Can supplements such as magnesium, vitamin D3, and injectable tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist) contribute to the normalization of previously elevated serum ferritin and low transferrin saturation levels in a patient with a history of iron metabolism abnormalities?

Can Supplements Normalize Previously Abnormal Iron Studies?

No, magnesium, vitamin D3, and tirzepatide do not directly alter serum ferritin or transferrin saturation levels—the normalization of your patient's iron studies indicates resolution of the underlying condition that caused the initial abnormalities, not a supplement effect. 1, 2

Understanding the Initial Abnormal Pattern

Your patient's initial labs showed:

• Ferritin 313 ng/mL with transferrin saturation 15% represents a classic pattern of anemia of chronic inflammation (also called functional iron deficiency), where iron is sequestered in storage sites and unavailable for erythropoiesis 3
• When transferrin saturation is low (<20%) and ferritin is elevated (>300 ng/mL), this indicates inflammatory iron block rather than true iron overload 3, 4
• This pattern occurs because inflammatory cytokines (TNF-α, IL-6) increase hepcidin production, which blocks intestinal iron absorption and traps iron in reticuloendothelial macrophages 3, 4

Evidence Against Supplement-Mediated Changes

Vitamin D3

• A randomized, double-blind, placebo-controlled trial in 251 participants demonstrated that 16 weeks of daily vitamin D3 supplementation (10 or 25 μg) had no significant effect on serum ferritin, hemoglobin, serum iron, or transferrin saturation 1
• Despite increasing serum 25-hydroxyvitamin D from 29 nmol/L to 49 nmol/L, there was no difference in ferritin change (1.9 μg/L, 95% CI: -3.2,7.0) or transferrin saturation change (0.7%, 95% CI: -0.6,2.0) compared to placebo 1

Magnesium

• There is no established mechanism or clinical evidence that magnesium supplementation alters iron metabolism parameters 3
• Magnesium does not affect ferritin synthesis, iron absorption, or transferrin saturation 3

Tirzepatide (GLP-1 Receptor Agonist)

• GLP-1 receptor agonists are not known to directly affect iron metabolism or ferritin levels 3
• While tirzepatide may improve metabolic syndrome and reduce inflammation through weight loss and improved glycemic control, this would be an indirect effect on the underlying inflammatory state, not a direct drug effect on iron parameters 4

What Actually Explains the Normalization

The normalization of your patient's iron studies indicates resolution of the underlying inflammatory or metabolic condition that caused the initial abnormality:

Most Likely Explanations:

• Resolution of acute inflammation or infection that was present during the initial testing—ferritin is an acute-phase reactant that rises during inflammation independent of iron stores 3, 4, 2
• Improvement in metabolic syndrome/NAFLD if the patient lost weight on tirzepatide—metabolic syndrome commonly causes elevated ferritin with low transferrin saturation, and ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload 4, 5
• Resolution of occult infection—active infection causes ferritin to rise acutely as part of the inflammatory response 4
• Improvement in chronic inflammatory condition that was subclinical during initial testing 3

Critical Clinical Pearls

Ferritin as an Acute-Phase Reactant

• Ferritin is misleading when inflammation is present—it can be falsely elevated in acute or chronic inflammation, making interpretation difficult 3, 2
• The combination of elevated ferritin with low transferrin saturation specifically indicates inflammatory iron sequestration, not iron overload 3, 4

Transferrin Saturation is Key

• Transferrin saturation <20% essentially rules out iron overload—when TS is low, secondary causes (inflammation, metabolic syndrome, liver disease) predominate over true iron excess 4, 6
• Over 90% of elevated ferritin cases in outpatients are NOT due to iron overload but rather chronic alcohol consumption, inflammation, cell necrosis, tumors, or metabolic syndrome 4

The Indirect Tirzepatide Effect

While tirzepatide didn't directly alter iron parameters, if your patient achieved significant weight loss and metabolic improvement, this could have:

• Reduced hepatocellular inflammation in NAFLD, lowering ferritin 4, 5
• Decreased systemic inflammatory cytokines, allowing iron to mobilize from storage sites and increasing transferrin saturation 3, 4
• Improved insulin resistance, which is associated with dysmetabolic hyperferritinemia 5

Recommended Follow-Up

• No iron supplementation is needed since both parameters normalized—the patient never had true iron deficiency or overload 3
• Consider checking inflammatory markers (CRP, ESR) if not already done to assess for occult inflammation that may have resolved 4
• Evaluate for metabolic syndrome components if tirzepatide was prescribed for weight loss or diabetes, as improvement in these conditions explains the ferritin normalization 4, 5
• Repeat iron studies only if clinical symptoms develop or if there's concern for recurrent inflammatory condition 3