• Metabolic acidosis is defined as decreased serum bicarb (HCO3-) concentration with or without acidemia (low pH).
• Metabolic acidosis is further categorized into 2 major types based on anion gap, which is the difference between anions (Na+, K+) and cations (Cl-, HCO3-):
Anion gap metabolic acidosis (AGMA): caused by overproduction or accumulation of strong acid (H+ ions) other than hydrochloric acid as a result of cellular metabolism, ingested acid-producing substance, or kidney’s inability to excrete acids (phosphate, urate, sulfate). Anion gap is elevated because the strong acid’s H+ is consumed by the body’s HCO3- thereby decreasing total HCO3-
Normal anion gap metabolic acidosis (NAGMA): caused by HCO3- loss in the urine or gut lumen, or by dilution of serum HCO3- by extracellular volume expansion. Anion gap is not elevated because the lost HCO3- is replaced by Cl- thus this type of metabolic acidosis is also called “hyperchloremic” metabolic acidosis
• Anion gap metabolic acidosis (AGMA) is caused by 3 main mechanisms:
Ingestion of acid-producing substances such as toxic alcohols, aspirin
Cell & tissue H+ production in ketoacidosis, lactic acidosis
Decreased renal HCO3 reabsorption & acid excretion in renal failure
• The etiologies of AGMA are summarized in the mnemonic "GOLDMARK" (see below).
• Additional diagnostic tests for AGMA include:
Serum ketones: preferably direct β-hydroxybutyrate test, more sensitive than urine ketones in diagnosing ketoacidosis
Serum lactate: measures L-lactate, elevated in lactic acidosis
Serum osmolality: used to calculate serum osmol gap (see formulas below)
Serum salicylate, methanol, ethylene glycol: elevated in aspirin, methanol, and ethylene glycol intoxication, respectively
Urine 5-oxoproline (pyroglutamic acid): elevated in chronic acetaminophen use
Urine D-lactate: elevated in D-lactic acidosis
• In simple or uncomplicated anion gap metabolic acidosis (AGMA) (without other concurrent acid-base disorders nor renal dysfunction), anion gap elevation (from normal gap of 12) is often proportional to the fall in serum bicarb concentration (from normal HCO3- of ~24). This relationship is presented as “delta gap”, Δanion gap/ ΔHCO3 ratio, which is roughly equal to 1. Due to the same reason, the corrected HCO3 will also be normalized to 22-28 mEq/L.
• The delta gap and corrected serum HCO3 can be used to determine whether AGMA is simple/ uncomplicated or mixed with other acid-base disorders or complicated by renal dysfunction.
• Generally, if there is a co-existing--
Renal impairment (in chronic kidney disease, renal tubular acidosis type 4, or acute kidney injury due to lactic acidosis): urine excretion of acid anions (accompanied with excretion of Na and K) decreases thereby increasing anion gap, while ΔHCO3 is relatively unchanged; as a result, delta gap increases (between 1-2)
Normal anion gap metabolic acidosis (NAGMA): there is less HCO3 dropping HCO3 further from normal level, increasing ΔHCO3, while anion gap does not change (HCO3 replaced by Cl-); as a result, delta gap decreases (< 1), corrected HCO3 is below normal range < 22 mEq/L
Metabolic alkalosis or chronic respiratory acidosis: there is more HCO3, narrowing ΔHCO3; therefore, delta gap increases (> 1), corrected HCO3 is above normal range > 28 mEq/L
• Normal anion gap metabolic acidosis (NAGMA) is caused by 3 main mechanisms:
HCO3 dilution by extracellular volume expansion by Cl- rich fluid such as normal saline
GI HCO3 loss in diarrhea, small bowel or pancreatic fistula, or ureteral diversion to colon, ileum
Decreased renal HCO3 reabsorption or H+ excretion in renal insufficiency, renal tubular acidosis (RTA), or acetazelomide
• Additional diagnostic tests for NAGMA include:
Urine electrolytes (Na, K, Cl): used to calculate urine anion gap (see formulas below) which differentiates renal vs non-renal causes
Urine osmolality, Na, K, urea, glucose: used to calculate urine osmol gap which is low in renal causes of NAGMA
Urine pH and serum K: used to diagnose different types of RTA
Urine Ca: elevated in type 1 RTA (+presence of renal stones)
Serum aldosterone: differentiates between 2 types of hyperkalemic distal RTA, hypoaldosteronism vs voltage-dependent
