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      Plasma and urine biomarkers in acute viral hepatitis E

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          Abstract

          Background

          Hepatitis E, caused by the hepatitis E virus (HEV), is endemic to developing countries where it manifests as waterborne outbreaks and sporadic cases. Though generally self-limited with a low mortality rate, some cases progress to fulminant hepatic failure (FHF) with high mortality. With no identified predictive or diagnostic markers, the events leading to disease exacerbation are not known. Our aim is to use proteomic tools to identify biomarkers of acute and fulminant hepatitis E.

          Results

          We analyzed proteins in the plasma and urine of hepatitis E patients and healthy controls by two-dimensional Differential Imaging Gel Electrophoresis (DIGE) and mass spectrometry, and identified over 30 proteins to be differentially expressed during acute hepatitis E. The levels of one plasma protein, transthyretin, and one urine protein, alpha-1-microglobulin (α1m), were then quantitated by enzyme immunoassay (EIA) in clinical samples from a larger group of patients and controls. The results showed decreased plasma transthyretin levels (p < 0.005) and increased urine α1m levels (p < 0.001) in acute hepatitis E patients, compared to healthy controls. Preliminary results also showed lower urine zinc alpha glycoprotein levels in fulminant hepatitis E compared to acute disease; this remains to be confirmed with more fulminant cases.

          Conclusion

          Our results demonstrate the utility of characterizing plasma and urine proteomes for signatures of the host response to HEV infection. We predict that plasma transthyretin and urine α1m could be reliable biomarkers of acute hepatitis E. Besides the utility of this approach to biomarker discovery, proteome-level changes in human biofluids would also guide towards a better understanding of host-virus interaction and disease.

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          Most cited references 41

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          Alpha-1-acid glycoprotein.

          Alpha-1-acid glycoprotein (AGP) or orosomucoid (ORM) is a 41-43-kDa glycoprotein with a pI of 2.8-3.8. The peptide moiety is a single chain of 183 amino acids (human) or 187 amino acids (rat) with two and one disulfide bridges in humans and rats,respectively. The carbohydrate content represents 45% of the molecular weight attached in the form of five to six highly sialylated complex-type-N-linked glycans. AGP is one of the major acute phase proteins in humans, rats, mice and other species. As most acute phase proteins, its serum concentration increases in response to systemic tissue injury, inflammation or infection, and these changes in serum protein concentrations have been correlated with increases in hepatic synthesis. Expression of the AGP gene is controlled by a combination of the major regulatory mediators, i.e. glucocorticoids and a cytokine network involving mainly interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF alpha), interleukin-6 and IL-6 related cytokines. It is now well established that the acute phase response may take place in extra-hepatic cell types, and may be regulated by inflammatory mediators as observed in hepatocytes. The biological function of AGP remains unknown; however,a number of activities of possible physiological significance, such as various immunomodulating effects, have been described. AGP also has the ability to bind and to carry numerous basic and neutral lipophilic drugs from endogenous (steroid hormones) and exogenous origin; one to seven binding sites have been described. AGP can also bind acidic drugs such as phenobarbital. The immunomodulatory as well as the binding activities of AGP have been shown to be mostly dependent on carbohydrate composition. Finally, the use of AGP transgenic animals enabled to address in vivo, functionality of responsive elements and tissue specificity, as well as the effects of drugs that bind to AGP and will be an useful tool to determine the physiological role of AGP.
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            Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection.

            Hepatitis E virus (HEV) infection is known to cause severe liver disease in pregnant women. It is unclear whether obstetric and fetal outcomes are worse in pregnant women with HEV infection than in women with other forms of viral hepatitis. To compare maternal, obstetric, and fetal outcomes in pregnant women with acute viral hepatitis caused by HEV and other hepatitis viruses. Observational cohort. Tertiary care hospital, New Delhi, India. 220 consecutive pregnant women presenting with jaundice caused by acute viral hepatitis. Maternal mortality and medical complications, obstetric complications, deliveries, and fetal outcomes. Infection with HEV caused acute viral hepatitis in 60% of included women. Fulminant hepatic failure was more common (relative risk, 2.7 [95% CI, 1.7 to 4.2]; P = 0.001) and maternal mortality was greater (relative risk, 6.0 [CI, 2.7 to 13.3]; P < 0.001) in HEV-infected women than in non-HEV-infected women. Women with HEV infection were more likely than those with other forms of viral hepatitis to have obstetric complications (relative risk, 4.1 [CI, 1.7 to 10.2] for antepartum hemorrhage and 1.9 [CI, 1.3 to 2.7] for intrauterine fetal death; P < 0.001 for both) and poor fetal outcomes (relative risk, 1.2 [CI, 1.0 to 1.4] for preterm delivery [P = 0.005] and 1.8 [CI, 1.2 to 2.5] for stillbirth [P = 0.026]). The findings may not apply to community settings, to women who are asymptomatic or have only minor symptoms, or in the setting of an HEV epidemic. Pregnant women with jaundice and acute viral hepatitis caused by HEV infection had a higher maternal mortality rate and worse obstetric and fetal outcomes than did pregnant women with jaundice and acute viral hepatitis caused by other types of viral hepatitis.
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              Hemopexin: structure, function, and regulation.

              Hemopexin (HPX) is the plasma protein with the highest binding affinity to heme among known proteins. It is mainly expressed in liver, and belongs to acute phase reactants, the synthesis of which is induced after inflammation. Heme is potentially highly toxic because of its ability to intercalate into lipid membrane and to produce hydroxyl radicals. The binding strength between heme and HPX, and the presence of a specific heme-HPX receptor able to catabolize the complex and to induce intracellular antioxidant activities, suggest that hemopexin is the major vehicle for the transportation of heme in the plasma, thus preventing heme-mediated oxidative stress and heme-bound iron loss. In this review, we discuss the experimental data that support this view and show that the most important physiological role of HPX is to act as an antioxidant after blood heme overload, rather than to participate in iron metabolism. Particular attention is also put on the structure of the protein and on its regulation during the acute phase reaction.
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                Author and article information

                Journal
                Proteome Sci
                Proteome Science
                BioMed Central
                1477-5956
                2009
                27 October 2009
                : 7
                : 39
                Affiliations
                [1 ]Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi - 110067, India
                [2 ]The Centre for genomic Applications, Okhla Industrial Area (Phase III), New Delhi - 110020, India
                [3 ]Department of Gastroenterology, Army Hospital, Delhi Cantonment, New Delhi - 110010, India
                [4 ]Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute for Medical Sciences, Rae Bareilly Road, Lucknow - 226014, India
                Article
                1477-5956-7-39
                10.1186/1477-5956-7-39
                2773234
                19860894
                Copyright © 2009 Taneja et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research

                Molecular biology

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