Metabolic Acidosis Causes and Classification

Classification by Anion Gap

• High anion gap metabolic acidosis is characterized by the presence of unmeasured organic anions in the body, with lactic acidosis being a primary contributor in shock states, resulting from inadequate oxygen delivery to tissues and tissue hypoperfusion, with lactate levels indicating tissue hypoxia, as recommended by the American Diabetes Association 1
• Diabetic ketoacidosis (DKA) is characterized by plasma glucose, arterial pH, bicarbonate, and positive serum/urine ketones, according to the American Diabetes Association 2, 3
• Alcoholic ketoacidosis is distinguished from DKA by plasma glucose levels and clinical history of alcohol use, as noted by the American Diabetes Association 3
• Starvation ketosis is characterized by serum bicarbonate and mildly elevated glucose, as reported by the American Diabetes Association 3
• Chronic renal failure can present as high anion gap acidosis due to impaired acid excretion by the kidney, as stated by the American Diabetes Association 2, 3
• Toxic ingestions, such as salicylate, methanol, and ethylene glycol, can cause high anion gap metabolic acidosis, according to the American Diabetes Association 2

Special Clinical Contexts

• Septic shock exhibits complex metabolic acidosis with multiple contributors, including lactic acidosis and hyperchloremic acidosis, as summarized by the American College of Critical Care Medicine 1
• Dietary-induced chronic low-grade acidosis can occur with high animal protein intake and low fruit and vegetable consumption, leading to an imbalance between nonvolatile acids and available alkali, as reported by the National Kidney Foundation 4

Diagnostic Approach

• The osmolal gap can be elevated in methanol, ethylene glycol, and propylene glycol ingestions, as noted by the American Diabetes Association 2
• Blood lactate measurement is essential in shock states, with serial measurements providing information about shock severity and treatment response, as recommended by the American College of Critical Care Medicine 1
• Serum ketones can distinguish ketoacidosis from other causes, according to the American Diabetes Association 2, 3

Metabolic Acidosis in Chronic Kidney Disease

Clinical Consequences and Treatment

• The American Journal of Kidney Diseases recommends maintaining serum bicarbonate at or above 22 mmol/L in dialysis patients to prevent increased protein degradation, decreased albumin synthesis, low plasma branched chain amino acids, and impaired growth 5
• Metabolic acidosis in chronic kidney disease and maintenance dialysis patients is associated with increased protein degradation, decreased albumin synthesis, low plasma branched chain amino acids, and impaired growth, according to the American Journal of Kidney Diseases 5

Diagnostic Criteria and Evaluation of Ketoacidosis, Toxic Ingestions, and Mixed Acid‑Base Disorders in Metabolic Acidosis

Ketoacidosis Definitions

• Diabetic ketoacidosis (DKA) is identified by markedly elevated blood glucose (typically >250 mg/dL), arterial pH < 7.3, serum bicarbonate < 15 mEq/L, and the presence of ketones in serum or urine. 6
• Alcoholic ketoacidosis (AKA) is characterized by low or normal blood glucose (rarely >250 mg/dL) together with a clinical history of recent heavy alcohol intake. 6
• Starvation‑related ketosis usually shows serum bicarbonate ≥ 18 mEq/L and only mild hyperglycemia. 6

Toxic Ingestion Causes

• Ingestion of salicylates, methanol, ethylene glycol, or paraldehyde can produce a high‑anion‑gap metabolic acidosis. 6

Diagnostic Approach to High Anion‑Gap Metabolic Acidosis

• Measurement of serum or urine ketones is essential to differentiate ketoacidosis from other high‑anion‑gap etiologies. 6
• Plasma glucose assessment aids in distinguishing the type of ketoacidosis: values >250 mg/dL favor DKA, whereas normal‑to‑low glucose suggests AKA or starvation ketosis. 6
• Evaluation of renal function (BUN/creatinine) helps identify uremic acidosis as a contributing factor. 6

Mixed Acid‑Base Disorders

• In critically ill patients, concurrent high‑anion‑gap and normal‑anion‑gap metabolic acidosis are common; clinicians should actively search for mixed disorders rather than assuming a single cause. 6

Key Diagnostic Indicators for Distal (Type 1) Renal Tubular Acidosis

Laboratory Ratios Excluding Advanced CKD

• A markedly low blood urea nitrogen‑to‑creatinine ratio (≈ 0.8) effectively rules out stage V chronic kidney disease, which characteristically shows a ratio > 20 : 1, indicating that the patient’s renal function is not end‑stage. 7

Associated Syndromes in Proximal (Type 2) RTA

• Proximal renal tubular acidosis is commonly linked to Fanconi syndrome, which presents with concurrent urinary losses of phosphate, uric acid, glucose, and amino acids (hypophosphatemia, hypouricemia, glycosuria, and aminoaciduria). 8

High Anion Gap Metabolic Acidosis: Rare Metabolic Disorders

Organic Acidemias

• Organic acidemias—such as methylmalonic acidemia, propionic acidemia, and isovaleric acidemia—are rare metabolic disorders that can produce a high anion‑gap metabolic acidosis and commonly present with toxic encephalopathy, vomiting, and neurologic symptoms. 9