Revisiting the Obesity-Anaemia Paradox: Inflammation and Iron Homeostasis in the BMI-Haemoglobin Relationship

Obesity and anaemia are global epidemics with complex, overlapping pathophysiology. While excess adiposity is known to induce chronic inflammation that disrupts iron homeostasis, multiple population studies paradoxically report higher haemoglobin levels and lower anaemia prevalence among obese individuals. The nonlinear and potentially suppressive role of inflammation in this relationship remains understudied.

We analysed adults aged 18-64 from the 2015-2023 National Health and Nutrition Examination Survey (NHANES). Haemoglobin was modelled as a function of body-mass index (BMI) using survey-weighted linear regression with restricted cubic splines. Interactions with log-transformed CRP were assessed, and ferritin was corrected for inflammation using BRINDA regression-residual methods. Causal mediation analysis decomposed the total effect of BMI on haemoglobin into indirect (mediated by CRP) and direct effects. Secondary models examined anaemia (Hb < 13.0 g/dL in men, < 12.0 g/dL in women) using logistic regression.

Haemoglobin increased steeply across lower BMI ranges but plateaued above 30 kg/m² (p-nonlinearity < 0.001). The haemoglobin-BMI curve flattened significantly at higher CRP levels, with strong evidence of interaction (p-interaction < 0.001). Mediation analysis showed that CRP significantly suppressed the BMI-haemoglobin relationship (ACME = -0.044 g/dL, p < 0.001; ADE = 0.216 g/dL, p < 0.001). In contrast, BRINDA-adjusted ferritin mediated < 2% of the association. Logistic models showed that anaemia risk declined sharply with increasing BMI but rose consistently with CRP. Anaemia mediation analysis revealed suppression as well (ACME > 0; ADE < 0), precluding interpretation of proportion mediated.

BMI is positively associated with haemoglobin in a non-linear, CRP-dependent fashion. Inflammation significantly suppresses the haematologic benefit of excess adiposity, while inflammation-adjusted ferritin plays a minimal mediating role. These findings underscore the importance of modelling non-linearity and correcting iron biomarkers for inflammation when studying obesity-related anaemia.