Combination‐therapy with concurrent deferoxamine and deferiprone is effective in treating resistant cardiac iron‐loading in aceruloplasminaemia

Abstract

(2013) High-dose cyclophosphamide compared with antithymocyte globulin for treatment of acquired severe aplastic anemia. Experimental Hematology, 41, 328-334.Combination-therapy with concurrent deferoxamine and deferiprone is effective in treating resistant cardiac iron-loading in aceruloplasminaemia Aceruloplasminaemia is a rare disorder of iron metabolism with a prevalence of around 1 in 2 million people (Miyajima, 2015). Ceruloplasmin, a plasma ferroxidase, is involved in the oxidation of ferrous (Fe 2+ ) iron so that it can be released from intracellular stores to be transported by transferrin. Absence or dysfunction of ceruloplasmin leads to iron accumulation, mainly in the liver, pancreas and central nervous system (CNS). We report the combined use of two iron-chelating drugs, deferiprone (DFP) and deferoxamine for the management of iron overload with resistant cardiac ironloading in a patient with aceruloplasminaemia. Although potentially beneficial, treatment with DFP has not hitherto been described in managing this condition.A 28-year-old man with a provisional diagnosis of Ehlers Danlos syndrome Type III with Raynaud syndrome was referred after persistently high alanine aminotransferase levels (109 u/l) were noted. Neurological examination was normal. Blood tests showed a high serum ferritin (1766 lg/l), markedly low serum copper [0Á09 lmol/l, normal range (NR) 11-20] and ceruloplasmin levels <0Á07 g/l (NR 0Á2-0Á6), leading to a diagnosis of aceruloplasminaemia. A T2 magnetic resonance imaging (MRI) brain scan demonstrated hypointensities within the dentate nuclei, red nuclei, substantia nigra and globus pallidi, reflecting increased iron deposition. T2* MRI showed moderate iron loading in the liver (1Á86 ms) and heart (11Á9 ms). A liver biopsy revealed severe iron loading (19 mg/g dry weight). There was no clinical evidence of endocrine dysfunction. Thyroid function tests (thyroid-stimulating hormone 0Á35 mu/l, free thyroxine 14Á4 pmol/l) and a fasting blood glucose (5Á4 mmol/l) test were normal.The oral iron-chelating agent DFP was commenced at 1Á5 g/d and was increased over 1Á5 months to a target dose of 5Á5 g/d given in 3 divided doses (75 mg/kg/d). As there was CNS involvement DFP was used due to its ability to cross the blood-brain barrier and intracellular membranes (Pandolfo & Hausmann, 2013). After 6 months on this dose the serum ferritin had decreased to 1309 lg/l. The patient had weekly blood checks for the first month, then monthly thereafter, to monitor for agranulocytosis. DFP was well tolerated during this phase, with no gastrointestinal disturbance, or arthropathy. Blood tests showed stable haematological parameters and improving transaminase levels. A T2* MRI performed 18 months after the commencement of treatment showed improving mild liver iron-loading (3Á35 ms), but unimproved moderate cardiac ironloading (13Á0 ms) with normal cardiac function. This was surprising given the efficacy of DFP in alleviating cardiac iron-loading in patients with thalassemia (Pennell et al, 2006). In...

Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

“…In non-Japanese case series, retinopathy is far less frequent, and its attribution to ACP per se is often uncertain (Pelucchi et al, 2018). Finally, iron overload in other organs, such as heart and endocrine glands other than pancreas, has been sporadically reported in both Caucasian and Japanese patients, but the true prevalence may be actually under-investigated (Miyajima and Hosoi, 1993–2018; Badat et al, 2015). …”

Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports

“…At low transferrin saturation, deferiprone additionally mediates shuttling of iron from excess iron stores to erythroid cells by transferring iron to transferrin [6]. However, deferiprone monotherapy is not highly effective in reducing body iron stores in aceruloplasminemia [7,8], and needs to be combined with another chelator to achieve satisfactory rates of iron removal [8][9][10]. The deferiprone-induced redistribution of iron to hematopoietic tissues might permit a combination with phlebotomy as a new therapeutic approach for aceruloplasminemia.…”

Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature

“…We compared the present case with previous ones, limited to those referring to iron chelation therapy (Table) (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Neurological symptoms were improved in 5 of 10 cases (50%), including ours.…”