In addition to its familiar role in the synthesis of haemoglobin and myoglobin, iron is also an important component of mitochondrial enzymes involved in the production of cellular energy 1. Treating iron deficiency in patients with heart failure who are non-anaemic has been shown to improve exercise capacity in the absence of haemoglobin incrementation 2. These findings are also replicated in athletes 3. However, the impact of iron deficiency in patients who are non-anaemic and having surgery is not well described. We conducted a retrospective observational study to test our hypothesis that exercise capacity as measured by cardiopulmonary exercise testing is lower in patients who are iron deficient but non-anaemic compared with patients who are iron replete and non-anaemic undergoing hepato-pancreatobiliary resection surgery. All adult patients that underwent elective liver or pancreas resection at our institution between March 2023 and April 2025 were identified by searching electronic medical records. This study was deemed a service evaluation by the local research department and specific ethics approval was not required. Both cardiopulmonary exercise testing and iron studies are measured routinely for this cohort in our institution. Patients were not included if they received pre-operative iron supplementation or did not have cardiopulmonary exercise testing, haemoglobin concentration or iron studies recorded pre-operatively. For each patient, pre-operative haemoglobin, ferritin, transferrin saturation and C-reactive protein levels were reviewed. Based on the results, patients were categorised into three groups according to the international consensus statement on peri-operative management of anaemia and iron deficiency: iron deficiency anaemia; non-anaemic iron deficient; and non-anaemic iron replete 4. Missing data were limited to cases where the anaerobic threshold could not be determined, which occurred in < 5% of cases. In these cases, median imputation was used. A one-sided p-value was calculated using the Mann–Whitney U-test for the difference in the oxygen consumption peak between the non-anaemic iron deficient and non-anaemic iron replete groups. While other cardiopulmonary exercise testing values are reported, further tests for significance were not done to avoid family-wise error. The oxygen consumption peak was chosen as the variable of interest because its value in the peri-operative setting is clear and previous studies have not shown oxygen consumption at anaerobic threshold to vary in the iron deficient vs. replete state 5. The baseline characteristics of the non-anaemic iron deficient and non-anaemic iron replete groups were well matched for age, sex, weight and haemoglobin concentration, all of which are important predictors of peak oxygen consumption (Table 1). The higher proportion of males in the non-anaemic iron deficient and replete groups is likely a consequence of the definition of anaemia used, which does not include different thresholds for males and females. The non-anaemic iron deficient group had a higher proportion of patients who were of ASA physical status grade 3 compared with the non-anaemic iron replete group. This indicates greater comorbidity and is expected to be associated with both iron deficiency and reduced cardiorespiratory fitness, and, as such, is a confounding factor that may distort the observed relationship. Median (IQR range) peak oxygen consumption in patients in the non-anaemic iron deficient group was significantly lower than those in the non-anaemic iron replete group (17.8 (16.0–20.9 11.8–33.2) ml.kg-1.min-1 vs. 20.1 (16.9–22.7 11.2–37.5) ml.kg-1.min-1; p = 0.0137). This retrospective observational study showed an association between non-anaemic iron deficiency and reduced exercise capacity in patients undergoing liver or pancreatic resection surgery. Although no adjustment was made for confounding factors including greater comorbidity in the iron-deficient group, the finding aligns with evidence from non-surgical populations 2, 3. The clinical significance of this association remains uncertain. While peak oxygen consumption is an established predictor of postoperative outcomes, recent observational data have not shown worse postoperative outcomes for patients undergoing colorectal surgery who are non-anaemic and iron deficient 6. Therefore, it is unlikely that non-anaemic iron deficiency represents a universal therapeutic target for all patients undergoing major surgery. However, patients with both low cardiorespiratory fitness and iron deficiency represent a subgroup that may benefit from treatment. The 2.3 ml.kg-1.min-1 median difference in oxygen consumption peak observed in this study is likely to be more consequential for patients in the lowest fitness quartile (16.0 ml.kg-1.min-1 in the iron-deficient group) than for those with higher fitness levels. If iron supplementation is shown to improve cardiopulmonary fitness in surgical patients who are non-anaemic iron deficient, as it has done in medical patients, it could provide a valuable addition to prehabilitation strategies for patients with low fitness levels. This approach would support investigating for iron deficiency in patients who are non-anaemic and anticipating major surgery; this is not recommended in consensus guidelines currently 4. RRB has received educational grants from Pharmacosmos UK. No external funding or other competing interests declared.
Womersley et al. (Thu,) studied this question.