Simona Roggero

High nontransferrin bound iron levels and heart disease in thalassemia major

Although the presence of nontransferrin bound plasma iron (NTBI) in transfusional iron overload is well documented, knowledge about its clinical significance is limited. We assessed NTBI levels in a large and homogeneous series of thalassemia patients on regular transfusion and chelation and explored the hypothesis that NTBI levels may be associated with relevant clinical outcomes: in particular, heart disease. Among 174 patients with thalassemia major and intermedia, we showed the presence NTBI in 145 of 174 or 83.3% of cases. NTBI levels correlated with transferrin saturation, age, and ALT, and not with serum ferritin or liver iron concentrations. At a multiple regression analysis, transferrin saturation and heart disease but not age was independent predictors of NTBI. Patients with heart disease had NTBI levels significantly higher than those without. All patients with heart disease had transferrin saturation above 70%, and all were NTBI positive. Conversely, none of the patients without NTBI and/or with transferrin saturation less than 70% had preclinical or clinical heart disease. To our knowledge, this is the first documentation of a link between the presence of NTBI in thalassemic patients with transfusional iron overload and heart disease. Further investigation from these preliminary findings may clarify whether NTBI assessment may have a role in evaluating the risks and optimizing treatment for transfusion‐dependent patients. Am. J. Hematol., 2009.

Severe iron overload in Blackfan-Diamond anemia: a case-control study.

Chronic iron overload is a serious complication in transfusion‐dependent patients. Few studies have addressed this issue in Diamond‐Blackfan anemia (DBA). We describe a retrospective analysis of iron overload, and its related complications in 31 transfusion‐dependent Italian DBA patients whose records included one or more evaluation of liver iron concentration (LIC) by means of noninvasive magnetic liver susceptometry with a superconductive quantum interference device (SQUID). This cohort is also matched with a group of transfusion‐dependent β‐thalassemia major patients to look for differences. A severe iron overload was observed in 54% patients, especially among those inadequately chelated. The DBA patients displayed a significantly higher LIC than the regularly chelated β‐thalassemics. This difference may have been attributable to nonoptimal chelation (late onset, type, dose, prescription, and compliance), or an unknown biological mechanism that lead to an early severe iron overload. We therefore suggest that all transfusion patients should have an accurate record of their iron intake, a regular monitoring of iron overload, in order to start chelation when a critical transfusion load is reached, and to test the efficacy/compliance of chelation treatment. Physicians taking care of transfusion‐dependent DBA patients must be concerned about the frequent and early complications such as cardiac toxicity. Am. J. Hematol., 2009.

Deferiprone: New Insight

Abstract: Recent results from independent studies suggest that deferiprone is more cardioprotective than deferoxamine. Patients on long‐term treatment with deferiprone have a better myocardial magnetic resonance imaging pattern and less chance to develop a new cardiac disease or worsen an existing one. Most of these observations are retrospective and require confirmation from randomized controlled trials. Other new observations regard the effects of combining the two chelators. Most results indicate an additional effect on iron excretion and a significant reduction of the time required to mitigate severe iron overload and to reverse clinical heart disease. Again, these data require confirmation, as they were mostly obtained on individual cases or small groups of patients treated with a wide range of combinations of the two chelators, but the univocity of results is impressive. After many years of controversy, deferiprone is emerging as a useful oral iron chelator that enhances the chances for the patient to have optimal treatment. Well‐designed and ‐conducted studies will help in answering the questions still open.

Low protein diets in patients with chronic kidney disease: a bridge between mainstream and complementary-alternative medicines?

Dietary therapy represents an important tool in the management of chronic kidney disease (CKD), mainly through a balanced reduction of protein intake aimed at giving the remnant nephrons in damaged kidneys a “functional rest”. While dialysis, transplantation, and pharmacological therapies are usually seen as “high tech” medicine, non pharmacological interventions, including diets, are frequently considered lifestyle-complementary treatments. Diet is one of the oldest CKD treatments, and it is usually considered a part of “mainstream” management. In this narrative review we discuss how the lessons of complementary alternative medicines (CAMs) can be useful for the implementation and study of low-protein diets in CKD. While high tech medicine is mainly prescriptive, prescribing a “good” life-style change is usually not enough and comprehensive counselling is required; the empathic educational approach, on which CAMs are mainly, though not exclusively based, may support a successful personalized nutritional intervention.There is no gold-standard, low-protein diet for all CKD patients: from among a relatively vast choice, the best compliance is probably obtained by personalization. This approach interferes with the traditional RCT-based analyses which are grounded upon an assumption of equal preference of treatments (ideally blinded). Whole system approaches and narrative medicine, that are widely used in the study of CAMs, may offer ways to integrate EBM and personalised medicine in the search for innovative solutions respecting individualization, but gaining sound data, such as with partially-randomised patient preference trials.

Management of pulmonary arterial hypertension associated to thalassemia: when pulmonary endarterectomy is the best therapeutical option? A case report

Pulmonary arterial hypertension (PAH) has been reported with nearly all forms of the inherited as well as the acquired hemolytic anemias. Although screening studies suggested that PAH has emerged as major complication of thalassemia patients, its impact on survival is unknown; the pathophysiology of the PAH in these patients is multifactorial, and a thorough diagnostic evaluation is essential. Understanding the PAH pathogenesis, diagnostic options, prevention is critical for clinicians who care for the thalassemic patients; there are virtually no high-quality data on the safety/efficacy of PAH treatment strategy in this patient population. We are reporting the case of a thalassemic patient suffering from progressive severe PAH, not responding to medical treatment and related to chronic thromboembolic disease. After carefully considering all the options, we decided to proceed with vascular disobliteration by pulmonary endarterectomy (PEA), the first line choice in these cases. This intervention led to a significant improvement in the clinical status and in the functional parameters. Therefore, even if haemolytic anemia-associated-PAH is included in the group I of the Dana-point classification, an individualized approach is recommended as well as a particular management with disease-specific measures and a comprehensive evaluation of other causes of PAH; this current report supports the feasibility and effectiveness of PEA also in the thalassemic patients with surgically accessible chronic thromboembolic pulmonary hypertension.

Deferasirox for cardiac siderosis in β-thalassaemia major: a multicentre, open label, prospective study

Silver, R.T., Vannucchi, A.M., Deeg, H.J., Gisslinger, H., Thomas, D., Odenike, O., Solberg, L.A., Gotlib, J., Hexner, E., Nimer, S.D., Kantarjian, H., Orazi, A., Vardiman, J.W., Thiele, J. & Tefferi, A. (2007) Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leukemia research, 31, 737–740. Nangalia, J., Massie, C.E., Baxter, E.J., Nice, F.L., Gundem, G., Wedge, D.C., Avezov, E., Li, J., Kollmann, K., Kent, D.G., Aziz, A., Godfrey, A.L., Hinton, J., Martincorena, I., Van Loo, P., Jones, A.V., Guglielmelli, P., Tarpey, P., Harding, H.P., Fitzpatrick, J.D., Goudie, C.T., Ortmann, C.A., Loughran, S.J., Raine, K., Jones, D.R., Butler, A.P., Teague, J.W., O’Meara, S., McLaren, S., Bianchi, M., Silber, Y., Dimitropoulou, D., Bloxham, D., Mudie, L., Maddison, M., Robinson, B., Keohane, C., Maclean, C., Hill, K., Orchard, K., Tauro, S., Du, M.Q., Greaves, M., Bowen, D., Huntly, B.J., Harrison, C.N., Cross, N.C., Ron, D., Vannucchi, A.M., Papaemmanuil, E., Campbell, P.J. & Green, A.R. (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New England Journal of Medicine, 369, 2391–2405. Passamonti, F., Thiele, J., Girodon, F., Rumi, E., Carobbio, A., Gisslinger, H., Kvasnicka, H.M., Ruggeri, M., Randi, M.L., Gangat, N., Vannucchi, A.M., Gianatti, A., Gisslinger, B., Mullauer, L., Rodeghiero, F., d’Amore, E.S., Bertozzi, I., Hanson, C.A., Boveri, E., Marino, F., Maffioli, M., Caramazza, D., Antonioli, E., Carrai, V., Buxhofer-Ausch, V., Pascutto, C., Cazzola, M., Barbui, T. & Tefferi, A. (2012) A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood, 120, 1197–1201. Reilly, J.T., McMullin, M.F., Beer, P.A., Butt, N., Conneally, E., Duncombe, A., Green, A.R., Michaeel, N.G., Gilleece, M.H., Hall, G.W., Knapper, S., Mead, A., Mesa, R.A., Sekhar, M., Wilkins, B., Harrison, C.N. & Writing group: British Committee for Standards in Haematology (2012) Guideline for the diagnosis and management of myelofibrosis. British Journal of Haematology, 158, 453–471. Rotunno, G., Mannarelli, C., Guglielmelli, P., Pacilli, A., Pancrazzi, A., Pieri, L., Fanelli, T., Bosi, A. & Vannucchi, A. (2014) Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood, 123, 1552–1555.

The Case | Microhematuria in a patient with beta-thalassemia major: a casual or a causal association?

A 42-year-old woman, with transfusion-dependent thalassemia major (CD39/CD39) since 1 year of age, seeks nephrological attention for microhematuria. Her medical history includes most of the long-term problems known to occur in long-standing beta-thalassemia: she is HCV positive (genotype 1b), with HCV-related chronic liver disease with type III cryoglobulinemia and arthritis (treated with steroids and cyclosporine A, and later switched to methotrexate); she also developed steroid-induced diabetes and hypogonadism because of iron overload, and thalassemia-related osteoporosis (moderate-severe reduction of the bone density) with a possible steroid-related component; she underwent splenectomy at the age of 17 years. She complained of two episodes of renal colic in the past 5 years without stone passing.

Revisiting nephrocalcinosis: A single-centre perspective. A northern Italian experience.

Nephrocalcinosis is a clinical‐pathological entity characterized by the deposition of calcium salts within the kidney parenchyma. Both the protean presentation and multiple causes may explain the lack of data regarding its prevalence. The aim of this study is to report the prevalence and main clinical features of nephrocalcinosis diagnosed in a newly opened nephrology outpatient unit.

Revisiting nephrocalcinosis: A single‐center perspective

Nephrocalcinosis is a clinical‐pathological entity characterized by the deposition of calcium salts within the kidney parenchyma. Both the protean presentation and multiple causes may explain the lack of data regarding its prevalence. The aim of this study is to report the prevalence and main clinical features of nephrocalcinosis diagnosed in a newly opened nephrology outpatient unit.