Medicine – Metabolic Acidosis

Metabolic acidosis is an acid–base disorder in which there is a primary reduction in serum bicarbonate (HCO₃⁻), resulting from either loss of bicarbonate, accumulation of acid, or impaired renal acid excretion.

The typical blood-gas pattern is:

↓ pH + ↓ HCO₃⁻.

The respiratory system compensates by increasing ventilation, which lowers:

PaCO₂.

Therefore:

METABOLIC ACIDOSIS → HYPERVENTILATION → ↓ PaCO₂.

1. Classification of Metabolic Acidosis

A useful first step is to calculate the:

Anion gap – AG.

The anion gap helps determine whether the fall in bicarbonate has been replaced predominantly by chloride or whether unmeasured acids have accumulated.

2. Anion Gap

The usual calculation is:

Anion gap = Na⁺ − (Cl⁻ + HCO₃⁻).

Potassium is usually omitted from the calculation.

The exact normal range depends on the laboratory, but a commonly used reference is approximately:

8–12 mmol/L.

Therefore metabolic acidosis can be divided into:

Normal anion gap metabolic acidosis

and

High anion gap metabolic acidosis.

3. Normal Anion Gap Metabolic Acidosis

In normal anion gap metabolic acidosis – NAGMA, bicarbonate falls but chloride rises to maintain electrical neutrality.

Therefore it is also called:

Hyperchloraemic metabolic acidosis.

The basic pattern is:

↓ HCO₃⁻ + ↑ Cl⁻ → normal anion gap.

4. Main Mechanisms of Normal Anion Gap Acidosis

The major mechanisms are:

Loss of bicarbonate from the gastrointestinal tract.

Loss of bicarbonate through the kidneys.

Failure of renal hydrogen-ion excretion.

Important causes include:

Diarrhoea.

Renal tubular acidosis.

Acetazolamide.

Adrenal insufficiency, particularly through type 4 RTA physiology.

5. Diarrhoea

The original notes correctly identify:

Diarrhoea

as an important cause of normal anion gap metabolic acidosis.

Intestinal secretions contain significant amounts of:

Bicarbonate.

Prolonged or severe diarrhoea causes bicarbonate loss in stool.

Therefore:

DIARRHOEA → GI HCO₃⁻ LOSS → ↓ HCO₃⁻ → HYPERCHLOREEMIC METABOLIC ACIDOSIS.

6. Diarrhoea and Potassium

Diarrhoea can also cause gastrointestinal loss of:

Potassium.

Therefore the patient may develop:

Hypokalaemia

together with:

Normal anion gap metabolic acidosis.

This can help distinguish diarrhoeal bicarbonate loss from some forms of renal tubular acidosis, particularly type 4 RTA, which causes hyperkalaemia.

7. Renal Tubular Acidosis

Renal tubular acidosis – RTA refers to disorders in which the renal tubules fail to handle acid or bicarbonate normally despite relatively preserved glomerular function, particularly early in the disease.

The characteristic acid–base disturbance is:

Normal anion gap metabolic acidosis.

8. Type 1 – Distal RTA

In type 1 distal RTA, the distal nephron cannot adequately secrete:

Hydrogen ions.

Therefore the kidney cannot acidify the urine appropriately.

The result is:

Metabolic acidosis.

9. Features of Distal RTA

Typical features include:

Normal anion gap metabolic acidosis.

Hypokalaemia.

Inappropriately high urine pH, classically above about 5.5 during systemic acidosis.

Nephrolithiasis.

Nephrocalcinosis.

The stone tendency occurs partly because of alkaline urine and:

Hypocitraturia.

10. Causes of Distal RTA

Important associations include:

Sjögren syndrome.

Other autoimmune disorders.

Certain drugs and toxins.

Inherited tubular defects.

A useful association is:

DISTAL RTA → HYPOKALAEMIA + ALKALINE URINE + RENAL STONES.

11. Type 2 – Proximal RTA

In type 2 proximal RTA, the proximal tubule cannot reabsorb bicarbonate normally.

Therefore excessive bicarbonate is lost in:

Urine.

This causes:

Normal anion gap metabolic acidosis.

12. Proximal RTA and Fanconi Syndrome

Proximal RTA may occur as part of:

Fanconi syndrome.

Generalised proximal tubular dysfunction may produce:

Bicarbonaturia.

Glucosuria despite normal plasma glucose.

Phosphaturia.

Aminoaciduria.

Uricosuria.

Therefore:

FANCONI SYNDROME → MULTIPLE PROXIMAL TUBULAR LOSSES.

13. Type 4 RTA

Type 4 RTA is particularly important because, unlike most other RTAs, it is associated with:

Hyperkalaemia.

The underlying problem is usually:

Aldosterone deficiency

or

Resistance to aldosterone.

14. Type 4 RTA Mechanism

Reduced aldosterone activity decreases distal:

Potassium secretion

and impairs effective renal acid excretion, including through effects on ammonium generation and excretion.

Therefore:

↓ ALDOSTERONE EFFECT → ↑ K⁺ + IMPAIRED ACID EXCRETION → METABOLIC ACIDOSIS.

15. Addison’s Disease

The original notes include:

Addison’s disease.

This association is correct, but the mechanism is better understood as:

Primary adrenal insufficiency → aldosterone deficiency → type 4 RTA physiology.

Therefore the characteristic combination can be:

Hyperkalaemia + normal anion gap metabolic acidosis.

16. Important Clarification About Addison’s Disease

Addison’s disease does not primarily cause acidosis by directly losing bicarbonate.

Instead:

Aldosterone deficiency → impaired distal K⁺ and H⁺ handling → hyperkalaemic metabolic acidosis.

Other features of primary adrenal insufficiency may include:

Hypotension.

Hyponatraemia.

Hyperkalaemia.

Hyperpigmentation.

17. Acetazolamide

Acetazolamide inhibits:

Carbonic anhydrase.

It acts predominantly in the:

Proximal tubule.

This reduces bicarbonate reabsorption.

Therefore more bicarbonate is lost in urine.

18. Acetazolamide and Acidosis

The sequence is:

Acetazolamide → carbonic anhydrase inhibition → ↓ proximal HCO₃⁻ reabsorption → bicarbonaturia → metabolic acidosis.

The resulting pattern is typically:

Normal anion gap hyperchloraemic metabolic acidosis.

19. High Anion Gap Metabolic Acidosis

In high anion gap metabolic acidosis – HAGMA, additional acids accumulate in the blood.

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

Unmeasured anions.

Therefore:

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

20. Important Causes of High Anion Gap Acidosis

The original notes correctly include:

Diabetic ketoacidosis.

Lactic acidosis.

Kidney failure.

Salicylate poisoning.

Methanol poisoning.

Ethylene glycol poisoning.

Additional important causes include other forms of:

Ketoacidosis

and selected:

Drug/toxin-related acidoses.

21. Diabetic Ketoacidosis

Diabetic ketoacidosis – DKA is a classic cause of high anion gap metabolic acidosis.

Severe insulin deficiency causes increased:

Lipolysis.

Free fatty acids are transported to the liver and converted into:

Ketone bodies.

22. Ketone Bodies

Important ketone bodies include:

β-hydroxybutyrate.

Acetoacetate.

Their accumulation produces:

High anion gap metabolic acidosis.

Therefore:

INSULIN DEFICIENCY → LIPOLYSIS → KETONE PRODUCTION → HAGMA.

23. Clinical Features of DKA

Typical features include:

Polyuria.

Polydipsia.

Dehydration.

Nausea and vomiting.

Abdominal pain.

Kussmaul breathing.

Altered consciousness in severe disease.

A fruity or acetone-like breath odour may occur.

24. Kussmaul Respiration

The body attempts to compensate for metabolic acidosis by increasing ventilation.

Severe metabolic acidosis can therefore produce:

Deep, rapid breathing – Kussmaul respiration.

This removes CO₂ and partially compensates for the fall in pH.

Therefore:

METABOLIC ACIDOSIS → HYPERVENTILATION → ↓ PaCO₂.

25. Lactic Acidosis

Lactic acidosis occurs when lactate production exceeds its metabolism and clearance.

It is another major cause of:

High anion gap metabolic acidosis.

26. Tissue Hypoperfusion and Lactate

A common mechanism is inadequate tissue oxygen delivery or utilisation associated with severe illness.

Important causes include:

Shock.

Sepsis.

Severe hypoxaemia.

Cardiac arrest.

Severe circulatory failure.

These can increase lactate production.

27. Other Causes of Lactic Acidosis

Lactate may also rise with:

Generalised seizures.

Extreme exercise.

Certain drugs or toxins.

Severe liver dysfunction, particularly when lactate clearance is impaired.

Therefore not every raised lactate means that tissue hypoxia is the sole mechanism.

28. Kidney Failure

The kidneys normally remove the daily non-volatile acid load and regenerate bicarbonate.

With advanced kidney failure, there is reduced excretion of acids such as:

Sulphate.

Phosphate.

Organic anions.

These accumulate in the circulation.

29. Kidney Failure and the Anion Gap

Advanced kidney failure can therefore cause:

High anion gap metabolic acidosis.

However, earlier CKD can sometimes produce a:

Normal anion gap metabolic acidosis

before substantial accumulation of unmeasured anions develops.

So the acid–base pattern can change with disease severity.

30. Salicylate Poisoning

Salicylate poisoning is especially important because it commonly produces a:

Mixed acid–base disorder.

Initially, salicylates directly stimulate the medullary respiratory centre.

This causes:

Hyperventilation → ↓ PaCO₂ → respiratory alkalosis.

31. Salicylates and Metabolic Acidosis

Salicylates also cause accumulation of organic acids and interfere with cellular metabolism.

Therefore later or significant poisoning produces:

High anion gap metabolic acidosis.

The classic pattern is therefore:

RESPIRATORY ALKALOSIS + HIGH ANION GAP METABOLIC ACIDOSIS.

This combination is highly important in examinations.

32. Methanol Poisoning

Methanol itself is not responsible for most of the severe toxicity.

It is metabolised to:

Formaldehyde

and then:

Formic acid/formate.

Formate causes severe:

High anion gap metabolic acidosis

and particularly damages the:

Optic nervous system.

33. Clinical Features of Methanol Poisoning

Features may include:

Headache.

Nausea and vomiting.

Abdominal symptoms.

Visual disturbance.

Blurred or “snowfield” vision.

Severe metabolic acidosis.

Reduced consciousness.

Therefore:

HAGMA + VISUAL DISTURBANCE → THINK METHANOL.

34. Ethylene Glycol Poisoning

Ethylene glycol is metabolised into toxic organic acids, including metabolites that ultimately promote formation of:

Calcium oxalate.

This causes:

High anion gap metabolic acidosis

and can produce:

Acute kidney injury.

35. Calcium Oxalate Crystals

Calcium oxalate crystals may appear in the urine.

They may have:

Envelope-shaped

or other characteristic appearances depending on crystal form.

Hypocalcaemia can also occur because calcium binds oxalate.

Therefore:

HAGMA + AKI + CALCIUM OXALATE CRYSTALS → THINK ETHYLENE GLYCOL.

36. Other Forms of Ketoacidosis

Not all ketoacidosis is diabetic.

Other important causes include:

Alcoholic ketoacidosis.

Starvation ketoacidosis.

These can also produce:

High anion gap metabolic acidosis.

37. Modern Mnemonic for High Anion Gap Acidosis

An older mnemonic is:

MUDPILES.

A more modern mnemonic is:

GOLD MARK.

This represents important causes of high anion gap metabolic acidosis:

G – Glycols, such as ethylene glycol and propylene glycol.

O – Oxoproline, associated with chronic paracetamol exposure in susceptible patients.

L – L-lactate.

D – D-lactate.

M – Methanol.

A – Aspirin, meaning salicylates.

R – Renal failure.

K – Ketoacidosis.

38. Normal Anion Gap – Note Form

Diarrhoea:

GI bicarbonate loss.

↓

↓ HCO₃⁻.

↓

Compensatory ↑ Cl⁻.

↓

Normal anion gap metabolic acidosis.

Renal tubular acidosis:

Abnormal renal H⁺ secretion or HCO₃⁻ handling.

↓

Normal anion gap metabolic acidosis.

Acetazolamide:

Carbonic anhydrase inhibition.

↓

↓ proximal bicarbonate reabsorption.

↓

Bicarbonaturia.

↓

Normal anion gap metabolic acidosis.

Addison’s disease:

↓ Aldosterone.

↓

↓ K⁺ secretion + impaired renal acid excretion.

↓

Hyperkalaemia + normal anion gap metabolic acidosis.

39. High Anion Gap – Note Form

DKA:

Insulin deficiency.

↓

Ketone accumulation.

↓

High anion gap metabolic acidosis.

Lactic acidosis:

Lactate accumulation.

↓

High anion gap metabolic acidosis.

Advanced kidney failure:

Reduced acid excretion.

↓

Retention of sulphate/phosphate/organic anions.

↓

High anion gap metabolic acidosis.

Salicylates:

Respiratory-centre stimulation + organic acid accumulation.

↓

Respiratory alkalosis + HAGMA.

Methanol:

Formate accumulation.

↓

HAGMA + visual toxicity.

Ethylene glycol:

Toxic acid metabolites + oxalate.

↓

HAGMA + AKI ± hypocalcaemia/calcium oxalate crystals.

40. Important Corrections and Clarifications

The original classification is broadly correct, but:

Addison’s disease is not primarily a direct bicarbonate-loss disorder.

It causes metabolic acidosis mainly because:

ALDOSTERONE DEFICIENCY → TYPE 4 RTA PHYSIOLOGY → IMPAIRED RENAL ACID EXCRETION + HYPERKALAEMIA.

Renal failure is classically associated with high anion gap acidosis when advanced, but earlier kidney disease may produce:

Normal anion gap acidosis.

Salicylate poisoning should not be thought of as simply metabolic acidosis.

The classic acid–base abnormality is:

RESPIRATORY ALKALOSIS + HIGH ANION GAP METABOLIC ACIDOSIS.

Key Clinical Pattern

METABOLIC ACIDOSIS = ↓ pH + ↓ HCO₃⁻.

For rapid recall:

NORMAL ANION GAP = BICARBONATE LOST OR RENAL ACID EXCRETION IMPAIRED.

DIARRHOEA → HCO₃⁻ LOSS.

RTA → RENAL ACID/BASE HANDLING DEFECT.

ACETAZOLAMIDE → HCO₃⁻ LOSS.

ADDISON’S → TYPE 4 RTA + HYPERKALAEMIA.

HIGH ANION GAP = EXTRA UNMEASURED ACIDS HAVE ACCUMULATED.

DKA → KETONES.

LACTIC ACIDOSIS → LACTATE.

RENAL FAILURE → RETAINED ACIDS.

SALICYLATES → MIXED RESPIRATORY ALKALOSIS + HAGMA.

METHANOL → HAGMA + VISUAL DAMAGE.

ETHYLENE GLYCOL → HAGMA + AKI + CALCIUM OXALATE.

The simplest examination rule is:

LOW HCO₃⁻ → CALCULATE THE ANION GAP → NORMAL GAP: THINK BICARBONATE LOSS/RTA; HIGH GAP: THINK ACCUMULATED ORGANIC OR RETAINED ACIDS.