Anion gap can be classified as either high, normal or, in rare cases, low. Laboratory errors need to be ruled out whenever anion gap calculations lead to results that do not fit the clinical picture. Methods used to determine the concentrations of some of the ions used to calculate the anion gap may be susceptible to very specific errors. For example, if the blood sample is not processed immediately after it is collected, continued cellular metabolism by
leukocytes (also known as
white blood cells) may result in an increase in the HCO concentration, and result in a corresponding mild reduction in the anion gap. In many situations, alterations in renal function (even if mild, e.g., as that caused by dehydration in a patient with diarrhea) may modify the anion gap that may be expected to arise in a particular pathological condition. A high anion gap indicates increased concentrations of unmeasured anions by proxy. Elevated concentrations of unmeasured anions like
lactate, beta-hydroxybutyrate, acetoacetate, PO, and SO, which rise with disease or intoxication, cause loss of HCO due to bicarbonate's activity as a buffer (without a concurrent increase in Cl−). Thus, finding a high anion gap should result in a search for conditions that lead to excesses of the unmeasured anions listed above.
High anion gap The anion gap is affected by changes in unmeasured ions. In uncontrolled
diabetes, there is an increase in
ketoacids due to metabolism of
ketones. Raised levels of acid bind to bicarbonate to form carbon dioxide through the
Henderson-Hasselbalch equation resulting in metabolic acidosis. In these conditions, bicarbonate concentrations decrease by acting as a buffer against the increased presence of acids (as a result of the underlying condition). The bicarbonate is consumed by the unmeasured cation(H+) (via its action as a buffer) resulting in a high anion gap. Causes of high anion gap metabolic acidosis (HAGMA): •
Lactic acidosis •
Ketoacidosis •
Diabetic ketoacidosis •
Hazardous alcohol use •
Toxicants: •
Methanol •
Ethylene glycol •
Propylene glycol •
Lactic acid •
Uremia •
Aspirin •
Phenformin (no longer on market in U.S. since 1978 due to severe lactic acidosis, but still a problem globally. "Old metformin") •
Iron •
Isoniazid •
Cyanide, coupled with elevated venous oxygenation •
Kidney failure, causes high anion gap acidosis by decreased acid excretion and decreased HCO reabsorption. Accumulation of
sulfates,
phosphates,
urate, and
hippurate accounts for the high anion gap. Note: a useful mnemonic to remember this is MUDPILES – Methanol, Uremia, Diabetic Ketoacidosis, Paraldehyde, Infection, Lactic Acidosis, Ethylene Glycol and Salicylates
Normal anion gap In patients with a normal anion gap, the drop in HCO is the primary pathology. Since there is only one other major buffering anion, it must be compensated for almost completely by an increase in Cl−. This is therefore also known as
hyperchloremic acidosis. The HCO lost is replaced by a chloride anion, and thus there is a normal anion gap. •
Gastrointestinal loss of HCO (i.e.,
diarrhea) (note: vomiting causes hypochloraemic alkalosis) •
Kidney loss of HCO (i.e., proximal
renal tubular acidosis (RTA) also known as type 2 RTA) • Kidney dysfunction (i.e., distal renal tubular acidosis also known as type 1 RTA) • Renal hypoaldosterone (i.e., renal tubular acidosis also known as type IV RTA) characterized by elevated serum potassium. ::There are three types. ::1. Low renin may be due to diabetic nephropathy or NSAIDS (and other causes). ::2. Low aldosterone may be due to adrenal disorders or ACE inhibitors. ::3. Low response to aldosterone maybe due to potassium-sparing diuretics,
trimethoprim/sulfamethoxazole, or diabetes (and other causes). • Ingestions •
Ammonium chloride and
acetazolamide, ifosfamide. •
Hyperalimentation fluids (i.e.,
total parenteral nutrition) • Some cases of
ketoacidosis, particularly during rehydration with sodium-containing solutions (IV). • Alcohols (such as ethanol) can cause a high anion gap acidosis in some patients, but a mixed picture in others due to concurrent metabolic alkalosis. • Mineralocorticoid deficiency (
Addison's disease) Note: a useful mnemonic to remember this is FUSEDCARS – fistula (pancreatic), uretero-enterostomy, saline administration, endocrine (hyperparathyroidism), diarrhea, carbonic anhydrase inhibitors (acetazolamide), ammonium chloride, renal tubular acidosis, spironolactone.
Low anion gap A low anion gap is often due to
hypoalbuminemia.
Albumin is an anionic protein and its loss results in the retention of other negatively charged ions such as
chloride and
bicarbonate. As bicarbonate and chloride anions are used to calculate the anion gap, there is a subsequent decrease. The anion gap is sometimes reduced in
multiple myeloma, where there is an increase in plasma
IgG (
paraproteinaemia). ==Correcting the anion gap for the albumin concentration==