What are the common causes of metabolic acidosis and hypoglycemia?

Causes of Metabolic Acidosis and Hypoglycemia

The most common causes of combined metabolic acidosis and hypoglycemia include diabetic ketoacidosis (DKA), alcoholic ketoacidosis (AKA), severe sepsis with lactic acidosis, glycogen storage disease type I, and acetaminophen toxicity with hepatic failure. 1, 2

High Anion Gap Metabolic Acidosis with Hypoglycemia

Ketoacidosis Syndromes

Diabetic Ketoacidosis (DKA)

• DKA results from insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), leading to increased hepatic glucose production, impaired peripheral glucose utilization, lipolysis, and ketogenesis 1, 3
• While DKA typically presents with hyperglycemia (>250 mg/dL), approximately 10% of cases present as euglycemic DKA with glucose <200 mg/dL, particularly in pregnancy, SGLT2 inhibitor use, reduced food intake, or alcohol consumption 1
• Clinical presentation includes Kussmaul respirations, sweet-smelling breath, polyuria, polydipsia, weight loss, and altered mental status 3
• Diagnostic criteria require arterial pH <7.3, bicarbonate <15 mEq/L, and moderate ketonuria or ketonemia 1

Alcoholic Ketoacidosis (AKA)

• AKA is distinguished from DKA by plasma glucose concentrations ranging from mildly elevated (rarely >250 mg/dL) to frank hypoglycemia 1
• Can result in profound acidosis despite the presence of hypoglycemia 1
• Clinical history of alcohol abuse with recent binge drinking and poor oral intake is characteristic 1

Starvation Ketosis

• Presents with mild ketoacidosis where serum bicarbonate is usually not lower than 18 mEq/L 1
• Glucose levels range from mildly elevated to hypoglycemic 1
• Distinguished by clinical history of prolonged fasting or inadequate caloric intake 1

Lactic Acidosis with Hypoglycemia

Sepsis and Shock

• Lactic acidosis develops from tissue hypoperfusion and impaired oxygen delivery, leading to anaerobic metabolism 1, 4
• Hypoglycemia occurs due to depleted glycogen stores, impaired gluconeogenesis, and increased peripheral glucose utilization 1
• Clinical features include tachycardia (>160 bpm if <1 year, >140 bpm if 2-5 years, >120 bpm if >5 years), cold peripheries, prolonged capillary refill time (>2 seconds), decreased urine output (<1 ml/kg/hour), and altered consciousness 1
• Metabolic acidosis with base deficit >8 mmol/L is commonly associated with compensated shock 1

Severe Malaria in Children

• Presents with respiratory distress, tachypnea, and increased work of breathing associated with underlying metabolic acidosis (base deficit >8 mmol/L) 1
• Hypoglycemia (blood glucose <3 mmol/L or <54 mg/dL) may precipitate seizures or posturing 1
• Features of compensated shock include hypoxia, tachycardia, altered peripheral pulse volume, cool peripheries, and prolonged capillary refill time 1

Acetaminophen Toxicity

• Type B lactic acidosis with hypoglycemia develops secondary to severe hepatic failure and/or toxic metabolites of acetaminophen 2
• Deficit in gluconeogenesis from hepatic failure causes hypoglycemia 2
• Both lactic acidosis and hypoglycemia together should prompt consideration of acetaminophen toxicity 2

Glycogen Storage Disease Type I (GSD I)

Clinical Presentation

• Symptomatic hypoglycemia appears when feeding intervals increase, typically when infants start sleeping through the night or during intercurrent illness 1
• Blood glucose may decrease to <40 mg/dL (2.2 mmol/L) within 3-4 hours of feeding in infancy 1
• Longer fasting intervals cause severe hypoglycemia accompanied by lactic acidemia and metabolic acidosis 1
• Patients present with hepatomegaly, protuberant abdomen, round face with full cheeks (cushingoid appearance), failure to thrive, and delayed motor development 1

Biochemical Characteristics

• Blood lactate levels increase rapidly as glucose concentrations decrease to <70 mg/dL (4 mmol/L) and are markedly elevated when glucose falls to <40-50 mg/dL (2.2-2.8 mmol/L) 1
• Blood β-hydroxybutyrate levels increase only modestly in GSD I, contrasting with marked hyperketonemia in other glycogen storage diseases 1
• Additional findings include hyperuricemia, hypercholesterolemia, and hypertriglyceridemia 1
• Elevated hepatic transaminases (AST and ALT) at diagnosis often return to normal with appropriate treatment 1

Distinguishing Features

• Unlike GSD III, VI, and IX, GSD I presents with elevated uric acid and lactate levels 1
• Glucagon stimulation test shows significant increase in blood lactate but little or no increase in blood glucose, though this test is not recommended due to risk of acute acidosis and decompensation 1

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis with Hypoglycemia

Gastrointestinal Losses

Acute Gastroenteritis (AGE) and Vomiting

• Most common diagnosis in young children (ages 1-71 months) presenting with metabolic acidosis and hypoglycemia 5
• Hypoglycemia present in 28% of children with metabolic acidosis, with children having acidosis and hypoglycemia being older (median 42 months vs 18.5 months) 5
• Children with AGE or vomiting and hypoglycemia have shorter hospitalizations (3 vs 5 days) and no mortality compared to those without hypoglycemia 5
• Bicarbonate loss through diarrhea combined with poor oral intake and depleted glycogen stores leads to hypoglycemia 6

Renal Tubular Acidosis (RTA)

• Proximal renal tubular dysfunction is common in inadequately treated GSD I patients 1
• RTA causes hyperchloremic metabolic acidosis through impaired renal acidification 6
• When combined with poor oral intake or intercurrent illness, hypoglycemia can develop 6

Diagnostic Approach Algorithm

Initial Assessment

1. Obtain arterial blood gas to confirm metabolic acidosis (pH <7.35, HCO₃⁻ <22 mEq/L) and assess respiratory compensation 1, 4
2. Measure serum glucose immediately to identify hypoglycemia (<70 mg/dL or 3.9 mmol/L) 1
3. Calculate anion gap: [Na⁺] - ([HCO₃⁻] + [Cl⁻]) to categorize as high anion gap (>12 mEq/L) or normal anion gap 3, 7

High Anion Gap Metabolic Acidosis Pathway

• Check serum ketones (β-hydroxybutyrate and acetoacetate) and urine ketones by dipstick 1
• If ketones elevated with hyperglycemia: Consider DKA; obtain HbA1c, complete blood count, electrolytes, blood urea nitrogen/creatinine, and electrocardiogram 1
• If ketones elevated with hypoglycemia or mild hyperglycemia: Distinguish between AKA (alcohol history) and starvation ketosis (fasting history) 1
• If lactate elevated: Measure serum lactate; if >4 mmol/L, evaluate for sepsis (obtain cultures, chest X-ray), shock (assess perfusion), or severe malaria in endemic areas 1, 6
• If both ketones and lactate normal: Check salicylate, methanol, ethylene glycol levels, and acetaminophen level; assess renal function (BUN/creatinine) 1, 2

Normal Anion Gap Metabolic Acidosis Pathway

• Assess hydration status and gastrointestinal symptoms: History of diarrhea, vomiting suggests bicarbonate loss from AGE 5
• Check urine pH and electrolytes: Urine pH >5.5 with systemic acidosis suggests RTA 6
• Evaluate for GSD I if hepatomegaly present: Obtain liver function tests, uric acid, lipid panel, and consider molecular genetic testing 1

Critical Management Considerations

Immediate Interventions

• Treat hypoglycemia first: Administer 15-20 grams of rapid-acting carbohydrate or intravenous dextrose if unable to take oral 1
• In DKA with hypoglycemia: Add dextrose to hydrating solution once blood glucose reaches 250 mg/dL to prevent cerebral edema while continuing insulin therapy 1
• In septic shock with hypoglycemia: Volume resuscitation with 20 ml/kg bolus of colloid or 0.9% saline, followed by repeat bolus if shock persists 1

Common Pitfalls to Avoid

• Do not assume DKA based solely on acidosis and diabetes history—verify glucose level, as euglycemic DKA occurs in 10% of cases 1
• Do not overlook acetaminophen toxicity when lactic acidosis and hypoglycemia coexist, especially with hepatic dysfunction 2
• Do not delay treatment of hypoglycemia to complete diagnostic workup—correct glucose immediately while investigating etiology 1
• Do not confuse sweet breath odor from ketoacidosis with alcohol intoxication 3
• Do not mistake Kussmaul respirations for primary respiratory disease or hyperventilation syndrome 3
• In young children with AGE, anticipate hypoglycemia due to poor metabolic reserve and limited glycogen stores 5
• In GSD I patients, recognize that normal serum potassium may mask total body potassium depletion during metabolic crises 8