Could the elevated ferritin in a 48‑year‑old woman on estrogen hormone replacement therapy, semaglutide, and a vitamin B12 supplement be caused by the B12 supplement?

Could Vitamin B12 Supplementation Cause Elevated Ferritin?

No, vitamin B12 supplementation does not cause elevated ferritin levels. The elevated ferritin in this 48-year-old woman is far more likely related to her estrogen hormone replacement therapy, metabolic factors associated with semaglutide use, or underlying inflammatory/metabolic conditions—not her B12 supplement.

Why B12 Does Not Elevate Ferritin

Vitamin B12 and ferritin are independent markers that reflect different physiological processes. Ferritin measures iron storage and serves as an acute-phase reactant that rises with inflammation, liver disease, metabolic syndrome, and tissue injury—none of which are caused by B12 supplementation 1.

• B12 deficiency can actually be associated with elevated ferritin in untreated megaloblastic anemia, where red cell ferritin levels increase significantly (mean 579 ag/cell in B12 deficiency vs. 10.7 ag/cell in normal subjects) and correlate with plasma ferritin levels 2.
• B12 supplementation, if anything, may help normalize ferritin by correcting ineffective erythropoiesis. In adolescent girls receiving iron-folic acid supplementation, adding vitamin B12 resulted in significantly better ferritin status (only 6.4% remained ferritin-deficient vs. 15.2% without B12, P=0.01) 3.
• There is no biological mechanism by which B12 supplementation would increase ferritin. B12 acts as a coenzyme in DNA synthesis and nervous system function, not in iron metabolism or inflammatory pathways 4.

Actual Causes to Investigate in This Patient

The most common causes of hyperferritinemia include chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome, which account for over 90% of cases 1.

Estrogen Hormone Replacement Therapy

• Estrogen can influence iron metabolism and ferritin levels through effects on hepcidin regulation and hepatic function, though this is not the primary mechanism in most cases 1.

Semaglutide and Metabolic Factors

• Metabolic syndrome and NAFLD are major causes of elevated ferritin, where the elevation reflects hepatocellular injury and insulin resistance rather than true iron overload 1.
• Semaglutide-induced weight loss may unmask or improve underlying metabolic liver disease, potentially affecting ferritin levels through changes in hepatic inflammation 1.

Diagnostic Algorithm

Step 1: Measure transferrin saturation (TS) simultaneously with ferritin to distinguish true iron overload from secondary causes 1, 5.

• If TS ≥45%: Suspect primary iron overload and proceed with HFE genetic testing for C282Y and H63D mutations 1.
• If TS <45%: Iron overload is unlikely; investigate secondary causes including inflammation, liver disease, alcohol use, and metabolic syndrome 1.

Step 2: Evaluate for inflammatory and metabolic causes 1:

• Check liver enzymes (ALT, AST) to assess hepatocellular injury
• Measure inflammatory markers (CRP, ESR) to detect occult inflammation
• Consider abdominal ultrasound to evaluate for NAFLD, especially given semaglutide use
• Assess alcohol consumption history
• Screen for metabolic syndrome components (obesity, glucose intolerance, dyslipidemia)

Step 3: Risk stratification by ferritin level 1:

• Ferritin <1,000 μg/L: Low risk of organ damage (94% negative predictive value for advanced fibrosis)
• Ferritin 1,000-10,000 μg/L: Higher risk if iron overload present; consider liver biopsy if TS ≥45% with elevated liver enzymes
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; requires urgent specialist referral

Common Pitfalls to Avoid

• Never attribute elevated ferritin to vitamin supplementation without evidence of iron overload (TS ≥45%) 1.
• Do not use ferritin alone to diagnose iron overload, as it is an acute-phase reactant elevated in inflammation, liver disease, and malignancy independent of iron stores 1.
• Do not overlook liver disease as the primary cause when ferritin is elevated with normal TS, especially in patients on medications affecting metabolism 1.
• Recognize that ferritin <1,000 μg/L with normal TS and liver enzymes requires no invasive testing—focus on treating the underlying condition (likely metabolic/inflammatory) rather than the ferritin number itself 1.