Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload

AbstractIntroductionCardiovascular events and complications are the leading cause of mortality and morbidity in patients with sickle cell disease. Cardiac abnormalities occur frequently and at an early stage in sickle cell anaemia patients, despite being more evident in adulthood. Sickle cell anaemia patients are increasingly able to reach adulthood owing to improved healthcare, and may, therefore, suffer the consequences of chronic cardiac injury. Thus, the study of cardiac abnormalities is essential in childrenObjectiveThe aim of this study was to determine the echocardiographic changes in left ventricular function in children suffering from sickle cell disease in Mumbai, Western India.MethodsThe study comprised of 48 cases of sickle cell anaemia and 30 non-anaemic controls with normal haemoglobin and electrophoresis pattern. M-mode, two-dimensional, and Doppler echocardiographic measurements of patients and controls were performed according to the criteria of the American Echocardiography Society.ResultsOn Doppler study, the A wave height was increased and the E/A ratio was decreased, whereas the deceleration and isovolumetric relaxation times were prolonged, which is typically seen in slowed or impaired myocardial relaxation (p<0.001). Although chamber dilatations were present, echocardiographic parameters showed no statistically significant correlation with severity of anaemia and age among the sickle cell patients.ConclusionsWe conclude that the increased left ventricular stiffness, compared with controls, might be due to fibrosis related to ischaemia caused by SS disease in addition to wall hypertrophy.

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Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease

Seminars in Hematology ◽

10.1053/shem.2001.20142 ◽

2001 ◽

Vol 38 (1, Suppl 1) ◽

pp. 30-36 ◽

Cited By ~ 14

Author(s):

Samir K. Ballas

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Adult Patients ◽

Morbidity And Mortality ◽

Cell Disease

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Myocardial T2* Is Not Affected by the Structural Effects of Myocardial Fibrosis, Ageing or Impaired Left Ventricular Function.

Blood ◽

10.1182/blood.v106.11.1675.1675 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1675-1675

Author(s):

Paul Kirk ◽

Dudley J. Pennell

Keyword(s):

Myocardial Infarction ◽

Iron Overload ◽

Left Ventricular Function ◽

Ventricular Function ◽

Age Distribution ◽

Left Ventricular ◽

Lv Function ◽

Chronic Myocardial Infarction ◽

Myocardial Iron ◽

The Mean

Abstract Background The myocardial T2* technique has been validated as a reproducible non-invasive measurement of myocardial iron load and is now widely used for measurement of myocardial iron in iron overload diseases such as thalassaemia. The reduction in myocardial T2* seen in iron overload conditions is substantially greater than is seen in any other clinical circumstance, but there has been no direct comparison of myocardial T2* in normals and other conditions such as increasing age, myocardial infarction or impairment in left ventricular function. We aimed therefore to compare the findings in patients affected by these conditions with normals. Method A total of 38 patients in total were scanned using the myocardial T2* technique. Fifteen patients had normal hearts, 18 had impaired LV function and 6 had chronic myocardial infarction affecting the anteroseptal wall, where myocardial T2* measurements are normally made. Results The mean myocardial T2* in normals was 36.0 +/− 6.4 ms, yielding a lower limit of normal of 23ms. In patients with impaired LV function, the mean myocardial T2* was 39.0 +/− 11.7ms (p= 0.37 vs normals). In patients with anteroseptal myocardial infarction, the mean myocardial T2* was 34.7ms +/− 3.9ms (p= 0.64 vs normals). The frequency distribution of the myocardial T2* values are shown in figure 1. These approximate to normal, and are very similar in distribution. In addition, the age distribution of myocardial T2* in the 15 normals is shown in figure 2. There was no significant relation between myocardial T2* and age (r2 = 0.066, p=0.82). Conclusion There is no significant reduction in myocardial T2* associated with fibrosis from chronic myocardial infarction, impairment of left ventricular function, or increasing age. This suggests that structural changes associated with remodelling, infarction and fibrosis, and ageing do not have significant effects on the absolute measure of myocardial T2*, and in particular do not cause a reduction below 20ms as is seen in myocardial overload conditions. Thus these date suggest that myocardial T2* is robust to these structural alterations, and that myocardial iron overload can be ascertained from reduced myocardial T2* values, in a similar manner to that which can be achieved in normals. Figure 1 Figure 1. Figure 2 Figure 2.

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Plasma level of matrix metalloproteinase-9 in patients with sickle cell disease and its correlation to myocardial iron overload

10.21203/rs.3.rs-109357/v1 ◽

2020 ◽

Author(s):

Tamer Hassan ◽

Mohamed Badr ◽

Mohamed Arafa ◽

Doaa Abdel Rahman ◽

Manar Fathy ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Plasma Levels ◽

Restrictive Cardiomyopathy ◽

Myocardial Iron ◽

Cell Disease ◽

Cardiac Iron ◽

Cardiac Iron Overload

Abstract Cardiac iron overload is secondary to chronic blood transfusion in patients with sickle cell disease (SCD). Iron overload cardiomyopathy is a restrictive cardiomyopathy associated with systolic and diastolic dysfunction. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling. Many studies offer strong evidence for the role of MMP-9 in LV remodeling. We aimed to detect plasma levels of MMP-9 in patients with SCD and its correlation to myocardial iron overload. A case control study was carried out on 50 patients with SCD and 50 age and sex matched healthy controls. Assessment of cardiac iron overload in patients by MRI T2* was performed. Plasma MMP-9 levels were measured for patients and controls using ELISA. SCD patients had significantly higher levels of MMP-9 than controls. There was highly significant correlation between plasma levels of MMP-9 and serum ferritin. Patients with vaso-occlusive crises (VOC) > 5/year had significantly higher levels of MMP-9 than those with VOC ≤ 5 /year. No significant correlation was found between MMP-9 and cardiac T2*. MMP-9 seems to be a useful marker in SCD patients. Patients with serum ferritin > 1000 ng/ml, recurrent VOC > 5 /year had significantly higher MMP-9 serum levels than others.

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Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease

Seminars in Hematology ◽

10.1016/s0037-1963(01)90058-7 ◽

2001 ◽

Vol 38 ◽

pp. 30-36 ◽

Cited By ~ 84

Author(s):

Samir K Ballas

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Adult Patients ◽

Morbidity And Mortality ◽

Cell Disease

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Average Monthly Cost of Iron Chelator Treatment in Adult Patients with Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.4858.4858 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4858-4858

Author(s):

Samip Master ◽

Richard Preston Mansour

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Retrospective Analysis ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Private Insurance ◽

Iron Chelator ◽

Adult Patients ◽

Cell Disease ◽

Monthly Cost

Introduction: Iron overload in adult patients with sickle cell disease (SCD) can lead to variety of complications like liver dysfunction/cirrhosis, cardiac enlargement, diabetes mellitus, hypogonadism and arthropathy. These complication can be prevented by iron chelation therapy .We did retrospective analysis to find incidence of iron over load in this population and also did a survey to find the insurance status in this population. Methods: We take care of approximately 300 adult patients with SCD at out hematology clinic. We did retrospective analysis to investigate the prevalence of iron overload in this population. We also did survey on 100 adult patients with SCD to find out about the insurance converge for them. Web search was done to find out the average monthly cost of iron chelators. Results: On retrospective analysis of 458 adult patients with SCD, we found that 117/458(25.58%) had iron over load. Majority of them, 93/117 were SS type of SCD. Results of survey done on 100 adult patients with SCD showed that 61 had Medicaid, 2 were free care, 25 had Medicare and 12 had private insurance. The average monthly cost of Deferiprone is $ 18762, while that of Deferasirox is $ 13,082. Conclusions: Iron over load is a common complication affecting a quarter of the adult patients with SCD. The treatment of iron overload is expensive, as just the iron-chelator therapy costs approximately 160 to 220 K per year. In an attempt to minimize additional iron accumulation in our chronically transfused patient population we encourage the schedule of exchange of 1 unit phlebotomy and 1 unit of red cell infusion every two weeks. Disclosures No relevant conflicts of interest to declare.

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Left Ventricular Function Declines with Increasing Myocardial Ferritin Iron in Thalassemia Major.

Blood ◽

10.1182/blood.v106.11.3852.3852 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3852-3852

Author(s):

Sujit Sheth ◽

Haiying Tang ◽

Jens H. Jensen ◽

Karen Altmann ◽

Ashwin Prakash ◽

...

Keyword(s):

Magnetic Resonance ◽

Iron Overload ◽

Left Ventricular Function ◽

Ventricular Function ◽

Thalassemia Major ◽

Left Ventricular ◽

Ferritin Iron ◽

The Relationship ◽

Forms Of Iron ◽

Iron Concentrations

Abstract Using a new magnetic resonance method that separately estimates the two principal forms of storage iron, ferritin and hemosiderin, in the heart, we examined the relationship between myocardial storage iron fractions and left ventricular function in thalassemia major. In patients with iron overload, the amount of iron in functional and transport pools changes only slightly. Virtually all of the excess is sequestered in storage forms of iron, as ferritin, a diffuse, soluble fraction, and as hemosiderin, an aggregate, insoluble fraction. The two storage forms of iron strongly affect signal intensity in both T2 and T2* weighted images but influence MRI signal decay through different means because of their differences in solubility and in intracellular distribution (Magn Reson Med2002; 47:1131–8). Separate estimates of the iron concentrations of the two forms of storage iron may be obtained by measuring two distinct relaxation parameters, the “ferritin iron index” (“reduced” transverse relaxation rate) RR2, and the “hemosiderin iron index”, A. We studied 14 patients with thalassemia major, all being treated with subcutaneous deferoxamine. Study participants were examined with a Philips 1.5 T Intera scanner using three Carr-Purcell-Meiboom-Gill (CPMG)-like multi-echo spin echo sequences with varied inter-echo times, using electrocardiographic triggering and respiratory navigator gating to estimate RR2 and A. The left ventricular shortening fraction was measured using standard echocardiographic methods. The Figure shows the relationship (R=0.91, p<0.0001) between the ferritin index, RR2, and the left ventricular shortening fraction. Figure Figure Overall, variation in the ferritin index explained more than 80% of the variation in ventricular function. For comparison, variation in the hemosiderin index, A, accounted for only about 33% of the variation in shortening fraction. Using an empirical calibration to estimate iron concentrations, variation in total (ferritin + hemosiderin) iron accounted for only about 40% of the variation in ventricular function. In patients with thalassemia major, the concentration of ferritin iron may provide a better indicator of the magnitude of the toxic iron pool than the total storage iron concentration. Magnetic resonance determinations of the partition of storage iron between ferritin and hemosiderin may be clinically valuable in evaluating tissue iron toxicity in patients with transfusional iron overload.

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Manual Erythro-Exchange (MEEX) to Prevent Complications of Sickle Cell Disease in Patients Unresponsive to Hydroxyurea: A Long-Term Follow-up

Blood ◽

10.1182/blood.v112.11.4815.4815 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4815-4815

Author(s):

Gianluca Forni ◽

Manuela Balocco ◽

Laura Terenzani ◽

Paola Carrara

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Long Term Follow Up

Abstract Background: Hydroxyurea (HU) therapy reduces considerably mortality and morbility in sickle cell disease (SCD). In about 10–25% of adult patients HU is ineffective therefore other therapeutic options such as chronic red cell transfusions (CRT) or erythroexchange (EEX) are needed. From 1981 to 2007 in our Center 40 patients affected by homozygous sickle cell (S-S) and sickle-β0 thalassemia (S/β0) with a previous history of major events, pregnancy or prior to surgery were treated with periodic Manual Erithroexchange (MEEX). 1133 MEEX procedures were performed with only one case of immunization in a pregnant woman. Consequentely MEEX resulted to be safe and efficacious in preventing SCD manifestations as well as significantly inexpensive. Even if, since 1995 HU has been accepted as first line therapy, seven out of 40 patients, unresponsive to HU treatment, had been continuing on a program of periodic EEX. On the basis of our own experience, we decided to use manual EEX instead of automatic one. We retrospectively report the data referring to a long-term follow-up (11–26 yrs, medium 16,5 yrs) of these 7 patients. Methods and Patients: MEEX always started with an infusion of a 500 ml Ringer lactate solution followed by a phlebotomy (400–600 ml depending on weight and HbS level); autologous plasma derived from drawn blood centrifugation was re-infused to the patient. Thereafter a second phlebotomy was performed as previously described. Finally, depending on Hb level, each patient received two or three packed, Rh matched, leuko-filtered and plasma-depleted red cells units. A single peripheral venous access was required. The gap between each MEEX ranged from 45 to 90 days in order to maintain HbS levels below 60%. The seven patients (3 males and 4 females) affected by S/beta° (6 pts) and S-S (1pts), at the beginning of the MEEX program were aged 8 to 26 years (mean 14yrs). They were enrolled because of acute chest syndrome (2 pts) and >3 painful crises/yr (5pts). Patients underwent a median of 109 (61–180) MEEX procedures. Results: In the seven observed patients no adverse events related to the procedure (i.e. alloimmunization) was reported. During the follow-up neither typical acute complications of SCD, such as acute chest syndrome, splenic sequestration, stroke, bone necrosis, priapism, nor long term complications like renal failure, cerebrovascular or retinic damage, pseudoxanthoma like manifestations were observed. None of the typical iron overload consequences (hypogonadism, growth failure, hypotiroidism and diabetes) were noted. Concerning cardiac function, all subjects showed a left ventricular ejection fraction > 60% with no evidence of pulmonary hypertension, evaluated by echocardiography. LIC, assessed by SQUID or liver biopsy, was normal in all patients except one. This patient developed iron overload, requiring steady iron chelation therapy, due to CRT before entering the MEEX program at the age of 26 yrs. Cardiac T2* measured by MRI resulted >22mms in each patient. During the observation period 5 hospitalizations (4 acute cholecystitis and 1 Venous Occlusive Crisis) occurred. Only one patient needed chronic analgesic therapy to relieve head femur necrosis pain developed before starting periodic MEEXes. According to age all patients attended school or had a regular job. Discussion: The long-term follow-up revealed the above described procedure to be safe and efficacious in preventing acute and chronic complications of SCD in patients unresponsive to HU therapy, allowing them to have a good quality of life. This approach is less invasive and significantly less expensive than both CTR-chelation and automated EEX. Furthermore since MEEX is feasible and easy to manage it should be considered a treatment option also in developing countries, according to ASH SDC Policy Statements.

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Hyperferritinemia and Hemophagocytic Lymphohistiocytosis. Single Institution Experience in Adult and Pediatric Patients.

Blood ◽

10.1182/blood.v120.21.2135.2135 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2135-2135 ◽

Cited By ~ 5

Author(s):

Alice D. Ma ◽

Yuri D. Fedoriw ◽

Philip Roehrs

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Liver Failure ◽

Sickle Cell ◽

Hemophagocytic Lymphohistiocytosis ◽

Pediatric Patients ◽

Adult Patients ◽

Cell Disease ◽

Clinical Criteria ◽

Shock Liver

Abstract Abstract 2135 Hemophagocytic lymphohistiocytosis (HLH) is a multisystem disorder characterized by immune dysregulation and hypercytokinemia. Diagnostic criteria include a genetic mutation consistent with familial HLH or the presence of 5 of 8 defined clinical criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK cell function, hyperferritinemia, and elevated soluble CD25). In pediatrics, a ferritin value of >10,000 mχγ/L has been reported to have 90% sensitivity and 96% specificity in defining the presence of HLH (Allen, C. E., Yu, X., Kozinetz, C. A. and McClain, K. L. (2008). Pediatr. Blood Cancer). We examined if hyperferritinemia (all patients with ferritin level >10,000 mχγ/L between 2007 and 2012) correlated with diagnosis of HLH in 94 patients (73 adult; 21 pediatric) at our institution. Chart reviews were performed to evaluate the presence or absence of HLH criteria, additional clinical features that may be indicative of HLH, and diagnosis. These data resulted in our classification of patients into four groups (Table 1): (1) “clinically defined HLH” when predetermined criteria were met; (2) “potential HLH” when clinical criteria was suggestive of HLH, but not all criteria were met; (3) “possible HLH” when rheumatologic syndromes, liver disease, or fever/DIC was present of unknown etiology; or (4) “Non-HLH” when the elevated ferritin was a result of a known etiology (Table 2). As expected, 18 (86 %) of pediatric patients with a ferritin > 10,000 mχγ/L had clinically defined or potential/possible HLH. Notably, 44 (60 %) of adult patients with a ferritin > 10,000 mg/L had clinically defined or potential/possible HLH. Such an incidence of HLH in the adult population with elevated ferritin raises caution for appropriate diagnosis of this population and clearly warrants further study. If patients with sickle cell disease, GVH, or known causes for liver failure are excluded, then HLH should be suspected in 83% of adult patients with ferritins >10,000 mcg/L. Table 1: HLH classifications of 94 patients with ferritin > 10,000 mχγ/L Adult, n = 73 n (%) Pediatric, n = 21 n (%) Clinically defined HLH 18 (25) 12 (57) Potential HLH 9 (12) 5 (24) Possible HLH 17 (23) 1 (5) Non-HLH 29 (40) 3 (14) Table 2: Diagnoses of non-HLH patients with ferritin > 10,000 mcg/L (some diagnoses overlap) Liver failure of clear etiology (10) APAP toxicity (4) Shock liver (4), EtOH, Other Sickle cell disease (9) 7 adult, 2 peds, all with probable iron overload Other tumors (9) CMML+VT+shock liver, prostate ca with bone mets, CMML to AML, MDS/MPD with infection, AML, T lymphoblastic lymphoma with cholestasis, allo txp for AML with iron overload, ALL+ abd wall hematoma Iron overload (11) 9 sickle cell, 1 Castlemans, 1 allo txp for AML Other Pancreatitis, GVH (3) Table 3: Clinical suspicion for HLH Potential HLH (%) Possible HLH (%) Total Adult 9 17 Peds 5 1 HLH suspected? Adult 1 (11) 2 (12) Peds 4 (80) 1 (100) All criteria sent? Adult 1 (11) 1 (6) Peds 2 (40) 1 (100) Hematology involved? Adult 6 (67) 11 (64) Peds 5 (100) 1 (100) Did hematologist note ferritin? Adult 1 (17) 3 (27) Peds 5 (100) 0 Disclosures: Ma: Novo Nordisk Inc.: Consultancy, Speakers Bureau.

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