Medicine – Acid–Base Homeostasis and the Anion Gap

Acid–base homeostasis refers to the mechanisms that keep blood pH within a narrow physiological range despite continuous production of acids by normal metabolism. The major systems involved are chemical buffers, the lungs, and the kidneys.

A central buffer system in extracellular fluid is the:

Bicarbonate–carbon dioxide buffer system.

1. Bicarbonate Buffer Equation

The original reaction is:

H⁺ + HCO₃⁻ ↔ H₂O + CO₂.

This is a simplified way of showing how hydrogen ions are buffered by bicarbonate.

More completely:

H⁺ + HCO₃⁻ ↔ H₂CO₃ ↔ H₂O + CO₂.

Here:

H⁺ = hydrogen ion.

HCO₃⁻ = bicarbonate.

H₂CO₃ = carbonic acid.

CO₂ = carbon dioxide.

2. How the Buffer System Works

If excess acid is added to the blood:

H⁺ combines with HCO₃⁻.

This forms:

Carbonic acid.

Carbonic acid then becomes:

Water + carbon dioxide.

The CO₂ can be eliminated through the:

Lungs.

Therefore:

EXCESS H⁺ → CONSUMES HCO₃⁻ → PRODUCES CO₂ → CO₂ EXHALED.

3. Role of the Lungs

The lungs regulate the:

CO₂ component

of the bicarbonate buffer system.

If ventilation increases:

More CO₂ is exhaled.

Therefore:

PaCO₂ falls

and pH tends to:

Rise.

If ventilation decreases:

CO₂ is retained.

Therefore:

PaCO₂ rises

and pH tends to:

Fall.

This is why respiratory disorders alter acid–base balance so rapidly.

4. Role of the Kidneys

The kidneys regulate acid–base balance more slowly but very powerfully.

They help by:

Reabsorbing filtered bicarbonate.

Generating new bicarbonate.

Excreting hydrogen ions.

Excreting acid as ammonium and titratable acid.

Therefore the kidneys mainly control the:

HCO₃⁻ component

of the system.

5. Relationship Between pH, Bicarbonate and CO₂

Blood pH depends largely on the ratio between:

Bicarbonate

and

Dissolved CO₂.

The practical principle is:

pH ∝ HCO₃⁻ / PaCO₂.

Therefore:

↑ HCO₃⁻ → pH tends ↑.

↓ HCO₃⁻ → pH tends ↓.

↑ PaCO₂ → pH tends ↓.

↓ PaCO₂ → pH tends ↑.

6. Metabolic Versus Respiratory Disturbance

A primary abnormality in:

HCO₃⁻

produces a:

Metabolic acid–base disorder.

A primary abnormality in:

PaCO₂

produces a:

Respiratory acid–base disorder.

This gives the four major disorders:

Metabolic acidosis.

Metabolic alkalosis.

Respiratory acidosis.

Respiratory alkalosis.

7. Anion Gap

The anion gap – AG estimates the concentration of unmeasured negatively charged ions in plasma.

The original formula includes potassium:

Anion gap = ([Na⁺] + [K⁺]) − ([Cl⁻] + [HCO₃⁻]).

Using this formula, a traditional normal range is approximately:

10–18 mmol/L.

This matches the range in the original notes.

8. Why an Anion Gap Exists

Plasma must always remain electrically neutral.

Therefore:

Total positive charges = total negative charges.

However, routine blood chemistry measures only some ions.

Common measured cations include:

Na⁺

and sometimes:

K⁺.

Measured anions include:

Cl⁻

and

HCO₃⁻.

9. Unmeasured Anions

Several important negatively charged substances are not included directly in the standard calculation.

These include:

Albumin.

Phosphate.

Sulphate.

Lactate.

Ketone bodies.

Other organic acids.

The difference between measured cations and measured anions is called the:

Anion gap.

10. Modern Formula Without Potassium

In modern clinical practice, potassium is often omitted because its plasma concentration is small compared with sodium.

The commonly used formula is:

AG = Na⁺ − (Cl⁻ + HCO₃⁻).

With this formula, the traditional normal range is approximately:

8–12 mmol/L, although laboratory ranges vary.

Therefore it is important to know:

Whether potassium has been included in the calculation.

11. Why the Normal Range Changes

If potassium is included:

AG ≈ 10–18 mmol/L.

If potassium is omitted:

AG ≈ 8–12 mmol/L.

These ranges are approximate and depend on the:

Laboratory method and reference interval.

12. Clinical Importance of the Anion Gap

The anion gap is particularly useful when investigating:

Metabolic acidosis.

It helps divide metabolic acidosis into:

Normal anion gap metabolic acidosis

and

High anion gap metabolic acidosis.

13. Normal Anion Gap Metabolic Acidosis

In normal anion gap metabolic acidosis, bicarbonate is lost and is largely replaced by:

Chloride.

Therefore:

↓ HCO₃⁻ + ↑ Cl⁻

with no major accumulation of unmeasured anions.

This is also called:

Hyperchloraemic metabolic acidosis.

14. Causes of Normal Anion Gap Acidosis

Important causes include:

Diarrhoea.

Renal tubular acidosis.

Acetazolamide.

Type 4 RTA due to hypoaldosteronism, including Addison’s disease.

The general mechanism is:

Bicarbonate loss or impaired renal acid excretion.

15. High Anion Gap Metabolic Acidosis

In high anion gap metabolic acidosis, additional acids accumulate.

Their hydrogen ions consume bicarbonate, while their negatively charged conjugate bases remain in the circulation as:

Unmeasured anions.

Therefore:

↓ HCO₃⁻ + ↑ unmeasured anions → ↑ anion gap.

16. Causes of High Anion Gap Acidosis

Important causes include:

Diabetic ketoacidosis.

Lactic acidosis.

Advanced kidney failure.

Salicylate poisoning.

Methanol poisoning.

Ethylene glycol poisoning.

17. Example – Diabetic Ketoacidosis

In DKA:

Ketone acids accumulate.

Hydrogen ions are buffered by bicarbonate.

Therefore:

HCO₃⁻ falls.

The ketone anions remain in plasma.

Therefore:

Anion gap rises.

So:

DKA → ↓ HCO₃⁻ + ↑ ketone anions → HIGH ANION GAP.

18. Example – Diarrhoea

In diarrhoea:

Bicarbonate is directly lost from the gastrointestinal tract.

To maintain electrical neutrality, chloride rises.

Therefore:

↓ HCO₃⁻ + ↑ Cl⁻ → normal anion gap.

This explains why diarrhoeal acidosis is called:

Hyperchloraemic metabolic acidosis.

19. Albumin and the Anion Gap

A very important modern point is that:

Albumin is the major unmeasured plasma anion.

Therefore a patient with:

Hypoalbuminaemia

may have a deceptively low or apparently normal anion gap even when abnormal acids are accumulating.

20. Corrected Anion Gap

A commonly used approximate correction is:

For every 1 g/dL fall in albumin below 4 g/dL, add about 2.5 mmol/L to the measured anion gap.

Therefore severe hypoalbuminaemia can:

Mask a high anion gap metabolic acidosis.

This is particularly relevant in critically ill patients.

21. Bicarbonate Buffer – Note Form

H⁺ + HCO₃⁻

↓

H₂CO₃

↓

H₂O + CO₂

↓

CO₂ eliminated through lungs.

Therefore:

BICARBONATE BUFFERS H⁺.

LUNGS REMOVE CO₂.

KIDNEYS CONTROL HCO₃⁻ AND H⁺.

22. Anion Gap With Potassium – Note Form

AG = (Na⁺ + K⁺) − (Cl⁻ + HCO₃⁻).

Traditional normal range:

Approximately 10–18 mmol/L.

This corresponds to the formula in the original notes.

23. Anion Gap Without Potassium – Note Form

More commonly used clinically:

AG = Na⁺ − (Cl⁻ + HCO₃⁻).

Typical reference range:

Approximately 8–12 mmol/L.

Always interpret according to the local laboratory.

24. Normal Gap Acidosis – Note Form

HCO₃⁻ lost.

↓

Chloride rises.

↓

No major increase in unmeasured anions.

↓

NORMAL ANION GAP.

Examples:

Diarrhoea.

RTA.

Acetazolamide.

Hypoaldosteronism/type 4 RTA.

25. High Gap Acidosis – Note Form

Extra acid accumulates.

↓

H⁺ consumes HCO₃⁻.

↓

Acid anion remains unmeasured.

↓

ANION GAP INCREASES.

Examples:

DKA.

Lactic acidosis.

Renal failure.

Salicylates.

Methanol.

Ethylene glycol.

26. Important Clarifications

The original equation:

H⁺ + HCO₃⁻ ↔ H₂O + CO₂

is correct as a simplified representation of the bicarbonate buffer system.

The intermediate:

H₂CO₃

is often included when showing the full chemical reaction.

The original anion gap formula:

([Na⁺] + [K⁺]) − ([Cl⁻] + [HCO₃⁻])

is also valid.

However, modern clinical practice often omits:

K⁺.

Therefore the normal range depends on which formula is being used.

Key Clinical Pattern

Remember:

H⁺ + HCO₃⁻ ↔ H₂CO₃ ↔ H₂O + CO₂.

LUNGS regulate CO₂.

KIDNEYS regulate H⁺ and HCO₃⁻.

For the anion gap:

WITH K⁺ → approximately 10–18 mmol/L.

WITHOUT K⁺ → approximately 8–12 mmol/L.

And clinically:

NORMAL GAP ACIDOSIS → think bicarbonate loss or impaired renal acid excretion.

HIGH GAP ACIDOSIS → think accumulation of unmeasured acids.