Can TMPRSS6 and HFE variants together cause discordant iron studies?

Genetic variations in hepatic iron-sensing pathways can exert opposing physiological forces, disrupting the typical diagnostic patterns of systemic iron status.

Molecular mechanisms of opposing hepcidin signaling

• TMPRSS6-mediated restriction: The TMPRSS6 gene encodes matriptase-2, which cleaves membrane hemojuvelin to downregulate BMP/SMAD signaling. Hypofunctional variants (such as rs4820268 GG or rs855791) result in inappropriately elevated hepcidin levels, which restricts intestinal iron absorption and leads to depleted ferritin stores.
• HFE-mediated loading: Pathogenic HFE variants (such as C282Y or H63D) disrupt the hepatic iron-sensing complex, suppressing hepcidin relative to body iron stores to promote permissive intestinal iron absorption and elevate transferrin saturation.
• Genetic epistatic interactions: Evidence from mouse double-knockout models and human patient cohorts demonstrates that TMPRSS6 variants can override or modulate the low-hepcidin signal and iron-loading phenotype typically driven by HFE deficiency.

Clinical implications of discordant iron panels

• Phenotypic discordance: The coexistence of these genetic variants pulls iron indicators in opposite directions. The TMPRSS6 variant drives lower ferritin levels and depleted tissue stores, while the HFE variant maintains elevated transferrin saturation.
• Superimposed transient spikes: When transient serum iron spikes—driven by diurnal fluctuations, dietary intake, or the timing of blood draws—are superimposed on these chronically depleted ferritin stores, it creates a highly discordant clinical picture of elevated transferrin saturation paired with low ferritin.

Bottom line

• Coexisting TMPRSS6 and HFE variants disrupt classic clinical profiles, producing discordant iron panels of high transferrin saturation alongside depleted ferritin stores when accompanied by transient serum iron spikes.