The components of updated MELD score (used for 12 years and older patients after 2016).
\r\n\tThe protection of biodiversity is a major target of the European Union Marine Strategy Framework Directive, requiring an assessment of the status of biodiversity on the level of species, habitats, and ecosystems including genetic diversity and the role of biodiversity in food web structure and functioning. The restoration of marine ecosystems can support the productivity and reliability of goods and services that the ocean provides to humankind, to maintain ecosystem integrity and stability. Some of the goods produced by the marine ecosystem services are fish harvests, wild plant and animal resources, water, some of the services provided recreation, tourism, breeding and nursery habitats, water transport, carbon sequestration, erosion control, and habitat provision.
",isbn:"978-1-83968-460-9",printIsbn:"978-1-83968-459-3",pdfIsbn:"978-1-83968-544-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"727e7eb3d4ba529ec5eb4f150e078523",bookSignature:"Dr. Ana M.M. Marta Gonçalves",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10845.jpg",keywords:"Non-indigenous Species, Dynamics, Ecosystem Maturation, Ecological Succession, Water Quality, Recovery, Biodiversity, Environmental Status, Ecosystem Services, Goods Production, Carbohydrates, Carrageenan",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 14th 2022",dateEndSecondStepPublish:"June 22nd 2022",dateEndThirdStepPublish:"August 21st 2022",dateEndFourthStepPublish:"November 9th 2022",dateEndFifthStepPublish:"January 8th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Ana Marta Gonçalves (h-index 19) holds a Ph.D. in Biology, from the University of Coimbra, Portugal, in collaboration with Ghent University, in 2011. During her research career obtained several grants is highly international competitive calls, including the MARS award for young scientists funded by The Royal Netherlands Institute for Sea Research (NIOZ) and the Foundation for Science and Technology (FCT, Portugal) grants.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320124",title:"Dr.",name:"Ana M.M.",middleName:"Marta",surname:"Gonçalves",slug:"ana-m.m.-goncalves",fullName:"Ana M.M. Gonçalves",profilePictureURL:"https://mts.intechopen.com/storage/users/320124/images/system/320124.jpg",biography:"Ana Marta Gonçalves obtained a Ph.D. in Biology with a specialization in Ecology from the University of Coimbra, Portugal, in collaboration with Ghent University, Belgium, in 2011. Currently, she is an auxiliary researcher at the Marine and Environmental Sciences Center (MARE), Portugal, where she is also a member of the Directive Board. Since 2016, she has been a member of the Scientific Council of the Institute for Interdisciplinary Research, University of Coimbra (IIIUC). Dr. Gonçalves holds various administrative and management positions in international networks, societies (e.g., Society of Environmental Toxicology and Chemistry, AIL), and associations (e.g., PROAQUA). She is an editorial board member and reviewer for several indexed journals. She has published more than 70 journal articles, 50 book chapters, and 165 communications in international scientific events. She participated as a member and/or coordinator in more than twenty-five national and international projects and is currently the coordinator of four research projects. She has supervised more than ninety-five national and international undergraduate and graduate students. She has experience as a teacher of university courses and in accredited training sessions for teachers. Additionally, she has coordinated several ocean literacy and environmental education activities for kindergarten and school students. During her research career, Dr. Gonçalves obtained several grants and a MARS award for young scientists funded by The Royal Netherlands Institute for Sea Research (NIOZ).\n\nShe has expertise in biosafety, biochemical pathways, and impacts of stressors in aquatic species. Her research focus is on the valorization of marine resources and their applications in the industrial sector, such as the food and pharmaceutical industries. 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Lipids are characterized according to their solubility (physical property) rather than their structure, in which they are insoluble in water, but soluble in nonpolar organic solvents, such as chloroform and benzene [1, 2]. All lipids are composed of carbon, hydrogen, and oxygen atoms; however, some lipids contain phosphorus, sulfur, nitrogen, or other elements [3]. Lipids are divided into three classes, (a) triacylglycerol’s (TGs), which are used as long-term energy stores such as fats and oils; (b) phospholipids (PLs), which function primarily in cell membranes; and (c) steroids, like cholesterol which is a component of animal cell membranes and a precursor in the synthesis of various steroid hormones [1, 3]. Lipids play a structural role in the cell membranes in combination with proteins to give the membranes their semipermeable property [1]. In addition, lipids give the membranes their shape and protect them from the external environment [3].
Fatty acids are the building blocks for the majority of lipids especially TGs and PLs [3, 4]. FAs are composed of a long hydrocarbon chain (nonpolar) that is conjugated to a carboxyl group (polar) which is an acidic functional group [5]. FAs hydrocarbon chains range in length from 2 to 80 but commonly from 12 up to 24. Chain length from 2 to 6 are called short-chain, from 6 to 10 are called medium-chain, and 12 up to 24 are called long-chain [6]. FAs containing 16 and 18 carbons are the most prevalent. The majority of FAs have an even number of carbon atoms because they are synthesized by combining the C2 units of acetyl CoA [7, 8]. FAs are usually synthesized by the enzyme fatty acid synthase that is responsible to convert acetyl CoA into fatty acid [5]. The hydrocarbon chains of FAs are usually unbranched and can be divided into saturated and unsaturated [9]. Saturated fatty acids (SFAs) have no double bond in their hydrocarbon chain, while unsaturated fatty acids (UFAs) have one or more double bonds in their chain. These double bonds cause the formation of bents or “kinks” in the fatty acid chains making them liquid at room temperature [3].
UFAs are divided into monounsaturated fatty acids (MUFAs) which have one double bond in their chain and polyunsaturated fatty acids (PUFAs) which have two or more double bonds [10]. The double bonds locations follow a unique pattern; the MUFAs usually have the double bond between carbons 9 and 10 (Δ9) where C1 is the carboxyl carbon. The second double bond in PUFAs is mostly between carbons 12 and 13 (Δ12). PUFAs do not normally have conjugated double bonds (─CH〓CH─CH〓CH─), instead their double bonds are usually separated by at least one methylene group (─CH〓CH─CH2─CH〓CH─) [7, 8, 9, 10]. The stereochemistry of the double bond in the naturally occurring UFAs is usually
Fatty acids can be named using (a) systematic naming addressed in detail by the International Union of Pure and Applied Chemists and the International Union of Biochemistry and Molecular Biology (IUPAC-IUBMB) and (b) common naming [4]. The systematic naming of FAs ends with the suffix “oic acid” on to the name of the parent hydrocarbon. However, the ionized form of the fatty acid at physiological pH ends with the suffix “ate” rather than “oic acid.” FAs are named according to the total number of carbon atoms, in addition to the number and position of double bonds, if present. The carbon atoms in FAs are numbered from the carboxylic acid residue (C1), and the position of the double bond is described by the symbol delta (Δ) followed by the number of the first carbon involved in the bond. For example, the full systematic name for palmitoleic acid (common name) is
The common names for FAs reflect their prominent food sources such as palmitic acid (C16:0) found in palm oil and
Omega (ω, n) system is an alternative system of naming fatty acids. In this system, carbon atoms are numbered relative to the methyl end of the molecule. Omega system can be distinguished from the IUPAC naming system in the bases of the following: (a) omega nomenclature is only applied to unsaturated fatty acids, (b) omega system does not identify whether the double bond have
Fatty acids that the body needs but cannot synthesize in sufficient amounts to meet physiological needs due to the absence of the required enzymes are called essential fatty acids. The body cannot synthesize two polyunsaturated fatty acids: linoleic acid (C18:2n6, LA) and alpha-linolenic acid (C18:3n-3, ALA); therefore, they must be supplied by the diet [12]. Animal cells are unable to introduce double bonds in the n-3 and n-6 positions because they are deficient in certain required desaturase enzymes. However, these cells have the ability to introduce double bonds into all other positions in fatty acid hydrocarbon chain [13]. Dietary EFAs are used to produce long-chain polyunsaturated fatty acids [14].
Although omega-6 FAs were the first to be described as an essential fatty acids in the 1920s, omega-3 FAs take more attention than omega-6 [13]. Linolenic acid (ω-3) is the parent of the omega-3 FA family in which it can be used to produce other members of the family (Figure 1) [12, 15].
Omega-6 and omega-3 PUFAs and their respective sources and metabolic derivatives [
Alpha-linolenic acid is the precursor for linolenic acid that is used to synthesize two active biological components: eicosapentaenoic acid (C20:5n-3, EPA) and docosahexaenoic acid (C22:6n-3, DHA) [12, 14, 16]. ALA is found in plant oils, nuts, and seeds such as flaxseeds, walnuts, soybeans [12].
Aquatic ecosystems are the principal sources of DHA and EPA in the biosphere provided by the fish and fish oils in human diet [12, 16]. On the other hand, linoleic acid can be used to produce other members of the omega-6 family like arachidonic acid (C20:4n-6, AA) that acts as a starting material for a number of eicosanoids, i.e., biologically active molecules that regulate body functions [12].
Omega-6 FAs are found in seeds, nuts, and vegetable oils of corn, sesame, and sunflower [12]. Before the industrialization, the ratio of omega-6 to omega-3 (n-6/n-3) was around 1:1 to 2:1 due the abundant consumption of vegetables and seafood high in omega-3 fatty acids. However, there is a gradual change in this ratio with the industrialization, mainly due to the consumption of refined oils and seeds with a high content of omega-6 fatty acids in which the (n-6/n-3) average ratio has been around 10:1 to 20:1 [17].
This imbalanced n-6/n-3 ratio can even be worsened by the overnutrition habit associated with the Western diet around the world. Overnutrition, associated with an increased amount of FAs made available for oxidation in the liver, favors the pro-inflammatory state due to the depletion of n-3 long-chain PUFA (n-3 LCPUFA) such as EPA and DHA, elevated n-6/n-3 ratio, hyperinsulinemia, and insulin resistance (IR). Such changes may result in the development of nonalcoholic fatty liver disease (NAFLD), steatosis [hepatocyte triacylglycerol accumulation, and cirrhosis (steatohepatitis)] [18].
The consumption of omega-3, omega-6 PUFAs, and their derivatives has various beneficial effects, ranging from fetal development to cancer prevention [19]. PUFAs have a preventive effect against arterial hypertension, asthma, inflammatory diseases, human breast cancer, and disorders of the immune system [20]. n-3 FAs protect against several types of cardiovascular diseases such as myocardial infarction, atherosclerosis, arrhythmia, hypertension, and human coronary artery disease [19, 21]. Moreover, consumption of n-3 FAs interferes with prostaglandin metabolism, which can reduce the platelet aggregation and adhesion to blood vessels, which reduce the blood pressure [22]. Omega-3 PUFAs can reduce the incidence of high cholesterol level in the blood, psoriasis, cancer, and arthritis [23].
The n-3 LCPUFA DHA plays a major role in the development of the nervous system during the life of fetus and neonates [24]. The study of Barrera et al. (2018) has shown that a low dietary intake of n-3 LCPUFA in pregnant Chilean women has resulted in a significant decline in their erythrocytes and breast milk DHA levels. Therefore, the improvement of the quality of FAs intake specifically DHA was recommended during pregnancy and lactation periods in order to supply adequate amount of DHA to embryos and neonates [25]. In addition, n-3 supplements intake was suggested to improve the low level of n-3 LCPUFA associated with NAFLD patients in order to lower their n-6/n-3 ratio and thus reduce the inflammatory status as a treatment for the nutritional hepatic steatosis in adults [24].
Omega-6 PUFAs are converted to other important compounds through various enzymatic reactions to the key intermediate arachidonic acid, which is subsequently converted to eicosanoids that act somewhat like hormones such as prostaglandins, thromboxanes, and leukotrienes [15]. Eicosanoids play an important role in muscle relaxation and contraction, blood clot formation, blood vessel contraction and dilution, blood lipid regulation, and immune response to injury and infections [12].
Omega-3 PUFAs are considered as more potent anti-inflammatory agents than n-6 PUFAs, but the effects of n-6 PUFAs are more dominant due to the abundance of these compounds in the diet [15].
Alpha-linolenic acid can be used in the body as a precursor to produce EPA; however, EPA can be directly obtained through the consumption of fish oils. Moreover, EPA can be converted to DHA and also to eicosanoids that are essential for inflammatory signaling, such as prostaglandins, thromboxanes, and leukotrienes. DHA can also be converted to eicosanoids to produce anti-inflammatory mediators such as protectins and resolvins [15]. In 2004, The International Society for the Study of Fatty Acids and Lipids (ISSFAL) has recommended the minimum intake of 0.5 g/day of EPA and DHA for the prevention of cardiovascular disease [26].
ALA and LA obtained from diet can be converted into longer chains of PUFAs by the help of two important enzymes, desaturase and elongase, that work to increase the degree of unsaturation. Elongase works by adding carbon atoms into the chain, while desaturase works to introduce double bonds by removing hydrogen atoms [27]. The n-3 and n-6 FA families compete especially at the rate-limiting Δ6 desaturase enzyme that both pathways start with. Usually desaturase enzymes display highest affinity to ALA (n-3 family) more than LA (n-6 family) [28]. The n-3 pathway starts with ALA (C18:3n-3) and ends with DHA (C22:6n-3), while the n-6 pathway starts with LA (C18:2n-6) and ends usually with AA (C20:4n-6) [27, 29].
The major difference between n-3 and n-6 pathways is that n-6 pathway usually does not proceed beyond AA; however, the n-3 pathway involves more complex steps. In the n-3 pathway, there are two elongation steps after the formation of EPA (C20:5n-3), leading to the formation of tetracosapentaenoic acid (C24:5n-3), followed by the reduction by Δ6 desaturase enzyme to produce tetracosahexaenoic acid (Nisinic acid) (C24:6n-3). The final step in n-3 pathway yields DHA (22:6n-3) by the retroconversion of (24:6n-3) to (22:6n-3) which involves peroxisomal ß-oxidation step (Figure 2) [27, 30]. In the mammalian cells, the FAs from (n-3) and (n-6) families cannot be interconverted because of lack of Δ12 or Δ15 desaturase enzymes, while the interconversion step takes place in plants [28].
The elongation-desaturation pathway for the metabolism of n-6 and n-3 polyunsaturated fatty acids [
Fish is a major source of animal protein diet in many countries that is easily digestible than red meat because fish flesh contains long muscle fibers [18]. Consumption of fish have many benefits for human health due to its high content of essential n-3 PUFAs, namely, EPA and DHA [14, 31, 32].The FAs content of fish varies according to diet, i.e., availability of planktons [33], environmental conditions [15], and seasonal variation [34]. A regular consumption of fatty fish prevents cardiovascular disease and neural disorders [35].
PUFAs are important for brain and retina development since studies with animals have shown that deficiencies in n-3 FAs decrease the concentration of DHA in the brain and retina tissues [16]. Fish and terrestrial animals are not able to synthesize n-3 or n-6 PUFAs. The primary producers for PUFAs are marine photosynthetic organisms including phytoplankton, macroalgae, and seaweeds [36].
Only some microalgae species are effective producers for EPA and DHA; therefore, aquatic ecosystems are the principal sources of these two essential PUFAs in the biosphere, in which humans obtain these FAs through the consumption of fish and other marine products (Figure 2) [30, 37]. Fish need PUFAs to tolerate low water temperature; thus, low amounts are expected in wormer water like tropical waters [38]. Fish oil become very popular and plays an important role in the prevention of cardiovascular disease and some type of cancers like breast, colon, and prostate [39]. It was observed that there are lower incidence of cardiovascular diseases, hypertension, and autoimmune disorders in populations that consume diet rich in marine fish like Eskimos and Japanese [40].
Fresh fish is prone to spoilage which is caused by both microbiological and chemical reactions [41]. Lipid deterioration limits the shelf life of oily fish during storage [42]. Lipid hydrolysis induced by lipases and phospholipases produce free FAs that are susceptible to further oxidation to produce low molecular weight compounds responsible for the rancid of fish products [43]. Fish quality may decline during processing and storage mainly due to the oxidation of the PUFAs which is related to the production of unpleasant flavors and odors [44, 45].EPA and DHA are especially susceptible to oxidation during heating or other culinary treatments [46].
A long time ago, people used to preserve food either by sun drying or salting methods [47]. Salting of fish is an old-age technology that is still in use nowadays even in developing countries due to its simplicity and low cost [47, 48]. Salting fatty fish involves a certain degree of fermentation which is brought by autolytic enzymes from the fish and microorganisms in the presence of high concentrations of salt [47]. Fish fermentation is the transformation of organic substances into simpler compounds like peptides and amino acids by the action of endogenous enzymes or microorganisms, normally in the presence of salt [48, 49, 50].
Lactic acid bacteria (LAB) are used to ferment fish along with other food materials like dairy, meat, vegetables, and beverage products [51] resulting in shelf life extension and the addition of new aromas and consistencies [32]. Fermentation by lactic acid bacteria preserves food by the production of lactic acid and other organic acids, which help to reduce pH of the food and inhibit the growth of pathogenic and spoilage organisms [52].
Many types of fish sauce and paste are famous in Japan, Southeast Asia, and India. Traditional fermented Japanese seafood is Hatahata-zushi which is processed with boiled rice. Hatahata-zushi is prepared by soaking the sandfish (
Scandinavia is the main producer of fermented fish products in Europe. Surstromming is produced in Sweden and rakefish in Norway. These fermented fish are made by immersing whole herring and trout in brine (salty water) for 1–2 days, eviscerating, and retaining the roe or milt in barrels with fresh brine. The final fermented product is packed in cans and usually consumed on special occasions [49]. “Tidbits” is another Scandinavian product that is canned with vinegar, sugar, and spices after maturation. In France, the fish
Many types of fermented fish are prepared in the Middle East. “Fseekh” is a famous fermented fish prepared in Egypt and Sudan from different types of fish [49]. Kejeik is a fermented dried fish produce that is common in Sudan and central Africa which is powdered and thickened with okra after boiling [48]. The FA content of Bouri fish varies with fish size; in which it was much greater in small size than large size fish because of the higher activity of lipolytic enzymes in small fish as stated by the authors [48]. However, the fresh and fermented product Fseekh of both fish sizes had the same FA profile. The high salt content was found to have no effect on those enzymes responsible for the liberation of free fatty acids from the lipids [48]. The ratio of UFAs/SFAs decreased as the amount of UFAs decreased significantly after the salting and fermenting process. Moreover, all SFAs except palmitic acid (C16:0) increased significantly. The major SFA was C16:0, and the major UFAs were palmitoleic acid (C16:1n-7) and oleic acid (C18:1n-9). Appreciable amounts of PUFAs such as C18:2n-6, C18:3n-3, stearidonic acid (C18:4n-3, SDA), C20:5n-3, docosapentaenoic acid (C22:5n-3, DPA), and C22:6n-3 were also present. The presence of the odd-chain pentadecylic acid (C15:0) and heptadecanoic acid (C17:0) FAs is considered a unique characteristic of the Bouri fish oil [48].
The analysis of fatty acid compositions was done for different fermented seafoods all over the world. For example, the analysis of Hatahata-zushi which is a Japanese fermented fish product of sandfish has shown no change in the fatty acid compositions throughout the fermentation process; however, the content of SFAs and MUFAs increased, while the content of PUFAs decreased markedly during the process of fermentation. The highest concentrations of the FAs in “Hatahata-zushi” were C18:1n-9, C16:0, C22:6n-3, C20:5n-3, and C16:1n-7, respectively [53].
It has been noticed that bacterial enzymes play an important role in fish fermentation in which the aroma in fermented fish products is claimed to be derived from the activity of halophilic bacteria [47]. The enzymes that participate in the production of PUFAs are thought to be either fish tissue enzymes or microbial enzymes [47]. The traditional fermented fish product Lona ilish of Northeast India has shown that salting plays an important role in the fermentation and preservation of food. Salt preserves the fermented products through the reduction of water activity (aw) of the system, thus rendering a condition less suitable (low moisture) for the microbial growth. Generally, food pathogenic bacteria are inhibited when the water activity is 0.92 or less which is equivalent to NaCl concentration of 13% (w/v). It was reported that halophilic bacteria were responsible for the fermentation process of fish product Lona ilish since these bacteria can tolerate high salt conditions. The bacterial flora of
The two main products of fish fermentation in the Arabian Gulf region are fish paste and sauce. It is difficult to classify these products due to the lack of standardization throughout the world. Generally, fish paste is a thick product with whole fermented fish, while fish sauce is a thinner product with additives such as spices and cereals. The color of fish paste or sauce is usually brown resembling soy sauce. Fish paste is more nutritious than fish sauce [49]. Tareeh is a salt fermented fish paste in the Arabian Gulf countries prepared from a high-fat fish
The fatty acid contents of the fish product Tareeh and Mehiawah of white sardinella (Oom) were recently investigated [56, 57]. The study of Freije et al. (2018) was conducted in order to determine the effect of fermentation under high salting conditions (20%) for 8 weeks on weekly basis on the fatty acid compositions of white sardinella (Sardinella albella) [57]. The fatty acid compositions of Tareeh have shown a great deal of variation as the fermentation process proceeded. The concentrations of SFAs and MUFAs significantly declined in Tareeh samples compared to raw fish, whereas the concentrations of UFAs and PUFAs were significantly increased starting from week 4 of fermentation. The amount of n-6 FAs as well as n-3 FAs increased during the fermentation process, and the enzymatic activities of the elongases and desaturases were found to have higher affinity to n-3 FAs than n-6 FAs. The ratio of n-6/n-3 was decreased after 8 weeks of fermentation, while the proportions of EPA + DHA were increased. This unique fermentation process might have a great application in the food industry [56]. It was also concluded that the elongation and desaturation process was carried out by single new bacterial strain from the
The studies that investigated fatty acid compositions in fermented fish products all over the world are limited. Each of those studies has given different results without any common consistency among them. Some of those studies have reported a decrease in UFAs and an increase in SFAs, while others reported increased SFAs and MUFAs but decreased PUFAs during fermentations. On the contrary, the most recent studies have reported declined levels of SFAs and MUFAs and a rapid increase in PUFAs. Such contradicted results can be attributed to the difference in the type of fermented fish, fermentation conditions, and the addition of different additives. Therefore, this process requires thorough investigations in order to reveal the mystery behind such contradictions.
The authors are grateful to the Department of Biology, College of Science, University of Bahrain, where the study was conducted and financially supported.
The increased need for transplantation cannot be met because of the shortage of the available grafts. In the last decades, the number of heart transplantation has not increased. As a consequence, the patients will be longer on the waiting list, becoming older and having more severe end organ dysfunction, or even they lose their candidacy for transplantation because of the irreversible hepatic or liver failure. Bridging techniques, such as temporary extracorporeal circulation or implantable mechanical assist devices, may improve and reverse the end-organ failure and transplantation can be done. The physician of the transplantation team must be familiar with the diagnosis and possible treatment of these organ dysfunctions. Recently, recognition and extended investigation of the end-stage heart-failure-related hepatic failure have been highlighted, since the liver dysfunction can worsen in the posttransplantation period through hypoxic hepatitis or by the immunsuppressive medications, which should be taken lifelong.
Besides the liver, another important system, the endocrine hormones, must be strictly followed in the perioperative period. End-stage heart failure can cause thyroid dysfunction, and it can lead to circulatory failure or hemodynamic instability. Amiodarone, a frequently applied antiarrhythmic drug, can cause severe hypo- or hyperthyreosis. In the postoperative period, the physicians must distinguish the nonthyroidal illness syndrome from the chronic illness-related thyroid dysfunction. Endocrine replacement must be also initiated during the donor procurement to decrease the graft loss or the graft dysfunction in the posttransplant period.
In this chapter, we aimed to describe briefly the basic liver function, the diagnostic modalities in the preoperative evaluation, and the special considerations related to transplantation care. The endocrine part will overview the thyroid dysfunction, the treatment of central diabetes insipidus, and the posttransplantation endocrine management.
The human liver is wedge-shaped with two lobes, and it weighs cca 1.5 kg [1, 2]. The hepatic artery via the celiac trunk and the portal vein are the main blood supply of the liver. The liver receives approximately one-fourth of the cardiac output, which secures one-third of the blood supply, and the rest will be supplied by the portal system. These blood vessels divide into small capillaries, called hepatic sinusoids, which then build the lobules. Lobules are the functional units of the liver. Each lobule is made up of hepatocytes. The lobules are held together by fibroelastic connective tissue that extends from a fibrous capsule covering the entire liver [3]. The function of the liver is very complex and diversified. Liver has excretion function, including synthesis and excretion of biliary acids. Furthermore, liver also plays a key role in endocrine homeostasis in the metabolism of various hormones. To understand the potential perioperative issues, it is necessary to review the complex role of the liver in the human body. Oxidative capacity decreases with the age and congestive disorders, which may cause delayed drug metabolism [4].
Heart failure with reduced ejection fraction can alter many pathways in the liver. As a forward failure due to (the) low cardiac output syndrome, reduced systolic function leads to hypoperfusion, while backward failure caused by biventricular or isolated right ventricular dysfunction will result in venous congestion. As a response for the constantly elevated high pressure in the inferior caval and hepatic veins, the perivenular space of the lobule will be dilated, and fibrotic transformation will be initiated. As the congestive state persists, perivenular-perivenular bridging develops, which has less effect on centrally located portal tracks. This pattern is the reverse lobulation. As the circulatory failure progresses, the portal part also undergoes fibrotic transformation and complete congestive hepatopathy may develop. The collagen is deposited in the subendothelial region and in the Disse space. The elevated right ventricular pressure can now affect the portal circulation, causing cirrhotic portal hypertension. The well-known symptoms of cirrhosis, such as ascites and development of the varices of esophageal veins, are often present. Laboratory parameters remain unchanged or minimally elevated in the early phase of the congestion. Only elevation of aspartate aminotransferase (AST) and alanine transaminase (ALT) may be abnormal, an increase in bilirubin or obstructive enzyme (alkaline phosphatase, ALP) levels is frequently seen. Highly elevated transaminase levels and increased bilirubin levels are more common in advanced or end-stage liver failure, usually associated with acute on chronic heart failure.
Routine laboratory tests, including hepatic function tests, are good but rough indicators of hepatic dysfunction in the pre-transplant period. It should be stressed that normal transaminase and serum bilirubin levels are not suitable for early detection of hepatic problems. As shown in the scores presented, elevated serum bilirubin levels and spontaneous prolonged coagulation are strong predictors of a negative outcome. Nonalcoholic fatty liver disease is a sign that the congestion has reached a distinct stage caused by heart failure with or without reduced ejection fraction. Transient elastography is a good and reliable method to measure fibrotic transformation of the liver. In the decompensated period of advanced heart failure, fibroelastography shows higher than real fibrotic results.
Liver biopsy is the most accurate way to assess fibrotic transformation of liver tissue. In some advanced cases, a liver biopsy can be used to rule out candidates for a heart transplantation or to determine the need for combined heart and liver transplantation [4]. Existing gallstone should be removed before surgery as it is potential infectious focus.
The classic laboratory tests for estimating hepatic function are serum bilirubin, transaminases (ALT, AST), alkaline phosphatase, lactate dehydrogenase, total serum protein and albumin, serum bilirubin, and coagulation parameters, especially prothrombin time. Most patients with advanced heart failure were found to have moderately elevated levels of transaminase in random blood samples. Chronic anticoagulation can influence the prothrombin levels and must be considered in the calculation of model for end-stage liver disease (MELD) scores.
In acute hypoxic hepatitis, transaminases (AST, ALT) can rise more than 100-fold above normal ranges. This increase reflects the severity of centrolobular hepatic necrosis. Peak transaminase is usually expected within 12–24 hours, and normalization take 2 weeks with treatment. Abnormalities in alkaline phosphates and serum bilirubin levels are less common. Prolonged prothrombin time has important prognostic value. Thrombocytopenia, if present, occurs simultaneously with prolonged prothrombin time. Renal failure is often associated with global hypoperfusion.
Nowadays, hepatic vein flow measurement using duplex Doppler technic is an arising increasingly common method of assessing changes caused in heart failure. It may also be useful and feasible for noninvasive hemodynamic monitoring in acute conditions. Accurate interpretation of spectral Doppler tracing from hepatic veins is valuable, because they reflect important cardiac and hepatic physiology. There are usually four phases: A, S, V, and D; the S and D waves indicate the antegrade flow toward the heart. In hepatic and cardiac disease, these normal waves may be absent, indicating non-physiological flow in the hepatic circulation. In addition, transient patient factors, such as phase of the respiratory cycle, may can affect the appearance of the spectral trace. Knowledge of the normal and abnormal spectral Doppler waveforms of the hepatic veins and the corresponding physiology and pathophysiology provide valuable insights. Systematic analysis of the direction, regularity, and phasing of the spectral trace and the ratio of S- and D-wave amplitudes allows in most cases a correct differential diagnosis [5].
Under abnormal conditions, the normal triphasic pattern is altered, and the original waves may not exist or be distinguishable. The biphasic pattern may indicate severe tricuspid valve regurgitation and/or acute right ventricular overload. Normally, the hepatic vein spectrum shows the normal S-wave to D-wave ratio, where the S-wave is larger than the D-wave. According to Scheinfeld, there are three types of right-sided heart failure. (According to its classification, in mild tricuspid regurgitation, the relationship between the S-wave and the D-wave changes, with the S-wave being smaller than the D-wave.) Type 1 tricuspid regurgitation is classified as a change in the relationship between the S-wave and the D-wave, with the S-wave being smaller than the D-wave. However, there is still antegrade flow during the ventricular systole. In type 2 tricuspid regurgitation, there is no systolic flow during the ventricular systole. In type 3 tricuspid regurgitation, there is retrograde flow during the ventricular systole [5].
In the early state of fibrotic hepatic transformation or nonalcoholic fatty liver disease (NAFLD). the hepatic vein waveform may be remarkably damped due to stiffness of hepatic tissue and vessel walls. Flow pattern changes, such as monophasicity or blunt waveform, are also often observed in these conditions. Hepatic vein flow patterns also suitable for follow-up of the right ventricular function, the severity of tricuspidal regurgitation, and the venous congestion during the perioperative period. On the pictures 1 and 2, hepatic vein flow patterns are shown (Figure 1).
Hepativ vein flow pattern.
Transient elastography (TE) is a noninvasive, simple, fast, and highly accurate clinical examination method. During TE, a special probe is used to measure the liver stiffness, which correlates well with the fibrotic hepatic remodeling [6]. However, the test has high reliability and may overestimate the level of liver fibrosis depending on the severity of decompensation. Thus, the examination should be planned in an elective setting with relatively well-compensated patient [7, 8].
In the literature reports could be seen with examination of the relationship between chronic coronary syndrome and nonalcoholic fatty liver disease (NAFLD). Reports have appeared in the literature examining the association between chronic coronary syndrome and nonalcoholic fatty liver disease (NAFLD). These findings are noteworthy because the liver structure transformation begins before the presence of a notable reduction in global cardiac function or congestive right heart failure [9].
Precise multidisciplinary risk assessment in the pre-transplant period is a key factor. The possible contraindicating coexisting diseases and states should be ruled out. The risk estimation can be helpful in planning, preparing, and managing the intraoperative and postoperative period. For preoperative hepatic dysfunction, two scores are mostly used. The Child-Pugh score is a traditional risk estimation method. The Child-Pugh score was based on serum bilirubin and albumin levels, international normalized ratio (INR), and the presence of ascites and encephalopathy. While the Child-Pugh score is useful for risk stratification in the clinical practice, MELD score(s) are more feasible for patients admitted to intensive care unit (ICU) due to their better prognostic value and lower negative likelihood ratio [10].
MELD score was originally developed to predict mortality in patients with hepatopathy and/or cirrhosis after porto-jugular shunt placement. The baseline MELD score gives an estimate of 3-month mortality as a function of the need for dialysis, INR, serum bilirubin, and creatinine (Table 1) [11].
Parameter, factor | Range |
---|---|
Dialysis twice at the last week (or continuous veno-venosus hemodialysis ≥24 hours at last week) | yes/no |
Creatinine | normal range: 62–115 μmol/L (0.7–1.3 mg/dL) |
Bilirubin | normal range: 5.13–32.49 μmol/L |
INR | 0.8–1.2 |
Sodium | normal range: 136–145 μmol/L (mEq/L) |
The components of updated MELD score (used for 12 years and older patients after 2016).
The MELD score has several modifications according to the patients’ comorbidities. MELD XI score excludes INR from the equation. MELD XI is promoted for use in patients receiving anticoagulant therapy. Frequent anticoagulant therapy in end-stage heart failure emphasizes the INR-independent MELD score.
Since UNOS (United Network for Organ Sharing) started using the MELD score, its importance for estimating the risk of liver complications and mortality before heart transplantation is unquestioned. Use of Na-corrected or XI (INR excluded) MELD scores in patients with end-stage heart failure in the pre-transplant period is the basics for liver failure risk estimation [12].
Decreased serum albumin levels are present in 30–50% of patients, but the serum level is usually not less than 25 g/L. Low albumin levels do not correlate with hepatic injury, but are associated with nutritional impairment and protein wasting. The serum albumin level is an independent risk factor for mortality after heart transplantation [13]. Multiple studies suggest that serum albumin level under 35 g/L is related with worse mortality. Intravenous albumin substitution was not proven useful in the perioperative period.
Mild increase of the prothrombin time (PT) indicates a secondary impairment of the coagulation factor synthesis. In case of portal hypertension, the protein content of the ascites is usually more than 25 g/L and the ratio higher than 1:1 (serum albumin to ascites albumin). Some studies have reported a significant relationship between central venous pressure, low cardiac index, and elevated total bilirubin, AST, or ALT levels [14]. Increased transaminase levels correlate with the severity of hepatocellular injury caused by hypoperfusion. Increased direct bilirubin and ALP with ALT/ALP levels are markers of cholestatic injury and increased venous congestion. Increased bilirubin levels have been reported to be associated with high inotropic requirement, low cardiac output states, early readmission, in patients with advanced heart failure [15].
End-stage heart failure patients with significantly impaired end-organ dysfunction often need a bridging method to become candidates for heart transplantation. For these patients, more frequent use of various mechanical circulatory supports may be a solution. However, even short to medium periods of support for planned pathophysiological changes caused by devices should be of concern. Short-term devices (veno-arterial extracorporeal membrane oxygenation, VA-ECMO) and various mid-term ventricular assist devices, such as left ventricular assist device (LVAD) or biventrular assist devices (BIVAD), also have a major impact on complex physiological processes. In case of LVAD implantation—similar than in heart transplantation cases—the low serum albumin level (≤35 g/L) is related to worse survival (Figures 2 and 3) [16].
Normalization of hepatic vein flow pattern in a patient with end-stage heart failure on BiVAD treatment for 85 days. The flow pattern is normal with minimal retrograde flow in venticular systole.
Hepatic vein flow in a patient with end-stage heart failure treated with implantable LVAD for 22 days. Regarding grade 3 tricuspidal regurgitation, prominent V wave could be seen. Often the A, S, and V waves are fusional and indicate severe retrograde flow during the global systole.
The liver is 60% responsible for the elimination of lactate via the Cori cycle, (lactate is therefore a glycogen precursor molecule). Renal lactate excretion is meaningful as serum lactate levels above 6–8 mM. In cirrhosis patients, lactate clearance is decreased, which can lead to type B lactic acidosis caused by reduced activity of lactate dehydrogenase. A parallel problem is the dysregulated carbohydrate balance. Without a well-functioning hepatic enzyme system, accumulated substrate levels slowly return to normal.
In intraoperative settings, hepatic impairment is often associated with hemostatic disorders. The liver plays a crucial role in hemostasis through the synthesis of procoagulants, anticoagulants, and components of the fibrinolytic system, as well as the clearance of activated clotting factors. In hepatic dysfunction, these synthetic functions are insufficient, and hemostatic changes within and between procoagulant, anticoagulant, and fibrinolytic systems result in a new balance, defined as a rebalanced hemostatic state. This conception is defined as a) dysfunction in thrombin generation/disturbance in thrombus production and b) instability in the face of relatively small disturbances that commonly lead to a disruption of the balance between bleeding or thrombotic events [17].
The most sensitive laboratory parameters are prothrombin time (PT) and partial thromboplastin time (PTT), which are sensitive to reduced levels of procoagulants but not to anticoagulants; this has led to the erroneous assumption in the past that patients with liver disease are auto-anticoagulated and are protected against thrombosis. Nevertheless, PT and INR are not reliable risk factors for bleeding after surgery or invasive procedures [17, 18].
Under VA-ECMO support, patients with preexisting hepatic dysfunction have increased morbidity and mortality, with obviously serious implications for the planning and further bridging [19]. According to the current recommendations for the implantable LVAD devices, the candidacy for implantation must fulfill strong criteria in their hepatic function. Mid-term and especially long-term LVADs are associated with serious side effects by altering the molecular mass spectrum of von Willebrand factor (vWf). A kind of degradation (more precisely multimerization into smaller molecules) of von Willebrand factor caused by shear stress associated with mechanical circulatory devices can lead to device specific coagulopathy and unexpected and defective angiogenesis—smaller multimers of vWf may act as vascular endothelial growth factor. The clinical context is often driven by unexplained bleeding from interstitial angiodysplasias. The acquired von Willebrand factor dysfunction type of hemostatic dysfunction is diagnosed mostly by viscoelastic tests [20].
Furthermore, coagulopathy based on hepatic dysfunction is often accompanied by thrombocytopenia. Platelet function seems to be normal in patients with cirrhosis, but intrinsic dysfunction has not yet been confirmed [21].
A major function of the liver is drug metabolism. Drugs given in the perioperative period, lifelong immunosuppressive therapy often interact with the liver. In the perioperative period, special attention should be paid to hepatic function problems caused by immunosuppressive therapy. The impaired liver condition before surgery makes these interactions more complex and difficult.
In heart transplant patients, the drugs that induce immunosuppression are mostly antithymocyte globulin (ATG). ATG is safe to use in liver failure; however, some case reports have reported extremely elevated transaminase levels within a few hours of infusion. Liver damage associated with ATG therapy is usually mild and asymptomatic, self-limited [22].
Calcineurin inhibitors are metabolized by the liver’s P450 enzyme system (CYP 3A4). The most commonly used calcineurin inhibitors are cyclosporin and tacrolimus. Initiation of cyclosporine therapy may sometimes be associated with a slight increase in serum bilirubin levels, often without a considerable increase in serum ALT or alkaline phosphatase. Tacrolimus therapy is associated with a mild to moderate increase in serum aminotransferase levels in 5–10% of patients. Rises in serum aminotransferase levels are usually mild, asymptomatic, and self-limiting, but occasionally persistent and may require a dose modification. Tacrolimus has also been implicated in the development of cholestatic hepatitis, but clinically apparent liver damage is rare [22].
Corticosteroids are the basis of the immunosuppressive therapy, particularly in the early period and in case of rejection. Corticosteroids also have major effects on the liver, particularly when given in long term and in higher doses. Glucocorticoid usage may result in liver enlargement, steatosis, or glycogenosis. Hepatomegaly and moderate elevation of serum aminotransferase levels are common in glycogenosis. There is little or no change in alkaline phosphatase and serum bilirubin levels. Furthermore, steroids can aggravate nonalcoholic fatty liver disease. Long-term therapy can also worsen chronic viral hepatitis. Thus, hepatic complications of corticosteroids are mostly associated with high intravenous dosing and usually represent the worsening or triggering of an underlying liver disease, and rarely are the result of drug hepatotoxicity. High doses of intravenous corticosteroids, such as those used in anti-rejection shot therapy, are rarely associated with fatal acute liver injury [22].
Among antiproliferative agents, azathioprine and mycophenolate-mofetil (MMF) are commonly used in heart transplant patients. Azathioprine has a worse side effect profile, including severe hepatic problems, so MMF is usually preferred. In mild cases, azathioprine has been associated with a transient and asymptomatic rise in serum aminotransferase levels, which is associated with acute cholestatic damage in the first year after initiation of therapy. Chronic damage to the liver characterized by peliosis hepatis, veno-occlusive disease or nodular regeneration is typical with long-term use. Hepatocellular carcinomas have also been reported with long-term azathioprine use. In contrast, MMF use is safe, with side effects mostly nausea and digestive problems that respond well to dose reduction (Table 2) [22].
Modality | Information | Pathology | Optimal timing |
---|---|---|---|
Laboratory tests | Transaminase levels | Hepatocellular injury caused by congestion Excessively increased levels often seen in hypoperfusion NB: viral hepatitis, medical therapy | Routinely preoperative examination and heart failure care (monthly) |
Serum bilirubin level | Indicator of severe hepatic (conjugation) function loss | ||
Albumin, Total protein | Related to the hepatic synthetic function and nutritional state (NB: adsorption problems, protein loss in enteropathy) | ||
INR, PT | Indicator of hemostatic disorders regarding synthesis of coagulation system factors | ||
Transient elastography | Classification of hepatic fibrotic transformation | Before transplantation in well compensated state | |
Biopsy | Microscopic structure of liver tissue | Classification of fibrotic transformation/cirrhosis | Before transplantation in case of serious indication |
The preoperative examination modalities, their focus and optimal timing before the heart transplantation.
Nonthyroidal illness (NTI) is a syndrome that is observed in critically ill patients. As the name suggests, it is not a primary endocrine disease, but a result of severe systemic stress. Many conditions can lead to a generalized stress, such as severe infection, sepsis, prolonged starvation, bone marrow transplantation, extensive myocardial infarction, end-stage heart failure, heart transplantation, or any potentially life-threatening condition [23]. As for the changes in hormone levels, plasma T3 levels decrease, followed by a decrease in plasma T4 levels, while rT3 levels show an increasing trend. This is due to both altered protein binding and altered deiodinase enzyme activity. However, in the vast majority of cases, plasma TSH levels remain unchanged or decrease slightly [24]. In the international literature, several synonyms for nonthyroidal illness are common, such as euthyroid sick syndrome or low T3 syndrome (Table 3) [23].
Nonthyroidal illness syndrome | ||
---|---|---|
Acute phase | Chronic phase | |
other names | “Low T3 syndrome” | “Central hypothyroidism” |
CAUSE | Starvation, stress, inflammation | Endo−/exogen dopamine, cortisol |
T3 | ↓ | ↓↓ |
T4 | ↑ | ↓ |
rT3 | ↑↑ | ↑ |
TSH | ↑/normal (no peak) | norm./↓ (no pulsatility) |
TRH | Normal | ↓ |
TBG, albumin | ↓ | ↓ |
D1 (T4 → T3) | ↓ | ↓ |
D3 (T4 → rT3) | ↑ | ↑ |
D2 (T4 → T3) | Normal | ↑ (feedback) |
Receptor sensitivity | Normal | ↑ |
Result | Adaptive, useful | Maladaptive |
Hormonal replacement | Not recommended | Considerable |
Hormonal changes in NTI.
The course of nonthyroidal illness can be divided into two basic phases, an acute phase and a chronic phase. The first acute phase is observed during a sudden change in critical condition. The main laboratory parameters in the acute phase are characterized by decreased peripheral free T3 levels and elevated rT3 concentrations. This is due to mechanisms such as reduced binding of plasma proteins to thyroid hormones and altered activity of certain deiodinase enzymes (D1, D3). In fact, the acute phase of NTI is an adaptive response to a reduced nutrient supply to the body due to a critical condition. Consequently, this phase of NTI, whose primary purpose is to reduce the catabolism of the body, has a positive effect on the body [24]. Other research has also observed that during starvation, the catabolism of peripheral skeletal muscle slows down as T3 levels decrease, while thyroid hormone administration increases its breakdown again [25, 26]. However, some research is in stark contrast to this view, as there is no correlation between a decrease in T3 levels during starvation and a concomitant decrease in peripheral skeletal muscle breakdown [27].
In the event that the acute phase is prolonged, the adaptive response that initially seems beneficial is replaced by a phase that is already less beneficial to the body. This is the chronic phase of NTI. In terms of thyroid laboratory parameters, not only the T3 but also the T4 levels start to decrease, while the plasma TSH levels fall below the lower limit of the normal range [24]. According to one study, these changes are due to a decrease in hypothalamic TRH secretion for an as yet unknown reason. This is because the research team found an association between TRH gene expression and plasma T3 and TSH levels [28]. During the chronic phase, adaptive mechanisms are developed in the peripherical located tissues to maximize the utilization of reduced thyroid hormones: increased transcription and activity of the D2 enzyme, increased localization of certain transporters, and increased activity of active isoforms of TRs’ expression [24].
A clear, definite pathomechanism for the nonthyroidal illness syndrome has not been established. Samples of muscle and liver tissue from several patients who died in intensive care units (ICU) were collected. Biopsies from liver and muscle tissue from died patients were found to be increased in the expression of type 3 deiodinase enzymes and decreased in the expression of type 1 deiodinase enzymes. Blood collected from died patients showed decreased total T3, T4, TSH levels, while rT3 levels were higher than normal. In this study, a correlation was found that the plasma T3/rT3 ratio was positively correlated with the expression of type 1 deiodinase enzyme [29]. rT3 level, T3/rT3 ratio and D3 enzyme expression measured on the very first day of ICU admission may have prognostic value for mortality [30].
In the chronic phase of NTI, decreased TRH gene expression may be strongly influenced by increased D2 enzyme activity mediated by inflammatory mediators, transcription factor NFκB (nuclear factor κB), and corticosterone [31, 32]. Certain drugs, such as dopamine can keep plasma T3, T4, and TSH levels, are low [33]. The role of different drugs in the suppression of the hypothalamic–pituitary-thyroid axis is conversely discussed [34, 35]. This association could not be demonstrated by another study group that used dopexamine and dobutamine simultaneously in high-risk surgical patients (Figure 4) [35].
Regulation of hypothalamic–pituitary-thyroid axis.
Amiodarone is a commonly used antiarrhythmic drug in patients with end-stage heart failure. Moreover, antiarrhythmic treatment of atrial or ventricular arrhythmias with amiodarone is an effective and widely known phenomenon in clinical practice. Amiodarone maintains normal sinus rhythm in patients with atrial fibrillation (AF) and also reduces the recurrence rate of ventricular tachycardia. Amiodarone remains the preferred treatment, particularly for patients awaiting heart transplantation (HTX). Due to its slow distribution in body’s tissue, amiodarone may take several months to reach steady-state tissue concentrations and to exert a sufficient antiarrhythmic effect. In addition, the registered half-life of amiodarone is highly variable. Because of this phenomenon, the administration of amiodarone before transplantation has been controversially discussed in the literature, and different results have been reported for morbidity and mortality after heart transplantation [36, 37].
The administration of this antiarrhythmic medication may increase the probability of one-year mortality, graft failure, transplantation, and permanent pacemaker implantation [38]. Amiodarone-induced hypothyroidism (AIH) and amiodarone-induced thyrotoxicosis (AIT) can also occur during chronic administration. In addition, there is a mixed/indefinite form to which both pathogenic mechanisms mentioned above contribute. Type 1 AIT develops in patients with preexisting thyroid disorders, while type 2 AIT occurs in substantially normal thyroid gland. On the one hand, the rate of serious adverse cardiovascular events was three times higher in AIT compared with euthyroid patients [39]. On the other side, several studies demonstrated the safety of amiodarone in end-stage heart failure and in early postoperative atrial fibrillation [36, 37].
Endocrine dysfunction is common in severe brain injury. Traumatic brain injury is usually associated with increased intracranial pressure, which can be followed by a brainstem herniation, resulting in brainstem infarction [40]. Ischemic lesions can cause dysfunction in the hypothalamic–pituitary axis. One of the most frequent complications is the posterior pituitary deficiency, characterized by central diabetes insipidus (CDI). Arginine vasopressin (AVP) deficiency can cause inadequate diuresis with hypovolemia, hyperosmolality, and hypernatremia [41]. Anterior pituitary gland dysfunction has also been detected with hypothyroidism and hypocortisolemia. Lack of these hormones may lead to hemodynamic instability, with reduced myocardial function, hypovolemia, inadequate stress response, increased proinflammatory condition. Each of them can impair graft function [42, 43]. Endogenous catecholamine release is enhanced in both neurological death and acute critical illness. Although it causes increased systemic vascular resistance, cardiac output is compromised by myocardial suppression induced by neurological death and by a reduced thyroid hormone release due to pituitary gland deficiency. Therefore, a theoretical advantage exists for exogenous thyroid hormone supplementation [44].
Arginine-vasopressin should be considered if hypotension persists despite adequate volume resuscitation or if central diabetes insipidus (CDI) occurs. Damage of the posterior lobe of the pituitary gland, hypothalamic paraventricular nuclei, and supraoptic nuclei results in undetectable or low levels of AVP. The deficiency of AVP can lead to inadequate diuresis and is associated with hyperosmolality, hypovolemia, and hypernatremia, which is consistent with DI. In addition, even in patients who do not meet the criteria for DI, baroreflex-mediated secretion of AVP can be impaired in response to decreased hypotension and decreased circulatory volume. Appropriate therapy with early intervention can restore hemodynamic stability and prevent end-organ damage. A recent analysis of the OPTN database has shown that the administration of AVP in organ donors is independently associated with an increased rate of organ recovery. The study did not recommend indications for AVP use (such as DI and hypotension). Prolonged hypernatremia (Na+ > 155 mmol/L) due to untreated DI has been associated with postoperative graft dysfunction in several retrospective studies and one prospective study; however, this association was not generally reported. Maintaining normal sodium levels remains a reasonable goal of the appropriate treatment. Hypernatremia, excessive diuresis, and volume depletion can occur for reasons other than DI (e.g., osmotic diuresis due to hyperglycemia or mannitol administration) and should be investigated [45]. Treatment of AVP deficiency could be considered if hypotension persists despite adequate resuscitation or in the presence of DI, which is likely to occur if one or more of the following criteria are identified, unless there is another cause of the disorder: polyuria (urinary output>3–4 l/d or 2.5–3.0 ml/kg/h); normal or increased serum motility; inadequately diluted urine (specific gravity <1.005, urinary osmolality <200 mOsm/kg H2O); hypernatremia (Na+ > 145 mmol/L) [45].
The use of corticosteroids can reduce the inflammation caused by brain death and modulating immune functions can improve the quality of donor organs (e.g., lungs) and posttransplant graft function. Corticosteroid administration for brain-dead organ donors is highly recommended for two reasons. The first reason is the treatment of hypothalamic–pituitary–adrenal (HPA) axis failure, which could potentially lead to hemodynamic instability. However, like the axis of the thyroid gland, the HPA axis is generally not deficient after brain death. Additionally, in observational studies, the donor’s hemodynamic instability was not associated with hypocortisolemia or lack of adrenal corticotropin sensitivity. Nevertheless, corticosteroids may improve hemodynamics through their vasopressor effects. The second possible reason for the administration of corticosteroids is reduced inflammation, which can have a negative effect on graft function. Observational studies highlight the increased organ procurement and improved graft and survival of the recipient by administration of corticosteroids. However, good-quality RCT evidence is lacking. With high heterogeneity of the study design and concomitant therapies, as well as poor quality, most RCTs rule out a strong conclusion. Several studies analyzed the effect of high-dose methylprednisolone. Theoretically, corticosteroid-induced hyperglycemia may outweigh all possible benefits. Recently, lower doses of hydrocortisone have been studied. Improved blood glucose was improved by a small observational study control by such strategy without any benefit on patient-centered outcomes. In summary, the indications of corticosteroid use in possible organ donors remain controversial, but can be considered in hemodynamic instability. It is important that it could be administered only after sampling for tissue typing, as it can reduce the expression of human leukocyte antigen [43]. Administration of high-dose corticosteroids (methylprednisone 1000 mg IV, 15 mg/kg IV, or 250 mg IV bolus followed by an infusion at a rate of 100 mg/h) reduces the potential adverse effects of the inflammatory cascade on donor organ function after brain death. Ideally, it should be administered after taking blood for tissue typing as it is able to suppress human leukocyte antigen expression [45].
Changes in the axis of the thyroid are common after brain death, and levels of biologically active T3 are generally low. However, several studies with brain-dead organ donors have shown that the majority of patients have maintained pituitary function with normal or elevated thyroid-stimulating hormone levels due to internal carotid supply. T4 levels generally remain in the normal range and inactive reverse T3 levels are normal or elevated. This constellation points to non-thyroid disease rather than central hypothyroidism in the presence of thyroid gland with increased peripheral inactivation of thyroid hormone, as is the case in patients in the general intensive care unit. Because prolonged and severe hypothyroidism can lead to myocardial dysfunction, low T3 levels are thought to induce hemodynamic instability in the potential donor.
The changes in the neuroendocrine axes have a biphasic manner. During the acute phase of critical illness, it seems to be evolutionarily selective and is likely to be beneficial for survival. Therefore, exogenous intervention may not be required at this stage of critical illness. If these profound changes last longer, a maladaptive phase begins. Although treatment with exogenous active hormones in the chronic phase seems to be a reasonable option, experimental studies have highlighted the difficulties of optimal dosing and posology [46]. In addition, a large study has highlighted the fact that thyroid hormone supplementation may be associated with an increased risk of early graft loss (EGL) and early graft dysfunction (EGD) [47, 48]. However, reliable data have shown that thyroid hormone supplementation in combination with methylprednisolone may reduce the likelihood of developing of primer graft dysfunction (PGD). In addition, thyroxine administration may also have a beneficial effect on long-term survival after HTX [49].
However, it remains unclear whether non-thyroid disease following cerebral death should be treated. An extensive observational study that included data from 63,593 brain-dead organ donors independently linked thyroid hormone replacement to an increased number of procured organs. The apparent benefits of thyroid hormone replacement were not confirmed by another RCT. However, the relatively low number of patients with hemodynamic stability in RCTs can preclude a conclusion in this subset of patients. Consensus guidelines have suggested that thyroid hormone replacement should be considered in hemodynamically unstable donors. Both T4 and T3 substitutions have been used for this purpose, although T4 is increasingly degraded to inactive reverse T3(46). One commonly utilized protocol is the following: T4 IV administration with a 20 μg bolus, followed by an infusion at 10 μg/h, or administer T3 IV with a 4.0 μg bolus, followed by an infusion at 3 μg/h [45].
Although target glucose levels for intensive insulin therapy in critically ill patients are still a matter of debate, hyperglycemic organ donors should be treated in the same way as other critically ill patients [45].
Although donor organ replacement therapies are still a matter of debate, there are some reliable data on HRT for cardiac recipients [50]. The use of triiodothyronine (T3) and thyroxine (T4) should be considered in patients with hemodynamic instability or potential cardiac donors with reduced ejection fraction [45]. The perioperative l-thyroxine treatment supplementation of cardiac recipients revealed that thyroid hormone administration initiated preoperatively was associated with a significantly better survival than either no thyroid hormone substitution or postoperative thyroid hormone substitution [50]. According to our institutional practice, thyroid hormone levels should be measured before the transplantation and thereafter weekly. While T3 levels are usually low and considered as a consequence of a natural response for huge stress, T4 levels should be closely monitored and values lower than the normal range must be treated. TSH levels in the perioperative period have also become interest of recent research (Figure 5).
Kaplan–Meier curve. Survival function according to the initiation of l-thyroxine supplementation in recipients. Preoperatively initiated supplementation was associated with significantly better survival function than no or postoperatively initiated supplementation.
Detection of hepatic dysfunction during preoperative evaluation, even in subclinical form, is the cornerstone of postoperative mortality estimation. As discussed above, hepatic dysfunction can affect both the intraoperative and postoperative period. In early-stage liver fibrosis, higher transaminase levels after surgery were associated with worse survival [51]. Moderate and elevated MELD XI scores predict increased short- and mid-term mortality after heart transplantation [52]. A remarkable increased MELD XI score is also associated with higher rates of postoperative stroke, need of dialysis, infection, and rejection [53].
Hepatic vein flow patterns are an intensively researched topic. Results suggest that pathological changes in flow patterns, such as damped, reduced, and reversed flow, may be an early predictor of hepatic tissue fibrotic transformation. Therefore, it can be an important marker of adverse outcome after adult heart transplantation. Moreover, hepatic vein congestion signs seem to be not only the marker of the right heart failure but can also estimate the severity of the abdominal venous insufficiency. After a successful heart transplantation [or LVAD implantation], congestive problems no longer exist as they did before the operation. In a manner, hepatic functions may improve. MELD scores are usually improving during the first postoperative year. In the vast majority of cases, normalization occurs within the first two months [54]. However, our findings indicated that a rise in the transaminase levels after transplantation was associated with higher risk of two-year mortality [19]. Hypoxic hepatitis in the early perioperative period must be followed, as it can worsen survival.
Endocrine abnormalities can develop during end-stage heart failure, and it should be monitored to detect early the chronic phase of the maladaptive response, which requires thyroid hormone substitution. Certain hormone replacements during donor procurement, such as treatment of central diabetes insipidus with arginine-vasopressin, are well established. In the current guidelines, use of thyroid hormones has been debated. After transplantation, the steroids can cause impaired glucose tolerance or diabetes. Thyroid hormone levels should be regularly checked.
We would like to thank you Veronika Rajki RN, PhD, for English editing.
The authors declare no conflict of interest related to this chapter.
AF | atrial fibrillation |
AIH | amiodarone-induced hypothyroidis |
AIT | amiodarone-induced thyrotoxicosis |
ALP | alkaline phosphatase |
ALT | alanine aminotransferase |
AST | aspartate aminotransferase |
ATG | anti-thymocyte globulin |
AVP | arginine vasopressin |
BIVAD | biventricular assist device |
CDI | central diabetes insipidus |
CYP | cytochrome P450 enzymes |
D1 | type 1 iodothyronine deiodinase |
D2 | type 2 iodothyronine deiodinase |
D3 | type 3 iodothyronine deiodinase |
EGD | early graft dysfunction |
EGL | early graft loss |
HRT | hormone replacement therapy |
HTX | heart transplantation |
ICU | intensive care unit |
IL-1 | interleukin-1 |
IL-6 | interleukin-6 |
INR | international normalized ratio |
LVAD | left ventricular assist device |
MCS | mechanical circulatory support |
MELD | model for end-stage liver disease |
MMF | mycophenolate-mofetil |
NAFLD | nonalcoholic fatty liver disease |
NFκB | nuclear factor κB |
NTI | nonthyroidal illness |
PGD | primer graft dysfunction |
PT | prothrombin time |
PTT | partial thromboplastin time |
RAAS | renin-angiotensin-aldosterone system |
rT3 | reverse triiodothyronine |
SERCA | sarcoplasmic reticulum calcium adenosine triphosphatase |
SVR | systemic vascular resistance |
T3 | triiodothyronine |
T4 | thyroxine |
TE | transient elastography |
TNF-α | tumor necrosis factor |
TRH | thyrotropin-releasing hormone |
TRα1 | thyroid hormone receptor alfa-1 |
TSH | thyroid-stimulating hormone |
UNOS | United Network for Organ Sharing |
VA-ECMO | veno-arterial extracorporeal membrane oxygenation |
vWF | von Willebrand factor |
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. 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Their association is unclear. In this chapter, we briefly summarized the epidemiology of liver cirrhosis in stroke, reviewed the current evidence regarding the association between liver cirrhosis and stroke, and discussed the potential mechanisms for explaining such an association, such as coagulopathy, hypoperfusion, cardiac diseases, diabetes, and dyslipidemia.",book:{id:"7031",slug:"liver-pathology",title:"Liver Pathology",fullTitle:"Liver Pathology"},signatures:"Kexin Zheng, Xiaozhong Guo, Xinhong Wang and Xingshun Qi",authors:[{id:"197501",title:"Dr.",name:"Xingshun",middleName:null,surname:"Qi",slug:"xingshun-qi",fullName:"Xingshun Qi"}]},{id:"70754",title:"Diagnosis and Treatment of Hepatoblastoma: An Update",slug:"diagnosis-and-treatment-of-hepatoblastoma-an-update",totalDownloads:768,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Hepatoblastoma is a rare but the most common solid tumor in children. The incidence is gradually increasing. The international collaboration among four centers in the world has greatly improved the prognosis of hepatoblastoma. They formed the Children’s Hepatic Tumor International Collaboration (CHIC) to standardize the staging system (2017 PRETEXT system) and the risk factors for tumor stratification. Multimodal therapy has become the standard for the management of hepatoblastoma, including surgical resection, liver transplantation, chemotherapy, and so on. Surgery is the primary treatment of early stage hepatoblastoma. Three-dimensional reconstruction is helpful for preoperative evaluation of large tumors, assisting extended hepatectomy for patients in PRETEXT III or IV. Neoadjuvant therapy is useful for reducing the tumor volume and increasing the resectability. Primary liver transplantation is recommended for advanced hepatoblastoma. The lungs are the most common metastatic organ, the treatment of which is critical for the patient’s long-term survival. 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The diagnosis should be keep in mind at all ages in patients with hepatic disease, neurological disease, or psychiatric symptoms.",book:{id:"7031",slug:"liver-pathology",title:"Liver Pathology",fullTitle:"Liver Pathology"},signatures:"Nese Karadag Soylu",authors:[{id:"324100",title:"Prof.",name:"Neşe",middleName:null,surname:"Karadağ Soylu",slug:"nese-karadag-soylu",fullName:"Neşe Karadağ Soylu"}]}],onlineFirstChaptersFilter:{topicId:"1102",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. 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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. 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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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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). 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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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. 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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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He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar 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:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{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:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. 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He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. 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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. 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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. 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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. 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This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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