Iron metabolism disorders of patients with chronic paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its reproduction. However, Paracoccidioides spp. can evade the immune defense and, even under limited iron conditions, use this mineral for growth and dissemination. This study evaluated the iron metabolism of 39 patients who were diagnosed with chronic PCM from 2013 to 2021. The forms of iron before treatment and at the time of clinical cure were evaluated based on the following: serum ferritin levels (storage iron); total iron-binding capacity (TIBC) and transferrin saturation (TSAT) level (transport iron); red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), and soluble transferrin receptor (sTfR) levels; and sTfR/log ferritin ratio (functional iron). The mean age of the patients was 54.5 years (±6.7 years). Most patients were men (97.4%), rural workers (92.1%), and smokers (84.6%); furthermore, most had moderate disease severity (66.7%). After achieving clinical cure, we observed that serum ferritin levels decreased, and parameters of functional iron increased. The extent of alteration in these parameters were more pronounced in severe cases than in to mild or moderate cases. Furthermore, moderate correlations were observed between C-reactive protein and the Hb (r = -0.500; p = 0.002), RBC (r = -0.461; p = 0.005), HCT (r = -0.514; p = 0.001), and iron levels (r = -0.491; p = 0.002). However, it is possible to infer that PCM interferes with functional and storage iron because improvements in these parameters after treatment as well as associations with disease severity were observed. PCM can lead to anemia of inflammation, which can be differentiated from iron deficiency anemia by a careful investigation of the iron form parameters.

Economic impact of ferric carboxymaltose in haemodialysis patients / Impatto economico dell'utilizzo di carbossimaltosio ferrico nei pazienti in emodialisi

Intravenous iron supplementation is essential in hemodialysis (HD) patients to recover blood loss and to meet the requirements for erythropoiesis and, in patients receiving erythropoietin, to avert the development of iron deficiency. In a recent real-world study, Hofman et al. showed that a therapeutic shift from iron sucrose (IS) to ferric carboxymaltose (FCM) in HD patients improves iron parameters while reducing use of iron and erythropoietin. The objective of this economic analysis is to compare the weekly cost of treatment of FCM vs IS in hemodialysis patients in Italy. The consumption of drugs (iron and erythropoietin) was derived from Hofman's data, while the value was calculated at Italian ex-factory prices. The analysis was carried on the total patient sample and in two subgroups: patients with iron deficiency and patients anemic at baseline. In addition, specific sensitivity analyses considered prices currently applied at the regional level, simulating the use of IS vs iron gluconate (FG) and epoetin beta vs epoetin alfa. In the base-case analysis, the switch to FCM generates savings of -€12.47 per patient/week (-21%) in all patients, and even greater savings in the subgroups with iron deficiency -€17.28 (-27%) and in anemic patients -€23.08 (-32%). Sensitivity analyses were always favorable to FCM and confirmed the robustness of the analysis. FCM may represent a cost-saving option for the NHS, and Italian real-world studies are needed to quantify the real consumption of resources in dialysis patients.

Intravenous ferric carboxymaltose for iron deficiency anemia or iron deficiency without anemia after poor response to oral iron treatment: Benefits and risks in a cohort of 144 children and adolescents.

OBJECTIVE: The objective of this single-center observational study was to determine the clinical and hematologic responses to intravenous ferric carboxymaltose (FCM) in a cohort of pediatric patients with poor response to oral iron therapy. The occurrence of adverse events was systematically recorded for up to 96 hours after infusion. STUDY DESIGN: A retrospective cohort of 144 consecutive patients aged 18 months to < 18 years with iron deficiency anemia (IDA) or iron deficiency (ID) without anemia was investigated. All patients had failed oral iron therapy. The assessments before and after FCM treatment followed a predefined protocol. RESULTS: One hundred of 117 (85 %) of patients with complete data achieved the target ferritin level ≥ 30 µg/L after a single FCM dose. Of 77 patients with IDA and complete data, 38 (49%) showed a complete hematological response within 6-12 weeks; a complete or partial response was achieved by 83%. Clinical symptoms improved in 85% of all patients. In 92% of patients (n = 133 /144), FCM infusion was uneventful. During the 96-hour follow-up, five patients reported potentially related symptoms. No serious adverse events occurred. CONCLUSION: The study confirms the safety and efficacy of FCM in children (aged 18 months and older) and adolescents unresponsive to oral therapy, in real-world experience. Single-dose FCM treatment was followed by clinical improvement with advantages of safety, compliance, and lower cost compared with previous generation parenteral iron preparations that had to be administered in fractionated sessions.

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

BACKGROUND: Aceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. The effects of iron chelation on neurological outcomes have only been described in case studies, and are inconsistent. Aggregated case reports were analyzed to help delineate the disease-modifying potential of treatment. METHODS: Data on clinical manifestations, treatment and neurological outcomes of treatment were collected from three neurologically symptomatic Dutch patients, who received deferiprone with phlebotomy as a new therapeutic approach, and combined with other published cases. Neurological outcomes of treatment were compared between patients starting treatment when neurologically symptomatic and patients without neurological manifestations. RESULTS: Therapeutic approaches for aceruloplasminemia have been described in 48 patients worldwide, including our three patients. Initiation of treatment in a presymptomatic stage of the disease delayed the estimated onset of neurological manifestations by 10 years (median age 61 years, SE 5.0 vs. median age 51 years, SE 0.6, p = 0.001). Although in 11/20 neurologically symptomatic patients neurological manifestations remained stable or improved during treatment, these patients were treated significantly shorter than patients who deteriorated neurologically (median 6 months vs. median 43 months, p = 0.016). Combined iron chelation therapy with deferiprone and phlebotomy for up to 34 months could be safely performed in our patients without symptomatic anemia (2/3), but did not prevent further neurological deterioration. CONCLUSIONS: Early initiation of iron chelation therapy seems to postpone the onset of neurological manifestations in aceruloplasminemia. Publication bias and significant differences in duration of treatment should be considered when interpreting reported treatment outcomes in neurologically symptomatic patients. Based on theoretical grounds and the observed long-term safety and tolerability in our study, we recommend iron chelation therapy with deferiprone in combination with phlebotomy for aceruloplasminemia patients without symptomatic anemia.

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

The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.

Iron deficiency in pregnancy.

Iron is essential for the function of all cells through its roles in oxygen delivery, electron transport, and enzymatic activity. Cells with high metabolic rates require more iron and are at greater risk for dysfunction during iron deficiency. Iron requirements during pregnancy increase dramatically, as the mother's blood volume expands and the fetus grows and develops. Thus, pregnancy is a condition of impending or existing iron deficiency, which may be difficult to diagnose because of limitations to commonly used biomarkers such as hemoglobin and ferritin concentrations. Iron deficiency is associated with adverse pregnancy outcomes, including increased maternal illness, low birthweight, prematurity, and intrauterine growth restriction. The rapidly developing fetal brain is at particular risk of iron deficiency, which can occur because of maternal iron deficiency, hypertension, smoking, or glucose intolerance. Low maternal gestational iron intake is associated with autism, schizophrenia, and abnormal brain structure in the offspring. Newborns with iron deficiency have compromised recognition memory, slower speed of processing, and poorer bonding that persist despite postnatal iron repletion. Preclinical models of fetal iron deficiency confirm that expected iron-dependent processes such as monoamine neurotransmission, neuronal growth and differentiation, myelination, and gene expression are all compromised acutely and long term into adulthood. This review outlines strategies to diagnose and prevent iron deficiency in pregnancy. It describes the neurocognitive and mental health consequences of fetal iron deficiency. It emphasizes that fetal iron is a key nutrient that influences brain development and function across the lifespan.

Palliative care in 9 children with neurodegeneration with brain iron accumulation.

AIM: Evaluation of pediatric palliative home care of families with children suffering from neurodegeneration with brain iron accumulation (NBIA) and their parents. MATERIAL AND METHODS: The children were treated at home by a multidisciplinary team. Densitometry was used to evaluate the condition of the skeletal system. Botulinum toxin was injected into the muscles in doses between 22 and 50 units/kg. The quality of palliative care was assessed on the basis of a specially designed questionnaire for parents. RESULTS: The observations were performed on a group of 9 patients with NBIA. On admission, the median age of patients was 9 years (7-14). The average time of palliative home care was 1569 days (34 days-17 years). The median age at death (6 patients) was 11 years (7-15). The botulinum toxin injections gave the following results: reduction of spasticity and dystonia, reduction of spine and chest deformation, relief of pain and suffering, facilitation of rehabilitation and nursing, prevention of permanent contractures, and reduction of excessive salivation. Bone mineral density and bone strength index were reduced. Two patients experienced pathological fracture of the femur. The body mass index at admission varied between 9.8 and 14.9. In 7 cases, introduction of a ketogenic diet resulted in the increase of body mass and height. The ketogenic diet did not worsen the neurological symptoms. The parents positively evaluated the quality of care. CONCLUSION: Palliative home care is the optimal form of treatment for children with NBIA.

The safety and efficacy of ferumoxytol in the treatment of iron deficiency: a systematic review and meta-analysis.

INTRODUCTION: Ferumoxytol is an intravenous (IV) iron formulation for treatment of iron deficiency (ID) that faced post-marketing reports of serious adverse events (SAEs). OBJECTIVES: To determine the safety and efficacy of ferumoxytol compared to other iron formulations and placebo. METHODS: We searched the Cochrane Library, Medline, and EMBASE from inception until February 2018 as well as trial registries and reference lists of relevant articles for randomized or quasi-randomized controlled trials. RESULTS: The review included nine studies with 5691 participants. Studies were at low risk of bias. When comparing ferumoxytol to other IV iron formulations, there is moderate quality evidence (QE) of little to no difference in treatment emergent adverse events (TEAEs) (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.80-0.97), treatment related adverse events (TRAEs) (RR 0.73, 95% CI 0.61-0.88), SAEs (RR 1.13, 95% CI 0.77-1.67), hypotension or hypersensitivity reactions (RR 0.58, 95% CI 0.31-1.09), or composite cardiovascular outcomes (RR 0.56, 95% CI 0.24-1.29), low QE of little to no difference in related SAEs (RR 0.55, 95% CI 0.05-6.16), and high QE of little to no difference in the number of patients with an increase in hemoglobin by at least 1 g/dL (RR 1.04, 95% CI 0.96-1.12). Ferumoxytol had less TEAEs compared to oral iron (RR 0.78, 95% CI 0.61-0.98), but more compared to placebo (RR 1.62, 95% CI 1.01-2.61). DISCUSSION: Ferumoxytol is as efficacious and safe as alternative IV iron formulations with no clear safety concerns.

[Iron and stable ischemic heart disease - lessons from heart failure]. / Ferro e cardiopatia ischemica stabile ­ lezioni dallo scompenso cardiaco.

Iron is an essential element for cardiomyocyte viability and contractility. Systemic iron deficiency, even without anemia, is reflected by iron deficiency in cardiomyocytes. As in other cells, there is here a complex, local and autonomous regulation of iron metabolism, based on two molecular systems: the hepcidin/ferroportin/transferrin receptor-1 axis; and the iron regulatory proteins-1,2 system. These molecular pathways allow cardiomyocytes to react to changes in serum iron availability. In mice, dietary manipulations of serum iron availability or cardio-specific deletions and mutations of regulatory genes for intracellular iron metabolism have clarified some aspects of the causal relationship between cardiomyocyte iron deficiency and the development of severe heart failure, prevented by intravenous iron treatment even without the occurrence of iron deficiency (sideropenic) anemia. The deleterious effects of iron deficiency and hypoxia on gene expression of the main regulators of intracellular iron and oxygen metabolism and on cardiac function are very similar in heart failure and in chronic stable ischemic heart disease, and conjure towards cardiomyocyte injury. We here hypothesize that in non-anemic patients with stable ischemic heart disease a chronic or acute serum iron deficiency can amplify the chronic activation of the cardiomyocyte hypoxia-inducible factor-1α. As a consequence, cardiac adaptative responses to chronic hypoxia/ischemia are significantly impaired, and cardiac dysfunction exacerbated. We hypothesize that, in such patients, iron replacement through forced iron supplementation may replete cardiomyocyte iron deficiency and improve ischemic heart disease. This hypothesis requires further experimental studies, but also, and already now, specific clinical trials.

The treatment of black stain associated with of iron metabolism disorders with lactoferrin: a litterature search and two case studies.

Among the various pathologies of the oral cavity, the formation of "unsightly black spots" on the surface of the tooth, universally known as Black Stain (BS) has recently been acquiring more interest. Usually BS is typically found in individuals in prepubertal age, even though it has been identified in adults associated with microbial exchange and / or with iron metabolism disorders. Microbial exchange concerns the possible exchange of bacteria between family members which can take place directly, through effusions, or indirectly, through brushes, cutlery or glasses. For this reason, it is recommended that toothbrushes of family members not be left damp and in contact with each other. The bathroom, being a warm-humid environment, is in fact an optimal habitat for microbial proliferation. Of specific importance in BS is the accumulation of iron in tissues and secretions which, together with chromogenic bacteria, are the primary cause of this pathology. In fact, among the metabolic products synthesized by bacteria in the oral cavity, hydrogen sulfide is of considerable interest, since upon reacting with iron available in saliva, in pathological conditions (iron metabolism disorders), it forms black precipitates consisting of ferric sulfide. These precipitates bind to the surface of the teeth, tending to form a stria that usually follows the contour of the gingiva, with an unsightly and variable chromatic intensity. In physiological situations, iron homeostasis is defined as the state of equilibrium between iron present in tissues and in secretions and that which is present in the circulation. Instead, in pathological conditions, defined as iron metabolism disorders, there is an accumulation of iron in tissues and secretions and a lack of it in the circulation. It is also important to remember that subjects affected by BS are more protected from carious processes than healthy subjects, probably due to a significant predominance of chromogenic bacteria compared to those responsible for caries. It should also be remembered that in young subjects BS tends to regress with pubertal development and the transition to adult life. In any case, using common professional hygiene procedures, it is possible to remove BS as well as plaque and tartar deposits. In particular, with ultrasonic scalers, polishing pastes and powders carried by air and water jets, the surfaces of the teeth can be restored to their natural healthy state. All the techniques for removing the precipitates, are not enough however, to fix and permanently eradicate their appearance, as these precipitates last only for short periods and recur very frequently. Due to the frequent recurrences, new oral microbiota control therapies are emerging; among these the use of lactoferrin (Lf) in the dental field and particularly in the treatment of BS appears to be very promising. Taken togheter, here the effect of Lf in subjects affected by BS has been investigated.

Anaemia and iron dysregulation: untapped therapeutic targets in chronic lung disease?

Hypoxia is common in many chronic lung diseases. Beyond pulmonary considerations, delivery of oxygen (O2) to the tissues and subsequent O2 utilisation is also determined by other factors including red blood cell mass and iron status; consequently, disruption to these mechanisms provides further physiological strains on an already stressed system. O2 availability influences ventilation, regulates pulmonary blood flow and impacts gene expression throughout the body. Deleterious effects of poor tissue oxygenation include decreased exercise tolerance, increased cardiac strain and pulmonary hypertension in addition to pathophysiological involvement of multiple other organs resulting in progressive frailty. Increasing inspired O2 is expensive, disliked by patients and does not normalise tissue oxygenation; thus, other strategies that improve O2 delivery and utilisation may provide novel therapeutic opportunities in patients with lung disease. In this review, we focus on the rationale and possibilities for doing this by increasing haemoglobin availability or improving iron regulation.

Treatment options for anemia in the elderly.

Anemia in elderly (AE), though often mild, is quite common and independently associated with important clinical outcomes, including decreased quality of life, risk of falls and fractures, cognitive decline, increased length of hospital stay, and even mortality. AE is generally overlooked, and hence undertreated, especially when comorbidities distract the attention of physicians and caregivers. This also partially reflects difficulties in dissecting the cause(s) of AE, which is typically multifactorial, as well as our limited diagnostic approach often categorizing AE as apparently "unexplained". Therapeutic approaches have been traditionally limited to transfusions, or supplementation with hematinics, including group B vitamins and iron. The latter has been largely underutilized, because of missing diagnosis of iron deficiency using inappropriate laboratory thresholds, as well as complex schedule and adverse effects associated with traditional preparations. After decades of stagnation, new oral and intravenous iron preparations look promising, particularly in the elderly. Moreover, a number of innovative anti-anemic drugs, like hepcidin modulators, Hypoxia Inducible Factor (HIF) stabilizers, and activin type II receptor agonists are entering the clinical arena and may substantially improve our therapeutic armamentarium to AE in the near future.

Retrospective analysis into differences in heart failure patients with and without iron deficiency or anaemia.

AIMS: The aim of this study was to assess the burden of heart failure (HF) patients with/without iron deficiency/iron deficiency anaemia (ID/A) from the health insurance perspective. METHODS AND RESULTS: We conducted a retrospective claims database analysis using the Institut für angewandte Gesundheitsforschung Berlin research database. The study period spanned from 1 January 2012 to 31 December 2014. HF patients were identified by International Statistical Classification of Diseases and Related Health Problems, 10th revision, German Modification codes (I50.-, I50.0-, I50.00, I50.01, I50.1-, I50.11, I50.12, I50.13, I50.14, I50.19, and I50.9). HF patients were stratified into HF patients without ID/A and HF patients with ID/A (D50.-, D50.0, D50.8, D50.9, and E61.1). HF patients with ID/A were stratified into three subgroups: no iron treatment, oral iron treatment, and intravenous iron treatment. A matching approach was applied to compare outcomes for HF patients without ID/A vs. HF patient with untreated incident ID/A without iron treatment and for HF patients receiving no iron treatment vs. oral iron treatment vs. intravenous iron treatment. Matching parameters included exact age, sex, and New York Heart Association functional class. An optimization algorithm was used to balance total health care costs in the baseline period for the potential matched pairs without sample size reduction. In total, 172 394 (4537.4 per 100 000) HF patients were identified in the Institut für angewandte Gesundheitsforschung Berlin research database in 2013. Of these, 11.1% (19 070; 501.9 per 100 000) were diagnosed with ID/A and/or had a prescription for iron medication in 2013. The mean age of HF patients was 77.0 years (±12.0 years). Women were more frequently diagnosed with HF (54.6%). HF patients with untreated incident ID/A (1.77%) had a significantly higher all-cause mortality than HF patients without ID/A (33.1% vs. 24.1%, P < 0.01). The analysis of health care utilization revealed significant differences in the rate of all-cause hospitalization (72.9% vs. 50.5%, P < 0.01). The annual health care costs for HF patients with untreated incident ID/A amounted to €17 347 with incremental costs of €849 (P < 0.01) attributed to ID/A. CONCLUSIONS: Heart failure is associated with a major burden for patients and the health care system in terms of health care resource utilization, costs, and mortality. Our findings suggest that there is an unmet need for treating more HF patients with ID/A with iron medication.

Effect of ferric carboxymaltose on calculated plasma volume status and clinical congestion: a FAIR-HF substudy.

AIMS: Iron deficiency worsens symptoms, quality of life, and exercise capacity in chronic heart failure (CHF) and might do so by promoting fluid retention. We assessed whether iron repletion improved congestion in CHF and appraised the prognostic utility of calculated plasma volume status (PVS), a novel index of congestion, in the FAIR-HF data set. METHODS AND RESULTS: In FAIR-HF, 459 iron deficient CHF patients were randomized to intravenous ferric carboxymaltose (FCM) or saline and assessed at 4, 12, and 24 weeks. Using weight and haematocrit, we calculated PVS in 436 patients. At baseline, PVS and weight were -5.5 ± 7.7% and 76.9 ± 14.3 kg, with peripheral oedema evident in 35% of subjects. Higher PVS values correlated to other congestion surrogates such as lower serum albumin. At 4 weeks, FCM was associated with greater reductions in weight (0.02) and PVS (P < 0.0001), and a trend for improved peripheral oedema at 24 weeks (0.07). Irrespective of treatment allocation, patients with a decrease in PVS from baseline to week 24 had higher increments in 6 min walking distance (61.4 m vs. 43.5 m, 0.02) and were more likely to improve their NYHA class (33.3% vs. 15.5%, 0.001). A PVS > -4% at baseline predicted worse outcomes even after adjustment for treatment assignment (hazard ratio 1.88, 95% confidence interval 1.01-3.51, 0.046). CONCLUSIONS: Intravenous iron therapy with FCM is associated with early reductions in PVS and weight, implying that decongestion might be one mechanism via which iron repletion aids CHF patients. Calculated PVS is of prognostic utility in this cohort.

Budget impact of intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency in France.

AIMS: This analysis aims to evaluate the budget impact of intravenous iron therapy with ferric carboxymaltose for patients with systolic chronic heart failure and iron deficiency, from the perspective of the French public health insurance. METHODS AND RESULTS: A budget impact model was adapted to forecast the budget impact over 5 years, according to two scenarios: one where patients receive ferric carboxymaltose according to market share forecast and another where patients are not treated for iron deficiency. Clinical data were extrapolated from pooled data from four randomized controlled trials. The time horizon was extended to 5 years by applying transition probabilities estimated from the CONFIRM-HF trial. Epidemiological parameters for France were derived from the literature. Cost parameters were derived from national available databases. In the base case analysis, the modelled 5 year cost difference between the scenarios with ferric carboxymaltose vs. no iron deficiency treatment in a population of 189 334 prevalent and incident patients led to €0.8m savings. The cumulative savings resulted from a reduction in the hospitalization costs associated with worsening heart failure (€-35.8m) as well as a reduction in the follow-up costs (€-2.9m). These cost savings outweighed the costs of ferric carboxymaltose treatment (€37.7m). Sensitivity analyses showed that the budget impact varied from €-34m to €+146m. Parameters with the most impact on the budget were the hospitalization rate for patients not treated for iron deficiency, the number of ambulatory sessions needed, the absence of hospitalization cost differentiation between New York Heart Association classes, and administration settings costs. CONCLUSIONS: Iron deficiency treatment with ferric carboxymaltose in systolic chronic heart failure patients results in an improvement of New York Heart Association class and thereby increases the well-being of the patients, while providing an overall cost saving for the French national health insurance.

Iron Metabolism: An Emerging Therapeutic Target in Critical Illness.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia.

INTRODUCTION: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. METHODS: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. RESULTS: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. CONCLUSION: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy.

Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia.

Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.