Complications of IO in patients undergoing HSCT [24]
\r\n\tNot all mixtures of particles and liquids can be considered slurries. A slurry has its character quite different from the carrying liquid (sometimes referred to as the vehicle). A Newtonian liquid has its shear stress directly proportional to its rate of deformation, but this is seldom the case for a slurry. In general, slurries are referred to as non-Newtonian liquids and ways of dealing with them are important threads in this text.
\r\n\r\n\tPipe blockages and pipe wear cause high costs to industry, in both maintenance and loss of production. This waste, and environmental damage which comes with it, can be shown to be reduced by careful application of slurry technology. This book will welcome recent research efforts to understand slurries related to the above-mentioned topics.
",isbn:"978-1-80356-669-6",printIsbn:"978-1-80356-668-9",pdfIsbn:"978-1-80356-670-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"a3de73ad02868797334aa3024ec3f018",bookSignature:"Dr. Trevor Jones",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11907.jpg",keywords:"Slurry Rheology, Non-Newtonian Flows, Wastewater Treatment, Blood Rheology, Slurry Measurement, Slurry Tomography, Pipeline Pigs, Pipeline Cleaning, Wear, Swirl Induction, Electrical Resistance Tomography, Electrical Capacitance Tomography",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"May 25th 2022",dateEndThirdStepPublish:"July 24th 2022",dateEndFourthStepPublish:"October 12th 2022",dateEndFifthStepPublish:"December 11th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"6 hours",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Jones is a world-leading expert in naturally-occurring particle products - slurries, sludges, coal, ore, and gravel. 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Although remarkable advances in transplant immunology and supportive care allowed widespread use of HSCT, transplant related morbidity and mortality remain as a problem [1-7]. Early complications including sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis, engraftment syndrome, idiopathic pneumonia syndrome (IPS), infections and graft versus host disease (GVHD) are the major causes of morbidity and non relapse mortality (NRM). High doses of radiotherapy and chemotherapy of the conditioning regimen have adverse effects on all organs and tissues of the recipient, which also triggers several early and late effects of variable intensity [1, 3, 5-8]. Iron overload (IO) is a relatively common condition in patients with hematological malignacies and HSCT recipients. Free iron which accompanies IO might contribute to the already existing prooxidant state in HSCT recipients by inducing the formation of reactive oxygen species (ROS). Tissue peroxidation and organ damage, as a consequence, contribute to the development of some early transplant complications [2, 4, 5, 9]. Increasing number of transplants performed each year and improved transplant techniques result in a rise in the number of long term survivors. The primary goal of HSCT is to cure the primary disease. However long term transplant related morbidity might be very challenging and might significantly impair the quality of life. Late effects might be the consequence of the direct toxicity of chemoradiotherapy and/or the immunologic complications mainly consisting of GVHD. Besides the secondary late effects including osteoporosis and dental caries, very late effects, namely cardiovascular toxicity considered as tertiary late effect may also occur. Among this wide spectrum of complications, IO has a substantial role as a contributor to liver toxicity, infections and SOS and as a predictor of transplant outcome. Hematopoietic SCT recipients have been demonstrated to have a high degree of liver iron content (LIC) almost in the range of hereditary hemochromatosis (HH) and IO was shown to cause liver fibrosis, heart failure, hypogonadism, diabetes and endocrinopathy in HSCT recipients in the long run [4, 6, 7, 10].
Iron is an essential element which plays a key role in several biochemical reactions including oxygen transport and electron transfer. It mediates the conversion of hydrogen peroxyde (H2O2) to highly toxic free radicals leading to tissue damage by oxidation of proteins, peroxidation of membrane lipids and modification of nucleic acids [4]. Under normal circumstances, an appreciable concentration of free iron does not exist outside physiological sinks. Any released ferrous iron (Fe+2) is immediately chelated in cells by compounds such as citrate or adenosine diphosphate. Thus, labile iron could not participate in the Haber–Weiss reaction, which catalyses the formation of ROS. Free iron may directly initiate lipid peroxidation which destroys membrane structure resulting in increased oxidative stress and cellular damage. Excess iron accumulation causes chronic free radical induced tissue damage in multiple organs and leads to progressive organ dysfunction, which results in significant morbidity and mortality. In this respect, IO should be prevented in order to preclude the adverse impact of free iron on natural homeostasis [9, 11].
This chapter will focus on iron balance and the course of excess iron in HSCT recipients. The adverse impact of IO on transplant outcome and the preventive strategies will also be discussed.
Iron is vital for all living organisms and takes part in several metabolic processes, including DNA synthesis, oxygen and electron transport. Although iron is a critical element in cell growth and multiplication, it is potentially toxic in excess amounts by generating ROS [5, 11-13]. Reactive oxygen species have a potential to damage DNA and proteins by lipid peroxidation. Labile iron participates in free radical formation via Fenton reaction which was first recognized in 1894. Namely, trace amounts of iron as Fe+2 could catalyze the oxidation of tartrate by H2O2. Consequently, superoxide anion (O2-) or H2O2 is converted to toxic free radicals such as hydroxyl radical (OH-). This process is mediated by the Fenton reaction catalyzed by iron, where O2- reduces ferric iron (Fe+3) to produce oxygen and Fe+2. This reduced iron becomes reoxidized by H2O2 to produce OH- [5, 11].
a. Fenton reaction; b. Iron catalyzed Haber–Weiss reaction or the superoxide driven Fenton reaction [
There are no physiological mechanisms in humans to excrete excess iron and iron homeostasis is primarily regulated at the level of absorbtion [4, 9, 11, 14-16]. The majority of iron absorbtion occurs via enterocytes in the proximal small intestine. The conversion of dietary inorganic non–heme iron to Fe+2 is facilitated by the brush border ferri reductases. Iron is transported across the cellular membrane by the divalent metal transporter 1 (DMT1) which transfers Fe+2 across the apical membrane and into the cell through a proton coupled process [9, 15, 16]. Ferroportin is an iron efflux pump that mediates the export of Fe+3 from the enterocyte. Prior to transport, Fe+2 is converted to Fe+3 by either hephaestin or ceruloplasmin both of which have ferroxidase activity. Subsequently, iron is uploaded to transferrin which is the primary iron transporter in the circulation. Ferric iron bound to transferrin is soluble and non reactive. The majority of iron (60–70%) is incorporated into hemoglobin while the rest is stored in hepatocytes, myoglobin and reticuloendothelial macrophages [9]. Hepcidin, the main regulator of iron absorbtion, inhibits intestinal absorbtion and release of storage iron in iron-overloaded states, whereas its expression is markedly decreased in iron deficiency states. Hepcidin interacts directly with ferroportin, causing its internalization, degradation and blocking iron release from cells to plasma. Hepcidin acts as an acute phase reactant which is responsible for the anemia of inflammation. Its production is upregulated by body iron excess and inflammation whereas downregulated by anemia and hypoxia [9, 14, 16].
Cell survival depends on the balance between the destructive and beneficial effects of iron [9, 12]. Natural iron homeostasis comprises regulation mechanisms to control iron excess. The primary protective pathway is the sequestration of iron in ferritin or transferrin. Ferritin is the chief storage molecule while transferrin is functionary for the transport of iron. Ferritin captures and buffers the intracellular iron pool, thus it makes iron available for critical cellular processes while protecting lipids, DNA and proteins from potentially toxic effects of iron. Iron stored in ferritin is not capable of catalyzing radical reactions and is considered as safe. It is well known that serum ferritin concentration closely parallels body iron reserves. However, as free iron is the main form of iron which can precipitate in oxidative stress, any measure of unbound iron will result in deleterious effects. The balance of free iron to bound iron changes and free iron becomes available to catalyze free radical reactions in iron overloaded states [5, 9]. Large amounts of excess iron in the circulation are likely to exceed the serum iron binding capacity (SIBC) and non transferrin bound iron (NTBI) will emerge eventually. Non transferrin bound iron bypasses the normal regulatory mechanism of receptor mediated iron uptake and is able to stimulate the peroxidation of membrane lipids and the formation of ROS. The intracellular counterpart of NTBI is considered as labile iron pool (LIP) which is bound mainly to low molecular weight compounds. Labile iron pool is catalytically active and capable of initiating free radical reactions. The expansion of the LIP and simultaneously increased NTBI may trigger cell toxicity. Generation of LIP leads to unregulated iron uptake and subsequent intracellular storage either within ferritin molecules or as hemosiderin. The adverse effects of IO can arise from the elevation of NTBI and LIP in plasma and might as well cause organ damage mediated by the accumulation of tissue iron in target organs. The equilibrium between the LIP and iron locked in the ferritin shell is critical to maintain the normal function of cellular iron enzymes. Imbalance in this equilibrium results in the uncontrolled loading of organs, such as the liver, heart and endocrine glands, with free iron which generates free radicals and causes cell damage [12, 17]. Eventually, NTBI and LIP may be more relevant iron markers than serum ferritin and transferrin as a predictor of IO induced tissue damage. Alterations in ferritin levels are seen commonly in clinical practice often reflecting perturbations in iron homeostasis or metabolism. Serum ferritin differs markedly from tissue ferritin in molecular weight, iron and carbonhydrate content, subunit size and amino acid sequence. The extracellular form of ferritin, termed as serum ferritin, is used as a clinical marker of iron status. Tissue ferritin is the more efficient storage form of iron than is serum ferritin and the function of serum ferritin has to be clarified in these circumstances [9, 12]. Serum ferritin is usually correlated with NTBI, whereas inflammation, acute and chronic liver diseases and malignancies may also cause elevated serum ferritin levels regardless of the iron stores [12].
Iron overload is a significant problem in autologous (auto) and allogeneic (allo) HSCT recipients and may adversely affect transplant outcome [4, 18]. The diagnosis of IO has been reported in up to 88% of long term survivors of HSCT on the basis of serum ferritin levels [19]. Iron overloaded state may last for a long time after transplantation. In a cross sectional study by Majhail et al, in which LIC on MRI was used for diagnosis, the prevalence of IO was reported to be 32% in allo-HSCT recipients who had survived 1 year or more following HSCT [20]. In another study by the same group, serum ferritin levels were found to be above 1000 ng/ml in 34% of allo-HSCT and 13% of auto-HSCT recipients. Thus, IO may be less prevalent among recipients of auto-HSCT compared to allo-HSCT as expected [21].
The main causes of IO in HSCT are prolonged dyserythropoiesis, increased intestinal iron absorbtion due to anemia and chemotherapy associated mucositis which leads to increased iron absorbtion, transfusion burden and release of iron from injured tissues [8, 22].
Iron overload is particularly common in HSCT recipients with hemoglobinopathies and hematological malignancies which require frequent transfusions and is associated with ineffective erythropoesis such as acute leukemia and myelodysplastic syndrome (MDS). Transfusion load is considered to be the principal cause of IO in this group, as each unit of packed red blood cells (PRBC) contains approximately 200–250 mg iron. Since there is no physiological mechanism for excreting excess iron, iron accumulation is inevitable after 10–20 transfusions [22-24]. Ineffective erythropoiesis might be a contributing factor leading to excessive iron absorbtion particularly in MDS and thalassemia which is mediated by erythroid regulators of iron metabolism which suppress hepcidin and result in increased iron absorbtion. Elevated growth differentiation factor 15 (GDF–15) levels are considered to be the initiating event in this context. Ineffective erythropoiesis either as a feature of the underlying disease or a consequence of intensive treatment leads to inhibition of hepcidin possibly due to overexpression of GDF–15 and thus increases iron absorbtion and toxicity. Hematopoietic SCT recipients are at risk of IO due to prior transfusion load, increased iron absorbtion related to elevated GDF–15 levels and peri–tansplant transfusions [22, 24, 25].
Bone marrow (BM) and tumor cell destruction which occurs as a consequence of high dose therapy and release of iron from damaged cells as well as underutilization of iron due to the inhibition of erythropoiesis as a result of cytotoxic therapy are important factors in the etiology of IO. Erythropoiesis, which is the main route of iron utilization, is temporarily halted by the conditioning regimen [8, 22, 23, 26]. Conditioning treatment with chemo/radiotherapy during HSCT causes toxicity and immunosuppression leading to organ damage and infectious complications mainly in the first 3 months of the procedure [27]. Free iron, which acts as a free radical catalyser, might increase the toxicity of the conditioning regimen during HSCT. Serum iron parameters were demonstrated to be elevated 2–3 days during conditioning chemotherapy prior to stem cell infusion in a report by Gordon et al [13]. Non transferrin bound iron appears shortly after conditioning regimen and remains detectable in most patients throughout the peri–transplant period. Transferrin saturation (TS) increases during the conditioning regimen, often reaching to levels above 80% with the consequent emergence of NTBI [28]. The ability of ferritin to sequestrate iron and binding of iron to transferrin is exhausted in HSCT recipients receiving conditioning regimen, thus leading to excess NTBI formation. The extent of BM suppression caused by the conditioning regimen is correlated with the elevation of NTBI [27]. A substantial decrease in plasma anti-oxidant defense has also been demonstrated in HSCT recipients, and NTBI levels were found to be inversely correlated with plasma antioxidant capacity in a report by Yegin et al [29]. A derangementof the prooxidative/antioxidative balance was demonstrated as antioxidants only partially recover to baseline values until day 14 after HSCT [30, 31].
Hepatic toxicity due to chemotherapy and radiation might lead to hepatocellular damage with subsequent further release of hepatic iron stores. Liver damage may also disturb transferrin synthesis [28, 30]. A decrease in transferrin due to hepatic toxicity, stored iron leaking from injured liver to blood and a suppression of erythropoietic activity during treatment may causes elevated TS levels. Thus, increasing TS succeeds and contributes to the appearance of potentially toxic NTBI in the circulation. Iron in its NTBI form is a potent catalyst in Fenton’s reaction which produces ROS capable of causing cellular damage through various mechanisms. Tissue damage such as mucositis and liver injury is common after HSCT and may be partly mediated by NTBI during cytotoxic chemoradiotherapy [28, 29, 32]. It is indicated that increased NTBI levels may contribute to organ toxicity and infectious complications in the early post–transplant period [29].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Infection | \n\t\t\tVariable | \n\t\t\tImmune dysregulation, mediated in part by IO, iron-rich microbial environment | \n\t\t
Chronic liver disease | \n\t\t\tCommon | \n\t\t\tMultifactorial, including IO | \n\t\t
SOS | \n\t\t\tCommon (up to 54%) | \n\t\t\tConditioning regimen, prior irradiation, possibly IO | \n\t\t
IPS | \n\t\t\tUncommon (2-8%) | \n\t\t\tPro-inflammatory events and increased ROS (mediated by IO) | \n\t\t
Complications of IO in patients undergoing HSCT [24]
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The Role of IO in Early and Late Complications of HSCT [4]
Iron toxicity may play an important role in the pathogenesis of transplant related complications [Table 1, 2]. In a series of 25 patients who underwent HSCT, very high levels of ferritin (>3000 ng/ml) and TS (>100%) dramatically increased transplant related mortality (TRM) and decreased overall survival (OS) which was particularly attributed to infections [32]. As iron is an essential element for all pathological microorganisms, excess amounts of free iron might increase microbial growth and the probability of severe infections [33]. The coexistence of excess plasma iron with the damage to the mucosal barrier may also predispose to infectious events with bacterial translocation. Hypoferraemia is a normal response to infection and appears to be a part of a natural resistance mechanism whereas hyperferremia can predispose to bacterial and fungal infections. In this context, elevated TS and ferritin levels are proven risk factors for the development of systemic fungal infections in patients with hematological malignancies [1, 33, 34]. Furthermore, an increase in late fungal infections, especially mucormycosis, has been reported in iron loaded patients after HSCT [35]. Elevated pre–transplant ferritin levels seem to effect prognosis adversely in myeloablative HSCT primarily due to increased NRM. On the other hand, elevated iron stores apart from providing a milieu for infection and organ toxicity, may also be in relevance to tumor growth. Thus elevated ferritin levels might be in association with relapse and relapse mortality [36]. Mahindra et al reported that elevated pre–transplant serum ferritin level was an independent adverse risk factor for OS in patients undergoing non myeloablative HSCT. Inferior survival in patients with elevated ferritin was related to both higher rates of treatment related mortality and relapse mortality [37]. On the other hand it should also be noted that ferritin is an acute phase reactant and a marker of inflammation besides its role as a surrogate marker of iron status. Thus, elevated ferritin levels might as well indicate a group of patients with more agressive primary disease biology and a subgroup of patients who are already more likely to experience disease relapse. Thus the association of elevated ferritin levels with relapse might be unrelated to IO.
The adverse impact of IO on transplant outcome has been demonstrated most convincingly in patients with thalassemia where class III patients with extensive liver damage had higher TRM [38]. Besides increased TRM, other complications attributed to IO includes fungal infections, hepatic dysfunction and hepatic SOS/Veno occlusive disease (VOD) [4, 27, 38, 39]. In fact, thalassemia is a benign disorder and ferritin is directly a marker of excess iron and elevated levels could not be attributed to the biology of an underlying malignant pathology. As a result of the above mentioned data, pre–transplant serum ferritin was included in a prognostic scoring system for acute leukemia and MDS patients undergoing allo–HSCT [40]. The late morbidity of IO is primarily due to the involvement of heart and liver. Although iron related liver function test (LFT) abnormalities have been reported, there are no studies that describe the role of IO in late onset cardiomyopathy and hepatic fibrosis/cirrhosis in patients transplanted for diseases other than thalassemia. Post–transplant iron depletion therapy has been shown to reverse hepatic fibrosis and cardiomyopathy in children with thalassemia who have undergone allo–HSCT [4].
Liver disease is a frequent cause of morbidity and mortality following allo–HSCT and affects 90% of recipients and up to 5–10% of toxic deaths are liver related. Liver injury in the early post–transplant period may be secondary to drug toxicity, SOS, acute GVHD, opportunistic infections, total parenteral nutrition, tumor invasion and cholestatic disorders [3, 41]. Long term liver disease is also a common complication of HSCT, as 57, 5% of survivors developed chronic liver disease (CLD) at 2 years after transplantation in a retrospective series of 106 patients reported by Tomas et al. In this retrospective study, the combination of chronic hepatitis C and IO was presented as the most frequent cause of CLD [41]. On the other hand, chronic GVHD also contributes to liver toxicity. The timing and pattern of LFT abnormalities, history of pre or post transplantation hepatitis, presence of GVHD at other sites and transfusion burden might be helpful in determining the etiology of liver disease. Accurate diagnosis of the etiology of liver dysfunction is generally problematic even though the patterns of biochemical, clinical and histological abnormalities can aid diagnosis. Liver biopsy in patients following HSCT is not without risks, particularly due to thrombocytopenia during the early post–transplant period. The most common indication for liver biopsy is to assess the possibility of GVHD in allo–HSCT in the late post–transplant period with persistently abnormal LFTs and no evidence of GVHD on other sites. In this clinical setting, the sensitivity and specifity of serum ferritin as a marker of IO is not well defined due to its concomittant role as an acute phase reactant [3, 5, 8, 24, 41-43]. Liver biopsy may be performed when atypical clinical features are present or multiple disease processes are likely to occur simultaneously or when there is poor response to therapy that has been instituted [44]. The management of liver dysfunction under these conditions may be complicated as overlapping features often complicate the diagnosis and establishing the correct diagnosis is crucial to institute disease specific therapy. Autopsies performed in 10 patients who died early after HSCT showed iron accumulation in a range equivalent to that of patients suffering from HH [26]. A cumulative cirrhosis incidence of 3, 8% by 20 years after HSCT has been reported previously [8]. This rate seems to be an underestimation as the majority of long term survivors have not been subjected to liver biopsy. In a retrospective study by Sucak et al, severe IO was demonstrated in 75% of 24 liver biopsies which were performed with the presumptive diagnosis of hepatic GVHD in 20 patients with persistent elevation of liver enzymes in the post–transplant setting. The initial clinical diagnosis of GVHD was refuted in 43, 5% of the patients. Median number of post–transplant transfusions, TS and ferritin levels were found to be significantly higher in patients who had histologically proven hepatic IO. A significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes was also demonstrated [10]. In another study by Iqbal et al, the diagnosis obtained at laparoscopic liver biopsies altered targeted therapy in 31% of patients. Iron overload was found in 81, 25% of a total of 32 biopsies [45]. A diagnosis of IO after HSCT was demonstrated based on histological evidence of siderosis found in 52, 4% of liver biopsies performed at 15–110 days post-transplant in another study. Liver biopsies were performed for diagnostic purposes in patients with chronic liver dysfunction. An improvement in LFT was observed in 21 of the 23 patients (91%) with IO who underwent phlebotomy [41]. Namely, IO seems to be underestimated as a cause of liver dysfunction in HSCT setting and liver biopsy which allows disease specific therapy could be life saving.
Hepatic IO may also worsen the natural course of chronic viral hepatitis and the response to antiviral therapy. Fujita et al demonstrated that liver iron deposition was more common in chronic hepatitis C compared to hepatitis B and was associated with liver disease progression. Increased hepatic iron stores in chronic hepatitis C were related to resistance to Interferon/Ribavirin treatment [46]. Thalassemic patients with liver fibrosis and hepatomegaly who undergo HSCT, have a markedly reduced OS and event free survival compared to patients without evidence of liver disease. The liver disease in these patients is due to a combination of severe IO and chronic viral hepatitis both of which improve with effective iron chelation therapy [19, 26, 47]. Iron is also deposited in other tissues such as myocardium or BM. Slow and spontaneous decrease in iron stores has been reported in thalassemic children in the years following HSCT. This natural iron depletion could normalize iron stores in individuals with mild siderosis. However, in patients with moderate to severe IO this slow depletion could not prevent the development of liver dysfunction. For this reason, iron depletion protocols have been developed for patients with severe IO [19, 23, 26, 47].
Sinosoidal obstruction syndrome is a treatment related toxicity associated with auto and allo–HSCT which is seen in 6–54 % of the recipients. The severity of SOS ranges from a mild reversible to a progressive course with a mortality rate close to 100% [5, 24].
The role of pre–transplant hyperferritinemia in the development of SOS was first demonstrated by Morado et al in a cohort of 180 auto–HSCT recipients. In this prospective study, SOS was defined in 12, 2% of patients based on McDonald criteria. Patients with pre–transplant ferritin levels above 300 mg/dl were shown to have a higher risk of developing SOS [48]. In a recent report by Maradei et al, a pre–transplant serum ferritin level above 1000 ng/dl was identified as an independent risk factor for the development of SOS [39]. A retrospective study of 250 HSCT recipients by Sucak et al, in which SOS incidence was reported to be 29, 7%, demonstrated significantly higher pre–transplant serum ferritin levels in patients with SOS [49]. In another study reported by Sucak et al, pre–transplant ferritin levels were found to be higher in HSCT recipients who developed SOS in the post–transplant setting [50]. Serum ferritin may be increased in conditions other than IO in this particular group of patients, including chronic inflammation and infection. Nevertheless, values higher than 1000 ng/ml were rarely reported in these inflammatory conditions [1, 25, 29, 39, 48-51].
Iron induced hepatotoxicity is multifactorial which involves oxidative stress and modulation of gene expression of Kuppfer cells. Cellular injury is induced by iron generated ROS and peroxidation of lipid membranes [39]. Risk factors associated with the development of SOS are defined as preexisting liver dysfunction, previous abdominal irradiation, high dose total body irradiation, high dose preperative regimens, advanced disease and HLA mismatch or unrelated HSCT. The typical hepatocellular lesion of SOS mainly occurs in zone 3 of hepatic acines including a characteristic endothelial lesion which is shown to be associated with hypercoagulability. The oxidant effect of iron on endothelial and and hepatocyte membranes mediated by ROS contributes to the development of these typical lesions of SOS [48, 50]. The risk of SOS is higher in carriers of at least one allele of the hemochromatosis gene, HFE, which predisposes to iron deposition in the liver [24].
Patients with HH and other diseases with IO are considered to be more susceptible to infections, as iron adversely affects the phagocytic, chemotactic and bactericidal capacity of granulocytes and monocytes and inhibits the activity of natural killer cells and macrophages [35, 52]. A number of studies have demonstrated the adverse impact of IO on the development infections in HSCT recipients. Tachibana et al observed an association between IO and blood stream infections (BSI) in 114 patients who underwent allo–HSCT. They found that pre–transplant serum ferritin levels significantly predicted BSI within the 100–day period after allo–HSCT [1]. A direct correlation between hepatic IO and BSI was demonstrated in a retrospective cohort of 154 allo – HSCT recipients, as patients with hepatic IO tended to experience more frequent and prolonged episodes of lethal BSI [53]. Altes et al reported a ferritin level above 1500 μg/l was associated with the occurence of bacteremia and febrile days in first 3 months after auto–HSCT [27]. A prospective study investigated the risk factors for 140 early infection episodes which occured in 367 multiple myeloma (MM) patients undergoing auto–HSCT. Bone marrow iron stores were identified as significant risk factors for early severe infections [54]. Pre–transplant serum ferritin levels were demonstrated to be associated with fungal infections after allo–HSCT in several studies [33-35, 49, 55, 56]. Tunçcan et al identified the predictive role of pre–transplant serum ferritin level in the development of hepatosplenic candidiasis among 255 HSCT recipients. Hepatosplenic candidiasis was diagnosed in 6 (2, 3%) patients. Pre–transplant serum ferritin levels were significantly higher in patients with hepatosplenic candidiasis [55]. Özyilmaz et al studied the relationship between serum ferritin level and pulmonary fungal infections in 148 allo – HSCT recipients. In this study, the sensitivity and specifity of ferritin > 1000 ng/ml for the prediction of fungal pulmonary infections were found to be 67% and 70%, respectively [56].
Idiopathic pneumonia syndrome comprises a group of disorders that result in interstitial pneumonitis and/or widespread alveolar injury with an incidence of 2–8 % and a mortality of up to 70% in the HSCT setting. There is increasing evidence implicating ROS and pro–inflammatory events as major contributing factors to IPS [5, 24]. The mechanism of iron induced IPS probably involves endothelial injury by catalytically active iron released from heme groups, which can trigger a cascade of events leading to acute lung injury and pulmonary fibrosis [24]. Currently, there are no studies regarding the direct association of IO and IPS, except the oxidative milieu, which is partly a consequence of IO.
The role of IO in the pathogenesis of GVHD has been evaluated in a number of studies. There are conflicting results regarding the relationship between IO and GVHD in HSCT recipients. In a prospective cohort of 190 allo – HSCT recipients reported by Pullarkat et al, the effect of elevated pre–transplant ferritin on acute GVHD was assessed. Grade 2 or above acute GVHD was diagnosed in 48% of patients. Acute GVHD was more frequent in patients with high ferritin levels (≥1000 ng/ml). This was attributed to the increased ROS mediated injury on exposure to the conditioning regimen in iron overloaded patients, as antigen exposition following tissue injury was indicated to be the initiating event in the pathogenesis of GVHD [38]. Similarly in a report by Platzbecker et al, which was performed in 172 patients with MDS, transfusion burden reflected by ferritin levels, was found to be correlated with a higher probability of acute GVHD [57]. On the other hand, Mahindra et al investigated 222 patients who underwent myeloablative allo–HSCT and demonstrated that pre–transplant ferritin level >1910 μg/l was associated with decreased incidence of chronic GVHD [58]. Furthermore, in a study of 264 patients who underwent allo–HSCT for various hematological malignancies, no significant difference in the cumulative incidence of acute and chronic GVHD was demonstrated in high (≥599 ng/ml) and low (<599 ng/ml) ferritin groups [59]. Alessandrino et al reported that transfusion dependency was an independent risk factor for the development of acute GVHD, but not for chronic GVHD [60]. On the other hand, IO might as well mimic GVHD resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD [18]. Apart from hepatocellular, cardiac and other organ dysfunction, IO may worsen the natural course of liver GVHD, similar to the status with chronic hepatitis and its response to therapy [3, 18, 23, 51, 57]. It is speculated that intestinal iron absorbtion is increased as a result of epithelial injury related to chemotherapy or GVHD. Suggesting that IO might be the consequence rather than being the cause of intestinal GVHD [23]. The liver and the intestinal mucosa, which express essential iron regulatory genes including hepatic antimicrobial protein (HAMP), the gene that encodes hepcidin and ferroportin 1, are targets of conditioning related toxicity as well as GVHD, initiated by donor derived T lymphocytes. The ensuing release of cytokines including IL-6, might directly affect the expression of hepcidin as IL-6 is a potent inducer of hepcidin via STAT3 [61]. Graft versus host disease also involves the interaction of Fas ligand expressed on activated donor T lymphocytes with host tissue including enterocytes and hepatocytes. T lymphocyte induced tissue damage disrupts iron homeostasis leading to uncontrolled iron accumulation which may aggravate tissue damage related to the development of GVHD and infections [15]. The pattern of the relationship between IO and GVHD remains to be confirmed in future studies.
Several recent reports demonstrated that IO is an adverse prognostic factor for patients undergoing allo–HSCT [1, 17, 22, 36, 59, 62-66]. In a retrospective cohort of 114 AML and MDS patients, the OS rate at 5 years was found to be significantly better in patients with ferritin levels < 1000 ng/ml [1]. Tanaka et al evaluated the outcome of 47 patients with acute leukemia or MDS who underwent reduced intensity HSCT. High ferritin level which was defined as >1000 ng/ml was associated with worse 2 year OS on multivariate analysis [62]. Another study by the same group demonstrated the adverse impact of elevated ferritin levels on 5 year OS in a cohort of 143 patients with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) who received allo–HSCT with myeloablative and non myeloablative conditioning regimens [63]. Transfusion dependency, predicted by serum ferritin levels, was found to be independently associated with reduced OS and increased NRM in a retrospective cohort of 357 MDS patients undergoing allo–HSCT [60]. The transplant iron score which included serum ferritin level above 1000 ng/ml was tested in 78 patients who received allo or auto–HSCT. The independent impact of IO on transplant survival was indicated with the most pronounced predictive power of the iron score restricted to allo–HSCT recipients. A high iron score (≥2) was associated with 50% absolute decrease in OS at 1 year [67]. Lim et al reported the adverse impact of elevated serum ferritin on OS in 99 MDS patients who underwent reduced intensity HSCT [64]. Altes et al demonstrated that serum ferritin levels ≥3000 μg/l and TS ≥100% were associated with a decreased OS and increased TRM, which was attributed to a high infectious mortality [32]. On the other hand Pullarkat et al analyzed 190 patients and demonstrated that elevated pre–transplant ferritin levels were associated with increased risk of death and day 100 mortality, mainly due to acute GVHD and infections [38]. Mahindra et al demonstrated a pre–transplant serum ferritin > 685 ng/ml was associated with lower OS and relapse free survival in 315 patients with Hodgkin and non Hodgkin lymphoma who received auto–HSCT, whereas same ferritin level exhibited a higher incidence of relapse and relapse mortality. They identified the baseline ferritin level was best correlated with poor survival. They concluded that elevated iron stores may also increase tumor growth, as tumor cells require more iron for DNA synthesis due to rapid proliferation [36]. Same group confirmed their results in a study of 222 allo–HSCT recipients with a serum ferritin level >1910 μg/l associated with lower OS, lower relapse free survival and higher NRM rates [58]. Furthermore they demonstrated inferior survival rates related to higher rates of TRM and relapse mortality in patients with elevated ferritin levels who received non myeloablative conditioning [37]. In a large retrospective study by Armand et al, an elevated pre–transplant serum ferritin level was significantly associated with lower OS and disease free survival. This association was particularly restricted to patients with acute leukemia and MDS which was particularly attributed to transfusion load. They suggested a possible role of iron chelation therapy in the pre and post – transplant setting, as they showed an absolute difference of 37% in 5–year OS for patients with MDS between the highest and lowest ferritin quartiles [66]. Sucak et al demonstrated an adverse impact of a pre–transplant serum ferritin level >500 ng/ml on OS and TRM in 250 patients who received auto and allo–HSCT, underscoring the prognostic effect of IO in auto transplants [49]. The same group confirmed their results with a more toxic form of iron, NTBI, in a retrospective cohort of 149 patients. In concordance with the previous report, a significant impact of NTBI on day 30 and day 100 survival was shown in auto–transplanted patients for the first time in iron and transplant connection [29]. Notwithstanding, in a prospective study by Armand et al, pre–transplant IO predicted by LIC which is considered to be the gold standard indicator of IO, was not found to be associated with increased mortality, relapse, SOS or GVHD [68]. Therefore, they assumed that the adverse prognostic impact of pre–transplant hyperferritinemia may be related to factors independent of IO. Taken together, it is speculated that ferritin may be prognostic not because it reflects iron stores but because it is an acute phase reactant [68, 69].
Liver remains to be the most accessible parenchymal organ that can be used to estimate tissue iron load after HSCT. Iron overload is not uncommonly seen in various other primary liver diseases such as alcoholic liver disease, chronic viral hepatitis, non alcoholic steatohepatitis, liver cirrhosis and HH. Histological evaluation of liver specimens is essential in the management of these disorders. The reported incidence of significant liver fibrosis in HSCT recipients varies from 5% to 80% and LIC has been demonstrated to have a particular role in the progression of fibrosis [26, 41, 70]. Though ferritin continues to be the mainstay for the initial clinical evaluation of IO, liver biopsy is still the gold standard for quantifying iron. Measurement of hepatic iron stores provides the most reliable estimate of body iron burden. Liver iron content exceeding 80 mcmol/g of liver dry weight was found to be consistent with IO with a hepatic index greater than 1, 9 mmol/kg/year. However, the need for a relatively large volume of tissue as well as its invasive nature has made this procedure less appealing to most clinicians and patients [4, 9, 53]. Although liver biopsy is an invasive procedure and can not be safely administered in patients with very low platelet counts, a liver biopsy can be advantageous in some HSCT recipients as it can also exclude alternative causes of hepatic dysfunction, such as infections and GVHD. In high risk patients, liver biopsy using a transjuguler approach may be a feasible alternative to percutaneous biopsy [4, 17].
Superconducting quantum interference device (SQUID) assesses total body iron by using biomagnetic susceptometry. Ferritin and hemosiderin are the only paramagnetic materials in the human body, thus the magnitude of these parameters is directly related to the amount of iron in a certain volume of tissue. The device utilizes the magnetic property of iron in ferritin and hemosiderin to estimate hepatic iron stores. Furthermore, it is considered to be the non invasive reference standard for estimation of LIC as it has an excellent correlation with liver biopsy. However, widespread clinical use is limited by its cost, complexity and very limited availability [4, 9, 17].
Liver iron content measurement has limited predictive value for extrahepatic iron deposition. The liver is the dominant iron reservoir for the body, accounting for more than 80% of the total body iron and has high capacity mechanisms for clearing both transferrin and NTBI species from the circulation. The heart and endocrine tissues have tightly regulated transferrin uptake and develop IO only when there is circulating NTBI. High liver iron (15-20 mg/g dry weight) damages liver parenchyma and increases circulating NTBI levels dramatically. As no liver iron can be considered safe from a cardiac and endocrinological perspective, extrahepatic monitoring by magnetic resonance imaging (MRI) is essential [71]. Magnetic resonance imaging becomes increasingly important in the evaluation of iron status as it is non invasive, more rapidly and widely available. Designating liver iron by older MRI techniques and equipment showed variable correlation with the biopsy estimates of LIC. More recent MRI techniques T2* and R2* MRI are reproducible methods for non invasive estimation of LIC with reported sensitivity and specifity of 89% and 80%, respectively [4, 17, 72-74]. It has the additional benefit of identifying relatively early IO within organs prior to the onset of dysfunction. Magnetic resonance imaging can be used to co-measure iron deposition within the heart, liver and pituitary gland as it does not appear that a single organ gives the full picture of total body IO. In fact, patients can accumulate cardiac iron, despite apparently normal hepatic iron levels and thus be at risk for arrhythmia or congestive heart failure. The discordance of values in two tissues can be resolved with the use of MRI to detect cardiac iron. Cardiovascular MRI could potentially be used not only to determine myocardial iron content but also cardiac function and therefore could be used to investigate the effects of iron mediated organ damage. Non invasive measurement of LIC has also been achieved using an MRI technique based on the proton transverse relaxation rates within the liver. The technique can be implemented on, most clinical 1, 5–T MRI measurements, making it readily available to the clinical community. This technique resulted in a high specifity and sensitivity over a greater range of LIC than any other MRI–based method of LIC assessment [9].
High prevalence of IO in long term survivors of HSCT emphasizes the need for routine screening for IO in this population. Ferritin is a cellular iron storage protein that buffers iron in a soluble and non toxic form. Under normal conditions ferritin levels in the serum are low but steadily increase in conditions of IO. Therefore, assessment of serum ferritin levels serves as a simple and widely used surrogate marker for IO. Serum ferritin levels are however subject to natural fluctuation and can also be greatly affected by a range of inflammatory conditions that are particularly relevant in HSCT recipients. Although being a useful test for initial screening of IO in HSCT recipients, serum ferritin is not a reliable indicator of total body iron burden particularly in patients who have ongoing acute infections or inflammatory diseases [2, 4, 17, 20, 22, 23, 38, 75, 76]. Serial serum ferritin measurements can compensate the potential fluctuations and help to establish a general picture of IO over time. Nevertheless, at 1 year after–transplantation when inflammatory stress has largely subsided, most patients have a serum ferritin of <1000 ng/ml and no clinical evidence of IO; serum ferritin in these patients decline slowly with time [23]. Unlike tissue ferritin a substantial proportion of serum ferritin is glycosylated which suggests that plasma ferritin is actively secreted from reticuloendothelial system or parencymal cells. Serum ferritin in contrast to tissue ferritin was claimed to have a low iron content even in iron loaded patients in some earlier studies. It is therefore claimed that serum ferritin does not provide a major source of hepatic iron either in normal individuals or in patients with IO diseases [4, 20, 22, 23, 75]. On the contrary a direct correlation between serum ferritin levels and transfusion burden has been observed with a level of 1000 ng/ml after a median of 21 PRBC transfusions. Thus repeated measurement of serum ferritin levels seems to be a valid method to monitor secondary IO in patients with transfusion dependent anemias and MDS [17]. Majhail et al studied the prevalence of IO in 56 allo–HSCT recipients and demonstrated the poor predictive value of ferritin for estimating LIC. The overall prevalence of IO was 32%. Clinically significant IO (LIC>7 mg/g) was uncommon in patients with serum ferritin levels less than 1000 ng/ml. However, the LIC on MRI was moderately correlated with serum ferritin. As a result, they indicated ferritin to be a good screening test but a poor predictor of tissue IO and recommended estimation of LIC before initiating chelation therapy. They considered that this lack of association between ferritin and LIC might be related to the variability in ferritin levels because of ineffective erythropoiesis or underlying inflammation or infection [20]. Whereas in a study by Bazuave et al, serum ferritin, transferrin, TS, iron, soluble transferrin receptor (sTfR) and C reactive protein levels in 230 HSCT recipients were measured. All iron parameters were found to be significantly associated with survival. A combination of ferritin and TS was shown to have the highest prognostic power. They concluded that the predictive power of ferritin was derived from its association with IO rather than inflammation. Inferior survival in patients with IO was related to both TRM and relapse. As sTfR and TS were found to have superior prognostic value when compared to ferritin, they suggested to combine serum ferritin with TS for prediction of IO [2].
Recent evidence suggests that the determination of iron status before HSCT has important prognostic implications. There is a gap between the time that patients are identified for HSCT and the time that actual transplant takes place. During this period, most patients stay transfusion dependent. After patients are exposed to conditioning regimen and stem cell infusion, serum ferritin levels are prone to a false elevation due to its role as an acute phase reactant. Thus, accurate evaluation and diagnosis of iron toxicity after HSCT remains as a challenge [53, 67] [Table 3].
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t
Liver Biopsy | \n\t\tReference method, can assess degree of hepatic fibrosis, can evaluate other causes of hepatic dysfunction (GVHD) | \n\t\tInvasive procedure, not feasible in patients with thrombocytopenia or coagulopathy | \n\t
SQUID | \n\t\tGood correlation with liver biopsy, noninvasive | \n\t\tVery limited availability | \n\t
MRI | \n\t\tGood correlation with liver biopsy (T2 or R2 MRI), noninvasive, widely available | \n\t\tVariety of MRI techniqueshave not been validated with liver biopsy, contraindications (metal implants, claustrophobia) | \n\t
Serum ferritin and TS | \n\t\tNoninvasive, widely available | \n\t\tSensitive but not specific for IO, poor correlation with liver biopsy | \n\t
Diagnostic Tests for Assessment of Body Iron Stores in HSCT Recipients [4]
Non transferrin bound iron is toxic to living systems because it can act as a catalyst in the formation of ROS which in turn stimulate lipid peroxidation in membranes. In iron-overloaded states when SIBC becomes fully saturated, NTBI complexes appear in the serum. In a study by Harrison et al, serum ferritin was raised in 21 of 28 patients following treatment for hematological malignancy, whereas only 16% of them had LFT abnormalities. However, NTBI was detected in 4 of 6 patients with an unexplained elevated LFTs. Therefore, they considered that NTBI might be a more specific indicator of IO than the serum ferritin concentrations [77]. Assessment of NTBI is a potentially useful approach that allows the estimation of toxic iron levels. However, the methods for determining this free fraction of body iron and its precise prognostic significance require fine tuning [17].
The current paradigm of managing post–transplant IO is based on extensive experience in children with transfusion dependent anemias [4]. Post–transplant iron depletion therapy has been shown to reverse hepatic fibrosis and cardiomyopathy in patients with thalassemia [4, 78]. However, there is no published data indicating the benefit of iron removal therapy on long term morbidity and mortality in HSCT recipients, especially for diseases other than thalassemia [4].
Decisions regarding the management of IO should be individualized and based on a review of several factors including the need for ongoing PRBC transfusion therapy, time since transplantation, ability to tolerate iron depleting therapy and urgency to reduce body iron stores [Table 4]. For instance, coexisting anemia can preclude the use of phlebotomy whereas renal impairment might increase the risk of toxicity from iron chelating drugs. Also depletion of iron stores would be more imperative in patients with IO related liver test abnormalities or cardiac dysfunction compared to those without end organ toxicites [4].
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t
Phlebotomy | \n\t\tExtensive experience with proven efficacy, no significant side effects | \n\t\tNot feasible in patients with anemia or poor venous access | \n\t
Deferoxamine | \n\t\tExtensive experience with proven efficacy | \n\t\tInconvenient administration route and schedule, side effects (ototoxicity, growth retardation) | \n\t
Deferiprone | \n\t\tOral iron chelator | \n\t\tUnproven efficacy, side effects (neutropenia, hepatic fibrosis) | \n\t
Deferasirox | \n\t\tOral iron chelator, efficacy similar to deferoxamine | \n\t\tLong term toxicity profile not established, side effects (nephrotoxicity) | \n\t
Treatment Options for Iron Overload after HSCT [4]
Iron overload may be a cause of persistent hepatic dysfunction after HSCT. Patients with LIC>15 mg/g dry weight should be treated aggresively with both phlebotomy and chelation; when LIC is 7–15 mg/g dry weight, phlebotomy is indicated; when LIC is under 7 mg/g dry weight treatment is indicated only if there is evidence of liver disease. Mobilization of iron from heavily overloaded patients improves cardiac function, normalizes serum alanine transaminase levels and results in improved liver histology [24, 79].
In patients with extreme IO, effective pre–transplant chelation therapy is suggested to improve post–transplant survival, as IO is clearly related to treatment related morbidity and mortality after HSCT [4, 24, 67, 79]. In the pre–transplant period vigorous iron chelation may be important but prospective studies are required to prove a survival benefit after HSCT. In the post–transplant period phlebotomy sometimes combined with erythropoiesis stimulating agents (ESA) may be successfully applied in thalassemia. For those patients who can not be phlebotomized iron chelation can be considered. Prospective studies of the impact of iron chelation therapy before and after HSCT on post–transplant morbidity and mortality are mandatory [4, 24].
The American Society for Blood and Marrow Transplantation (ASBMT) 2012 guidelines recommend annual serum ferritin measurement in patients who received PRBC transfusions pre or post–transplantation. Subsequent monitoring with serum ferritin should be considered among patients with elevated levels, especially in the presence of abnormal LFTs, PRBC transfusions or HCV infection. Additional diagnosting testing including liver biopsy, MRI or SQUID may be indicated if therapy is intended for presumptive IO. Current prescribing guidelines recommend continuation of iron reduction till ferritin levels are below 500 ng/ml [3, 9, 51, 60, 72].
Phlebotomy is a feasible option for the treatment of IO following HSCT. Many studies have documented its efficacy in early and late post–transplant setting. It has been shown that subclinical left ventricular diastolic dysfunction and impaired left ventricular contractility in patients with thalassemia may be reversed by phlebotomy initiated after HSCT [51]. Iron overload should be treated by means of phlebotomy and/or chelation therapy especially when IO coexists with chronic viral hepatitis. Phlebotomy has the advantage over chelation of better compliance, fewer side effects and lower costs. The use of ESA may facilitate the success of this strategy in patients with low hemoglobin levels [4, 19, 22, 26, 70].
After normalization of transaminases and serum ferritin with aggressive phlebotomy, maintenance phlebotomy is required every 3-6 months to prevent iron reaccumulation and keep serum ferritin in a low normal range. The gradual rise in ferritin after successful iron depletion suggests that there is a signal for increased iron absorbtion and the signal persists well beyond the peri–transplant period. It may be that post–transplant immunosuppressants reduce the level of cytokines that normally stimulate hepcidin production and allow increased absorbtion of dietary iron. In addition hepatic GVHD may result in disordered hepcidin regulation, as it likely does in chronic viral hepatitis and might explain increased risk of IO and the need for maintenance phlebotomy after successful iron depletion [23].
Treatment with phlebotomy is not possible in patients who are transfusion dependent. Chelation may be preferred for iron depletion [9]. There are limited data on the pharmacological chelation of iron during the post–transplant period including the safety, optimal dose, time for initiation of treatment and duration of therapy [51, 80, 81].
Deferoxamine, the first available iron chelator, has a proven efficacy and safety with decades of experience and has also been studied in HSCT recipients. Recommended treatment schedule is at least 5 nights per week subcutaneous delivered via a pump for 8-12 hours [4, 9]. It is effective in lowering serum ferritin levels and LIC and prevents endocrinological complications. Long term treatment is also associated with a reduction in cardiac complications and improved survival. Redness and induration at the infusion site are the most common side effects. Audiological, ophthalmological, growth and bone toxicities may be minimized by avoiding overchelation. Deferoxamine treatment in the HSCT setting is complicated by the short half life and the ability to release iron to bacteria and fungi. Deferoxamine supports the growth of zygomycetes because it acts as xenosidephore delivering iron to iron uptaking molecules of the species [22, 51, 81]. The greatest challenge with DFO is patient adherence with therapy because the need for parenteral administration is cumbersome, uncomfortable, inconvenient and time consuming [51]. Cardiac morbidity and mortality continue to occur in patients treated with DFO, likely related to difficulties with adherence [4, 9, 22, 51, 81].
Deferiprone is an oral iron chelator which was first identified in 1980s and subsequently approved for clinical use in Canada and Europe especially when DFO is contraindicated. Deferiprone is not commercially available in all countries and has not been investigated in HSCT recipients. It has a short half life of only 1, 5 hours and thus requires 3 times daily dosing. Unfortunately, it does not control liver iron as effective as DFO even after years of continued treatment. In contrast, a recent study in patients with thalassemia showed better myocardial function in those receiving Deferiprone. Retrospective studies have also demonstrated reduced cardiac morbidity and mortality and lower myocardial iron deposition among patients treated with Deferiprone compared with DFO and Deferasirox (DFX). A reduction or stabilization of serum ferritin levels and LIC in most patients with transfusional IO was demonstrated. The high risk of agranulocytosis necessitates weekly blood monitoring. Thus, toxicity profile of the drug may be inappropriate for transplant recipients [4, 9, 81].
A novel oral iron chelator, DFX was approved by the US Food and Drug Administration in 2005 and represents a significant advancement in the treatment of IO. It is a tridentate oral iron chelator which is lipid soluble but highly protein bound. It has a plasma half life about 12 hours and thus is ideal for once daily dosing. It binds iron in a 2/1 ratio. It is excreted by the hepatobiliary system and the chelated iron is excreted via the feces. The effective dose is between 20-40 mg/kg. It is generally well tolerated by patients although some dose modifications may be necessary for diarrhea. Phase III trials demonstrated that DFX at 20-30 mg/kg/day led to the maintenance or reduction of iron burden as measured by LIC in chronically transfused patients. Reductions in LIC and serum ferritin are similar to those found in the subcutaneous use of DFO. Commonly reported side effects include skin rash, nausea, vomiting and diarrhea and elevations in serum creatinine levels, which may be important in patients treated with calcineurin inhibitors. Gastrointestinal disturbances often improve with continued administration of the drug. Elevations in serum creatinine occur in approximately 1/3 of subjects. Side effects associated with DFX therapy may overlap or exacerbate early complications such as calcineurin induced renal injury seen after allo–HSCT, which Mkes it complicated to use early after HSCT. The availability of an oral iron chelator has simplified the treatment of IO, but more experience with its use in HSCT recipients is needed [4, 9, 22, 80, 81].
The role of IO in HSCT recipients and guidelines for screening strategies warrants further studies. The value of routine screening for IO, the method of determining it, whether it should be with serum ferritin, by determining LIC with non invasive MRI or biopsy and identifying a subgroup of patients who might benefit from phlebotomy and/or iron chelating agents requires future prospective studies. The possibility of IO should be considered in patients who are candidates for HSCT. Red blood cell transfusion should be limited whenever possible and chelation and/or phlebothomy should be considered in the course of documented IO. pre–transplant preventive measures should also be adopted to avoid IO and improve survival in these patients.
The liver is a reddish-brown multifunctional organ that lies beneath the diaphragm in the abdomen’s right upper quadrant and overlies the gallbladder. It performs varieties of biological and metabolic functions, but one significant of them is xenobiotic metabolism/detoxification, in which exogeneous lipophilic xenobiotics (drugs and herbal supplements) are converted to hydrophilic compounds via biochemical processes catalysed by cytochrome P450 enzyme systems. The metabolic products obtained are then actively transported by hepatocyte transporter proteins into the plasma or bile for excretion by the kidney or gastrointestinal tract [1, 2]. However, sometimes, these xenobiotics produce reactive (or toxic) metabolites or electrophiles that bind covalently to hepatocytes, resulting to changes in protein conformation, DNA mutation or induce lipid peroxidation respectively, thereby leading to hypersensitivity reaction or liver necrosis. This is known as drug-induced injury (or hepatogenous poisoning, toxic-liver disease, chemical-driven injury). This situation often leads to hospitalisation and/or liver transplantation, depending on the magnitude of the liver injury [3]. There are over 1000 hepatotoxic agents available, however, drugs account for about 20–40% of the cases associated with liver failure/injury [4]. Notably, there are two categories of drug-induced liver injury (DILI) namely: intrinsic (or pharmacological) and idiosyncratic DILI respectively. Intrinsic DILI, refer to a form of liver toxicity caused by a drug in a projectable and dose-dependent manner (e.g. acetaminophen). In this circumstance, liver injury sets-in after an elevated concentration of the drug is attained. On the other hand, idiosyncratic DILI (which occurs relatively), is a non-projectable, non-dose-dependent response to drug and differs in the period of latency (e.g. Trovafloxacin and Troglitazone). It is worthy of note, that approximately 75–80% cases of idiosyncratic reactions end up in death or liver transplantation and as such precautionary measures should be observed in the use of drugs [5, 6]. The dreadful incidences of DILI can be checked by creating drug pharmacovigilant awareness, in which cases of adverse side effects after drug administration should be withdrawn or stopped abruptly to avoid further harm to the body. Besides the harmful effects of acetaminophen (APAP) overdose that has been well documented, studies provide us with wide spectrum of drug inducible agents like, Atypical antipsychotic (AAP), D-galactosamine ((D-GalN)), N-nitrosodiethylamine (NDEA), thioacetamide, Anti- Tuberculosis Drugs (ATD), Anti- Retroviral Drugs (ARDs), Antimalarial Drugs, NSAIDs (Non-Steroidal Anti-inflammatory Drugs), azacytidine, to mention but a few [3]. Therefore, this chapter focuses on discussing the mechanism of action and toxicological implications of drug-induced hepatotoxicity of the aforementioned drugs to human health.
As much as there are several analgesic drugs consumed by man as pain killer agents, paracetamol seems to be the commonly used and contains acetaminophen - the active ingredient, which has been shown to be well-tolerated in prescribed dose but in the event of overdose, liver damage occurs. This is because, acetaminophen metabolism catalysed by cytochrome P450 enzymes in the liver produces N-acetyl-p-benzoquineimine (NAPBQI) – a highly reactive (toxic) intermediate metabolite [7]. In the normal sense, this metabolite gets detoxified by glutathione conjugation in phase II reaction. Nevertheless, during acetaminophen’s overdose, a high concentration of the toxic metabolite is produced, and thus overwhelms the detoxification process, leading to hepatocellular necrosis. Reports have shown that liver injury caused by this metabolite can be reduced by the administration of acetylcysteine - a precursor of glutathione, by scavenging the toxic metabolite from the system [8].
Antipsychotic drugs are detoxified via the cytochrome-P450 system in the phase 1 and phase 11 reactions. In its metabolism, the enzyme known as mono-oxygenase converts the drugs into less toxic metabolites through hydrolysis, oxido-reduction and dealkylation processes. However, sometimes, the phase products may display high level of toxicity, hence, phase 11 reaction becomes inevitable. The phase II reaction mainly involves a biochemical process called conjugation reaction which makes use of glucuronic acid, sulphate, acetate, amino acids and glutathione to convert phase 1 products to a more body friendly form and subsequently for excretion. Many antipsychotic drugs beside antisulpride, risperidone, and paliperidone are catabolised primarily via the CYP2D6 and CYP3A4 systems while clozapine and olanzapine use the CYP1A2 system for its drug metabolism. Experimentation shows that antipsychotic drugs potentially damages liver cells through three mechanisms (i) By increasing bile secretion and excretion leading to cholestasis which relates to immune-mediated hypersensitivity (a typical mechanism of chlorpromazine) (ii) Accumulation of toxic or reactive intermediates (or metabolites) that eventually attacks liver cells (iii) By Increasing the risk of metabolic idiosyncratic syndrome leading to high risk of non-alcoholic fatty liver diseases which is typical of olanzapine and clozapine. Indiscriminate consumption of antipsychotic drugs presents some clinical manifestations (or side effects) and this can be encapsulated into four categories namely:
Hepatocellular disorder in which hepatic bio-indicators such as aminotransferases, ALP (alkaline phosphatase) and γ-glutamyl transferase (GGT) activities as well as the levels of albumin and total bilirubin are found to increase significantly in the serum.
Gastrointestinal disorders ranging from fatigue, appetite loss, excruciating pains in the liver region and epigastric discomfort
Cholestasis and steatosis like coloured stool
Immunological or hypersensitivity disorders including eosinophilia, anthralgia, rashes, acute liver failure (ALF), auto-immune diseases among others [9, 10].
Galactosamine, one of the commonly used experimental model for hepatotoxicity study in animals, is an amino sugar derivative found majorly as glycoprotein in living cells. In addition, it forms a component of some hormonal systems like Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) respectively. Biochemical investigation into the hepatotoxic effect of D-galactosamine revealed that it induces liver damage by interfering with the products of galactosamine metabolism via Leloir pathway of galactose metabolism. Firstly, galactosamine is transformed to galactosamine-1-phosphate (Gal-1-P) catalysed by galactokinase while the second phase involves the conversion of galactosaminr-1-phosphate to Uridine diphosphate-galactosamine (UDPG) by galactose uridyltransferase. At low substrate specificity, UDPG inhibits the activity of UDP-galactose-41-epimerase, thereby causing a significant accumulation in the hepatic cells and others like UDP-N-acetylglucosamine and UDP-N-acetyl galactosamine with corresponding depletions of uridine triphosphate (UTP), uridine diphosphate (UDP), uridine monophosphate (UMP) as well as uridine diphosphate-glucose (UDP-Glu) and uridine diphosphate-galactose (UDP-Gal), respectively. The outcome of this process then causes the loss of intracellular Ca2+ homeostasis, inhibits hepatocyte ATP metabolism and hepatitis which invariably affects cell membrane, inhibits mRNA, protein and nucleic acid biosynthesis. These effects increase protein gene (p53) expression and decreases Bcl-2 mRNA levels in the liver. It is noteworthy, that the hepatoxic action of galactosamine is effective when in combination with lipopolysaccharide (GalN/LPS). This combination induces the Kupffer cells to secrete pro-inflammatory mediators that leads to liver cell apoptosis [11]. Experimental design that involves the treatment of animals with D-GalN alters albumin mRNA, glucose-6-phosphatase, histone-3 mRNA, alpha fetoprotein mRNA (αFP mRNA), gamma-glutamyl transpeptidase (GGTP) expressions. Furthermore, it also upregulates expression of tumour nuclear factor (TNF-α mRNA) that has activity of necrotic factor-kappa B (NF- κB10) and alter membrane cofactor protein (MCP-1) level in serum. Also, serum ALT and AST activities increases substantially [12, 13].
N-nitrosodiethylamine (NDEA), is a member of the nitrosamine family and are found in various foodstuff and underground water with high nitrate level. It has hepatocarcinogenic property by yielding adducts of DNA carcinogen in the liver and induces hepatic cancer. NDEA’s mechanism of hepatic damage is such that after treatment, it stimulates increase in liver mitochondrial transitional permeability (MTP), leading to increase hydrogen peroxide (H2O2) production, resulting in peroxidative stress [14, 15]. Alternatively, cytochrome P450 activates NDEA, generating reactive electrophilic molecules capable of increasing oxidative stress and liver cytotoxicity and carcinogenicity [16].
Thioacetamide (TAA), is a white crystalline, organosulfur compound with high affinity for water and alcohol. It is chemically designated as C2H5NS and generally classified as class 2B human carcinogenic agent. NDEA exhibits wide range of relevance such as serve as sulphide source in the synthesis of compounds (organic and inorganic), controls the deterioration of orange fruits (fungicidal role), precipitates cadmium sulphide from acidic solutions, drug development, pesticide production, serve as cross-linking agent but to mention a few. However, scientific reports documented that long-term oral consumption of TAA causes liver cell adenomas, cholangiomas and hepatocarcinomas as well as affects protein, nuclei acid synthesis and GGTP activity. The bio-transformation of TAA via oxidative bioactivation in the liver microsomes catalysed by flavin-containing mono-oxygenases (FMOs) and cytochrome P450 systems produce two toxic metabolites. Firstly, TAA is catalysed by thioacetamide-S-oxygenase to form a reactive intermediate, thioacetamide-S-oxide (TAASO) adduct through oxidation process, which then induces hepatocytic oxidative stress, resulting to increase in nucleoli and Ca2+ concentrations as well as inhibit mitochondrial activity, thereby leading to hepatotoxicity with a resultant effect of centrilobular necrosis. However, the action of CYP2E1 inhibitors (such as 4-methylpyrazole and diallyl sulphide) and TAA, block TAASO toxicity in a relative and absolute manner respectively. The second phase of metabolism involves the conversion of TAASO to thioacetamide-S-S-dioxide (TAASO2 - a reactive species) by the action of thioacetamide-S-oxide-S-oxygenase and then covalently binds with protein and nucleic acid causing hepatotoxicity with consequential effect of liver damage/injury [17, 18]. The characteristic validation of the hepatotoxic effect of TAA includes decrease in microRNA gene expression (miR-122, miR-192 and miR-194) and increase in AST and ALT activities, mitochondrial membrane protein gene expression (MMP-9 and MMP-2) as well as myeloperoxidase, interleukin-10 (IL-10) and tumour nuclear factor (TNFα) respectively [19, 20, 21].
This is a fluorine derivative compound with carcinogenic tenacity. Its incorporation in diet and subsequent administration induces increased incidences of liver and urinary bladder carcinomas in animal model. Acetylaminofluorene, a by-product of diethyl nitrosamine (DEN) initiates carcinogenesis by increasing reactive oxygen species (ROS) production and facilitate hyperproliferation [22]. Acetylaminofluorene metabolism by cytochrome P450 produces metabolites like 2-aminofluorene (AF), 2-glycoloylaminofluorene (2-GAF), N-hydroxy-2-acetylaminofluorene (NH-2-AAF), 2-acetylaminofluoren-3-,-7-,-9-ol (3-, 7-, 9-hydroxy-AAF) and 2-acetylaminofluoren-9-one (AAF-9-one) respectively and exhibits different toxicity pathway. For instance, N-hydroxy-2-acetylaminofluorene and AAF binds covalently at Carbon - 8th positions in guanine; causing single strand breaks in DNA with resultant effect of severe apoptosis. Sometimes, AAF exposure increases expression of genes implicated in p53-signalling pathway, mRNA genes [encode mitochondria drug resistance proteins (Mdr1b, Mrp1 and Mrp3)] and microRNA genes respectively, thereby resulting in apoptosis [23, 24, 25]. Studies showed that at small dose of 2-AAF for long (2.24 or 22.4 mg/kg, 3 times/week for 31 days) or high dose (448 mg/kg BW, i.g., 5 days/week for 8 weeks) produces maximum hepatocellular carcinogenesis through AAF- DNA adducts [26, 27]. Interestingly, lower dose of 2-AAF (50 mg/kg BW, i.p.) was reported to increase lipid peroxidation, deplete GSH level while the activities of glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferase (GST) were significantly reduced [28].
Anti-tubercular drugs are the most auspicious prescription medication used for the treatment of cases of tuberculosis - an infectious disease with high mortality rate [29]. However, long- term administration of anti-tubercular drugs like rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (first line anti-tubercular drugs), significantly increase hepatotoxicity and induces liver injury in mammals [30]. The mechanism that precipitates anti-tubercular drug’s liver damage maybe unclear, nevertheless, studies show significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities. Furthermore, lipid peroxidation, intracellular calcium (Ca2+) level and CYP4502EI activity also increases while GSH level, GPx and catalase activities decreases [31]. Recently, research shows that acetylators generate high level of acetylated drug which undergo further metabolism to yield other toxic intermediates which causes liver disruption, for instance, Isoniazid acetylation by N-acetyltransferase (NTA2) enzyme produces mono-acetyl hydrazine (MAH) that increases liver toxicity [32]. Notably, polymorphism at gene loci of NTA2, CYP2E1 and GST (detoxifying enzymes) modulate the activities of these enzymes and hence increases the risk of hepatotoxicity [33]. Studies have shown some administrable dose regimen of anti-tubercular drugs that can be used for biochemical evaluation, for example, intraperitoneal administration of 50 mg/kg BW of isoniazid, 100 mg/kg BW of rifampicin and intragastric administration of 350 mg/kg BW of pyrazinamide respectively. Also, when they are in combined form such as INH and RIF as well as INH, RIF and PZA induces hepatotoxicity. This observation was in agreement with previous work as reported by [34] that daily oral administration of isoniazid (15 mg/kg BW), rifampicin (20 mg/kg BW) and pyrazinamide (35 mg/kg BW) in combined form for 45 days, increases malondialdehyde level (MDA).
The therapeutic action of highly active antiretroviral drugs (HAART) like Protease inhibitors (PI), non-Nucleoside reverse transcriptase inhibitors (nNRTI) and Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTI) used in the management of human immunodeficiency virus (HIV) undergo various pathways, nonetheless, their adverse effects are targeted/localised at the hepatic cells [35, 36]. Take for example, all anti-retroviral therapy-native (ART-naïve) like atazanavir or ritonavir and NRTIs (such as zidovudine or didanosine) alongside N-Apostolova Efavirenz (nNRTI) causes hepatic mitochondrial dysfunction and acute mitotoxic effect and oxidative stress respectively [37, 38]. Furthermore, administration of 50 μM of Efavirenz (EFV) can activate the activities of caspase-3 and caspase −9, trigger apoptotic mitochondrial intrinsic pathway and directly inhibit mitochondrial complex 1 subunit (MC1s) expression [39, 40]. The therapeutic efficacy of antiretroviral drugs is seen when used in combinations such as nNRTI and NRTIs but reports have documented that this combination produces deleterious effects on the mitochondria and also cause hepatic steatosis [41]. Another typical mechanism of action of some antiretroviral drug like stavudine (NRTI) is its ability to arrest cell cycle in growth phase (G1 phase) through upregulation of cyclic-dependent kinase inhibitor (CDKN2A) as well as p21 genes and inhibiting mitochondrial DNA replication [42].
Amodiaquine (an anti-malarial drug) hepatotoxic effect is achieved in humans when it is being oxidised by liver microsomes and peroxidases, produces iminoquinone, (a reactive metabolite) which binds to proteins irreversibly, causing direct liver toxicity by disrupting the hepatocyte function [43].
This class of drugs act mainly by hepatocellular or mixed reactions and rarely by cholestatic reaction. The Niacin and Statin are the commonly used drugs in the treatment of hyperlipidemic conditions, however, they have potential to induce liver injury. Studies revealed that the administration of Lovastatin and Simvastatin in animal model (rabbits or Guinea pig) resulted in hepatocellular necrosis while Atorvastatin produced a mixed pattern of liver injury. It is noteworthy, that Simvastatin in combination with other drugs like flutamide, troglitazone and diltiazem gives a more pronounced hepatic effect and this has been attributed to the drug–drug interaction mechanism [1].
The liver damaging effects of NSAIDs like acetylsalicylic acid ranges from elevated ALT, AST and ALP activities to acute cytolytic, cholestatic or mixed hepatitis as well as increases in bilirubin and prothrombin time. The mechanistic action of NSAID-induced hepatotoxicity is unclear but both intrinsic (Aspirin and phenylbutazone) and idiosyncratic (Ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin) reactions have been documented [44]. Suggestively, hypersensitivity and metabolic aberrations are thought to responsible for liver injury. Unlike hypersensitivity reactions that are characterised by considerable anti-nuclear factor or anti-smooth muscle antibody titres as well as lymphadenopathy and eosinophilia, metabolic aberrations are caused by genetic polymorphisms, altering susceptibility to variety of drugs [45]. Diclofenac hepatotoxicity in humans and rats, for example, is linked to mitochondrial ATP synthesis impairment and the production of N-5-dihydroxydiclofenac (active metabolites), which causes cytotoxicity. Also, diclofenac-induced liver injury results in mitochondrial transition permeability (MTP), causing ROS formation, protein thiols production, mitochondrial swelling and oxidation of NADP+ (Nicotinamide adenine dinucleotide phosphate) respectively [45].
This anti-hypertensive drug called methyl dopa metabolises in the liver by Cytochrome P450, however, the oxidative reaction of methyl dopa by CYP450 produces superoxide anions (free radicals) to a reactive quinone or semi-quinone that binds tightly to the hepatic cells causing liver injury such as acute/chronic hepatitis and cholestasis with clinical evidence of elevated activities of ALT, AST and ALP respectively in the blood system [1].
Azacytidine (or Azacitidine), is a pyrimidine nucleoside analogue of cytidine which is metabolised to a triphosphate molecule in the intracellular domain and then introduced into the RNA and DNA molecule firmly held together covalently by DNA methyltransferase 1(DNMT 1) - an enzyme that adds methyl to DNA molecule at the carbon 5 position of cytosine. Azacitidine has an anticancer effect but at low doses, it inhibits DNA methylation resulting in its deactivation leading to DNA hypomethylation shortly after cell division in the absence of DNMT1. The antineoplastic activity of this drug comes from its hypomethylation, leading to tumour suppressor gene (TSG) reactivation which is rapidly lost in myelodysplastic syndrome (MDS) – a disorder associated with clonal haematopoietic stem cell, caused mainly due to ineffective cellular maturation with side effects as peripheral blood cytopenia and abnormalities in functional blood cell. The cytotoxic effect of azacytidine is achieved when the product of its phosphorylation is incorporated into RNA molecule, thereby leading to an elevated level of CDKN2B - a gene that encodes the protein p15 (a cell growth inhibitor responsible for myeloid differentiation as well as tumour suppression) in their bone marrow [46, 47].
Administration of tacrine (a reversible cholinesterase inhibitor) in the treatment of Alzheimer disease, gives rise to an elevated ALT activity in the bloodstream, inferring that there is disruption in the integrity of the hepatocytes. Tacrine’s mechanism of liver toxicity may be probably due to the inhibition of cholinesterase activity, resulting in the stimulation of cholinergic coeliac ganglion sensory (or afferent) sympathetic pathway, in which blood constricts, leading to impaired perfusion of the sinusoids and reperfusion injury-mediated by ROS [1].
Despite the basic biochemical indicators discussed above that are associated with drug-induced hepatotoxicity, recent studies have further identified other indicators and these are represented in Table 1 as shown below:
Drug-induced hepatotoxicity | Biomarkers of Liver toxicity | References |
---|---|---|
Acetaminophen (APAP) | Upregulation of mRNA expression of IL-10, IL-36, HO-1, TNFα, MT 1 and 2 and MMP 12 genes. | [48] |
D-Galactosamine | Increase in the expressions of NLRP3, NF-kBp65, IL-6, IL-1β and TNFα genes. | [49] |
N-nitrosodiethylamine (NDEA) | Increase MDA level and decrease SOD, CAT, GST, GR, GPx activity. | [50] |
Thioacetamide (TAA) | Increase in Anti-PLT Ig level, Increase in the expression of TNFα, HMGB-1 and IL-6 genes. Increase in AST and ALT activity. | [51] |
2-Acetylaminofluorene (2-AAF) | Overexpression of iNOS, COX-2, NF-KB, PCNA genes. Increase in xanthine oxidase (XO) activity. Decrease in the activity of SOD, CAT, GST, GR and GPx. Increase in AST and ALT activity. High density of mast cell infiltration. | [52] |
Anti-Tuberculosis drugs | Over-expression of NAT2, CYP2E1, ABCB1 genes. Increase in NAD and Bilirubin levels and decrease in HAT activity. Decrease in GST, SOD, CAT activity. | [53] |
Anti-retroviral drugs | Increase in ABCB1 gene expression (that is c3435C > T of ABCB1) and CYPs genes (CYP2B6, CYP3A4 and CYP3A5). Increase in IL-1RN, IL-1β, IL-10, HLA-B and C and HLA-DRB1 genes. ALP activity and Total bilirubin (TBil) level increases. | [54, 55] |
Anti-hyperlipidemic drugs | Increase in the expression of HLA-DRB1 and SREBP2 genes while CK and HMG-CoA reductase activities increases. | [56] |
Some recent findings on drug-induced liver toxicity.
Drugs primarily serve as therapeutic agents in the treatment and management of various diseases, but over dependent or illicit consumption of drugs, results in hepatotoxicity which confers a detrimental effect on the liver’s architecture and functions respectively. Our findings showed that drug-induced hepatotoxicity can cause liver inflammation (associated with excruciating pains), liver transplantation (economically burdensome) as well as death. As a result of these frightening effects outlined above, we hereby conclude that doctor’s prescription guideline should be adhered to strictly, indiscriminate use of illicit drugs should be discouraged while regulatory bodies and law enforcement agencies should be empowered to prosecute drug offenders promptly.
The expertise of Professor Iheanacho Kizito, Department of Biochemistry, Federal University of Technology, Owerri is well appreciated.
The authors declare no conflict of interest in this work.
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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. Gene editing is also emerging as an innovative tool. This topic will discuss the potential use of these techniques, novel strategies, and lines of research in progress in the fields mentioned above.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11417,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. She has over 25 years of experience working in reproductive biology and biotechnology areas with a special emphasis on embryo and gamete cryopreservation, for research and animal genetic resources conservation, leading research projects with several peer-reviewed papers. Rosa Pereira is member of the ERFP-FAO Ex situ Working Group and of the Management Commission of the Portuguese Animal Germplasm Bank.",institutionString:"The National Institute for Agricultural and Veterinary Research. Portugal",institution:null},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"90066",title:"Dr.",name:"Alexandre",middleName:"Rodrigues",surname:"Silva",slug:"alexandre-silva",fullName:"Alexandre Silva",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRt8pQAC/Profile_Picture_1622531020756",institutionString:null,institution:{name:"Universidade Federal Rural do Semi-Árido",institutionURL:null,country:{name:"Brazil"}}},{id:"176987",title:"Ph.D.",name:"María-José",middleName:"Carrascosa",surname:"Argente",slug:"maria-jose-argente",fullName:"María-José Argente",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9vOQAS/Profile_Picture_1630330499537",institutionString:null,institution:{name:"Miguel Hernandez University",institutionURL:null,country:{name:"Spain"}}},{id:"321396",title:"Prof.",name:"Muhammad Subhan",middleName:null,surname:"Qureshi",slug:"muhammad-subhan-qureshi",fullName:"Muhammad Subhan Qureshi",profilePictureURL:"https://mts.intechopen.com/storage/users/321396/images/system/321396.jpg",institutionString:null,institution:{name:"University of Agriculture",institutionURL:null,country:{name:"Pakistan"}}},{id:"183723",title:"Dr.",name:"Xiaojun",middleName:null,surname:"Liu",slug:"xiaojun-liu",fullName:"Xiaojun Liu",profilePictureURL:"https://mts.intechopen.com/storage/users/183723/images/system/183723.jpg",institutionString:null,institution:null}]},onlineFirstChapters:{},publishedBooks:{paginationCount:3,paginationItems:[{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",slug:"animal-reproduction-in-veterinary-medicine",publishedDate:"January 20th 2021",editedByType:"Edited by",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel 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