Plasma Chromogranin A as a marker of cardiovascular involvement in Erdheim–Chester disease

ABSTRACT

Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis (LCH) characterized by tissue infiltration with CD68⁺ foamy histiocytes. TNF-related chronic inflammation and mutations in the MAP kinase signaling pathway in histiocytes are recognized as the two major pathogenic events. Among pleomorphic clinical manifestations, cardiovascular involvement is frequent and prognostically relevant. Evaluation of ECD clinical course and response to treatment is, however, still challenging. Taking advantage of the two largest cohorts of ECD patients worldwide, we investigated the relevance and the potential of circulating Chromogranin A (CgA), a pro-hormone involved in cardiovascular homeostasis and inflammation, as a biomarker of response to therapy in ECD. Consistent with other TNF-related inflammatory diseases, we found that not only TNF-α and soluble TNF-Receptors (sTNF-Rs), but also CgA plasma levels were significantly increased in ECD patients compared to controls. CgA, but not sTNF-Rs, discriminated cardiovascular involvement in ECD patients and correlated with pro-Brain Natriuretic Peptide (pro-BNP). In a single case, where a cardiac biopsy was available, CgA was found expressed by cardiomyocytes but not by infiltrating histiocytes. In four ECD patients, where serial determination of these parameters was obtained, the kinetics of sTNF-Rs and CgA paralleled response to therapy with anti-cytokine inhibitors; specifically, sTNF-Rs overlapped TNF-associated inflammation, while CgA, together with pro-BNP, closely mirrored response of cardiac disease. Our data indicate that both sTNF-Rs and CgA are linked to ECD pathophysiology. Moreover, CgA, in concert with pro-BNP, can be further exploited to fulfill the unmet clinical need of non-invasive reliable biomarkers of cardiac disease in these patients.

KEYWORDS:

• Chromogranin A
• chronic inflammation
• Erdheim–Chester disease
• histiocytes
• soluble TNF-Receptors
• TNF-α

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank Kathy Brewer and the ECD Global Alliance (De Ridder, LA) for their continuous activities for patients with Erdheim–Chester disease and their unceasing support. We also thank Dr Barbara Vergani (Consorzio MIA) for histological analyses; Dr Giliola Calori (San Raffaele Scientific Institute) for her assistance in statistical analyses; and Dr Andrea Motta (San Raffaele Scientific Institute) for pro-BNP determination.

Funding

The work was supported in part by a Grant from the Italian Ministry of Health (GR 2009-1594586 to LD) and by a grant from ECD Global Alliance (to MF & LD).