Bit · Pharm/Tox
Non-anion-gap metabolic acidosis (HARDUP)
When acidosis comes without a high anion gap, the body is losing bicarbonate or unable to excrete acid. HARDUP is the differential.
Mechanism
A normal-anion-gap metabolic acidosis means HCO₃⁻ is being lost (and Cl⁻ replaces it — so it's also called hyperchloremic acidosis). The losses can be from the GI tract, the kidneys, or from infusion of acidic fluids:
- H — Hyperalimentation / Hyperchloremic infusion — large-volume normal saline (which has Cl⁻ 154 mEq/L) gives 'hyperchloremic acidosis' by dilution; TPN can do the same.
- A — Addison (adrenal insufficiency) / Acetazolamide — Addison: aldosterone deficiency → Type 4 RTA pattern. Acetazolamide: carbonic anhydrase inhibition → urinary HCO₃⁻ loss → proximal-RTA pattern.
- R — Renal tubular acidosis (Types 1, 2, 4) — see the RTA Bit for full differential.
- D — Diarrhea — large lower-GI HCO₃⁻ loss. Most common cause of non-AG acidosis in clinical practice. Urinary anion gap is negative (kidney compensating by excreting NH₄⁺).
- U — Ureteroenteric fistula / Ureteral diversion — surgical diversion of urine into bowel (e.g. ileal conduit) → bowel reabsorbs Cl⁻ in exchange for HCO₃⁻.
- P — Pancreatic fistula / Post-hypocapnia — pancreatic secretions are HCO₃⁻-rich; fistulous loss causes acidosis. Post-hypocapnia: rapid resolution of chronic respiratory alkalosis leaves a metabolic acidosis behind.
Differentiator Table
| Letter | Cause | Mechanism | Urinary anion gap (UAG) |
|---|---|---|---|
| H | Hyperalimentation / hyperchloremic IV fluids | Cl⁻ load + HCO₃⁻ dilution | Variable |
| A | Addison / Acetazolamide | Addison: aldo deficiency → Type 4 RTA pattern. Acetazolamide: ↑ urinary HCO₃⁻ loss | Positive |
| R | Renal tubular acidosis (1, 2, 4) | Defective renal acid handling | POSITIVE (kidney unable to excrete NH₄⁺) |
| D | Diarrhea | Lower GI loss of HCO₃⁻-rich fluid | NEGATIVE (kidney can still excrete NH₄⁺) |
| U | Ureteroenteric fistula / urinary diversion | Bowel reabsorbs Cl⁻ for HCO₃⁻ | Variable |
| P | Pancreatic fistula / Post-hypocapnia | Loss of HCO₃⁻-rich pancreatic juice; or compensatory metabolic acidosis persisting after rapid resolution of respiratory alkalosis | Variable |
The Pivot
Two questions:
- Is the urinary anion gap positive or negative? A positive UAG means the kidney is the problem (can't excrete NH₄⁺) → RTA, Addison's, acetazolamide. A negative UAG means the kidney is fine (still excreting NH₄⁺) → GI loss, diarrhea, pancreatic fistula.
- Clinical context — recent diarrhea, ileal conduit, large-volume saline, adrenal insufficiency suspicion, or a drug like acetazolamide — usually closes it.
UAG = (Na⁺ + K⁺) − Cl⁻ in urine. Memory aid: NEUT — Negative = Extra-renal (GI). UT (Up, positive) = renal Tubular cause.
NBME-Style Stem
A 56-year-old man with multiple sclerosis presents with chronic diarrhea over 6 weeks. He has lost 8 kg. Labs: Na⁺ 138, K⁺ 3.1, Cl⁻ 116, HCO₃⁻ 16 mEq/L. Anion gap is 6. Urinary anion gap is −24. Which of the following is the most likely cause of his acidosis?
Concept Anchor
Non-anion-gap acidosis = bicarbonate is leaving via either the kidney or the gut. The urinary anion gap tells you which: positive = kidney's fault (RTA), negative = GI's fault (diarrhea).