⚠️ An elevated anion gap should be treated as potentially life-threatening until proven otherwise.
It usually reflects the presence of an unmeasured acid such as lactate, ketones, or toxins such as methanol or ethylene glycol. It may also occur in uraemia. Always interpret the anion gap alongside the pH, bicarbonate, lactate, ketones, glucose, and the clinical picture.

📖 Definition and Normal Values

Formula	Expression	Typical normal range	Notes
Potassium excluded	AG = Na⁺ − (Cl⁻ + HCO₃⁻)	~8–12 mmol/L	Most commonly used in clinical practice
Potassium included	AG = (Na⁺ + K⁺) − (Cl⁻ + HCO₃⁻)	~10–18 mmol/L	Sometimes used in exams and older references

🧠 Why the Anion Gap Rises

Plasma must remain electrically neutral. When acids accumulate, hydrogen ions are buffered by bicarbonate, so bicarbonate falls. The accompanying anions — such as lactate, beta-hydroxybutyrate, formate, or glycolate — are not routinely measured, so the anion gap increases. A raised anion gap therefore suggests an unmeasured acid.

📊 High vs Normal Anion Gap Metabolic Acidosis

Feature	HAGMA (High anion gap)	NAGMA (Normal anion gap)
Definition	MA + raised AG	MA + normal AG
Main mechanism	Accumulation of unmeasured acids	Bicarbonate loss or impaired renal acid handling
Chloride	Usually normal	Usually raised → hyperchloraemic acidosis
Typical causes	Lactate, ketones, renal failure, toxins	Diarrhoea, RTA, saline excess, acetazolamide
Clinical urgency	Often immediately dangerous	Can still be serious, but often less toxin-driven

🩸 Causes of HAG Metabolic Acidosis (HAGMA)

Category	Examples	Key clue
Ketones	DKA, alcoholic ketoacidosis, starvation ketoacidosis	Ketonaemia, diabetes, fasting, alcohol history
Lactate	Sepsis, shock, hypoxia, mesenteric ischaemia, cyanide, CO, metformin	High lactate, tissue hypoperfusion or toxin exposure
Renal failure	Uraemic acidosis	Raised urea/creatinine, CKD or AKI
Toxins / drugs	Methanol, ethylene glycol, salicylates, iron, isoniazid, paraldehyde	Poisoning history, osmolar gap, neuro/visual features

💡 GOLD MARK Mnemonic

Letter	Meaning
G	Glycols (ethylene glycol, propylene glycol)
O	Oxoproline (5-oxoproline)
L	L-lactate
D	D-lactate
M	Methanol
A	Aspirin (salicylates)
R	Renal failure
K	Ketones

🧂 Causes of Normal Anion Gap Metabolic Acidosis (NAGMA)

Category	Examples	Mechanism
GI bicarbonate loss	Diarrhoea, small bowel fistula, pancreatic drainage	Direct bicarbonate loss
Renal causes	Renal tubular acidosis, hypoaldosteronism, Addison’s, ureteroenterostomy	Impaired acid excretion or bicarbonate handling
Drugs	Acetazolamide, ammonium chloride	Carbonic anhydrase inhibition or acid load
Iatrogenic	Large-volume 0.9% saline infusion	Hyperchloraemia lowers bicarbonate

⚠️ Important Caveat: Albumin

Issue	Why it matters
Low albumin	Albumin is a major unmeasured anion, so hypoalbuminaemia can make the anion gap look falsely normal
Clinical implication	A “normal” anion gap does not reliably exclude dangerous acids in sepsis, liver disease, nephrotic syndrome, or malnutrition

🔎 Practical Interpretation

Step	What to do	Why
1	Confirm metabolic acidosis	Look for low pH with low bicarbonate
2	Calculate anion gap	Separates HAGMA from NAGMA
3	If gap is raised, check lactate, ketones, renal function, toxins	These are the major dangerous causes
4	If gap is normal, think bicarbonate loss or RTA	Chloride usually rises to maintain electroneutrality
5	Check albumin and clinical context	A normal AG can be misleading

🖼️ Diagram

🩺 Clinical Cases

Case	Blood gas / labs	Diagnosis	Teaching point
🩸 Case 1 70-year-old diabetic, drowsy, Kussmaul breathing, fruity odour	pH 7.12, HCO₃⁻ 10, AG 26, glucose 28, ketones +++	DKA	High AG due to ketoacid accumulation
☣️ Case 2 45-year-old confused, tachypnoeic, hypotensive after overdose	pH 7.19, HCO₃⁻ 9, AG 28, lactate high	Lactic acidosis	Commonest hospital HAGMA; think shock, sepsis, toxins, ischaemia
🚽 Case 3 60-year-old with prolonged diarrhoea	pH 7.28, HCO₃⁻ 15, AG 10, lactate normal	NAGMA	Bicarbonate loss with compensatory hyperchloraemia

🌟 Summary Table

If you see…	Think…
Raised AG	Unmeasured acid: lactate, ketones, renal failure, toxins
Normal AG + low bicarbonate	Bicarbonate loss or renal tubular dysfunction
Normal AG but low albumin	Possible hidden HAGMA

📚 References

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Anion Gap and Metabolic Acidosis