Management of Low Serum Zinc with Elevated RBC Zinc
Do not supplement zinc when serum zinc is low but RBC zinc is elevated, as this pattern indicates redistribution rather than true deficiency. 1
Understanding the Discordance
The key insight from ESPEN 2022 guidelines is that erythrocyte zinc concentrations show little or no change during true zinc depletion, whereas plasma zinc falls significantly in experimental zinc deficiency studies. 1 This means:
- Low serum zinc with high RBC zinc is NOT true zinc deficiency 1
- This pattern suggests zinc redistribution from plasma to tissues, most commonly due to inflammation 1
- RBC zinc remains stable even when body stores are genuinely depleted 1
Essential Diagnostic Workup
Before making any treatment decisions, simultaneously measure CRP and albumin alongside zinc levels, as plasma zinc decreases significantly whenever CRP exceeds 20 mg/L. 1, 2
Check for these confounding factors:
- Inflammation/acute phase response: Zinc redistributes from plasma albumin to liver metallothionein during inflammation, causing falsely low serum zinc 1
- Hypoalbuminemia: 70% of circulating zinc binds to albumin; low albumin artificially lowers serum zinc 2, 3
- Hemolyzed sample: Produces falsely elevated zinc due to release from erythrocytes 2
- Timing of blood draw: Serum zinc fluctuates by 20% during 24 hours due to food ingestion; afternoon/evening draws show significantly lower values 1, 2, 4
Clinical Algorithm
If CRP >20 mg/L:
- The low serum zinc is due to inflammatory redistribution, not deficiency 1
- Recheck zinc levels after inflammation resolves 1
- Do NOT supplement zinc 1
If albumin is low:
- Correct for hypoalbuminemia before interpreting zinc levels 2, 4
- Hypoalbuminemia increases odds of being below serum zinc cutoff by 11-fold (OR: 11.2) 4
If both CRP and albumin are normal:
- The elevated RBC zinc with low serum zinc remains unexplained by standard deficiency patterns 1
- Consider familial hyperzincemia (heritable condition with excess zinc bound to serum proteins, typically asymptomatic) 5
- Evaluate for copper deficiency, as zinc-copper interactions are bidirectional 6, 3
Critical Pitfall to Avoid
Never rely on plasma zinc alone to diagnose deficiency. 7 Plasma zinc is influenced by infections, stress, medications (diuretics, ARBs), and diurnal variation 7, 3, 4. The discordance between low serum and high RBC zinc specifically argues against true deficiency, as experimental depletion studies show RBC zinc remains stable even when body stores are genuinely low 1.
When Zinc Supplementation Would Be Appropriate
Zinc supplementation is only indicated when there is true deficiency with clinical features (alopecia, characteristic skin rash on face/groins/hands/feet, impaired wound healing, immune dysfunction, diarrhea, taste/smell abnormalities) 1 AND confirmatory low plasma zinc in the absence of inflammation or hypoalbuminemia 1, 2.