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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Sometimes I pick up an assortment of scattered seashells while walking along the beautiful Torrey Pines Beach in San Diego. Likewise, this book contains an assortment of discussions of different aspects of serotonin to enrich our knowledge and understanding of this neurochemical. The book contains four different chapters: 1. Introductory chapter: From Measuring Serotonin Neurotransmission to Evaluating Serotonin Post-Receptor Signaling Transduction; 2. Serotonin Reuptake Inhibitors and Their Role in Chronic Pain Management; 3. Serotonin and Emotional Decision-Making; and 4. 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She received her BS and MS in Chemistry from Lanzhou University, China and her PhD in Neuroscience from the Catholic University of Leuven, Belgium. Dr. Qu has spent part of her career at the National Institutes of Health, USA, studying depression mechanisms underlying serotonin post-receptor regulated signaling transduction. She is also involved in a drug discovery program at Johnson and Johnson in the USA developing novel dual-acting antidepressants with selective serotonin reuptake inhibitors. In 2002, she received a Sevier Young Investigator Award from the Serotonin Club at the International Union of Basic and Clinical Pharmacology (IUPHAR) Satellite Meeting on Serotonin. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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All organisms are constantly and unavoidably exposed to xenobiotics including both man–made and natural chemicals such as drugs, plant alkaloids, microorganism toxins, pollutants, pesticides, and other industrial chemicals. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase I and phase II reactions. This chapter focuses on phase II biotransformation reactions (also called ´conjugation reactions´) which generally serve as a detoxifying step in metabolism of drugs and other xenobiotics as well as endogenous substrates. On the other hand, these conjugations also play an essential role in the toxicity of many chemicals due to the metabolic formation of toxic metabolites such as reactive electrophiles. Gene polymorphism of biotransformation enzymes may often play a role in various pathophysiological processes. Conjugation reactions usually involve metabolite activation by a high–energy intermediate and have been classified into two general types: type I (e.g., glucuronidation and sulfonation), in which an activated conjugating agent combines with substrate to yield the conjugated product, and type II (e.g., amino acid conjugation), in which the substrate is activated and then combined with an amino acid to yield a conjugated product (Hodgson, 2004). In this chapter, we will concentrate on the most important conjugation reactions, namely glucuronide conjugation, sulfoconjugation, acetylation, amino acid conjugation, glutathione conjugation and methylation.
\n\t\tUDP–glucuronosyltransferases (UGTs) belong among the key enzymes of metabolism of various exogenous as well as endogenous compounds. Conjugation reactions catalyzed by the superfamily of these enzymes serve as the most important detoxification pathway for broad spectrum of drugs, dietary chemicals, carcinogens and their oxidized metabolites, and other various environmental chemicals in all vertebrates. Furthermore, UGTs are involved in the regulation of several active endogenous compounds such as bile acids or hydroxysteroids due to their inactivation via glucuronidation (Miners & McMackenzie, 1991, Kiang et al., 2005). In humans, almost 40–70% of clinically used drugs are subjected to glucuronidation (Wells et al., 2004). In general, UGTs mediate the addition of UDP-hexose to nucleophilic atom (O–, N–, S– or C– atom) in the acceptor molecule (Mackenzie et al., 2008). The UDP–glucuronic acid is the most important co–substrate involved in the conjugation reactions (called glucuronidation) carried out by UGTs. Newly formed β–D–glucuronides exhibit increased water–solubility and are easily eliminated from the body in urine or bile. The scheme of typical glucuronidation reactions is shown in Figure 1. Glucuronidation O–linked moieties (acyl, phenolic, hydroxy) predominates the diversity in substrate recognition, and all of the UGTs are capable of forming O–linked glucuronides, albeit with different efficiencies and turn–over rates (Tukey & Strassburg, 2000). UGTs are membrane–bound enzymes similarly to cytochromes P450 with subcellular localization in the endoplasmic reticulum (ER). In contrast to cytochromes P450, the active site of these enzymes is embedded in the lumenal part of ER.
\n\t\t\t\tGlucuronides formation. The summary of chemical structures commonly subjected to glucuronidation.
To date, the mammalian UGT gene superfamily comprises of 117 members. Four UGT families have been identified in humans: UGT1, UGT2 involving UGT2A and UGT2B subfamily, UGT3 and UGT8. Enzymes included in the UGT1 and UGT2 subfamily are responsible for the glucuronidation of exo– and endogenous compounds, whereas members of the UGT3 and UGT8 subfamilies have their distinct functions (See section Substrates of UGTs, inhibition, induction) (Mackenzie et al., 2008). The members of the UGT1A subfamily have been found to be identical in their terminal carboxyl 245 amino acids, which are encoded by exons 2–5. Only the uniqueness of first exon in the UGT1A subfamily genes differentiates one enzyme from each other. In contrast to the UGT1A subfamily, the members of the UGT2 gene subfamily contain a different set of exons (Tukey & Strassburg, 2000). The UGT enzymes of each family share at least 40% homology in DNA sequence, whereas members of UGT subfamilies exert at least 60% identity in DNA sequence (Burchell et al., 1995). As of the time of writing, 22 human UGT proteins can be distinguished: UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, UGT2A2, UGT2A3, UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, UGT2B17, UGT2B28, UGT3A1, UGT3A2, and UGT8A1 (Mackenzie et al., 2008, Miners et al., 2006,Court et al., 2004, Patten, 2006, Sneitz et al., 2009). In general, human UGT enzymes apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many UGTs. The UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 belong among the main liver xenobiotic–conjugating enzymes, whereas UGT1A7, UGT1A8, and UGT1A10 are predominantly extrahepatic UGT forms. Moreover, glucuronidation activity was also detected in other tissues such as kidney (Sutherland et al., 1993), brain (King et al.,1999), or placenta (Collier et al., 2002).
\n\t\t\t\tFirst of all, the fact that most xenobiotic metabolising UGTs show overlapping substrate specificities should be noted. Two UGTs, namely UGT8A1 and UGT3A1, stand apart from other UGT enzymes since they possess specific functions in the body. UGT8A1 takes part in the biosynthesis of glycosphingolipids, cerebrosides, and sulfatides of nerve cells (Bosio et al., 1996). Recently, the UGT3A1 enzyme has been shown to have a certain role in the metabolism of ursodeoxycholic acid used in therapy of cholestasis or gallstones (Mackenzie et al., 2008). Although many substrates (therapeutic drugs, environmental chemicals) are glucuronidated by multiple UGTs, several compounds exhibit a relative specificity towards individual UGT enzymes. Bilirubin is exclusively metabolised by UGT1A1 (Wang et al., 2006). Conjugation reactions by the UGT2B7 enzyme constitute an important step in the metabolism of opioids (Coffman et al., 1998). Carboxylic acids including several non–steroidal anti–inflammatory agents are conjugated mainly by UGT1A3, UGT1A4, UGT1A9, and UGT2B7 (Tukey & Strassburg, 2000). Acetaminophen (paracetamol) is glucuronidated predominantly by UGTs of the UGT1A subfamily (UGT1A1, UGT1A6, and UGT1A9) (Court et al., 2001). Despite the fact that in most cases UGTs are responsible for O–glucuronidation of their substrates, members of the UGT1A subfamily have been found to catalyze N–glucuronidation of several amine–containing substrates (chlorpromazine, amitryptyline) (Tukey & Strassburg, 2000). The intestinal UGT1A8 and UGT1A10 enzymes were suggested to have a negative impact on the bioavailability of orally administered therapeutic drugs (Mizuma, 2009). For example, raloxifene, a selective estrogen receptor modulator used in therapy of osteoporosis, naturally has a low bioavailability and has also been shown to be extensively metabolised by UGT1A8 and UGT1A10 (Kemp et al., 2002). UGTs might also play a significant role in the inactivation of carcinogens from diet or cigarette smoke (Dellinger et al., 2006). Hanioka et al. (2008) proposed that the glucuronidation of bisphenol A (an environmental endocrine disruptor) by UGT2B15 serves as a major detoxification pathway of this molecule. UGTs are notably inhibited by various compounds. Analgesics, non–steroidal anti–inflammatory drugs (NSAIDs), anxiolytics, anticonvulsants, or antiviral agents have been shown to have possible inhibitory effect on the enzymatic activities of various UGTs (thoroughly reviewed by Kiang et al., 2005). Recently, non–steroidal anti–inflammatory drugs have been shown to partially impair an equilibrium between biological functioning and degradation of aldosterone due to involvement of renal UGT2B7 in both the glucuronidation of aldosterone (deactivation) and the glucuronidation of NSAIDs (Knights et al., 2009). Similarly to other drug metabolising enzymes, UGTs are subject to induction by various xenobiotics or biologically active endogenous compounds (hormones) via nuclear receptors and transcription factors. For example, the aryl hydrocarbon receptor plays role in induction of UGT1A1 while the activation of pregnane X receptor and the constitutive androstane receptor leads to induction of UGT1A6 and UGT1A9 (Lin & Wong, 2002, Mackenzie et al., 2003, Xie et al., 2003). Several classes of drugs including analgesics, antivirals, or anticonvulsants are suspected to act as human UGTs inducers.
\n\t\t\t\tMany human UGT enzymes were found to be genetically polymorphic. The mutations in UGT1A1 gene result in several syndromes connected with decreased bilirubin detoxification capacity of UGT1A1. Kadakol et al. (2000) summed up data about more than 50 mutations of UGT1A1 causing Crigler–Najjar syndrome type I and type II. Patients suffering from type I, also called congenital familial nonhemolytic jaundice with kernicterus, completely lack the UGT1A1 enzymatic activity resulting in toxic effects of bilirubin on the central nervous system. The most common deficiency of UGT1A1 enzyme is Gilbert‘s syndrome. 2–12% of the population suffer from this benign disorder characterized by intermittent unconjugated hyperbilirubinemia. In most cases, this syndrome is caused by a mutation in the promotor region of UGT1A1 gene (Monaghan et al., 1996). Increased toxicity of a pharmacologically active metabolite of irinotecan (SN–38) has been described in patients suffering from Gilbert’s syndrome as UGT1A1 is the main enzyme responsible for the formation of the inactive SN–38 glucuronide (Wasserman et al., 1997). The genetic variability in the UGT1 or UGT2 gene families was also suggested to alter risk of cancer either as a result of decreased inactivation of hormones such as estrogens or due to reduced detoxification of environmental carcinogens and their reactive metabolites (Guillemette, 2003).
\n\t\t\t\tSulfoconjugation (or sulfonation) constitutes an important pathway in the metabolism of numerous both exogenous and endogenous compounds. The sulfonation reaction was first recognized by Baumann in 1876. Baumann detected phenyl sulfate in the urine of a patient who had been administered phenol. The sulfonation reactions are mediated by a supergene family of enzymes called sulfotransferases (SULTs). In general, these enzymes catalyze the transfer of sulfonate (SO3\n\t\t\t\t\t–) from the universal sulfonate donor 3‘–phosphoadenosine 5‘–phosphosulfate (PAPS) to the hydroxyl or amino group of an acceptor molecule, Fig. 2. The incorrect term sulfation is sometimes used since sulfated products are formed in this type of reactions. PAPS is a universal donor of sulfonate moiety in sulfonation reactions and has been shown to by synthesized by almost all tissues in mammals from inorganic sulfate (Klaassen & Boles, 1997). Depletion of PAPS due to lack of inorganic sulfate or due to genetic defects of enzymes participating in PAPS synthesis may lead to reducing of sulfonation capacity which could affect the metabolism of xenobiotics or disrupt the equilibrium between synthesis and degradation of active endogenous compounds.
\n\t\t\t\tTo date, two large groups of SULTs have been identified. The first group includes membrane–bound enzymes with no demonstrated xenobiotic–metabolising activity. These enzymes are localized in the Golgi apparatus and they are involved in metabolism of endogenous peptides, proteins, glycosaminoglycans, and lipids (Habuchi, 2000). Cytosolic SULTs constitute the second group of sulfotransferases and play a major role in conjugation of a broad spectrum of xenobiotics including environmental chemicals, natural compounds, drugs (Gamage et al., 2006) as well as endogenous compounds such as steroid hormones, iodothyronines, catecholamines, eicosanoids, retinol or vitamin D (Glatt & Meinl, 2004). Moreover, cytosolic SULTs are presumed to play a crucial role in the detoxification processes occurring in the developing human fetus since no UGTs transcripts have been detected in fetal liver at 20 weeks of gestation (Strassburg et al., 2002). Sulfonation is generally described as a detoxification pathway for many xenobiotics. Addition of the sulfonate moiety to the molecule of a parent compound or most often to the molecule of its metabolite originating in the oxidative phase of drug metabolism leads to formation of a water–soluble compound which is then easily eliminated from the body. However, in several cases the sulfonation reaction can lead to formation of a more active metabolite compared to the parent compound as is the case for the hair follicle stimulant minoxidil (Buhl et al., 1990) or the diuretic agent triamterene (Mutschler et al., 1983). Furthermore, the role of sulfotransferases in the activation of various procarcinogens and promutagens was confirmed (Gilissen et al., 1994).
\n\t\t\t\tThe formation of sulfates (R–O–SO3\n\t\t\t\t\t\t\t– ) and sulfamates (R1–NR2–SO3\n\t\t\t\t\t\t\t– ). These reactions are catalyzed by 3‘–phosphoadenosine 5‘–phosphosulfate (PAPS)–dependent sulfotransferases.\n\t\t\t\t\t\t
In the following text we will focus only on cytosolic sulfotransferases, since this enzyme superfamily plays a key role in the biotransformation of multiple xenobiotics as well as endogenous substrates. Recently, a nomenclature system for the superfamily of cytosolic SULTs has been established analogously to those of other drug metabolising enzymes such as cytochromes P450 or UDP–glucuronosyltranferases (Blanchard et al., 2004). The superfamily of cytosolic sulfotransferases is subsequently divided into families and subfamilies according to the amino acid sequence identity among individual SULTs. In detail, members of one SULTs family share at least 45% amino acid sequence identity, whereas SULTs subfamily involves individual members with at least 60% identity. To date, four human SULT families, SULT1, SULT2, SULT4 and SULT6, have been identified. These SULT families include at least 13 different members. The SULT1 family comprises of 9 members divided into 4 subfamilies (1A1, 1A2, 1A3, 1A4, 1B1, 1C1, 1C2, 1C3 and 1E1). SULT2A (SULT2A1) and SULT2B (SULT2B1a and SULT2B1b) belong to SULT2 family. The SULT4A1 and SULT6B1 are the only members of the SULT4 and SULT6 family, respectively (Lindsay et al., 2008). Cytosolic sulfotransferases exert relatively broad tissue distribution. The members of SULT1A family were found in liver, brain, breast, intestine, jejunum, lung, adrenal gland, endometrium, placenta, kidney and in blood platelets. Figure 3 displays SULT expression “pies“ of the most important human cytosolic transferases in human tissues. SULT1A1 is predominantly expressed in the liver (Hempel et al., 2007). In contrast to SULT1A1, the SULT1A3 enzyme was not detected in human adult liver. SULT1B1 has been found in liver, small intestine, colon, and leukocytes (Wang et al., 1998). Members of SULT1C subfamily were identified in fetal human tissues such as liver (Hehonah et al., 1999) or lung and kidney (Sakakibara et al., 1998) as well as in adult human stomach (Her et al., 1997). The predominant expression of SULT1E1 was found in human liver and jejunum (Riches et al., 2009). Major sites of SULT2A1 expression are the liver, adrenal gland, ovary, and duodenum (Javitt et al., 2001). Members of SULT2B subfamily are localized in human prostate, placenta, adrenal gland, ovary, lung, kidney, and colon (Glatt & Meinl, 2004). Recently, an exclusive localization of human SULT4A1 in the brain was confirmed (Falany et al., 2000).
\n\t\t\t\tThe human SULT “pies”. The mean expression values for each enzyme are displayed as percentages of the total sum of immunoquantified SULTs (maximum five enzymes) present in each tissue. Expression values are shown for liver (A), small intestine (B), kidney (C), and lung (D) (Riches et al., 2009).
SULT1A1 has been shown to be one of the most important sulfotransferases participating in metabolism of xenobiotics in humans. It has also been termed phenol sulfotransferase (P–PST) or thermostable phenol sulfotransferase (TS PST1). In general, SULT1A1 is responsible for sulfoconjugation of phenolic compounds such as monocyclic phenols, naphtols, benzylic alcohols, aromatic amines or hydroxylamines (Glatt & Meinl, 2004). Acetaminophen, minoxidil as well as dopamine or iodothyronines undergo sulfonation by SULT1A1. SULT1A1 also takes part in transformation of hydroxymethyl polycyclic aromatic hydrocarbons, N–hydroxyderivatives of arylamines, allylic alcohols and heterocyclic amines to their reactive intermediates which are able to bind to nucleophilic structures such as DNA and consequently act as mutagens and carcinogens (Glatt et al., 2001). SULT1A2 also plays an important role in the toxification of several aromatic hydroxylamines (Meinl et al., 2002). SULT1A3, formerly known as thermolabile phenol SULT (TL PST) or monoamine sulfotransferase, exhibits high affinity for catecholamines (dopamine) and contributes to the regulation of the rapidly fluctuating levels of neurotransmitters. The human SULT1B1 was isolated and described by Fujita et al. (1997) and was shown to be the most important sulfotransferase in thyroid hormone metabolism. SULT1E1 plays a key role in estrogen homeostasis. This enzyme conjugates 17β–estradiol and other estrogens in a step leading to their inactivation. Since 17β–estradiol and relative compounds regulate various processes occurring in humans, inactivation of these compounds by the SULT1E1 enzyme constitute an important step in the prevention and development of certain diseases. Down regulation or loss of SULT1E1 could be to a certain extent responsible for growth of tumor in hormone sensitive cancers such as breast or endometrial cancer (Cole et al., 2010). SULT2A and SULT2B subfamilies include the hydroxysteroid sulfotransferases with partially overlapping substrate specifities. SULT2A1 is also termed as dehydroepiandrosterone sulfotransferase (DHEA ST) and conjugates various hydroxysteroids such as DHEA, androgens, bile acids and oestrone (Comer et al., 1993). Recently, a role of SULT2A1 in metabolism of quinolone drugs in humans was confirmed (Senggunprai et al., 2009). Clinically relevant substrates for other cytosolic sulfotransferases have not been identified yet.
\n\t\t\t\tGenetic polymorphism was detected in many SULT forms such as the SULT1A1, SULT1A3, SULT1C2, SULT2A1, SULT2A3 and SULT2B1 enzyme (Lindsay et al., 2008). Single nucleotide polymorphism in the SULT1A1 gene leading to an Arg213 → His amino acid substitution is relatively frequent in the Caucasian population (25.4–36.5%) (Glatt & Meinl, 2004). This mutation results in a variation of SULT1A1 thermal stability and enzymatic activity. Several authors have claimed that SULT1A1 polymorphism might play a role in the pathophysiology of lung cancer (Arslan et al., 2009), urothelial carcinoma (Huang, 2009), and meningiomal brain tumors (Bardakci, 2008).
\n\t\t\t\tSince the first detection of glutathione transferase activity in rat liver cytosol by Booth in the early 1960s, the family of glutathione transferases (synonymously glutathione S–transferases; GSTs) has been studied in detail. Undoubtedly, the members of glutathione transferase family play an important role in metabolism of certain therapeutics, detoxification of environmental carcinogens and reactive intermediates formed from various chemicals by other xenobiotic–metabolising enzymes. Furthermore, GSTs constitute an important intracellular defence against oxidative stress and they appear to be involved in synthesis and metabolism of several derivatives of arachidonic acid and steroids (van Bladeren, 2000). On the other hand, various chemicals have been shown to be activated into potentially dangerous compounds by these enzymes (Sherratt et al., 1997). In general, these enzymes catalyze a nucleophilic attack of reduced glutathione on lipophilic compounds containing an electrophilic atom (C–, N– or S–). In addition to nucleophilic substitutions, these transferases also account for Michael additions, isomerations, and hydroxyperoxide reductions. In most cases, more polar glutathione conjugates are eliminated into the bile or are subsequently subjected to other metabolic steps eventually leading to formation of mercapturic acids. Figure 4 shows the sequential steps in the synthesis of mercapturic acids. Mercapturic acids are excreted from the body in urine (Commandeur et al., 1995). For instance, industrial chemicals such as acrylamide or trichloroethylene are detoxified via mercapturic acids (Boettcher et al., 2005, Popp et al., 1994).
\n\t\t\t\tUp to now, two different superfamilies of GSTs have been described. The first one includes soluble dimeric enzymes localized mainly in cytosole but certain members of this superfamily have been also identified in mitochondria (Robinson et al., 2004) or in peroxisomes (Morel et al., 2004). The superfamily of human soluble GSTs is further divided into eight separate classes: Alpha (A1–A4), Kappa (K1), Mu (M1–M5), Pi (P1), Sigma (S1), Theta (T1–T2), Zeta (Z1) and Omega (O1–O2) (Hayes et al., 2005). Microsomal GSTs designated as the membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) consitute the second family of human GSTs. The human MAPEG superfamily includes six members: 5–lipoxygenase activating protein (FLAP), leukotriene C4 synthase (both involved in leukotriene synthesis), MGST1, MGST2, MGST3 (GSTs as well as glutathione dependent peroxidases) and prostaglandin E synthase (PGES) (Bresell et al., 2005). Both the soluble GSTs and MAPEG exhibit a broad tissue distribution; being found in liver, kidney, brain, lung, heart, pancreas, small intestine, prostate, spleen, and skeletal muscles (Hayes & Strange, 2000).
\n\t\t\t\tFormation of mercapturic acid. Glutathione S–transferase (1) catalyzes the conjugation between glutathione and various endogenous or xenobiotic electrophilic compounds. Subsequently, the resulting glutathione S–conjugate is broken down to a cysteine S–conjugate by γ-glutamyltranspeptidase (2) and dipeptidases (3). Finally, cysteine S–conjugate N–acetyltransferase (4) catalyses formation of mercapturic acid.
Various electrophilic compounds act as substrates for GSTs. They include a broad spectrum of ketones, quinones, sulfoxides, esters, peroxides, and ozonides (van Bladeren et al., 2000). Chemotherapeutics (such as busulfan, cis–platin, ethacrynic acid, cyclophosphamide, thiotepa); industrial chemicals, herbicides, pesticides (acrolein, lindane, malathion, tridiphane) are detoxified by GSTs (Hayes et al., 2005). Epoxides and other reactive intermediates formed from environmental procarcinogens mostly as a result of metabolism by cytochromes P450 (aflatoxin B1, polycyclic aromatic hydrocarbons, styrene, benzopyrene, heterocyclic amines) also undergo detoxification by soluble GSTs. Besides their enzymatic activity, cytosolic GSTs (such as class Alpha) exhibit an ability to bind various hydrophobic ligands (xenobiotics as well as hormones) and thus contribute to their intracellular transport and disposition. GSTs play an essential role in the fight against products of oxidative stress which unavoidably damage cell membrane lipids, DNA, or proteins. Reactive intermediates resulting from lipid peroxidation (4–hydroxynonenal), nucleotide peroxidation (adenine propenal) or catecholamine peroxidation (aminochrome, dopachrome, adrenochrome) are particularly inactivated by GSTs (Dagnino–Subiabre et al., 2000). Several specific substrates for GSTs have been identified. For instance, ethacrynic acid has been found to be predominantly metabolised by GSTP1, whereas trans–stilbene oxide is a specific substrate for GSTM1 (van Bladeren, 2000). The GSTT1 enzyme is responsible for conjugation of halogenated organic compounds such as dichlormethane or ethylene–dibromide (Landi, 2000). This step leads to activation of these compounds to their reactive electrophilic metabolites with potential mutagenic and cancerogenic effect. Ethylene–dibromide, a gasoline additive and a fumigant, is presumed to be potential human carcinogen because it is transformed by GSTs to DNA–reacting episulfonium ion (van Bladeren, 2000). The glucocorticoid response element and the xenobiotic response element activated by glucocorticoids and planar aromatic hydrocarbons respectively might play a role in the induction of expression of GSTs (Talalay et al., 1988).
\n\t\t\t\tMost members of both glutathione transferase superfamilies have been found to be genetically polymorphic. Several genetic variants of particular GSTs are supposed to contribute to the development of certain cancers or other diseases. Furthermore, genetic polymorphism in GSTs is pressumed to influence metabolism and disposition of various anticancerogenic drugs (Crettol et al., 2010). GSTP1 is responsible for metabolism of alkylating agents, topoisomerase inhibitors, antimetabolites, or tubulin inhibitors used in treatment of cancer. The common allele GSTP1*A is cytoprotective against the toxic effects of chemotherapeutics, whereas the functionally less competent allele GSTP1*B is thought to increase the toxicity of anticancerogenic drugs in patients with this gene variant due to decreased metabolic activity of impaired enzyme. Cyclophosphamide is biotransformed by GSTA1. Defective GSTA1*B allele was associated with increased survival in breast cancer patients treated with cyclophosphamide (Sweeney et al., 2003). On the other hand, several drugs activated by GSTs require a well–functioning enzyme. Patients with the active GSTM1 gene treated for acute myeloid leukemia with doxorubicin had a superior survival rate compared to patients with at least one null allele (Autrup et al., 2002). Individuals with lacking functional GSTM1, GSTT1, and GSTP1 have been shown to have a higher incidence of bladder, breast, colorectal, head/neck, and lung cancer. Genetically–based defects of these enzymes are also noteworthy because of their partial responsibility for increased risk of asthma, allergies, atherosclerosis, and rheumatoid arthritis (van Bladeren, 2000, Hayes et al., 2005).
\n\t\t\t\tCompared to sulfonations and glucuronidations, acetylations are modest in terms of the number and variety of substrates, but remain significant in a toxicological perspective. Drugs and other foreign compounds that are acetylated in intact animals are either aromatic amines or hydrazines, which are converted to aromatic amides and aromatic hydrazides (Parkinson, 2001). Acetylation reactions are characterized by the transfer of an acetyl moiety, the donor generally being acetyl coenzyme A, while the accepting chemical group is a primary amino function. As far as xenobiotic metabolism is concerned, three general reactions of acetylation have been documented, namely N– (Fig. 5a, b),\n\t\t\t\t\tO– (Fig. 5c), and N,O–acetylations (Fig. 5d). N–acetylation of aromatic amine is recognized as a major detoxification pathway in arylamine metabolism in experimental animals and humans (Hein et al., 2000). However, O– and N,O–acetylations occur in alternative metabolic pathways following activation by N–hydroxylation. The resulting N–acetoxyarylamines are highly unstable, spontaneously forming arylnitrenium ions that bind to DNA (Bland & Kadlubar, 1985) and ultimately lead to mutagenesis and carcinogenesis (Kerdar et al., 1993).
\n\t\t\t\tIn humans, acetylation reactions are catalyzed by two N–acetyltransferase isoenzymes (NATs), N–acetyltransferase 1 (NAT1) and 2 (NAT2). NATs are cytosolic enzymes found in many tissues of various species. The human NAT1 and NAT2 genes are located on chromosome 8 pter–q11, and share 87% coding sequence homology (Blum et al., 1990). NAT1 and NAT2 have distinct substrate specificities and differ markedly in terms of organ and tissue distribution. NAT2 protein is present mainly in the liver (Grant et al., 1990) and intestine (Hickman et al., 1998). NAT1 appears to be ubiquitous. Expression of human NAT1
\n\t\t\t\t\tReactions catalysed by N–acetyltransferases. (a,b) N–acetylation of arylamine and arylhydrazine, (c) O–acetylation of N–arylhydroxylamine, (d) N, O–acetyltransfer of an N–hydroxamic acid. These reactions use acetyl–coenzyme A as acetyl donor.
has been detected in adult liver, bladder, digestive system, blood cells, placenta, skin, skeletal muscles, gingiva (Dupret & Lima, 2005), mammary tissue, prostate, and lung by a number of methods (Sim et al., 2008). A notable difference between the two isoenzymes is the presence of NAT1 activity in fetal and neonatal tissue, such as lungs, kidneys, and adrenal glands (Pacifici et al., 1986). By contrast, NAT2 is not evident until about 12 months after birth (Pariente–Khayat et al., 1991). NAT1 has also been detected in cancer cells, in which it may not only play a role in the development of cancers through enhanced mutagenesis but may also contribute to the resistance of some cancers to cytotoxic drugs (Adam et al., 2003). NATs are involved in the metabolism of a variety of different compounds to which we are exposed on a daily basis. In humans, acetylation is a major route of biotransformation for many arylamine and hydrazine drugs, as well as for a number of known carcinogens present in diet, cigarette smoke, car exhaust fumes, and environment in general. Human NAT1 and human NAT2 have distinct but overlapping substrate profiles and also have specific substrates which can be used as ”probe“ substrates for each particular isoenzyme. Substrates of NAT1 include p–aminobenzoic acid, p–aminosalicylic acid, the bacteriostatic antibiotics sulfamethoxazole and sulfanilamide, 2–aminofluorene and caffeine (Ginsberg et al., 2009). Moreover, it has been proposed by Minchin that human NAT1 plays a role in folate metabolism through the acetylation of the folate metabolite p–aminobenzoylglutamate (Minchin, 1995). Human NAT2 is a xenobiotic–metabolising enzyme that provides a major route of detoxification of drugs such as isoniazid (an anti–tuberculotic drug), hydralazine and endralazine (anti–hypertensive drugs), a number of sulphonamides (anti–bacterial drugs) (Kawamura et al., 2005), procainamide (anti–arrhythmic drug), aminoglutethimide (an inhibitor of adrenocortical steroid synthesis), nitrazepam (a benzodiazepine) and the anti–inflammatory drug dapsone (Ginsberg et al., 2009, Butcher at al., 2002). Both NAT1 and NAT2 are polymorphic enzymes, with 28 NAT1 and 64 NAT2 alleles having been identified to date (see http://louisville.edu/medschool/pharmacology/NAT.html for details of alleles; last update May 24, 2011). N–acetylation polymorphism represents one of the oldest and most intensively studied pharmacogenetic traits and refers to hereditary differences concerning the acetylation of drugs and toxicants. The genetic polymorphism in NAT activity was first recognised in tuberculosis patients treated with isoniazid, which is metabolised principally by N–acetylation. The polymorphism causes individual differences in the rate of metabolism of this drug. Individuals with a faster rate are called rapid acetylators and individuals with a slower rate are called slow acetylators. Rapid acetylators were competent in isoniazid acetylation but the drug was cleared less efficiently in the slow acetylator group, which resulted in elevated serum concentration and led to adverse neurologic side effects due to an accumulation of unmetabolized drug (Brockton et al., 2000). Consistent with the toxicity of isoniazid in slow acetylators, there is an increased incidence of other drug toxicities in subjects carrying defective NAT2 alleles, such as lupus erythematosus in patients treated with hydralazine or procainamide (Sim et al., 1988), and haemolytic anemia and inflammatory bowel disease after treatment with sulfasalazine (Chen et al., 2007). The high frequency of the NAT2 and also NAT1 acetylation polymorphism in human population together with ubiquitous exposure to aromatic and heterocyclic amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. Many studies suggested a relationship between acetylation phenotypes (in particular, arising from NAT2 genotypes) and the risk of various cancer including colorectal, liver, breast, prostate, head and neck (Agúndez, 2008) and other disease conditions such as birth defects (Lammer et al., 2004) or neurodegenerative and autoimmune diseases (Ladero, 2008).
\n\t\t\t\tMethylation is a common but generally minor pathway of xenobiotic biotransformation. Unlike most other conjugative reactions, methylation often does not dramatically alter the solubility of substrates and results either in inactive or active compounds. Methylation reactions are primarily involved in the metabolism of small endogenous compounds such as neurotransmitters but also play a role in the metabolism of macromolecules for example nucleic acids and in the biotransformation of certain drugs. A large number of both endogenous and exogenous compounds can undergo N– (Fig. 6a),\n\t\t\t\t\tO– (Fig. 6b),\n\t\t\t\t\tS– (Fig. 6c) and arsenic–methylation during their metabolism (Feng et al., 2010). The co–factor required to form methyl conjugates is S–adenosylmethionine (SAM), which is primarily formed by the condensation of ATP and L–methionine.
\n\t\t\t\tMethylation reactions catalyzed by methyltransferases.
Several N–methyltransferases have been described in humans and other mammals; including indolethylamine N–methyltransferase (INMT), which catalyzes the N–methylation of tryptamine and structurally related compounds. The INMT exhibits wide tissue distribution. Human INMT was expressed in the lung, thyroid, adrenal gland, heart, and muscle but not in the brain (Thompson et al., 1999). Since INMT is predominantly present in peripheral tissues, its main physiological function is presumably non–neural. Nicotinamide N–methyltransferase (NNMT) is a SAM–dependent cytosolic enzyme that catalyzes the N–methylation of nicotinamide, pyridines, and other structural analogues. NNMT is predominantly expressed in the liver; expression has been also reported in other tissues such as the kidney, lung, placenta, and heart (Zhang et al., 2010). Several N–methylated pyridines are well–established dopaminergic toxins and the NNMT can convert pyridines into toxic compounds (such as 4–phenylpyridine into N–methyl–4– phenylpyridinium ion [MPP+]). NNMT has been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood–brain barrier (Williams & Ramsden, 2005). NNMT was one of the potential tumor biomarkers identified in a wide range of tumors such as thyroid, gastric, colorectal, renal, and lung cancer (Zhang et al., 2010). Histamine N–methyltransferase (HNMT), the second most important histamine inactivating enzyme, is a cytosolic enzyme specifically methylating the imidazole ring of histamine and closely related compounds in the intracellular space of cells. Levels of HNMT activity in humans are regulated genetically. HNMT is widely expressed in human tissues; the greatest expression is in the liver and kidney, but also in the spleen, colon, prostate, ovary, brain, bronchi, and trachea (Maintz & Novak, 2007). Common genetic polymorphisms for HNMT might be related to a possible role for individual variation in histamine metabolism in the pathophysiology of diseases such as allergy, asthma, peptic ulcer disease, and some neuropsychiatric illnesses (Preuss et al., 1998). Phenylethanolamine N–methyltransferase (PNMT) plays a role in neuroendocrine and blood pressure regulation in the central nervous system. PNMT, the terminal enzyme of the catecholamine biosynthesis pathway, catalyzes the N–methylation of the neurotransmitter norepinephrine to form epinephrine (Ji et al., 2005). PNMT is a cytosolic enzyme that is present in many tissues throughout the body, with particularly high concentration in the adrenal medulla, adrenergic neurons in the amygdala and retina and the left atrium of the heart (Haavik et al., 2008). Its activity increases after stress in response to glucocorticoids and neuronal stimulation (Saito et al., 2001). Several studies have suggested that two common PNMT promoter single nucleotide polymorphisms might be associated with risk of diseases such as essential hypertension, early–onset Alzheimer’s disease, or multiple sclerosis (Ji et al., 2008). Phosphatidylethanolamine N–methyltransferase (PEMT) converts phosphatidylethanolamine to phosphatidylcholine in mammalian liver. Phosphatidylcholine is nutrient critical to many cellular processes such as phospholipid biosynthesis, lipid–cholesterol transport, or transmembrane signaling. The human PEMT gene encodes for two isoforms of the enzyme, namely PEMT1, which is localized in the endoplasmic reticulum and generating most of the PEMT activity, and PEMT2, a liver specific isoform exclusively localized in mitochondria–associated membranes (Tessitore et al., 2003).
\n\t\t\t\tThe process of O–methylation of phenols and catechols is catalyzed by two different enzymes known as phenol O–methyltransferase and catechol O–methyltransferase. Phenol O–methyltransferase (POMT) is an enzyme that transfers the methyl group of SAM to phenol to form anisole. POMT is a localized in the microsomes of the liver and lungs of mammals but is also present in other tissues. Catechol O–methyltransferase (COMT) is a magnesium–dependent enzyme which was first described by Axelrod in 1957. It is an enzyme that plays a key role in the modulation of catechol–dependent functions such as cognition, cardiovascular function, and pain processing. COMT is involved in the inactivation of catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine, but also catecholestrogens and catechol drugs such as the anti–Parkinson´s disease agent L–DOPA and the anti–hypertensive methyldopa (Weinshilboum et al., 1999). Two forms of human COMT have been identified, a cytoplasmic soluble form (S–COMT) and a membrane–bound form (MB–COMT) located in the cytosolic side of the rough endoplasmic reticulum The S–COMT is predominantly expressed in the human liver, intestine and kidney (Taskinen et al., 2003), whereas the membrane–bound form is more highly expressed in all regions of the human central nervous system (Tunbridge et al., 2006). A common functional polymorphism at codons 108 and 158 in the genes coding for S–COMT and MB–COMT (COMT Val 108/158 Met), respectively, has been examined in relationship to a number of neurological disorders involving the noradrenergic or dopaminergic systems, such as schizophrenia (Park et al., 2002) or Parkinson\'s disease (Kunugi et al., 1997). It has also been suggested that a common functional genetic polymorphism in the COMT gene may contribute to the etiology of alcoholism (Wang et al., 2001).
\n\t\t\t\tThiol methylation is important in the metabolism of many sulfhydryl drugs. Human tissues contain two separate genetically regulated enzymes that can catalyze thiol S–methylation. Thiol methyltransferase (TMT) is a membrane–bound enzyme that preferentially catalyzes the S–methylation of aliphatic sulfhydryl compounds such as captopril and D–penicillamine, whereas thiopurine S–methyltransferase (TPMT) is a cytoplasmic enzyme that preferentially catalyzes the S–methylation of aromatic and heterocyclic sulfhydryl compounds including anticancer and immunosuppressive thiopurines such as 6–mercaptopurine, 6–thioguanine, and azathioprine. Thiopurine drugs have a relatively narrow therapeutic index and are capable of causing life–threatening toxicity, most often myelosuppression (Sahasranaman et al., 2008). TPMT genetic polymorphism represents a striking example of the clinical importance of pharmacogenetics. In 2010, 29 different variant TPMT alleles have been described (Ford & Berg, 2010) and this may be associated with large interindividual variations in thiopurine drug toxicity and therapeutic efficacy. Allele frequencies for genetic polymorphism are such that ~1 in 300 Caucasians is homozygous for a defective allele or alleles for the trait of very low activity, ~11% of people are heterozygous and have intermediate activity. Subjects homozygous for low TPMT activity have a high risk of myelosuppression after treatment with standard dose of azathioprine. Generally, TPMT–deficient patients (homozygous mutant) can be treated with 6–10% of the standard dose of thiopurines (Zhou, 2006). TPMT shows the highest level of expression in liver and kidney and the physiological role of this enzyme, despite extensive investigation, remains unclear.
\n\t\t\t\tArsenic is a well–known naturally occurring metaloid which is considered as a multiorgan human carcinogen. Occupational exposure to arsenic occurs in the smelting industry and during the manufacture of pesticides, herbicides, and other agricultural products. Arsenic plays a dual role as environmental carcinogenic pollutant and as a successful anticancer drug against promyelocytic leukemia (Wood et al., 2006). Its metabolism proceeds via a complicated enzymatic pathway, acting both as detoxification and producing more toxic intermediates. Methylation is an important reaction in the biotransformation of arsenic. Liver is considered to be the primary site for the methylation of inorganic arsenic (iAs) and arsenic (+3 oxidation state) methyltransferase (AS3MT) is shown to be critical specifically for the arsenic metabolism, and thus may be pharmacologically important as well. Methylated and dimethylated arsenic are the major urinary metabolites in human and many other species (Li et al., 2005). Two reaction schemes (Fig. 7) have been developed to describe the individual steps in the enzymatically catalysed conversion of iAs to methylated metabolites (Thomas, 2007). Although pentavalent methylated arsenicals (MAsV, DMAsV, TMAsV) are less toxic than inorganic ones (iAsV, iAsIII), the trivalent intermediated formed during the methylation process (MAsIII, DMAsIII) are much more cytotoxic and genotoxic (Hughes, 2009).
\n\t\t\t\t\tAlternative schemes for the conversion of inorganic arsenic (iAs) into methylated metabolites. (a) Scheme for the oxidative methylation of arsenicals in which reduction of oxidized arsenicals is interposed between each methylation reaction. (b) Scheme for methylation of arsenic involving formation of arsenic–glutathione (GSH) complex. SAM, S–adenosylmethionine; SAH, S–adenosylhomocysteine (According to Thomas, 2007).
Several single nucleotide polymorphisms in exons and introns in this gene are reported to be related to inter–individual variation in the arsenic metabolism (Fujihara et al., 2010). Polymorphism in AS3MT may influence arsenic metabolism and potentially susceptibility to its toxic and carcinogenic effects.
\n\t\t\t\tThe first description of glycine conjugation was published in 1842 by Keller. Xenobiotics containing a carboxyl group (–COOH) are widely used as drugs (for example simvastatin, valproic acid, or acetylsalicylic acid), herbicides, insecticides, and food preservatives. In addition, many xenobiotics are readily metabolized to carboxylic acids which may then be conjugated with amino acids. The ability of xenobiotics to undergo amino acid conjugation depends on the steric hindrance around the carboxylic acid group, and on substituents of the aromatic ring or aliphatic side chain. Amino acid conjugation is the most important route of detoxification, not only for many xenobiotic carboxylic acids but also for endogenous acids. It is known that amino acid conjugation of exogenous carboxylic acids occurs in a two–step process (Reilly et al., 2007). Amino acids conjugation of carboxylic acids is a special form of acetylation and leads to amide bond formation. The most common amino acid in such reactions is glycine, and its prototypical substrate is benzoic acid, more precisely its benzoyl–CoA cofactor (Fig. 8). Bile acids are also conjugated by a similar sequence of reactions involving a microsomal cholyl–CoA synthetase and a cytosolic enzyme bile acid–CoA: amino acid N–acyltransferase (Falany et al., 1994). In relation to xenobiotic carboxylic acids, amino acid conjugation involves enzymes located principally in the mitochondria of liver and kidney while conjugation of bile acids is extramitochondrial, involving enzymes located in the endoplasmic reticulum and peroxisomes (Reilly et al., 2007, Knights et al., 2007).
\n\t\t\t\tConjugation of a xenobiotic with amino acid, formation of hippuric acid.
Glycine and glutamate appear to be the most common acceptors of amino acids in mammals. In humans, more than 95% of bile acids are N–acyl amidates with glycine or taurine. Although products of amino acid conjugation are considered to be metabolically stable and nontoxic, it has been suggested that the first reaction of amino acid conjugation leads in some cases to formation of potentially toxic intermediates. This toxification pathway involves conjugation of N–hydroxy aromatic amines with the carboxylic acid group of serine and proline. Amino acid activated by aminoacyl–tRNA–synthetase (Fig. 9) subsequently reacts with an aromatic hydroxylamine to form N–ester that can degrade to produce a reactive nitrenium ion (Parkinson, 2001). In general, the toxicity of nitrenium ions is clinically relevant since these electrophiles possesing DNA–binding ability are responsible for carcinogenicity of aromatic amines.
\n\t\t\tConjugation of a xenobiotic with amino acid, formation of electrophilic nitrenium ion.
Xenobiotic biotransformation is a key mechanism for maintaining homeostasis during exposure to various xenobiotics, such as drugs, industrial chemicals, or food procarcinogens. In humans and other mammals, the liver is the major site of expression of xenobiotic–metabolising enzymes, but extrahepatically localized enzymes also appear to be of great importance. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Phase II of metabolism may or may not be preceded by Phase I reactions. Phase II enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Furthermore, they significantly contribute to maintaining of homeostasis by binding, transport or inactivation of biologically active compounds such as hormones, bile acids, or other mediators. In contrast to their beneficial effects, these enzymes also participate in formation of reactive intermediates of various compounds. The most–discussed example of toxification reactions is the conjugation of N–hydroxy aromatic amines. These compounds undergo activation to toxic metabolites by numerous reactions, including N–glucuronidation by UGTs, O–acetylation by NATs, O–sulfonation by SULTs, and conjugation with amino acids by aminoacyl–tRNA–synthetase. The newly formed reactive electrophilic nitrenium and carbonium ions can act as carcinogens and mutagens due to covalent binding to DNA or to other biomolecules. Genetic polymorphisms of Phase II enzymes is another noteworthy issue. Impaired metabolism of drugs due to genetically based dysfunction of competent enzymes may lead to manifestation of toxic effects of clinically used drugs. Moreover, it is evident that genetic polymorphisms in these enzymes are responsible for the developement of a number of neurological disorders or cancers. In conclusion, Phase II enzymes are an interesting research field since they play an essential role in the metabolism of hundreds of foreign compounds as well as in regulation of metabolism and disposition of various endogenous biologically active substances and thus maintaining homeostasis in the human body.
\n\t\tInfrastructural part of this project has been supported by CZ.1.05/2.1.00/01.0030 (Biomedreg).
\n\t\tAscites is a term used to describe the condition of accumulation of fluid in the peritoneal cavity. The word “ascites” could be used interchangeably with other terms such as abdominal dropsy, abdominal effusion, peritoneal fluid excess, hydroperitoneum and peritoneal cavity fluid. Ascites represents a form of general systemic state which could manifest in diverse disease conditions in animals. This implies that ascites is only a clinical manifestation of an underlying disease condition and not a disease in real sense. It further shows that ascites is not a treatable condition except the cause is properly diagnosed and treated accordingly. Ascites is often diagnosed in dogs between the ages of 5 and 7 years [1]. Cases between the ages of 1 and 4 years have also been recorded. The occurrence of ascites in dogs may be breed dependent with higher incidences in Pomeranian (33.35%) than in Labrador retriever (20%), Boxer (16.66%), Doberman pinscher (13.37%), mongrels (10%) and least in Alsatian (6.66%) [1]. Ascites manifests in several disease conditions such as hepatic disease, various types of neoplasm, portal hypertension, alteration in serum protein level (hypoproteinaemia), right-sided heart failure, decreased plasma oncotic pressure and increased permeability of capillary endothelium sequel to inflammatory conditions, bacterial infection (tuberculosis), kidney malfunction, pre-hepatic portal hypertension, post-hepatic portal hypertension, trauma (rupture of lymphatic vessels, blood vessels, urinary bladder),
ancylostomosis peritonitis, bleeding disorders and malnutrition [2, 3]. Other conditions may include heartworm infection and pulmonary stenosis [4]. In general, cardiac and hepatic disease conditions ranked highest as the cause of ascites in pets. Other manifesting signs which usually signify an underlying disease condition in ascetic pets may include syncope, vomiting, obtundation, seizure, anaemia which manifests as pale mucous membrane, weakness and rapid panting. The identification and diagnosis of the cause of ascites may not be a straightforward procedure and could be complicated due to the several causative factors. The veterinarian however has to be guided by the medical adage “if you hear the sound of hoof first look for a horse before a zebra”. This only means that diagnosis should start with the basis of thorough physical examination of the entire body and clinical examinations. A well and sequential conduction of physical and clinical examinations serves as a pointer to the underlying cause of ascites. However this may not always be so as diagnosis oftentimes is cumbersome. In such situations diagnosis would include a complete blood count which may reveal evidence of bacterial infection. Abdominal ultrasound/sonography is done to determine the abdominal content and aid in differentiating excess fluid accumulation from abdominal masses and organ enlargement. Knowledge of the blood biochemistry including total protein, albumin, creatinine and urea, liver enzymes and coagulation profile would help in revealing cases of hypoalbuminaemia, hypoproteinaemia and hepatic and kidney diseases [5]. Cardiac diseases may be diagnosed with the aid of electrocardiograph. Cardiac auscultation detects cases of cardiac murmurs and arrhythmia. Abdominal paracentesis is a useful procedure usually carried out to reduce the fluid level and alleviate complications of dyspnea. Paracentesis is a useful procedure in the management of ascites which is instituted in conjunction with appropriate treatment of the underlying cause. Once appropriate diagnosis is made, treatment usually comes easy by alleviating life-threatening conditions such as dyspnea and administering appropriate therapy as the case may be.
The purpose of this review is primarily focused on the various causes of ascites with emphasis on the hepatic origin. Based on this premise, ascites is classified broadly into hepatic, pre-hepatic and post-hepatic origin:
Pre-hepatic causes emanate from portal vein thrombosis, bacterial infection such as tuberculosis, malnutrition, hypoalbuminaemia and parasitic diseases such as strongyloidosis and entamoeba [6]. Other causes include trauma or rupture of the lymphatic vessels, blood vessels and urinary bladder, renal failure, lymphoma and neoplasm of various kinds including breast, bronchus, ovary, gastric, pancreatic or colonic neoplasms [7]. Up to 20% of neoplastic ascites arise from tumour of unknown origin [7].
Post-hepatic causes might include congestive heart failure often linked with pulmonary hypertension, left-sided heart failure, right-sided heart failure, constrictive pericarditis, Budd-Chiari syndrome and stricture web formation in the inferior vena cava [8, 9].
Hepatic origin emanates from various hepatic diseases including cirrhosis, portal hypertension and hepatitis. Approximately 85% of portal hypertension results in cirrhosis [8, 9, 10].
Earlier classification of ascites was centred on two broad categories, transudates and exudates, based on the total protein concentration of ascetic fluid. High total protein (>2.5 g/l) was described as exudates, while low total protein (<2.5 g/l) as transudate [11]. Both transudates and exudates were subcategorised into modified transudates and exudates based on the level of total protein concentration in the ascetic fluid. Transudates with <2.5 g/l of total protein usually occur with portal hypotension or hypoalbuminaemia [6]. Exudates with >2.5 g/l of total protein are associated with inflammatory disease conditions such as bacteria tuberculosis, neoplasm of unknown origin, pancreatitis, myxoedema, etc. Nevertheless, it has been observed that a total protein concentration of <2.5 g/l has an accuracy of only 56% [6] in detecting exudates from various conditions such as cardiac ascites and patients on diuretics and neoplasms [11]. The obvious challenge in the use of total protein concentration paved way to the discovery of serum ascites albumin gradient (SAAG) concentration as a more reliable tool in classification of ascites with efficacy ranging from 80 to 100% [11]. With the advent of SAAG, exudate ascites is replaced with (>1.1 g/l) high serum ascites albumin gradient and transudate with low (<1.1 g/l) serum ascites albumin gradient. The SAAG (>1.1 g/l) shows higher 94% sensitivity and 90% specificity in detecting portal hypertension than ascetic fluid total protein concentration of <2.5 g/dl at percentage sensitivity and specificity of 78 and 50%, respectively [12]. The prognostic index value of SAAG was at 82–97% compared to total protein concentration at 38–85% [12]. Ascites from cardiac origin produces greater(>2.5g/dl) SAAG compared to cases of cirrhosis [13].
A more recent classification of ascites has endorsed the use of serum ascites albumin gradient (SAAG) in diagnosis of ascites [14]. The SAAG is derived by subtracting the ascetic fluid albumin level from the serum albumin level obtained on the same day [14]. Gradients greater than 1.1 g/dl indicate ascites of portal hypertension with an accuracy of 97–100% [14]. Gradients less than 1.1 g/dl are considered ascites of other sources other than portal hypertension such as neoplasm [15, 16] (Table 1).
High gradient (>1.1 g/l) SAAG | Low gradient (<1.1 g/l) SAAG |
---|---|
Portal hypertension | Bacterial infection |
Cardiac diseases | Peritoneal tuberculosis |
Liver cirrhosis | Pancreatic ascites |
Myxoedema | Parasitic disease |
Budd-Chiari syndrome | Ancylostomosis |
Hepatitis | Nephrotic syndrome |
Portal vein thrombosis | Trauma and rupture of lymphatic and blood vessels |
Hypoalbuminaemia | Rupture of the urinary bladder, left-sided heart failure, right-sided heart failure, congestive heart failure |
Classification of ascites based on SAAG.
Ascites is one of the cardinal complications in liver cirrhosis in most patients [8]. Onset of ascites naturally connotes decompensated underlying liver cirrhosis which also signifies poor prognosis with short life expectancy [10, 17, 18]. Several factors contribute to the development of cirrhosis. The heart, for instance, plays an important role through a complex mechanism in the development of liver disease. The mechanism through which the heart and liver affect each other in the development of ascites is yet to be fully elucidated [14]. Several circulatory abnormalities observed in cirrhotic patients promulgated the peripheral arterial vasodilation hypothesis proposed in the last century [19]. The circulatory abnormalities manifest as increased cardiac output, portal hypertension, peripheral vascular resistance, arterial hypotension and splanchnic vasodilation [6, 20]. Circulatory abnormalities from cardiac disease affect circulatory volume with a resultant decrease in tissue perfusion affecting majorly the kidney functionality [21]. Earlier in the disease, renal dysfunction is less expressed; however, with disease advancement the patient may experience difficulty in sodium excretion and consequent sodium and water retention [22]. Cirrhotic ascites basically develop from failure in renal excretion of sodium [22]. Different mechanisms also play a role in ascites in cirrhosis. Intrinsic factors including arterial vasodilation affect the blood pressure hormones such as the renin-angiotensin-aldosterone system (RAAS) which stimulates sodium reabsorption from the distal nephron [22]. The sympathetic nervous system (SNS) induces renal constriction and sodium reabsorption from the tubules with ascites [23, 24]. The heart, SNS and RAAS play a synergistic role in sodium retention and development of ascites in cirrhosis.
The portal vein is a major vein comprising of a group of veins which supply the visceral organs including the abdomen, pancreas, intestine, etc. These veins bifurcate into smaller vessels in the hepatic tissue. Intrinsic factors and disease conditions such as cirrhosis result in blockage of these tiny veins in the hepatic tissue increasing the blood pressure in the veins with resultant portal hypertension. Other causes of portal hypotension include portal vein thrombosis, schistosomosis, idiopathy, etc. Ascites develops in portal hypertension when the post-sinusoidal gradient is above 12 mmHg [25]. Portal hypertension elevates the hydrostatic pressure within the hepatic sinusoids permitting seepage of transudate into the peritoneal cavity [26, 27]. The extent of ascites’ development is dependent on the level of hydrostatic pressure [28] and less on oncotic plasma albumin pressure [26, 29]. Signs and symptoms of portal hypertension include haematuria, dysentery, bloody vomitus due to spontaneous rupture and haemorrhage from varices, encephalopathy due to abnormal liver function and thrombocytopaenia. Factors such as abnormal increase in nitric oxide production and circulation of endogenous vasoconstriction such as catecholamines, leukotrienes and angiotensin II enhance hepatic vascular resistance and portal hypertension [30, 31].
One of the complications of activation of RAAS and SNS in cirrhosis is the resultant renal vasoconstriction leading to decrease in renal perfusion and glomerular filtrate rate which progresses to renal impairment [21, 22, 32, 33]. In hepatorenal syndrome, there are no significant morphological changes in renal histology, while the patients largely retain normal tubular function [5, 21]. The kidney analyte and serum creatinine concentration does not increase until the glomerular filtration rate becomes markedly reduced below 40 ml/min [22]. Most patients with cirrhosis have their creatinine level below 1.2 mg/dl, and diagnosis of HRS is only made when the creatinine concentration is higher than 1.5 mg/dl in the absence of other complicating aetiologies [22]. Hepatorenal syndrome manifests in two different types in cirrhotic patients. Type I HRS is a fulminating form of the disease rapidly progressing to acute renal failure often precipitated by variceal bleeding, septic infection and spontaneous bacteria peritonitis with poor prognosis of days to weeks [22]. Type 2 is a more chronic form of HRS. Most patients with this form of disease have a more stable creatinine concentration with only signs of refractory ascites due to unresponsive diuretics [34, 35].
With advancement in cirrhosis, there is also progressive increase in sodium and water reabsorption and decrease in renal blood flow and glomerular filtration [36]. Approximately 20% of cirrhotic patients with refractory ascites progress to HRS which results from severe liver and systemic circulatory dysfunction [28]. Hepatorenal syndrome results from marked overactivity of RAAS, SNS, AND and other endogenous vasoconstrictor factors which exceeds renal production of vasodilatory substances [PGE2, prostacyclin, nitric oxide]. The imbalance from renal vasodilatory mechanism and the intrinsic vasoconstrictor enhances vasoconstriction and hypoperfusion and decreases GFR with ultimate result of renal failure [22].
Usually there is no laid down procedure on the steps to diagnose ascites; however a systematic approach applied in various disease conditions is advantageous in making appropriate diagnosis. A step-by-step approach normally starts with physical examination.
In physical examination, the patient is examined for the presence of ticks and fleas which would contribute in physical discomfort of the pet. Ticks’ infestation contributes in depletion of blood volume and anaemia. Anaemia is detected by the appearance of pale mucous membrane of the eye and the gum. Ectoparasitism from ticks’ infestation may result in malnutrition due to competition with the host for essential nutrients necessary for the synthesis of protein and albumin. This could result in hypoalbuminaemia/hypoproteinaemia and a decrease in plasma oncotic pressure enhancing vascular permeability and seepage of fluid in the abdominal cavity. A distended or pulsating jugular vein in the neck region may indicate cardiovascular abnormality. Yellowish discoloration of the eye indicates jaundice and hepatic disease. Generalised lymphadenopathy may suggest lymphosarcoma and other inflammatory disease conditions. A “standback” observation reveals cases of dyspnea due to abdominal displacement of the diaphragm into the thoracic cavity compromising respiration. Respiratory distress could manifest in the form of rapid panting. Such condition presents a deviation from the normal respiratory pattern, from coastal to costo-abdominal or abdominal pattern. Black tarry-coloured faeces from gastrointestinal bleeding may signify ancylostomosis and portal hypertension. Physical examination of the trunk reveals a distended abdomen. The content of the abdomen could either be by pregnancy, abdominal masses, fluid of various consistencies or organ enlargement. The diagnosis of ascites starts from differentiating these possibilities through various procedures. First is to carry out abdominal ballottement using clinched fist. This technique can be used to differentiate abdominal masses from fluid. It can be used with other laboratory tests such as pregnancy test to rule out pregnancy. It however has some limitations in differentiating abdominal masses from organ enlargement. Abdominal ultrasound is a better option in differentiating abdominal contents. It has been proven effective in the detection of ascetic fluid, its site of production and differentiation of ascetic nature from transudates and exudates [11]. A recent research has shown the possibility of the use of echotexture of ascetic fluid in the detection of the cause of ascites in patients [11]. Abdominal paracentesis however is a very useful technique in differentiation of ascetic fluid [28].
A well-applied paracentesis without contamination of abdominal content is essential in differentiation of ascetic fluid. To achieve this, the following steps should be strictly applied:
First apply caution by the use of proper restrain technique on the dog.
Gently place the dog on a lateral decumbency exposing the larger part of the ventral abdomen.
Swab the ventral abdomen less covered with haircoat, along the linea alba down to the ventral abdomen between the left and right hindlimbs. (Linea alba is the preferred site of paracentesis due to its less vascularisation and less chance of contamination of the fluid with blood from puncture vessels and abdominal organs when approached through a different site on the abdomen.)
Puncture the linea alba using a 21 gauge needle and 10 mL gauge syringe, and aspirate the fluid.
Decant the content of the syringe into a clean and well-labelled tube for laboratory investigation.
Request for cytology of the fluid (Figure 1).
Removal of ascites through the linea alba in an Alsatian breed of dog.
The colour of ascetic fluid is a very essential marker in the diagnosis of the cause of ascites. The colour ranges from clear fluid to yellowish, reddish and opaque with flakes of fibrin and debris depending on the aetiology. It is therefore important to observe the above guidelines in paracentesis in order to avoid false discolouration of the fluid, thus affecting correct diagnosis. Various colours of ascetic fluid signify a different aetiology as shown below [37]:
Pinkish discolouration of the fluid: This is often seen in cases of exudation of fluid from bacterial infection which may become purulent. The exudates are often turbid in consistency and contains more than 2.0 gm of protein and greater than 6000 cells/μL composed mostly of neutrophils with evidence of +++ bacterial infection. This type of fluid is considered a medical emergency to prevent development of sepsis.
Clear straw-coloured fluid: This type of fluid is described as modified transudate often characterised by the presence of fibrin cells and white blood cells such as neutrophils and lymphocytes. It is often seen in cases of long-standing ascites from various conditions including right-sided heart failure, cancerous growth and hepatic disease giving chance to invasion of fibrinogens.
Clear opaque fluid: This fluid is described as collection of pure transudate into the peritoneal cavity free from contamination except with few invasions of mesothelial cells and tissue macrophages. This ascites may be seen in cases of portal hypertension, hepatic diseases, osmotic gradient deficit (hypoalbuminaemia), protein losing enteropathy, kidney impairment and albuminuria.
Reddish discolouration of fluid: This is seen in cases of haemorrhages and collection of frank blood in the peritoneal cavity due to conditions of trauma, coagulopathies and blood and blood vessel neoplasm. The fluid contains high levels of cells mainly red blood cells with PCV being above 20%.
Greenish discolouration of fluid: This is seen in cases of rupture and seepage of bile into the peritoneal cavity.
Milky/slightly yellowish discolouration: This describes a condition of collection of lymph in the peritoneal cavity due to trauma, infection, cancer or right-sided heart failure. This type of exudates is turbid and opaque and is often described as chyle. It gives a positive result in Sudan III stain test for lipids due to the high level of lipid in the fluid.
Clinical examination is considered a useful tool in the identification of the cause of ascites. An elevated temperature would signify an underlying infectious or inflammatory condition such as bacterial tuberculosis. An elevated capillary refill time would signify a decreased circulatory volume as a result of cancerous or infectious condition. Auscultation of the heat reveals various cardiovascular diseases such as muffled heart sound which is consistent with pericardial effusion and cardiac tamponade. Heart murmurs or irregular heartbeats are suggestive of right-sided heart failure. An elevated heartbeat or tachypnoea may result from dyspnea due to cranial displacement of the diaphragm into the thoracic cavity. Cardiovascular abnormalities are confirmed through the use of electrocardiograph and echocardiography.
The determination of biochemical profile such as the liver enzymes, total protein level, SAAG, albumin concentration, total bilirubin and kidney analytes such as creatinine and urea levels is useful in the diagnosis of the cause of ascites.
Serum ascites albumin gradient is presently the best tool in diagnosis of the cause of ascites especially that from portal hypertension [38]. A SAAG value of <1.1 g/dl or 11 g/l indicates causes of non-portal origin such as malignancy, etc. [5]. Gradients >1.1 g/dl or 11 g/l indicate ascites of portal hypertension.
Although the traditional classification of ascites according to the transudate and exudate concept has almost phased out following the introduction of SAAG, it however still has relevance in clinical practice for comparison and prognostic value. Concentrations below 15 g/l are often associated with risk of spontaneous bacteria peritonitis in cirrhosis [5, 39].
An elevated triglyceride concentration in ascetic fluid above 2.2 mmol/l indicates chylous ascites [38]. Chylous ascites is common in neoplastic cases although it may occur in 6% of cirrhosis [40].
Elevated levels in urea and creatinine concentrations in ascetic fluid indicate prerenal failure due to peritoneal absorption of urea [41]. Urinary ascites is often associated with bladder changes and urethra obstruction [41, 42].
Cytology of ascetic fluid is often indicated in suspected malignancy and idiopathic cases. Positive cytology is highly indicated in suspected cases of peritoneal carcinomatosis. The sensitivity of cytology can be enhanced by examination of three samples from separate paracenteses [38]. The sensitivity is also enhanced by prompt analysis of ascetic fluid and obtaining large volume of up to 50–1000 ml in patients with initial negative result.
Diagnostic laparotomy is indicated in cases of difficulty in identification of the aetiology of ascites. Often laparotomy presents adequate visual inspection of the peritoneal cavity and avenue for biopsy collection for histological and microbiological studies [38]. Diagnostic laparotomy provides ground for effective diagnosis of peritoneal carcinomatosis, tuberculous peritonitis, etc. [43, 44].
Several studies have shown the usefulness in the use of leucocyte esterase reagent strip in diagnosing spontaneous bacteria peritonitis and in urinary analysis with sensitivity ranging from 80 to 93% and specificity 93–98% [45]. The negative predictive value is markedly high from 97 to 99%, a good measure for an ideal tool to rule out SBP [45]. Recent development has discovered an ascite-specific reagent strip with a cut-off value of 250 cells/mm3 which would further enhance diagnostic accuracy [46].
Increased platelet indices such as mean platelet volume and platelet distribution width have been observed to increase in cirrhosis. The usefulness of the platelet indices is yet to be fully elucidated but has shown propensity as a potential diagnostic tool [47].
The use of tumour markers such as alpha - feto protein, des-gamma-carboxy prothrombin, cancer antigen 125, etc. in the diagnosis of cancer in ascetic fluid is presently a subject of controversy among several researchers. Although the increased level of these markers is associated with underlying malignancies, elevated levels are also observed in other conditions such as pancreatitis, gastritis, etc. [48].
Radiographical imaging is useful in detailing small amounts of ascetic fluid as well as diagnosis of aetiology of ascites [49]. Abdominal ultrasonography can detect as little as 100 ml of intraperitoneal fluid [50]. The sensitivity of radiography is enhanced through the use of computed tomography which detects minute quantities of ascetic fluid. Radiography enhances the picture of internal organs and aids in detection of cirrhosis, intra-abdominal tumour and organ enlargements. Thickening of mesentery and bowel wall, matting of bowel loops and enlargement of mesenteric lymph nodes may provide a guide in the diagnosis of tuberculosis peritonitis in affected patients. A contrast computed tomography (CT) may be used to demonstrate enhancement of peritoneal lining. Cases of cirrhosis and large hydrothorax can be diagnosed with the aid of scintigraphy with technetium sulphur colloid or radiolabelled albumin [6].
Spontaneous bacterial peritonitis may arise due to decreased level of compliments which serve as antibacterial factors in ascetic fluid. Suspected cases of SBP are cultured in both aerobic and anaerobic blood media for isolation of organisms [51]. Cultured ascetic fluid should be subjected to sensitivity test to identify effective antimicrobiological agent in treatment.
The DNA of Mycobacterium tuberculosis in ascetic fluid can be detected using polymerase chain reaction in suspected cases. PCR for Mycobacterium tuberculosis offers a high sensitivity (94%) test compared to microscopic acid-fast bacilli smear (−0%) and mycobacterial culture (−50) [38].
Ascites is treated symptomatically while addressing the primary cause of the condition. Efforts are geared towards relieving manifesting symptoms and preventing progression of ascites. The main goal in congestive heart failure is to improve cardiac contractility, normalise cardiac arrhythmias and enhance cardiac output. Cardiac drugs such as dopamine and digoxin can be used at recommended dosages in cases of congestive heart failure in dogs. Dogs with right-sided heart failure should be placed on cage rest and on sodium-restricted diet [52]. Paracentesis is applied to relieve abdominal tension on the diaphragm and enhance normal respiration. Repeated paracentesis is not required except in cases of failing treatment [52]. Paracentesis should not exceed 1.0 kg weight per day for dogs with both ascites and peripheral oedema and less than 0.5 kg weight per day for patients with only ascites. Serum albumin sometimes is depleted during paracentesis and therefore should be monitored and replaced intravenously in case of depletion at the same quantity of fluid removed. The administration of albumin dosed at 1.5 g/kg on the first day and 1.0 g/kg on the third day ensured renal preservation and reduced mortality [53]. In cases of syncope, a balanced isotonic crystalloid fluid replacement such as Plasma-Lyte A, Normosol R and 0.9% saline may be used in resuscitation and other conditions such as hypernatraemia, hyponatraemia, hypercalcemia, metabolic alkalosis or oliguria renal failure. Diuretics are used in addition to paracentesis to relieve ascites. Diuretics may be dosed once daily. Spironolactone has a half life of 24 hours and is given at the dose of 100 mg/day max 400 mg/day for response [54]. The dose may be spread out every 2 hours stat in dogs under hospitalisation and close monitoring at 2 mg/kg × im and at 3 mg/kg × per os at night. Spironolactone could be substituted with either triamterene or amiloride since both drugs have good antagonistic effect on aldosterone action on the collecting tubules [55]. Furosemide is often the first line of treatment in cases of ascites with a half life of 1.5 hours and given at the dose of 40 mg/day and max 160 mg/ day in case of nonresponders to furosemide [39]. The dose may also be spread in divided doses of 3 mg/kg × IV every 2 hours and at 4 mg/kg per os at night. Bumetanide and spironolactone could be used in combination with furosemide at the ratio of 100:40 to reduce chances of furosemide resistance. The dose ratio ensures efficient natriuresis and flow of water and also reduces the risk of potassium deficit from the use of furosemide [39, 56]. Other diuretics such as torsemide and bumetanide have shown better efficacy than most diuretics [57]. Torsemide has a longer half life than both furosemide and bumetanide [57]. Patient with cirrhotic ascites often presents with complications of SBP, portal hypertension and HRS [28]. Cases without such complications are described as “uncomplicated ascites” [58]. The standard treatment for SBP in humans involves immediate administration of third-generation cephalosporin such as intravenous ceftriaxone 1 to 2 g daily for 5 days [52]. The dose could be given at 1 g daily in dogs. The use of oral fluoroquinolones is equally effective in the treatment of SBP [59, 60]; alternatively piperacillin and tazobactam could be considered [61]. The choice of antibacterial agent depends on culture and sensitivity test to reduce problems of drug resistance. Antibiotic treatment is usually given for an extended period to ensure complete cure of the bacterial infection.
Portal hypertension is managed by the use of antihypertensive medications. A drug such as metolazone (Mykron, Zaroxolyn) aids in the elimination of oedema in congestive heart failure. It enhances sodium excretion by inhibition of sodium reabsorption from the distil tubules, a function which is beneficial in renal conditions [55]. Mannitol (Osmitrol) inhibits tubular reabsorption of electrolyte by increasing the osmotic pressure of glomerular filtrate and urine output [55]. Cases of recurrent ascites in humans from portal hypertension may require the use of TIPS [28]. TIPS functions as a side-to-side portacaval anastomosis between the high portal pressure end and low hepatic vein pressure end, thereby effectively decongesting the portal system which may be useful in pets. A reduction in the portal hypertension brings a secondary decrease in RAAS activation and consequent increase in sodium excretion [62]. Persistent ascites from cirrhosis may be managed through liver transplant and removal of the damaged liver. The hepatic cells naturally possess high regenerative capacity and can regenerate after undergoing severe degenerative condition. The hepatocytes in addition can perform at full capacity even with few viable cells, and therefore liver transplant is only required as a last resort after application of all remedial medications.
Renal failure is managed by controlling blood pressure with drugs; avoid the use of hepatotoxic medications in treatment of ascites and the use of non-steroidal anti-inflammatory agents (NSAIDs) such as acetaminophen. Kidney dialysis is recommended in severe kidney damage. A continuous venovenous haemodialysis (CVVHD) is recommended compared to intermittent renal dialysis.
Cases of complications of encephalopathies from hepatic failure are best managed in intensive care units (ICU) [18]. Cases of early complication of encephalopathy may be treated as outpatient; nevertheless such a patient is closely monitored for further deterioration to grade II encephalopathy which would require prompt transfer to an intensive care unit. Such a patient is placed on routine check on mental balance, and signs of restlessness could be slightly sedated with low dose of short-acting benzodiazepines. Patients under sedation are placed on undisturbed bed rest avoiding extensive movement which may enhance chances of intracranial pressure/hypertension. Dyspnea is prevented in late encephalopathy through placement of intratracheal intubation to avoid further complications of aspiration pneumonia. The conditions of cerebral oedema and intracranial hypertension manifest at the late phase of encephalopathy and are prevented through routine checks on the patient’s renal parameters; biochemical profile including liver enzymes, total protein, glucose, electrolytes and acid/balance; and neurological evaluations for signs of elevated levels [4]. Cases of severe bleeding result from problems of coagulopathies which can be treated by addressing the coagulopathy through transfusion of coagulation products such as fresh frozen plasma and platelets and administration of vitamin K. Severe conditions may be boosted by transfusion of packed red blood cells. Continuous bleeding after massive replacement infusions may indicate possible retroperitoneal bleeding [18]. A good number of herbal and antioxidant medications have shown to be beneficial in the treatment of ascites of hepatic origin. The use of these drugs remains controversial, but despite this the drug N-acetylcysteine and Silybum marianum still remain the drug of choice in the treatment of hepatic damage from acetaminophen toxicity and hepatic dysfunction, respectively [63].
Conclusion: Ascites is a disease condition commonly seen in pets of various age brackets with high incidences occurring in middle-aged dogs. Ascites is a common manifestation of a decompensate cirrhosis, cardiac diseases and several other aetiologies and is best diagnosed through established standard procedures of physical and clinical examinations, complete blood picture, cytology and various biochemical analyses. Recent novel techniques such as platelet indices, leucocyte esterase reagent strip, tumour markers, bacterial DNA, cytokines and other proteins are available for the advancement of biochemical laboratory techniques and efficient diagnosis of ascites. Treatment is centred on effective diagnosis of the aetiology.
I sincerely acknowledge the God Almighty for His enablement bestowed upon me during the course of this write-up.
difficulty in breathing degenerative condition in the brain obstruction of the bile duct red blood cell destruction study of both the stomach and intestines study of the blood study of the nervous tissues accumulation of fluid in the abdominal cavity accumulation of fluid in the abdominal cavity irregular heartbeat closure or blockage especially to stop bleeding problem with blood clotting mechanism reversibly combined with a compound compound in its natural form not transparent, cloudy, filmy the cause of a disease condition area supplied with blood vessels fluid produced from increased pressure in the hepatic, portal vein (>8 mmHg) usually around 20 mmHg, low in protein (<30 g/L), low in LDH, high pH, normal glucose and fewer cells fluid actively secreted from inflammation or malignancy, rich in protein, lactate dehydrogenase, low pH (<7.30), low glucose level and large numbers of white blood cells pertains to the kidney condition that affects both the liver and kidney active compound in milk thistle herbal preparation a poisonous species of mushroom unknown origin
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\n\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\n\nIn other words, publishing with IntechOpen guarantees compliance.
\n\nRead more about Open Access in Horizon 2020 here.
\n\nWhich scientific publication to choose?
\n\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\n\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\n\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
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