with eGFR 30-60 mL/min/1.73 m², history of hepatic impairment, alcoholism, heart failure, or those receiving intra-arterial contrast 3
• Re-evaluate eGFR 48 hours after imaging and restart only if renal function is stable 3

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs, particularly stavudine and didanosine used in HIV treatment, cause mitochondrial toxicity leading to lactic acidosis with incidence of approximately 1.3 cases per 1,000 person-years of NRTI exposure. 1

• Mechanism: NRTIs inhibit DNA polymerase γ, responsible for mitochondrial DNA synthesis, causing mitochondrial dysfunction 1
• Risk factors: obesity, female sex, prolonged use (>6 months), and pregnancy 1
• Incidence has decreased as newer antiretrovirals have replaced older NRTIs like didanosine, stavudine, and zidovudine 1

Organ Dysfunction Impairing Lactate Clearance

Liver Disease

• Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation 1
• The liver is a key organ for both metformin's antidiabetic effect and the development of lactic acidosis 5

Renal Impairment

• Renal impairment reduces lactate clearance as kidneys contribute to lactate removal 1
• Hyperlactatemia reported in 30-65% of adults with chronic kidney disease 1

Chronic Pulmonary Disease

• Acute decompensation of chronic pulmonary disease should prompt monitoring for lactic acidosis 1

Metabolic and Endocrine Causes

• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon, where bacterial overgrowth produces D-lactate 1
• Organic acidemias including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease are inborn errors of metabolism causing Type B lactic acidosis 1
• Deficiency of tetrahydrobiopterin can cause hyperlactatemia in up to 80% of affected patients 1
• Severe primary hypothyroidism can cause hyperlactatemia 1

Electrolyte Disturbances

Severe hypophosphatemia (<0.32 mmol/L or <1.0 mg/dL) triggers lactic acidosis, particularly in refeeding syndrome and during prolonged kidney replacement therapy. 1

• Refeeding syndrome causes both hypophosphatemia and lactic acidosis when nutrition is reintroduced after caloric deprivation, with prevalence reaching 60-80% in ICU patients 1
• Prolonged or intensive kidney replacement therapy causes hypophosphatemia in up to 80% of patients when standard phosphate-free dialysis solutions are used 1

Common Pitfalls and Caveats

Diagnostic Pitfalls

• Subtle early symptoms such as nonspecific gastrointestinal symptoms (nausea, vomiting), dyspnea, generalized weakness, and myalgias often precede severe acidosis and should not be ignored 1, 3
• Do not rely on creatinine alone for assessing renal function in metformin users—eGFR should be used as creatinine varies widely based on age, ethnicity, and muscle mass 1
• Labor itself elevates lactate levels—do not use lactate to diagnose sepsis during labor 1

Management Pitfalls

• Do not ignore hyperlactatemia even without hypotension—lactate ≥2 mmol/L indicates sepsis and persistent elevation may indicate occult tissue hypoperfusion 1
• In patients with lactate elevation, urea elevation, and abdominal pain, do not delay CT angiography for mesenteric ischemia—diagnostic delay is the dominant factor in mortality (30-70%) 1
• Acute renal failure was detected in 9 out of 11 patients on metformin who developed lactic acidosis in one ICU study, emphasizing the critical role of renal function monitoring 6