Iron-Deficiency Anemia in Castleman Disease: Implication of the Interleukin 6/Hepcidin Pathway

Abstract

In addition to occasional autoimmune hemolytic anemia, unexplained iron-deficiency anemia has been reported in childhood Castleman disease (CD). The recent discovery of hepcidin has regenerated the research on iron metabolism. This hormone is a key regulator of iron homeostasis, mainly by inhibiting intestinal iron absorption. Liver expression of hepcidin increases in response to interleukin 6 (IL-6). With chronic overproduction of IL-6 as a hallmark, CD could be an interesting human model for studying the contribution of the IL-6/hepcidin pathway in the pathogenesis of anemia of chronic disease. We report here the case of a 16-year-old boy with chronic iron-deficiency anemia (plasma ferritin: 19 μg/L; plasma iron: 2.2 μmol/L; negative bone marrow Perls' Prussian blue stain), inflammatory syndrome (C-reactive protein: 108 mg/L), and growth retardation for the previous 2 years. Diagnostic workup revealed a large mesenteric mass corresponding to localized CD of mixed histologic type. Resection of the tumor resulted in complete resolution of iron-deficiency anemia and inflammatory syndrome. Parallel variations of plasma IL-6, C-reactive protein, and hepcidin concentrations, together with tumor immunohistochemistry, strongly suggested that IL-6 synthesized by the tumor caused both the inflammation and iron deficiency through enhancement of hepcidin production by the liver. The results of this unique case study (1) explain the mechanism of iron deficiency observed in some children with CD, (2) confirm in vivo the regulatory effect of IL-6 in human hepcidin production, and (3) suggest that iron deficiency is a causal link between IL-6 and anemia of chronic disease.

Anemia associated with increased hepcidin in two children with Castleman disease

“…The regulation of hepcidin synthesis by IL‐6 has been found to be an important component in the pathogenesis of anemia in chronic disease . Hepcidin‐25, the bioactive form of hepcidin, secreted by hepatocytes, is a significant regulator of iron homeostasis, and is usually elevated in CD . In the present two cases, serum hepcidin‐25 was elevated, and decreased after resection of the tumor.…”

Castleman Disease: The Great Mimic

“…Abnormal proliferations of polyclonal plasmablasts are found in the mantle zone of B-cell follicles, either in the form of isolated cells or aggregates (9). Recently, in a case of mixed Castleman disease, the IL-6-related increase of the hormone hepcidin has been associated with iron deficiency anemia, which resolved after tumor resection (14). Increased IL-6 stimulates the production of C-reactive protein by hepatocytes, which contributes to the inflammatory syndrome (13).…”

Anemia and autoimmunity markers in an adolescent with Castleman disease

“…The raised IL‐6 may have induced hepcidin synthesis, as has been previously reported, but it was not possible to measure that due to technical reasons. The association of IL‐6 and hepcidin was also noted in six patients with anemia of inflammation due to multicentric CD .…”