Causes of Low Anion Gap
A low anion gap is uncommon but rarely benign — it points to a fall in unmeasured anions (usually albumin), a rise in unmeasured cations (paraproteins, calcium, magnesium, lithium), or a laboratory artifact such as bromide interference.
What does a low anion gap mean?
A low anion gap — conventionally AG < 8 mEq/L by the formula Na⁺ − (Cl⁻ + HCO₃⁻) — is uncommon, found in fewer than 1% of routine panels, but it should never be dismissed. The gap reflects the difference between unmeasured anions (albumin, phosphate, sulfate) and unmeasured cations (potassium, calcium, magnesium, paraproteins). A low gap therefore means either unmeasured anions have fallen, unmeasured cations have risen, or — most often — the chloride measurement is falsely elevated by another halide. Calculate yours with the anion gap calculator and read the full interpretation in our low anion gap guide.
The physiology is rooted in the unmeasured ions that define the gap: albumin is the dominant "unmeasured" anion and accounts for roughly 75% of the normal gap, so anything that lowers albumin lowers the gap proportionally (Figge et al., Critical Care Medicine). Conversely, positively charged paraproteins (IgG in multiple myeloma) and bromide (miscounted as chloride by some assays) are the classic reasons the gap drops below zero.
The causes of a low anion gap are hypoalbuminemia (most common, each 1 g/dL fall lowers the gap by ~2.5 mEq/L), paraproteinemia and multiple myeloma (cationic IgG), bromide toxicity (false hyperchloremia), hypercalcemia and hypermagnesemia, lithium toxicity, and laboratory error. A negative anion gap strongly suggests paraproteinemia or bromide poisoning.
Differential by category
| Category | Specific cause | Mechanism | Clue |
|---|---|---|---|
| ↓ Unmeasured anions | Hypoalbuminemia — cirrhosis, nephrotic syndrome, malnutrition, critical illness, inflammation (most common cause overall) | Albumin is ~75% of the normal gap; each 1 g/dL drop lowers the gap by ~2.5 mEq/L | Low serum albumin; clinical context |
| ↑ Unmeasured cations | Paraproteinemia / multiple myeloma — cationic IgG (rarely IgA) | Positively charged monoclonal immunoglobulins increase unmeasured cations; gap may be negative | High total protein with low albumin (γ-gap); anemia; renal failure |
| Hypercalcemia, hypermagnesemia | Excess divalent cations raise unmeasured cations modestly | Marked Ca²⁺ or Mg²⁺ elevation | |
| Lab artifact / toxin | Bromide toxicity (pyridostigmine bromide, herbal sedatives, old photographic chemicals) | Bromide is miscounted as chloride by colorimetric assays, falsely elevating Cl⁻ and lowering or negating the gap | Recent exposure; neurologic symptoms |
| Lithium toxicity | Li⁺ is a univalent cation that contributes to unmeasured cations at toxic levels | Psychiatric history; tremor, ataxia | |
| Laboratory error | Spuriously high Na⁺, Cl⁻, or HCO₃⁻ measurement; sample handling; hyperlipidemia interfering with older assays | Repeat chemistry resolves it |
Hypoalbuminemia — the most common cause
Hypoalbuminemia accounts for the overwhelming majority of low anion gaps seen in practice. Each 1 g/dL fall in serum albumin lowers the expected gap by ~2.5 mEq/L, so a critically ill patient with albumin of 1.5 g/dL has an expected baseline gap near 3–4 rather than 12 — a "low" gap of 5 in that patient actually masks a true HAGMA. Always compute the albumin-corrected anion gap (AG + 2.5 × (4.0 − albumin)) before concluding the gap is normal or low.
Paraproteinemia and multiple myeloma
A low or even negative anion gap is a classic, if rare, clue to multiple myeloma. Monoclonal IgG is positively charged at physiologic pH, so large amounts of IgG raise the unmeasured cation pool and narrow the gap (Kraut & Madias, StatPearls 'Serum Anion Gap'). The combination of a high total protein with a low albumin (the "γ-gap") should prompt serum and urine protein electrophoresis, serum free light chains, and a CBC for anemia. IgA myeloma can paradoxically widen the gap because IgA is anionic.
Bromide toxicity and other artifacts
Bromide has a similar ionic radius to chloride and is miscounted by colorimetric (thiocyanate) chloride assays, producing a falsely elevated chloride that drives the anion gap down — sometimes into negative territory. Sources include pyridostigmine bromide (myasthenia gravis), some herbal and organic sedatives, and historically photographic developers. Modern ion-selective electrode assays are less affected, so the artifact is now rarer but still reported. Lithium, similarly, is a univalent cation that at toxic concentrations raises unmeasured cations.
Always repeat the chemistry panel to rule out lab error first. If the gap stays low, check serum albumin (correct for it), then send serum and urine protein electrophoresis with free light chains if the total protein is high. A focused toxin and medication history closes the rest of the differential.
Key takeaways
- Hypoalbuminemia is the most common cause of a low anion gap — correct for albumin before reading the gap.
- A low or negative anion gap strongly suggests paraproteinemia (myeloma) or bromide toxicity.
- Hypercalcemia, hypermagnesemia, and lithium toxicity raise unmeasured cations and narrow the gap modestly.
- Always repeat the chemistry to exclude laboratory error before chasing a rare diagnosis.
Don't trust a low gap — work it up.
Calculate the anion gap, correct for albumin, and run the structured low-gap differential — all in one free hub.
Open the anion gap calculator