Influence of serum transferrin concentration on diagnostic criteria for iron deficiency in chronic heart failure

Abstract

Aims: Transferrin saturation (TSAT), a marker of iron deficiency, reflects both serum concentrations of iron (SIC) and transferrin (STC). TSAT is susceptible to changes in each of these biomarkers. Little is known about determinants of STC and its influence on TSAT and mortality in patients with heart failure. Accordingly, we studied the relationship of STC to clinical characteristics, to markers of iron deficiency and inflammation and to mortality in chronic heart failure (CHF).

Methods and results: Prospective cohort of patients with CHF attending a clinic serving a large local population. A total of 4422 patients were included (median age 75 (68-82) years; 40% women; 32% with left ventricular ejection fraction ≤40%). STC ≤ 2.3 g/L (lowest quartile) was associated with older age, lower SIC and haemoglobin and higher high-sensitivity C-reactive protein, ferritin and N-terminal pro-brain natriuretic peptide compared with those with STC > 2.3 g/L. In the lowest STC quartile, 624 (52%) patients had SIC ≤13 μmol/L, of whom 38% had TSAT ≥20%. For patients in the highest STC quartile, TSAT was <20% when SIC was >13 μmol/L in 185 (17%) patients. STC correlated inversely with ferritin (r = -0.52) and high-sensitivity C-reactive protein (r = -0.17) and directly with albumin (r = 0.29); all P < 0.001. In models adjusted for age, N-terminal pro-brain natriuretic peptide and haemoglobin, both higher SIC (hazard ratio 0.87 [95% CI: 0.81-0.95]) and STC (hazard ratio 0.82 [95% CI: 0.73-0.91]) were associated with lower mortality. SIC was more strongly associated with both anaemia and mortality than either STC or TSAT.

Conclusions: Many patients with CHF and a low STC have low SIC even when TSAT is >20% and serum ferritin >100 μg/L; such patients have a high prevalence of anaemia and a poor prognosis and might have iron deficiency but are currently excluded from clinical trials of iron repletion.

Keywords: Heart failure; Iron; Iron deficiency; Mortality; Transferrin; Transferrin saturation.

Figure 1

Measures of iron status in patients in the lowest quartile (≤2.3 g/L) of serum transferrin concentration (STC). Serum iron concentration (SIC) in μmol/L.

Figure 2

(A) Kaplan–Meier survival curves for all‐cause mortality in all patients (n = 4422) by quartiles of serum transferrin concentration (STC). Log‐rank P‐value provided. Unadjusted hazard ratios and 95% confidence intervals for each quartile of STC with quartile two (2.4–2.6 g/L) as reference.(B) Kaplan–Meier survival curves for all‐cause mortality for patients in the lowest quartile (≤2.3 g/L) of serum transferrin concentration (STC) according to serum iron concentration (SIC) above or below 13 μmol/L or TSAT above or below 20%. Log‐rank P‐values provided. Unadjusted hazard ratios and 95% confidence intervals for each group (SIC >13 μmol/L + TSAT ≥20% (reference group); SIC ≤13 μmol/L + TSAT ≥20%; SIC ≤13 μmol/L + TSAT <20%). No patient had SIC >13 μmol/L + TSAT <20%.

Figure 3

Heat maps detailing all‐cause mortality within 5 years by STC and SIC. Number of patients (A) and proportion (%) of patients with TSAT <20% and median and (Q1–Q3) TSAT (B) shown. Red indicates higher and blue lower risk. For instance, there were 298 patients with a STC ≤2.3g/L and SIC ≤10μmol/L, 98% of whom had a TSAT <20%, median TSAT 14 (12‐16)%. This was the highest risk subset in the cohort.

Figure 4

Diagram detailing number of patients, prevalence of anaemia, TSAT <20% and median (Q1–Q3) serum ferritin with mortality within 5 years displayed as Hazard Ratios and (95% confidence intervals) according to each quartile of serum transferrin concentration (STC) if serum iron concentration (SIC) was low (≤13 μmol/L) or normal (>13 μmol/L). Mortality analysis (all‐cause mortality) adjusted for age, NT‐proBNP, urea, haemoglobin, treatment with beta‐blockers, and loop diuretics.

Figure 5

Kaplan–Meier survival curves for all‐cause mortality for patients within quartiles 1 and 2 (A) and quartiles 3 and 4 (B) according to serum iron concentrations (≤13 μmol/L or >13 μmol/L) and TSAT (<20% or ≥20%). Log‐rank P‐values provided. Serum iron >13 μmol/L and TSAT ≥20% used as reference in each. P‐values between groups also provided. No patient had SIC >13 μmol/L + TSAT <20%.