What is the “Anion Gap”?
The term AG represents the concentration of all the unmeasured anions in the plasma.
What is the principle of electroneutrality that the AG is based on?
- For any body fluid compartment such as plasma, the concentration of cations and anions must be equal.
- In routine analysis of plasma, some cations and anions are measured and others are not.
- The cation that usually is measured is Na+; the anions that usually are measured are HCO3− and Cl−.
- When the Na+ concentration (in mEq/L) is compared with the sum of the HCO3− and Cl− concentrations (in mEq/L), there is an anion gap ( a gap that is left, the sum of HCO3 and Cl doesn’t reach the Na amount).
- Because electroneutrality is never violated, plasma must contain unmeasured anions that make up this difference, or “gap.”
- The unmeasured anions of plasma include plasma proteins, phosphate, citrate, and sulfate.
Which are the unmeasured anions that make up the AG?
The unmeasured anions of plasma include plasma proteins, phosphate, citrate, and sulfate.
What is the AG formula and range value?
Plasma anion gap = [Na+ ] − ([HCO3− ] + [Cl− ])
Range value: 8–16 mEq/L (older)
Range value: 4–12 mEq/L
What are the major clinical uses of the Anion Gap?
1- To signal the presence of a metabolic acidosis and confirm other findings. Metabolic acidosis is, by definition, associated with a decrease in plasma HCO3− concentration. Assuming that the Na+ concentration is unchanged, to preserve electroneutrality of the plasma compartment, the concentration of an anion must increase to replace the “lost” HCO3−. That anion can be one of the unmeasured anions, or it can be Cl−. If HCO3− is replaced by unmeasured anions, the calculated anion gap is increased. If HCO3− is replaced by Cl−, the calculated anion gap is normal.
2- Help differentiate between causes of a metabolic acidosis: high anion gap versus normal anion gap metabolic acidosis. In an inorganic metabolic acidosis (eg due HCl infusion), the infused Cl- replaces HCO3 and the anion gap remains normal. In an organic acidosis, the lost bicarbonate is replaced by the acid anion which is not normally measured. This means that the AG is increased.
3- To assist in assessing the biochemical severity of the acidosis and follow the response to treatment.
What are the causes of High AG metabolic acidosis?
1- Lactic acidosis (investigation to be done lactate);
2- Ketoacidosis: can be due to diabetes, alchool or starvation (investigations: glucose, urine ketones);
3- Uremic acidosis (renal function);
4- Drugs or toxins ingested.
In high AG acidosis
Explain the mechanism of lactic acidosis in high AG metabolic acidosis?
Accumulation of lactic acid during hypoxia.
- Lactic acid is produced from the metabolism of pyruvic acid during the process of anaerobic glycolysis.
- Lactate (can be produced by all cells of the body, maily in the GI tract) is metabolized by both the liver and the kidneys.
- Causes of lactic acidosis can be categorized by subtype (A or B), depending on the mechanism:
Type A lactic acidosis
1. Is the result of decreased tissue perfusion or decreased oxygen delivery that occurs in shock or carbon monoxide toxicity.
2. Anaerobic glycolysis is increased in these conditions, resulting in higher levels of lactic acid
3. In the setting of shock, reduced perfusion of the liver results in a simultaneous decrease in lactate metabolism.
Type B lactic acidosis
1. Occurs when mitochondrial or liver function is impaired.
2. The conversion of lactate to pyruvate requires adequate liver and mitochondrial function.
3. If either of these is impaired, lactic acid may accumulate.
Explain the mechanism of Type A lactic acidosis?
In high AG metabolic acidosis.
Type A lactic acidosis
1. Is the result of decreased tissue perfusion or decreased oxygen delivery that occurs in shock or carbon monoxide toxicity.
2. Anaerobic glycolysis is increased in these conditions, resulting in higher levels of lactic acid.
3. In the setting of shock, reduced perfusion of the liver results in a simultaneous decrease in lactate metabolism.
The liver and the kidneys are the organs resposible for lactate metabolism.
Explain the mechanism of Type B lactic acidosis?
In high AG metabolic acidosis.
Type B lactic acidosis
1. Occurs when mitochondrial or liver function is impaired.
2. The conversion of lactate to pyruvate requires adequate liver and mitochondrial function.
3. If either of these is impaired, lactic acid may accumulate.
4. Metformin and certain antiviral medications (such as zidovudine or stavudine) also can inhibit mitochondrial function.
5. Cyanide toxicity results in type B lactic acidosis because cyanide binds the final enzyme of the mitochondrial cytochrome complex (ie, the electron transfer chain), interrupting normal mitochondrial oxidative phosphorylation.
The liver and the kidneys are the organs resposible for lactate metabolism.
Explain the mechanism of Ketoacidosis?
In high AG metabolic acidosis.
Ketoacidosis occurs when glucose is not available to cells due to:
- Lack of insulin (insulin is responsible for cells uptake of glucose, cells uptake of K, inhibition of lypolisis; promotes fat deposition; promotes glycogen formation, inhiits glycogenolysis, inhibits gluconeogenesis)
- Glucose depletion (If glucose is unavailable, there must be another source of energy for the brain and other organs, so ketoacids become the main source);
- Cellular dysfunction.
The 2 major types of ketoacidosis that are:
* diabetic ketoacidosis
* alcoholic/starvation ketosis
The 2 mechanisms that result in the development of ketoacidosis are:
1. increase in free fatty acid delivery due to increased lipolysis, and
2. change in hepatocyte function so that free fatty acids are converted to ketoacids and not triglycerides.2,5
Explain the mechanism of Toxins and Drug Ingestions in high AG acidosis?
Drugs that cause a high AG metabolic acidosis are:
* Salicylate poisoning
* Methanol & Ethylene glycol poisoning
* Acetaminophen
Salicylate poisoning
* When plasma levels exceed 40 to 50 mg/dL, patients will present symp- toms such as tinnitus, vertigo, nausea, vomiting, and diarrhea. Severe overdose can cause hyperthermia, altered mental status, coma, and death.
* The major anions that accumulate in salicylate poisoning are ketoacids and lactic acid, as salicylate concentrations in serum are very small and do not significantly contribute to the anion gap.
* Salicylate toxicity stimulates respiratory centers in the brainstem, leading to a respiratory alkalosis in addition to the metabolic acidosis.
* The mainstay of management of salicylate toxicity includes administration of intravenous sodium bicarbonate to alkalinize the serum to a pH of 7.5 to 7.55.
* Salicylic acid diffuses easily into central nervous system (CNS) tissue, whereas salicylate ions can be trapped in alkaline serum and urine, and excreted.
* In a patient who presents with severe neurologic symptoms, renal failure, or fluid overload, hemo- dialysis should be initiated and continued until serum levels are below 20 mg/dL.
Acetaminophen poisoning
* The metabolic acidosis is secondary to the build-up of pyroglutamic acid.
Methanol & Ethylene glycol poisoning
* Methanol and ethylene glycol are toxic alcohols available in automotive antifreeze and commercial solvents.
* When ingested, are metabolized by alcohol dehydrogenase and alde- hyde dehydrogenase (enzymes) into toxic metabolites.
* Methanol is metabolized to formaldehyde and then to formic acid. Formic acid is extremely toxic to the retina and leads to blindness, coma, and death.
* Ethylene glycol is metabolized to glycolate and oxalate, which precipitate in the kidney to cause tubular injury and obstruction.
* Treatment of these toxic ingestions involves aggressive hydration to maximize renal clearance and use of fomepizole, a competitive inhibitor of alcohol dehydrogenase.
* It is recommended that fomepizole be administered if any of the below criteria are met:
1. Documented recent history of ingesting methanol or ethylene glycol and serum osmolal gap more than 10.
2. Strong clinical suspicion of methanol or ethylene glycol poisoning with 2 of the following:
a. Arterial pH less than 7.3
b. Serum bicarbonate less than 20 mEq/L
c. Osmol gap more than 10
d. Urinary oxalate crystals present
- Hemodialysis may be required in cases of severe ingestions, acidemia, or renal failure.
- It should also be noted that patients with methanol ingestion should be treated with folic acid (50 mg every 6 hours), as it assists with metabolism of formic acid to CO2 and water.
Explain the mechanism of Uremic acidosis (chronic renal failure) in high AG acidosis?
- Uremic acidosis is a complication of advanced renal failure that occurs when the kidney is unable to excrete daily dietary acids.
- When GFR begins to fall, the kidney will increase ammonium (NH4+) excretion to maintain acid balance.
- When the GFR falls to more significant levels (15–20 cc/min), daily nonvolatile acid generation cannot be excreted completely and plasma bicarbonate falls to levels between 12 and 20 mEq/L (buffering the acid).
- Severe acidosis usually does not occur due to buffering by release of calcium salts from the bone. This can produce a calcium loss over time that results in osteopenia in patients with advanced (stage 4 and 5) chronic kidney disease.
- There are also several unmeasured anions that accumulate in this process that increase the anion gap.
What are the causes of Normal AG metabolic acidosis?
Can be due to:
1. Loss of bicarbonate in the GI tract (diarrhoea, enterocutaneous fistula, or villous adenoma).
2. Failure to reabsorb bicarbonate in the proximal tubule (Type 2 renal tubular acidosis (type 2 RTA)).
3. Inability to secrete hydrogen in the distal tubule (type 1 RTA and type 4 RTA).
- Bicarbonate decreases relative to increase inchloride in a 1-to-1 ratio. Causing hyperchloremic (metabolic acidosis) as the reason why the AG is normal.
- The urinary anion gap (UAG) helps distinguish GI losses of bicarbonate from impaired urinary hydrogen excretion.
- In patients with acidosis, compensa- tory increased ammonium excretion is expected.
- Urinary ammonium is nout usually calculated, but its values can be predicted by calculating the Urinary Anion Gap.
- UAG = (Na⁺ + K⁺) − Cl⁻
- In metabolic acidosis due to diarrhea, normal renal compensation leads to an increase in NH4+ excretion. This would generate a negative UAG, since chloride excretion would have to increase to maintain electroneutrality (due to loss of HCO3-).
- In most cases of RTA where ammonium excretion cannot be increased, the UAG will be 0 or positive. It should be noted that proximal RTA may cause a positive UAG due the excretion of another anion other than chloride, namely bicarbonate.
Explain the mechanism of iatrogenic hyperchloremic acidosis?
- Large administration of unbuffered crystalloid solutions (eg, normal saline).
- This is most commonly seen in surgical and trauma patients, where large amounts of saline solution are given to resuscitate unstable patients.
- In these cases, the normal bicarbonate of the plasma is diluted down before appropriate renal compensation can take place to excrete supplemental ammonium and chloride.
What are the causes of Low AG metabolic acidosis?
Hypoalbuminaemia:
* Albumin is the major unmeasured anion and contributes almost the whole of the value of the anion gap (80%).
* Every one gram decrease in albumin will decrease anion gap by 2.5 to 3 mmoles.
* A normally high anion gap acidosis in a patient with hypoalbuminaemia may appear as a normal anion gap acidosis.
An increase in the number of cations:
* Organic cations (e.g. paraproteins as in multiple myeloma) or
* Inorganic (bromide, lithium, iodine or polymyxin B).
Causes of low albumin in low AG acidosis include:
- Decreased synthesis (liver disease)
- Increased catabolism (very slow)
- Increased loss:
* Nephrotic syndrome
* Exudative loss in burns
* Haemorrhage
* Gut loss - Redistribution:
* Haemodilution
* Increased capillary permeability (leakage into the interstitium)
* Decreased lymph clearance - Capillary leak syndrome. This occurs in systemic inflammatory response, which is often associated with sepsis. In this syndrome, albumin leaks into the extravascular space.
What is the clinical use of the urinary AG?
- It is used when we have a metabolic acidosis of normal AG (usually hyperchloaremic);
- It is used to determine the cause of HCO3- loss. If it is from GIT or from the kidneys.
- If the acidosis is due to loss of base via the bowel then the kidneys can response appropriately by increasing ammonium excretion to cause a net loss of H+ from the body. The UAG would tend to be decreased, That is: increased NH4+ (with presumably increased Cl-) => increased UC =>decreased UAG.
- If the acidosis is due to loss of base via the kidney, then as the problem is with the kidney it is not able to increase ammonium excretion and the UAG will not be increased.
What is the formula for Urinary AG?
UAG = (Na⁺ + K⁺) - Cl⁻
- A negative UAG suggests GIT loss of bicarbonate (eg diarrhoea);
- A positive UAG suggests impaired renal distal acidification (ie renal tubular acidosis).
