Metabolic Acidosis

1. Metabolic Acidosis (MA) is defined by a decreased serum bicarbonate and an arterial blood gas (ABG) indicating acidemia.
2. Metabolic acidoses are separated into those with a wide anion gap (WAGMA) and normal anion gap (NAGMA, aka hyperchloremic metabolic acidosis)
3. The anion gap (AG) is artificial in the sense that it is a lab artifact. In theory all the positive charges in the serum should equal the negative charges to achieve electrical neutrality. The serum anion gap is calculated as AG= Na - (Cl + HCO3). In other words, it is the measured cations minus the measured anions. Another way to think of it is the unmeasured anions minus the unmeasured cations. 
4. Albumin is the major unmeasured anion in the serum. One must correct for the albumin level. Generally, for every 10g/L below the normal value of 40g/L, one should add a correction factor of 2.5 for the corrected anion gap. 
5. The normal anion gap range depends on whether K (potassium) is used in the equation to calculate it. Generally, it is not. It also depends on the lab's way of measuring chloride. At LHSC a normal AG is 12-14. 
6. Causes of a low anion gap include anything that causes a high level of unmeasured cations (e.g. paraproteinemias, hypermagnesemia, hypercalcemia) or low level of unmeasured anions (e.g. hypoalbuminemia)
7. WAGMA is usually due to unmeasured organic acids. It is usually due to ketoacidosis, lactic acidosis, acute kidney injury/chronic kidney disease, or ingestions.

• Ketoacidosis: The ketoacids are beta-hydroxybutyrate and acetoacetic acid. Acetone is a ketone body but not a ketoacid. Ketoacidosis can result from diabetic ketoacidosis, starvation, or alcohol consumption. 
• Lactic Acidosis: Type A is due to impairment in tissue oxygenation (e.g. circulatory or respiratory failure, sepsis, ischemic bowel). Type B is due to impaired lactate clearance (e.g. liver disease), metastatic disease, or certain drugs (e.g. metformin when renal function is impaired, salicylates, NRTIs). D-Lactate (NB L-Lactate is measured routinely in the serum) can be due to short-gut syndrome in which bacteria in the colon metabolize glucose to D-Lactate. 
• AKI or CKD: Impaired clearance of organic acids, phosphates, sulfates, and urates. 
• Ingestions
• Salicylates (e.g. acetylsalicylic acid, methyl salicylate from oil of wintergreen, bismuth subsalicylate): Lactic acidosis can result from impaired oxidative phosphorylation since salicylate overdose can poison the mitochondria involved in the Kreb's cycle. 
• Acetaminophen: 5-oxoproline (aka pyroglutamic acid) can result from chronic acetaminophen use, usually in older, typically malnourished females. 
• Ethylene glycol: Metabolized into oxalic/glycolic acid. Used in antifreeze solution. 
• Propylene glycol: Can result in lactic acidosis. Used as diluent in IV lorazepam/diazepam infusions as well as IV nitroglycerin. 
• Methanol: Metabolized into formic acid. Used in engine coolants. 
• Iron: Can result in a lactic acidosis since excess iron can be toxic to mitochondria.
• Toluene: Can result in hippuric acidosis. Used as solvent for dyes, paints, rubbers. 

   8. NAGMA (hyperchloremic metabolic acidosis) are usually a result of a loss of bicarbonate, gain of chloride, or impaired excretion of acids. Causes include:

• Loss of HCO3 (e.g. for the GI tract from diarrhea, from the kidneys in type 2 RTA (renal tubule acidosis when HCO3 reabsorption in the proximal tubules is impaired)
• Impaired acid excretion (e.g. type 1 or type 4 RTA)
• Infusing HCO3-free fluid (e.g. IV normal saline infusions)
• Total parenteral nutrition (amino acids are broken into ammonium chloride which is an acid)
• Ureteral-ileal/colonic conduits or diversions. Urine makes contact with the GI tract and HCO3/Chloride exchange can occur, resulting in hyperchloremia. 
• Pancreatic fistulas
• Drugs (e.g. acetazolamide, cholestyramine, toluene)

   9. Remember that acid base disturbances are often mixed. For example, a WAGMA can coexist with a NAGMA or a metabolic acidosis can be combined with a respiratory acidosis. It is diagnostically convenient when a single acid-base imbalance occurs, but this is seldom the case. 

   10. Because of the above, the delta/delta gap, or the ratio of the extent of the anion gap divided by the extent of the metabolic acidosis (i.e. anion gap -12/24-HCO3, where 12 is considered a "normal" anion gap and 24 a "normal" HCO3 level), can be used to help evaluate a mixed versus pure NAGMA/WAGMA or the presence of a concurrent metabolic alkalosis. 

Reference Article:

Kraut, J.A. and Madias, N.E. Metabolic acidosis: pathophysiology, diagnosis and management. Nat. Rev. Nephrol. 6, 274-285 (2010).