scholarly journals Progressive dysfunction of monocytes associated with iron overload and age in patients with thalassemia major

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 105-109
Author(s):  
IJ Ballart ◽  
ME Estevez ◽  
L Sen ◽  
RA Diez ◽  
J Giuntoli ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Liver Damage ◽  
Thalassemia Major ◽  
Lytic Activity ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Cell Dysfunction ◽  
Positive Effect ◽  
Increased Susceptibility

We evaluated phagocytic and lytic activities of peripheral blood monocytes (PBMo) from patients with thalassemia major (ThP) using C pseudotropicalis as the target. PBMo from ThP showed decreased lytic activity (P less than .001), whereas the phagocytic activity did not differ from that of the controls. Significant inverse correlations were found between lytic activity of PBMo and age of patients (r2 = .47; P less than .01) and also between lytic activity and serum ferritin levels (r2 = .65; P less than .001). No association was found between lytic activity and other variables (blood transfusion regimens, therapy with desferrioxamine, liver damage, and the presence of sHBAg). Splenectomy showed no positive effect on PBMo functions from ThP. Our results suggest that PBMo from ThP have an intracellular defect in their microbicidal mechanisms associated with iron overload. This cell dysfunction could be responsible, at least in part, for the increased susceptibility to infections reported in ThP.

scholarly journals Progressive dysfunction of monocytes associated with iron overload and age in patients with thalassemia major

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 105-109 ◽  
Author(s):  
IJ Ballart ◽  
ME Estevez ◽  
L Sen ◽  
RA Diez ◽  
J Giuntoli ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Liver Damage ◽  
Thalassemia Major ◽  
Lytic Activity ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Cell Dysfunction ◽  
Positive Effect ◽  
Increased Susceptibility

Abstract We evaluated phagocytic and lytic activities of peripheral blood monocytes (PBMo) from patients with thalassemia major (ThP) using C pseudotropicalis as the target. PBMo from ThP showed decreased lytic activity (P less than .001), whereas the phagocytic activity did not differ from that of the controls. Significant inverse correlations were found between lytic activity of PBMo and age of patients (r2 = .47; P less than .01) and also between lytic activity and serum ferritin levels (r2 = .65; P less than .001). No association was found between lytic activity and other variables (blood transfusion regimens, therapy with desferrioxamine, liver damage, and the presence of sHBAg). Splenectomy showed no positive effect on PBMo functions from ThP. Our results suggest that PBMo from ThP have an intracellular defect in their microbicidal mechanisms associated with iron overload. This cell dysfunction could be responsible, at least in part, for the increased susceptibility to infections reported in ThP.

scholarly journals Liver Enzymes in Children with beta-Thalassemia Major: Correlation with Iron Overload and Viral Hepatitis

2015 ◽  
Vol 3 (2) ◽  
pp. 287-292 ◽  
Author(s):  
Khaled M. Salama ◽  
Ola M. Ibrahim ◽  
Ahmed M. Kaddah ◽  
Samia Boseila ◽  
Leila Abu Ismail ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Viral Hepatitis ◽  
Serum Ferritin ◽  
Liver Enzymes ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Elevated Liver Enzymes ◽  
Hcv Antibody

BACKGROUND: Beta Thalassemia is the most common chronic hemolytic anemia in Egypt (85.1%) with an estimated carrier rate of 9-10.2%. Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of Alanine transaminase (ALT) and Aspartate transaminase (AST).AIM: Evaluating the potentiating effect of iron overload & viral hepatitis infection on the liver enzymes.PATIENTS AND METHODS: Eighty (80) thalassemia major patients were studied with respect to liver enzymes, ferritin, transferrin saturation, HBsAg, anti-HCV antibody and HCV-PCR for anti-HCV positive patients.RESULTS: Fifty % of the patients were anti-HCV positive and 55% of them were HCV-PCR positive. Patients with elevated ALT and AST levels had significantly higher mean serum ferritin than those with normal levels. Anti-HCV positive patients had higher mean serum ferritin, serum ALT, AST and GGT levels and higher age and duration of blood transfusion than the negative group. HCV-PCR positive patients had higher mean serum ferritin and serum ALT and also higher age and duration of blood transfusion than the negative group.CONCLUSION: Iron overload is a main leading cause of elevated liver enzymes, and presence of HCV infection is significantly related to the increased iron overload.

Consequences and management of iron overload in sickle cell disease

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 447-456 ◽  
Author(s):  
John Porter ◽  
Maciej Garbowski
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

scholarly journals Iron Level and Monocyte Morphology Predict TLR4 Expression and Reactive Oxygen Species Production Which Influences Chronic Inflammation in β-Thalassemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 950-950
Author(s):  
Patrick B. Walter ◽  
Nick Slater ◽  
Paul Harmatz ◽  
Annie Higa ◽  
Vivian Ng ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Peripheral Blood ◽  
Thalassemia Major ◽  
Innate Immune ◽  
Ferric Citrate ◽  
Iron Loading ◽  
Blood Monocytes ◽  
Monocytic Cells ◽  
Peripheral Blood Monocytes

Abstract Introduction: β-thalassemia major requires a lifetime of transfusion and chelation therapy and despite improved chelation therapies, patients endure organ iron overload and increased hemolysis leading to organ injury and release of damage associated bio-markers. The structure of these markers are recognized by pattern recognition receptors (PRR) of the innate immune system as damage associated molecular patterns (DAMPs), which trigger inflammation and increased reactive oxygen species (ROS). The specificity of this recognition depends on PRRs, such as toll-like receptor 4 (TLR4), to provide the first line of defense against pathogens and DAMPS to initiate inflammation. Therefore, chronic organ iron loading is implicated in the chronic inflammation and morbidity of β-thalassemia major; however, the mechanism of how monocytes respond to iron loading in β-thalassemia remains largely unknown. This study investigated how chronic iron and heme overload affected innate immune cell morphology and expression of TLR4 and ROS by modeling THP-1 cellscompared to β-thalassemia monocytes. Methods: Cultured THP-1 monocytic cells were exposed to increasing concentrations of ferric citrate (0-250 μM) or heme (0-50 μM) for 24 hours or to chronic exposures of 40 μM ferric citrate for up to 3 weeks. Anti-human TLR4 phycoerythrin conjugated antibodies (TLR4-PE) were used to quantify TLR4 expression and 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) was used to measure ROS. Flow cytometry was done using a BD FACSCalibur. Peripheral-blood samples were obtained from 13 consenting β-thalassemia patients as part of the Novartis sponsored study investigating the effects of combined chelation therapy (CICL670AUS42T). Samples were also obtained from ethnically and age matched healthy controls. Peripheral-blood monocytes and THP-1 cells were gated on the parameters of forward and side scatter to stratify cells based on size and granularity, separating cells into two populations: larger more granular (LG) and smaller less granular (SG) cells. Results are reported as the MFI ratios of LG versus SG cells for TLR4-PE or DCFH-DA as a functional measure of the difference in TLR4 or ROS expression between these populations. Results: In vitro, LG THP-1 cells expressed 4-fold more TLR4 and 10-fold more ROS than SG cells (p < 0.001). Treatment of THP-1 cells with increasing concentrations of iron or heme for 1 day or 3 weeks, increased the ROS and TLR4 heterogeneity between LG and SG monocytes. The LG versus SG ratio of ROS production significantly correlated to the concentration of ferric citrate or heme added to the culture media (r = 0.64, p = 0.019 and r = 0.58 and p = 0.048, respectively). The mean ratio for iron but not heme treated THP-1 cells was significantly greater than for untreated cells (p = 0.008 and p = 0.406, respectively). Mean LG versus SG ratios of TLR4-PE MFI were 5.20 ± 1.56 for ferric citrate, 4.11 ± 0.90 for heme, and 3.78 ± 1.41 for untreated cells. We observed a similar TLR4 morphological heterogenic pattern in peripheral-blood monocytes from iron overloaded β-thalassemia patients. β-thalassemia LG monocytes had significantly greater TLR4 MFI than SG monocytes (LG mean = 11.91 ± 1.17, SG mean = 6.56 ± 1.02, p < 0.001). Long-term treatment of THP-1 monocytic cells for 3 weeks with 40 μM ferric citrate also resulted in the same phenomena regarding TLR4. No difference was observed in ROS production for control LG cells and SG cells; however, THP-1 cells treated for 3 weeks with 40uM ferric citrate revealed populations of LG cells that expressed 3 fold more ROS than SG cells. Conclusion: THP-1 monocytic cells and β-thalassemic peripheral-blood monocytes exhibit a morphological heterogeneity where LG cells express more TLR4 and in vitro, produce more ROS than SG cells. As TLR4 is one of the receptors for the initiation of inflammation, LG cells are likely greater contributors to the chronic inflammation experienced by β-thalassemia patients. Thus, we hypothesize that iron overload may give rise to monocytes that are larger and more granular and express more TLR4 and ROS. Disclosures Walter: Novartis: Research Funding. Porter:Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy.

scholarly journals Iron Chelation Therapy of Thalassemia Patients Is Still a Challenge. Single Centre Experience from United Arab Emirates

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4908-4908 ◽  
Author(s):  
Hani Yousif Osman ◽  
Khaled al Qawasmeh ◽  
Sabir Hussain ◽  
Amar Lal ◽  
Arif Alam ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
United Arab Emirates ◽  
Chelation Therapy ◽  
Iron Absorption ◽  
Ferritin Level ◽  
Thalassemia Major ◽  
Ineffective Erythropoiesis ◽  
Transfusion Requirements ◽  
The Uk

Abstract Thalassemia is a group of complex haemoglobin disorders common in the Mediterranean countries, the Middle East and South East Asia1. Thalassemia is common in the United Arab Emirates (UAE) affecting indigenous population and the expatriates. The exact prevalence of thalassemia is not known. The management of thalassemia has improved significantly due to improvement in transfusion support and the management it's complications. This has led to the improvement of the overall survival and most patients reaching their adulthood2. Despite this some die at young age mainly due to poor access to health care2, proper management and lack of compliance to chelation therapy which leads to the development of otherwise preventable complications2. Blood transfusion is the corner stone of the management of patient with thalassemia major and intermediate3. Blood transfusion improves the anemia and its symptoms but also suppress the resultant ineffective erythropoiesis. This is usually started once the patient has signs and symptoms of anemia and unable to compensate for the low haemoglobin3. The aim of blood transfusion is to maintain good quality of life and to prevent the skeletal abnormalities2. Although blood transfusion is essential in the management of patients with thalassemia, it will ultimately lead to iron overload. In addition there is excess of gastrointestinal iron absorption in these patients, secondary to the ineffective erythropoiesis4. To reduce the iron absorption the target is to maintain the pre-transfusion hemoglobin level between 9 and 10 g/dl. Iron overload is major cause of mortality and morbidity in patient's thalassemia major and intermedia5. In this retrospective analysis we reviewed the ferritin levels over 1 year in 25 patients with thalassemia major or intermedia attending the adult hematology department at Tawam hospital The patients received regular blood transfusion once every three weeks. Of the 25 patients 16 were males and 9 were females. The age range was 15 years to 47 years. Nineteen patients had their chelation therapy changed during the year from Exjade (Deferasirox tablets for oral suspension) to Jadenu (Deferasirox tablets) which improved our patient's compliance. The remaining 6 patients continued on Exjade. In addition to this 17 patients received additional Desferral infusion in connection with their blood transfusion. None of the patient was on subcutaneous desferral infusion. During our observation two patients were lost to follow up and one patient died. The medium ferritin level for our evaluable patients was at start of the review 2488 mcg/l, with a range between 609 mcg/l to 5147 mcg/l. The medium ferritin level at the end was 1691 mcg/l with a range between 470 mcg/l to 3731 mcg/l. Figure 1 one shows the ferritin value a start and end of the review for each patient. Our patients with the highest ferritin levels are despite repeated counselling not compliant with their medications. Despite significant improvement in the management of thalassemia patients, iron overload remain a challenge. The main problems to achieving full control over the iron overload are lack of compliance. Hopefully the newest oral formulation will increase the compliance and at least we have seen a decrease in the ferritin levels over the last year in most patients. References. 1 De Dreuzy E, Bhukhai K, Leboulch P, Payen E Current and future alternative therapies for Beta Thalassemia major. Biomedical Journal 39, 124-38 2 Modell, B., Khan, M., and Darlison, M. Survival in beta thalassaemia major in the UK: Data from the UK Thalassaemia Register. Lancet 355 [2000]: 2051-2052. 3 Rebulla P, Modell B. Transfusion requirements and effects in patients with thalassaemia major. Cooleycare Programme. Lancet 1991;337:277-80 4 Gardenghi S, Marongiu MF, Ramos P, et al. - Ineffective erythropoiesis in beta- thalassemia is characterized by increased iron absorption mediated by down- regulation of hepcidin and up-regulation of ferroportin. Blood 2007; 109:5027-35 5 Porter, J.B., and Davis, B.A. Monitoring chelation therapy to achieve optimal outcome in the treatment of thalassaemia. Best Practice & Research: Clinical Haematology 15 [2002]: 329-368 6 Ayidinok Y, Kattamis A, Cappellini MD, et al. Deferasirox- Deferoxamine combination therapy reduces cardiac iron with rapid liver iron removal after 24 months in patients with severe transfusional iron overload (abstract). Haematologica 2014;99:229. Disclosures No relevant conflicts of interest to declare.

Macrophage Motility Dysfunction in a Patient with Recurrent Infections.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3835-3835
Author(s):  
Paul T. Jubinsky ◽  
Mary Short ◽  
Anthony Ashton ◽  
Diane Cox ◽  
Fiona Pixley
Keyword(s):  
Peripheral Blood ◽  
Bacterial Infections ◽  
Cell Function ◽  
Time Lapse ◽  
Early Age ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Susceptibility To Infection ◽  
Normal Individuals ◽  
Increased Susceptibility

Abstract Three members of a family with normal parents had a common constellation of findings that included absent corpus callosum and recurrent bacterial infections. The older male and female siblings both died from infection at an early age. The patient’s CBC was significant for elevated numbers of monocytes that were large and vacuolated. Her T- and B-cell function was normal. These preliminary findings suggested a defect in innate immunity. Evaluation of the patient’s peripheral blood monocytes by flow cytometry showed normal size and maturity. Phagocytosis and activation of peripheral blood derived macrophages by cytokines were also similar to controls. In contrast, the patient’s cultured macrophages were significantly more spread than those from normal individuals and contained a disordered actin cytoskeleton when cultured on fibronectin. The ability of the macrophage to transmigrate across an endothelial cell barrier was impaired. However examination by time-lapse videomicroscopy showed that the mutant macrophages had increased protrusional activity and movement. This is the first report describing a genetic macrophage motility disorder that results in an increased susceptibility to infection.

scholarly journals Protective Effects of Selenium in Patients with Beta-Thalassemia Major

2020 ◽  
Vol 26 (1) ◽  
pp. 25-31
Author(s):  
Ajand Aboutalebi ◽  
Abolghasem Jouyban ◽  
Hadi Chavoshi ◽  
Aliakbar Movassaghpour Akbari ◽  
Elnaz Shaseb ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Kidney Function ◽  
Hair Loss ◽  
Binding Capacity ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Severe Renal Failure ◽  
Beta Thalassemia Major ◽  
Liver And Kidney

Background : Beta-thalassemia major patients require repeated blood transfusion which is associated with iron overload in different organs such as heart, liver, kidney and their related complications. In this study the effects of selenium in iron overload related complications of patients with beta-thalassemia major were assessed. Methods: In this clinical trial, 34 beta-thalassemia major patients over 12 years old were enrolled. Patients with severe renal failure, history of selenium consumption over the last three months, change of blood transfusion pattern, and any change of chelating agent were excluded from the study. For all patients, tablet of selenium 200 µg/day was administered for a month. Blood samples were taken at baseline and after one-month to assess the level of ferritin, total iron-binding capacity (TIBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (Scr), selenium. Hair loss was assessed by questionnaire before and after intervention. Results: From 34 patients, 27 (79.4%) had deficient level of selenium at baseline. The selenium level was increased after intervention (p=0.005). The level of serum ALT and Scr decreased remarkably after one-month selenium consumption (p=0.007 for both). In addition, the AST level decreased remarkably after intervention (p=0.053). Severe hair loss profile has improved significantly after supplementation (p=0.004). Conclusion: One-month selenium consumption improved liver and kidney function related markers remarkably. Moreover, selenium improved hair profile and severe hair loss in thalassemia patients. Further studies are needed on the effect of selenium administration on liver and kidney function.

Decreased Phagolysosomal Fusion of Peripheral Blood Monocytes from Patients with Thalassemia Major

1994 ◽  
Vol 92 (2) ◽  
pp. 66-70 ◽  
Author(s):  
M.G. Pittis ◽  
M.E.† Estevez ◽  
R.A. Diez ◽  
S.A. de Miani ◽  
L. Sen
Keyword(s):  
Peripheral Blood ◽  
Thalassemia Major ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes

Study of Serum Hepcidin in Hereditary Hemolytic Anemias

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5168-5168
Author(s):  
Amal El-Beshlawy ◽  
Ibrahim Ibrahim Alaraby ◽  
Mohamed Salah Eldin Mohamed Abdel Kader ◽  
Dina Hisham Ahmed ◽  
Hossam Eldin Maged Abdel Rahman
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Thalassemia Major ◽  
Blood Transfusions ◽  
Major Health Problem ◽  
Hepcidin Level ◽  
Positive Correlation ◽  
Reduction Of Iron ◽  
Serum Hepcidin

Abstract Abstract 5168 Background: Thalassemia is the most common genetic disorder in Egypt composes a major health problem with an estimated carrier rate of 5. 3%-9%. Registered cases in large centers in Egypt September 2007 were 9912 cases, and in Cairo University hematology clinic were alone 2597 cases. Patients with thalassemia major requiring regular blood transfusions accumulate iron that is toxic to the heart, liver, and endocrine systems. Hepcidin, is a 25 amino-acid peptide hormone synthesized in the liver is a key regulator of iron homeostasis. Recently, hepcidin was reported to bind to the trans-membrane iron exporter “ferroportin” which is present on macrophages, the basolateral site of entrecotes, and in hepatocytes. Hepcidin induces the internalization and degradation of ferroportin. liver hepcidin controls reduction of iron uptake and release. There is also evidence for local production of hepcidin by macrophages, fat cells and cardiomyocytes. Thus, hepcidin is involved in different regulatory mechanisms that control iron imbalance. Objective: The aim of this study is to assess the level of serum hepcidin in hereditary chronic hemolytic anemias and correlate its level to the need for blood transfusion (frequency of blood transfusion) and the serum ferritin level. Study design: Seventy pediatric patients with hereditary chronic hemolytic anemias were the subjects of this study; 53 thalassemia major (TM), 10 thalassemia intermedia (TI), 4 congenital spherocytosis(CS) and 3 sickle cell disease(SCD) patients, mean age 7. 8+3. 9 years (range 1–14). Seventy normal children age and sex matched were studied as controls. Serum hepcidin was measured in all patients and controls by ELISA technique. Serum Hepcidin was measured in all patients one day pre transfusion and in 20 TM patients 3–4 days post transfusion. Results: Significant decrease in serum hepcidin levels in all patients compared to controls (mean 22. 9 ±6 vs 132. 4±16. 7 ng/ml, P <0. 001). Hepcidin levels were higher in TM (mean 23. 7±6. 2 ng/ml) than in TI patients (mean =21. 8±4 ng/ml) (Fig 1). The median number of blood transfusions in TM was 70/year (range18–120), in TI the median was 7/year (range 6–17). A 280% increase of serum hepcidin levels of pre transfusion levels was found post transfusion in TM patients (n=20). A significant positive correlation was found between serum hepcidin and frequency of blood transfusion (r=0. 4, p<0. 001), serum ferritin (r=0. 28, p <0. 05) and CRP (r=0. 4, p<0. 05). The hepcidin to ferritin ratio a marker of the hepcidin expression relative to the degree of iron burden was significantly less than one in TM and TI patients (0. 03± 0. 004 and 0. 025± 0. 002 respectively) and far from the level in normal controls (mean 2. 3±0. 7, P<0. 001). Hepcidin and hepcidin/ferritin ratio as markers of iron overload in our patients showed high sensitivity and specificity (99% and 98%, 97% respectively) (table 1, fig 2). Discussion and Conclusion: This study examined serum hepcidin and hepcidin/ferritin ratio in hereditary chronic hemolytic anemias, significant low levels were detected. The increase in serum hepcidin level in TM than TI and its marked increase post transfusion in TM patients can be explained by the positive correlation between frequency of blood transfusion and serum hepcidin level in this study. Hepcidin and hepcidin/ferritin ratio can be used as valid markers of iron overload in hereditary chronic hemolytic anemias. Evidence from laboratories around the world have converged on hepcidin as a rational therapeutic agent for treatment of B-thalassemia. Treatment with a hepcidin agonist, at a carefully defined dose, has the potential to ameliorate several aspects of TI due to the specific reduction of iron overload and splenomegaly. Testing this approach provides an exciting opportunity to improve the current management strategies for these diseases, and our study agrees with this approach. Disclosures: No relevant conflicts of interest to declare.

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