**Standard formula (without K⁺)**: AG = Na⁺ - (Cl⁻ + HCO₃⁻). **Example**: Na 140, Cl 104, HCO₃ 24 → AG = 140 - (104 + 24) = **12 mEq/L** (normal). **Alternative formula (with K⁺, rarely used)**: AG = (Na⁺ + K⁺) - (Cl⁻ + HCO₃⁻) → increases AG by ~4 mEq/L. **Albumin-corrected AG**: Corrected AG = Measured AG + 2.5 × (4.0 - Albumin g/dL). **Example**: Measured AG 10, Albumin 2.0 → Corrected AG = 10 + 2.5 × (4.0 - 2.0) = **15 mEq/L** (high, would be missed without correction). **Normal ranges**: Traditional (with K⁺) 12-16 mEq/L, Modern (without K⁺) **8-12 mEq/L** (current standard), ISE method (ion-selective electrode) 3-11 mEq/L (lower due to different Cl⁻ measurement). **Clinical significance**: Represents unmeasured anions (albumin, phosphate, sulfate, organic acids)—elevated AG indicates accumulation of unmeasured acids.

**MUDPILES mnemonic** for high AG acidosis (AG >12 mEq/L + low pH <7.35 + low HCO₃ <22): **M**ethanol (formic acid, AG 20-30, osmolar gap >10), **U**remia (renal failure, AG 16-20, BUN >60), **D**KA/Diabetic Ketoacidosis (β-hydroxybutyrate + acetoacetate, AG 20-30, glucose >250), **P**araldehyde/Propylene glycol (rare), **I**soniazid/Iron tablets, **L**actic acidosis (Type A hypoxia/shock AG 20-30, Type B metformin/malignancy AG 15-25), **E**thylene glycol (glycolic/oxalic acid, AG 20-35, oxalate crystals), **S**alicylates (aspirin >30 mg/dL, AG 15-20, tinnitus). **Most common causes**: Lactic acidosis (50%), DKA (25%), uremia (15%), toxins (10%). **Delta-delta calculation**: (ΔAG / ΔHCO₃) ratio—1.0-2.0 suggests pure high AG acidosis, <1.0 suggests concurrent normal AG acidosis, >2.0 suggests metabolic alkalosis. **Severe AG >30**: Almost always lactic acidosis, DKA, or ethylene glycol/methanol poisoning.

Albumin is the **largest contributor to unmeasured anions** (~75% of AG).

Low albumin (hypoalbuminemia <3.5 g/dL) **falsely lowers AG** because albumin normally carries negative charge. **Example of missed acidosis**: Patient with sepsis, Albumin 2.0, AG 10 (appears normal). **Corrected AG** = 10 + 2.5 × (4.0 - 2.0) = **15 mEq/L** (high, reveals lactic acidosis). **Correction formula**: Add 2.5 mEq/L for every 1 g/dL albumin below 4.0. **Common in**: Cirrhosis, nephrotic syndrome, malnutrition, critical illness (albumin often 2.0-2.5). **Clinical impact**: 50% of ICU patients with AG <12 actually have high AG acidosis when corrected. **Alternative method**: Some use 3.7 mEq/L per 1 g/dL (older literature), but 2.5 is current standard. **Bottom line**: Always check albumin in critically ill patients—uncorrected AG can miss life-threatening acidosis (lactate, ketoacidosis).

Normal AG acidosis (AG 8-12 mEq/L + low pH + low HCO₃) means **loss of HCO₃⁻ or addition of Cl⁻**—also called hyperchloremic acidosis. **HARDUPS mnemonic**: **H**yperalimentation (TPN, amino acid metabolism), **A**cetazolamide/Addison disease (renal tubular acidosis type 2), **R**enal tubular acidosis (Types 1, 2, 4—impaired H⁺/HCO₃⁻ handling), **D**iarrhea (most common cause—GI HCO₃⁻ loss, Cl⁻ retention), **U**reterosigmoidostomy/Ureteral diversions (colonic HCO₃⁻ loss), **P**ancreatic fistula, **S**aline administration (large volume 0.9% NaCl dilutes HCO₃⁻). **Urine AG test**: Urine (Na + K) - Cl. **Positive** (>0): Renal HCO₃⁻ loss (RTA). **Negative** (<0): GI HCO₃⁻ loss (diarrhea) or exogenous acid. **Type 1 RTA** (distal): Urine pH >5.5, hypokalemia, kidney stones. **Type 2 RTA** (proximal): Urine pH <5.5 initially, then >5.5, Fanconi syndrome. **Type 4 RTA**: Hyperkalemia, aldosterone deficiency, diabetic nephropathy. **Treatment**: Normal AG acidosis often self-corrects with volume/electrolyte replacement, unlike high AG which requires specific toxin/metabolic treatment.

Low AG (<3-6 mEq/L) is **uncommon** and usually due to: **Hypoalbuminemia** (most common—albumin <2.0 can lower AG to 0-5, seen in cirrhosis, nephrotic syndrome). **Hypercalcemia/Hypermagnesemia** (unmeasured cations increase, cancer, hyperparathyroidism, milk-alkali syndrome). **Paraproteinemia** (IgG myeloma—cationic proteins increase, can cause AG <0). **Lithium toxicity** (cationic drug measured as Na⁺ by some analyzers). **Bromide/Iodide intoxication** (measured as Cl⁻ by older analyzers, falsely elevates Cl⁻). **Severe hyponatremia** (<120 mEq/L) or hyperchloremia (>115 mEq/L) can mathematically lower AG. **Clinical significance**: Low AG itself is **not dangerous**—it's a clue to underlying disease (e.g., multiple myeloma paraproteins). **Action**: If AG <3, check albumin (correct AG), serum protein electrophoresis (paraprotein), calcium, magnesium, lithium level if on medication. **Lab artifact**: Severe hyperlipidemia or hemolysis can cause pseudohyponatremia → artifactually low AG (resolves with direct ISE measurement).

Delta-delta ratio helps **identify mixed acid-base disorders** when AG is elevated. **Formula**: Δ ratio = ΔAG / ΔHCO₃ = (Measured AG - 12) / (24 - Measured HCO₃). **Interpretation**: **1.0-2.0 (normal)**: Pure high AG metabolic acidosis (every 1 mEq/L AG increase matches 1-2 mEq/L HCO₃ drop). **<1.0**: Mixed high AG + normal AG acidosis (e.g., DKA + diarrhea, lactic acidosis + RTA).

HCO₃ falls more than AG rises. **>2.0**: Mixed high AG acidosis + metabolic alkalosis (e.g., DKA + vomiting, uremia + diuretics).

HCO₃ doesn't fall as much due to concurrent alkalosis. **Example 1**: AG 24 (Δ12), HCO₃ 12 (Δ12) → Δ ratio = 12/12 = **1.0** (pure lactic acidosis). **Example 2**: AG 20 (Δ8), HCO₃ 18 (Δ6) → Δ ratio = 8/6 = **1.33** (normal, pure DKA). **Example 3**: AG 22 (Δ10), HCO₃ 14 (Δ10) → Δ ratio = 10/10 = **1.0**, but also respiratory compensation (check ABG). **Caveat**: Only valid if AG >20 (chronic kidney disease alters ratio), assumes normal baseline AG 12 and HCO₃ 24.