As mentioned in the previous chapter, metabolic acidosis occurs when the blood pH us below 7.35, usually due either to:

a) too little bicarbonate and/or

b) presence of organic acids or excessive ketone bodies in the blood.

Remembering that a gain of acids (whether organic or ketones) means an increase in H⁺ – meaning more cations are in the body, needing to be neutralized. Similarly, a loss of bicarbonate means less anions (negatively charged molecules) are available to neutralize the naturally occurring acids (H⁺) in the body. Thus metabolic acidosis has issues with lowering pH AND maintaining electroneutrality.

Electroneutrality

We know that solutes dissolved into aqueous solutions will usually travel with a concentration gradient (to areas of lower solute concentration) not against it (to areas of higher solute concentration). We also know that the concentration of reactants and products in an equilibrium reaction is always going to tend towards a certain ratio, expressed by the equilibrium constant. However in order to understand Metabolic Acidosis we also need to ensure we have grasped one more invisible force that moves solute concentration.

Solutions, like human blood, tend to an electrically neutral state, this means that when a solution has an overall positive charge, due to an imbalance between cations and anions, more anions will often migrate from the environment, attracted by the positive charge. Cell membranes take advantage of this and use energy to pump cations against their electrical gradients in order to maintain a membrane potential. This membrane potential acts as a store of potential energy which the cell can use to facilitate a function. Nerve and muscle cells use this potential energy to send signals in the form of action potentials, which is the pulsating equalization of a membrane potential to equilibrium. It is quite similar to how water towers use gravitational potential to provide a store of energy in the case they need to distribute water to a community at a constant rate. There is no active use of energy in the moment, but the potential energy is there ready to be accessed at any moment. In the blood the major cation (positive ion) is sodium, and the major anion (negative ion) is chloride. When one drops often the opposing Ion will migrate out of cells and interstitial space to balance serum electroneutrality. The serum’s tendency maintain electroneutrality means that if the sum of measured positive and negative charges (cations and anions, respectively) is not equal, there must be some unmeasured charged ion maintaining electroneutrality.^[2]

A test that determines the extent of electroneutrality is the anion gap.

What is an Anion Gap?

An anion gap blood test checks the difference between serum cations and anions. The most predominant being the cation sodium(Na⁺), and the most common anions are chloride (Cl^–), and bicarbonate (HCO₃^–).

Anion gap = Na⁺ – (Cl^– + HCO₃^–) ^[4]

Normal anion gap is between 10-12 ^[2]

Healthcare providers use anion gap to identify cases of metabolic acidosis – whether due to a gain of acid (i.e. increase in cations) or loss of base (i.e. decrease in anions).

Types of Metabolic Acidosis

We divide our causes of metabolic acidosis into two categories: High anion gap metabolic acidosis (HAGMA) or Non-anion gap metabolic acidosis (NAGMA).

High Anion Gap Metabolic Acidosis (HAGMA)

Consider then the implications of a large anion gap, if we have a massive discrepancy between our measured positive and negative ions, and we know that serum electroneutrality is maintained, we must then assume the presence of unmeasured ions. A high anion gap acidosis indicates the presence of organic acids, unmeasured positive charges ^[1][4]. For example, In lactic acidosis lactic acid dissociates a hydrogen ion into the serum, and becomes the conjugate base lactate. The free hydrogen contributes to acidosis but is not accounted for in the anion gap. The bicarbonate will bind to some of these new free hydrogens and become carbonic acid. This lowers the bicarbonate levels in the blood. If we calculate the anion gap now, we will see that the sodium level has stayed constant, however the bicarbonate has dropped, our calculated anion gap will be higher than it was before. Despite the drop in the concentration of negatively charged bicarbonate the blood serum maintains electroneutrality due to the replacement of one negative conjugate base (bicarbonate) with another (lactate) ^[3][4].

Many different organic acids can potentially cause a high anion gap metabolic acidosis; the following GOLDMARK mnemonic is commonly used.

GOLDMARK

Non Anion Gap Metabolic Acidosis (NAGMA)

Say we have a patient in an acidotic state, you have already ruled out respiratory acidosis, and their anion gap is 9 (i.e. less than the normal anion gap of 10-12). What is driving this patient’s acidosis? It is most likely that the acidotic state is secondary to some loss of bicarbonate. When we lose bicarbonate we will see a rise in proton concentration due to a lack bicarbonate buffer in our system. Since the acidosis is being driven by bicarbonate loss and not by the introduction of organic acids, there is no additional negative anions, in the form of conjugate bases, to add to the system without a replacement anion the electroneutrality of the blood is not maintained. There is a loss of negative charge, and the blood becomes more positively charged, as a result negative chloride ion’s begin to migrate into the serum. The chloride ion’s will not bind to protons, so acidosis is maintained. The chloride is calculated for in the anion gap which results in a low anion gap. It also has the negative effect of creating a hyperchloremic state within the patient.^[1]

Causes for NAGMA: Bicarbonate Loss

Hyperchloremia

As chloride levels rise the kidneys begin to excrete bicarbonate to maintain electroneutrality. Chloride does contribute to anion gap, therefore the anion gap is not increased. However, chloride is not a conjugate base and therefore does not assist in the uptake of protons. Therefore there are more free protons available in the serum. A rapid isotonic saline infusion can cause a hyperchloraemic acidosis in a patient.^[1]

Diarrhea

Bicarbonate is released into the stool primarily by the pancreas to neutralize stomach acids and other acids present in the diet. As the stool moves through the intestinal tract much of this bicarbonate is slowly absorbed back into systemic circulation. When a patient has diarrhea, the stool is not spending adequate time in the intestinal tract to allow for bicarbonate reabsorption. As bicarbonate drops, pH rises and the electroneutrality is compensated for by hyperchloremia.

Pancreatic Fistula

In the case of a pancreatic fistula, a hole without any sphincter control is allowing for the unregulated dumping of bicarbonate into the intestines. Bicarbonate levels quickly reach a point over the saturation level for reabsorption pumps. This results in a release of bicarbonate through the stool, once again resulting in a hyperchloraemia. ^[1]

Causes for NAGMA: Proton (H⁺) Accumulation

CKD, AKI or Renal Tubular Acidosis

Injury to the kidney, whether acute (acute kidney injury or renal tubular acidosis) or chronic (chronic kidney disease), will lead to a reduction of GFR. This causes a reduction in H⁺ excretion via urination. As a result protons begin to buildup in systemic circulation. ^[1]

Hypoaldosteronism

The distal tubule of the kidney is responsible for excreting protons and is regulated by aldosterone. If aldosterone is low than proton secretion is inhibited. If secretion is inhibited then the body cannot clear protons and it will accumulate them at suboptimal concentrations. ^[1][3]

The following HARDUP mnemonic is commonly used for causes of NAGMA:

HARDUP^[1]

Urine Anion Gap

Urine anion gap can be taken in the setting of a non-anion gap acidosis. This can be an indicator of kidney compensation in acidosis as the kidneys excrete protons in the form of ammonium. If the urine anion gap is high, you can infer that the kidneys are excreting too much ammonium and too many protons relative to the amount of anions being excreted.

Urine typically has higher potassium levels than the serum and lower bicarbonate, so our urine anion gap equation is different than our serum anion gap equation.

urine anion gap = (Na + K) − Cl

NH4+ ammonium, is usually accompanied by a chloride ion in the urine. Therefore a wide, and negative, urine anion gap presupposes the presence of a great deal of ammonium excretion. If there is low ammonium excretion in an otherwise acidotic patient, one can infer there is a dysfunction in kidney compensation.^[2]

Review questions

References

1. 1. Normal Anion Gap Metabolic Acidosis
   2. Fluid, Electrolyte and Acid-Base Disorders: Clinical Evaluation and Management
   3. Metabolic Acidosis – StatPearls
   4. Physiology, Acid Base Balance – StatPearls 4