High levels of zinc-protoporphyrin identify iron metabolic abnormalities in pulmonary arterial hypertension

Abstract

Iron homeostasis influences the development of pulmonary arterial hypertension (PAH) associated with hypoxia or hematologic disorders. To investigate whether severity of idiopathic PAH (IPAH) is impacted by alterations in iron metabolism, we assessed iron metabolic markers, including levels of zinc-protoporphyrin (Zn-pp), transferrin receptor, and red blood cell numbers and morphology in IPAH, associated PAH and sleep apnea-induced pulmonary hypertension patients in comparison to healthy controls and asthmatics. Despite similarly normal measures of iron metabolism, Zn-pp levels in IPAH and sleep apnea patients were elevated approximately twofold, indicating deficient iron incorporation to form heme and levels were closely related to measures of disease severity. Consistent with high Zn-pp, PAH patients had increased red cell distribution width (RDW). In an expanded cohort including patients with IPAH and familial disease, the RDW was validated and related to clinical parameters of severity; including pulmonary artery pressures and 6-minute walk distances. These results reveal an increased prevalence of subclinical functional iron deficiency in primary forms of PAH that is quantitatively related to disease severity. This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients.

Figure 1

Zinc‐protoporphyrin/heme ratio (μmol/mol heme) is increased in IPAH and sleep apnea PH patients. Zn‐pp is increased in IPAH and sleep apnea PH patients compared to controls, asthmatics, and APAH patients (p= 0.02).

Figure 2

Rouleaux formation in IPAH blood smears. The peripheral blood smears of IPAH patients (A) shows increased rouleaux formation compared to control subjects (B).

Figure 3

Zn‐pp is related to disease severity in IPAH. (A) Zn‐pp and pulmonary arterial systolic pressure in IPAH. In IPAH patients, the pulmonary artery systolic pressures increase with increasing Zn‐pp levels (R= 0.63, p= 0.02). (B) Zn‐pp and 6‐minute walk distance in IPAH. Functional status as assessed by distance able to walk within 6 minutes is inversely related to Zn‐pp levels (R=–0.57, p= 0.04).

Figure 4

RDW and parameters of disease severity in IPAH and FPAH. (A) RDW parallels pulmonary arterial systolic pressures (R= 0.47, p= 0.01). (B) RDW is inversely associated to 6‐minute walking distance (R=–0.52, p= 0.01). Open circles, FPAH; closed circles, IPAH.