Causes of Lactic Acidosis and Hypoglycemia
Primary Classification Framework
Lactic acidosis is classified into Type A (tissue hypoperfusion/hypoxia) and Type B (abnormal metabolism without hypoxia), while hypoglycemia results from insulin excess, impaired gluconeogenesis, or increased glucose consumption—both conditions can co-occur in specific clinical scenarios requiring immediate recognition and targeted intervention. 1
Type A Lactic Acidosis (Tissue Hypoperfusion)
Circulatory Causes
- Septic shock with inadequate tissue perfusion 1
- Cardiovascular collapse (shock state) 2
- Acute myocardial infarction 2
- Acute congestive heart failure, particularly with hypoperfusion and hypoxemia 2
- Conditions associated with hypoxemia causing prerenal azotemia 2
Respiratory Causes
Type B Lactic Acidosis (Metabolic Dysfunction)
Medication-Induced
- Metformin accumulation in renal impairment (eGFR <30 mL/min/1.73 m²) is the most common drug cause 2
- Metformin-associated lactic acidosis occurs primarily with significant renal impairment, hepatic disease, or excessive alcohol intake 2
- SGLT2 inhibitors can cause euglycemic diabetic ketoacidosis with associated lactic acidosis 4
Malignancy-Related (Warburg Effect)
- Hematological malignancies, particularly diffuse large B-cell lymphoma (DLBCL), acute leukemia, and high-grade non-Hodgkin's lymphoma 5, 6, 3
- Massive tumor burden with enhanced glucose metabolism and lactate overproduction 5, 3
- Elevated TNF-alpha associated with lymphoma can contribute to lactic acidosis 3
- This carries a very poor prognosis unless chemotherapy is initiated promptly 5
Organ Dysfunction
- Hepatic impairment causing impaired lactate clearance 2, 6
- Liver failure can precipitate euglycemic diabetic ketoacidosis with lactic acidosis 4
- Renal failure impairing both lactate clearance and gluconeogenesis 4
Other Metabolic Causes
- Excessive alcohol intake potentiating lactate metabolism 2
- Dehydration from vomiting, diarrhea, or osmotic diuresis 2
- Pregnancy in diabetic patients 4
Hypoglycemia Causes in Diabetes
Medication-Related
- Insulin excess relative to food intake or energy expenditure 7
- Sulfonylureas or active metabolites accumulating in renal impairment 4
- First-generation sulfonylureas (chlorpropamide, tolazamide, tolbutamide) should be avoided entirely in CKD 4
- Nateglinide accumulates with decreased kidney function 4
- Metformin combined with insulin or insulin secretagogues increases hypoglycemia risk 2
Renal Impairment
- Impaired renal gluconeogenesis with reduced kidney mass 4
- Prolonged insulin half-life due to decreased renal clearance (approximately one-third of insulin degradation occurs in kidneys) 4
- Patients with type 1 diabetes and creatinine elevations (mean 2.2 mg/dL) have a 5-fold increase in severe hypoglycemia frequency 4
Gastroparesis-Related
- "Gastric hypoglycemia" in insulin-treated patients due to mismatched nutrient delivery and insulin action 8
- Delayed gastric emptying affecting 30-50% of patients with longstanding diabetes 8
Physiological Factors
- Fasting for tests or procedures 4
- Intense exercise or prolonged physical activity 4
- Nocturnal hypoglycemia during sleep 4
- Hypoglycemia unawareness (hypoglycemia-associated autonomic failure) with deficient counterregulatory hormone release 4
Metabolic Disorders Causing Both Conditions
Glycogen Storage Disease Type I (GSD I)
- Glucose-6-phosphatase deficiency (Type Ia) or glucose-6-phosphate transporter deficiency (Type Ib) 4
- Hypoglycemia occurs within 3-4 hours of feeding in infancy 4
- Severe lactic acidosis accompanies hypoglycemia due to impaired gluconeogenesis 4
- Hyperuricemia, hypercholesterolemia, and hypertriglyceridemia are characteristic 4
- Hepatomegaly and nephromegaly are present 4
- Patients may present with hyperpnea simulating pneumonia due to lactic acidosis 4
Fructose-1,6-Bisphosphatase Deficiency
- Impaired hepatic gluconeogenesis causing hypoglycemia after prolonged fasting or during illness 4, 9
- Severe metabolic acidosis with lactic acidosis 9
- Presentation can occur from birth with recurrent hypoglycemia and acidosis 9
- Mean duration from presentation to diagnosis is 39.4 months as other diagnoses must be excluded 9
Other Gluconeogenesis Disorders
- Fructose-1,6-bisphosphatase deficiency causing hypoglycemia after prolonged fasting with reduced carbohydrate intake 4
Co-Occurrence of Type A and Type B Lactic Acidosis
Both types can occur simultaneously, particularly in critically ill patients with malignancy who develop sepsis or circulatory failure 1. This combination makes management extremely challenging and requires a systematic approach to diagnose underlying pathology 1.
Critical Clinical Scenarios
Diabetic Ketoacidosis (DKA)
- Euglycemic DKA (glucose <200 mg/dL) can occur with insulin deficiency, reduced food intake, pregnancy, alcohol use, liver failure, or SGLT2 inhibitor therapy 4
- Nausea and vomiting with hyperglycemia may indicate DKA, a life-threatening emergency requiring immediate medical care 4, 8
- Mixed acid-base disturbances can complicate diagnosis, particularly in pregnancy with hyperemesis 4
Acute Illness in Diabetes
- Stressful events (illness, trauma, surgery) frequently aggravate glycemic control and may precipitate DKA or hyperglycemic hyperosmolar state 4
- Infection or dehydration more likely necessitates hospitalization in diabetic patients 4
Key Diagnostic Pitfalls to Avoid
- Never perform glucagon stimulation testing in suspected GSD I as it worsens metabolic acidosis and causes acute decompensation 4
- Do not assume circulatory failure is always present in lactic acidosis; Type B can occur without hypoperfusion 6, 3
- Check for malignancy (especially hematological) in unexplained Type B lactic acidosis with hypoglycemia 5, 6, 3
- Measure metformin levels and assess renal function immediately in diabetic patients with lactic acidosis 2
- Stop SGLT2 inhibitors immediately if DKA is suspected, as they increase euglycemic DKA risk 8
- Assess for hepatic impairment as it increases metformin-associated lactic acidosis risk through impaired lactate clearance 2