To the editor:

Ceruloplasmin plays a major role in iron mobilization from the tissues stores through its ferroxidase activity.1,2  Hereditary aceruloplasminemia is an autosomal recessive iron overload disorder resulting from mutations in the ceruloplasmin gene.3,4  Acquired hypoceruloplasminemia is observed in copper deficiency, which has been reported to cause anemia, neutropenia,5  and, more recently, neurologic manifestations like myeloneuropathy with sensory ataxia and spastic gait.6  We report here the first case of iron overload related to acquired aceruloplasminemia in a patient suffering from copper deficiency.

A 57-year-old male presented severe normocytic nonregenerative anemia (Hb 3 g/dL; normal range, 12-16 g/dL) associated to leukoneutropenia (1.3 × 103 leukocytes, normal range, 4-10 × 103; neutrophils 0.23 × 103; normal range, 1.5-7 × 103) with dysplastic marrow (dyserythropoiesis, hypogranular neutrophils, hyposegmented megakaryocytes), severe sensory gait ataxia, and a pure nephrotic syndrome (with minimal glomerular changes). Spinal cord MRI showed increased T2 signal involving the dorsal column. Corticosteroids were ineffective. Serum copper and ceruloplasmin concentration were markedly decreased at 0.2 μM (normal range, 12.5-24 μM) and 0.02 g/L (normal range, 0.18-0.6 g/L), respectively. Urinary copper excretion was low at 0.2 μM (normal range, 0-1.6 μM). The patient was treated during 4 months by oral copper supplementation. Responses of the hematologic, copper, and ceruloplasmin parameters were prompt and complete within 2 months. Proteinuria disappeared within 8 months. Neurologic symptoms improved gradually and, 3 years later, ataxia was no longer present.

A special diagnostic aspect was major iron overload syndrome with plasma ferritin 2687 μg/L (normal range, 55-345 μg/L) and hepatic iron concentration (magnetic resonance imaging [MRI]) 230 μmol/g (N < 36 μmol/g dry weight). In contrast, serum iron, transferrin saturation and total ferroxidase activity7  were decreased at 4.3 μM (normal range, 12.5-25 μM), 8.6% (normal range, 23%-45%), and 0 IU/L (normal range, 482-614 IU/L), respectively. During follow-up, all biochemical iron parameters returned progressively to normal, including ferroxidase activity (443 IU/L). Liver iron overload decreased gradually and dramatically at MRI controls (60 μmol/g).

Severe copper deficiency was not due to chronic intestinal dysfunction. Whether it was related to zinc excess (zincemia was 21.3 μM, normal range, 12.5-18 μM), originating in the use of denture cream,8  is a possibility. The role of the nephrotic syndrome toward copper deficiency9  was unlikely because urinary copper was low and severe copper deficiency is not part of the usual clinical description of the nephrotic syndrome. Whether, conversely, copper deficiency played a causative role in the nephrotic syndrome remains an open issue. The present case revealed an interesting and novel situation of iron overload, related to acquired aceruloplasminemia. Hereditary aceruloplasminemia was ruled out on both genetic (no mutation was found in ceruloplasmin coding sequence) and family studies. The disappearance of iron overload under copper supplementation, with concomitant total restoration of plasma ferroxidase activity, represents a strong argument for attributing the iron disorder to aceruloplasminemia. Iron excess had no clinical expression in our patient. At variance with hereditary aceruloplasminemia, no MRI iron excess could be found within basal ganglia and no retinal degeneration was present.

Iron overload due to copper deficiency–related aceruloplasminemia represents a novel, easily treatable form of secondary iron excess, and provides further illustration of the close connection between iron and copper metabolism.10 

Acknowledgments: This study was supported by funding from EEC FP6 Euroiron1, LSHM-CT-2006-037296, Centre de Référence des Surcharges en Fer Rares d'origine Génétique, and Association Fer et Foie.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Dr Pierre Brissot, Service des Maladies du Foie, Hôpital Pontchaillou, Rue Henri le Guilloux, Rennes, France 35033; e-mail: pierre.brissot@univ-rennes1.fr.

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