Majumdar, A

Tsochatzis, E

PubMed

UCL Discovery

© 2016 Hellenic Society of Gastroenterology www.annalsgastro.grAnnals of Gastroenterology (2016) 29, 1-2E D I T O R I A LBiomarkers of bacterial translocation in advanced chronic liver disease: the key to individualizing prognosisAvik Majumdar, Emmanuel TsochatzisRoyal Free Hospital, London, UKTh e management of patients with liver cirrhosis has evolved signifi cantly in the past decade. No longer considered as having an invariably poor outcome, the need for better risk stratifi cation and prognostic models for this patient group has become increasingly apparent [1-3]. Th e defi nition and use of the term “cirrhosis” per se is also under scrutiny, with the recent Baveno VI consensus guidelines suggesting that the term “advanced chronic liver disease” (ACLD) should be used interchangeably [4]. Th is highlights the ongoing paradigm shift  where advanced fi brosis and cirrhosis are perceived as two oft en clinically indistinguishable points on the same spectrum, with both attributing the risk of developing complications of chronic liver disease.Portal hypertension has long been recognized as the main pathophysiological process governing the prognosis of patients with ACLD. However, the development of clinical signs of portal hypertension is an event already too late in the clinical trajectory of patients. Th is is illustrated by the substantial increase in the 1-year mortality of patients from 3.4% to 20% for stage 2 and stage 3 ACLD respectively, with the distinction between these stages being the development of ascites [5,6]. Earlier identifi cation of those at risk of disease progression is therefore urgently needed.Th e importance of bacterial translocation as an underlying mechanism for the clinical consequences of ACLD is being increasingly recognized. Th e migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes or other non-intestinal sites is a controlled physiological process in healthy individuals. However, this process becomes progressively deregulated in the presence of advancing chronic liver disease and culminates in pathological bacterial translocation (PBT), which in turn results in infl ammation, immune activation and eventual clinical sequelae such as spontaneous bacteremia and spontaneous bacterial peritonitis [7]. Once infection develops in patients with ACLD, their 1-year mortality increases four-fold [8,9]. Furthermore, the altered infl ammatory response to bacterially derived products has been implicated in the development of hepatic encephalopathy, hepatorenal syndrome and advancing portal hypertension [7,10].However, no reliable measure of PBT currently exists in the cirrhotic population, nor is a quantifi able threshold defi ned where bacterial translocation becomes pathologic [7,11,12]. Peripheral blood levels of bacterial DNA and endotoxin levels have traditionally been used as markers of PBT and have been correlated with severity of liver disease, as measured by Child-Pugh score. However, the correlation with the degree of portal hypertension has been less robust. Th is suggests that an alternative mechanism associated with immune activation may underlie the pathogenic process of translocation of bacterial products, as opposed to viable bacteria [13-15]. A  better understanding of the complex interactions between luminal bacteria, the innate mucosal defence system and downstream immune and infl ammatory responses are required.In this issue of Annals of Gastroenterology, Kaltsa et al investigate the role of human beta defensin-1 (hBD-1), an intestinal mucosal antimicrobial peptide, as a surrogate marker of pathological bacterial translocation using the pattern-recognition receptor, soluble CD14 (sCD14), as a reference  [16]. sCD14 is expressed primarily by monocytes and binds bacterial lipopolysaccharide (LPS) in the presence of LPS binding protein (LBP). Elevated concentrations of sCD14 have been previously demonstrated in patients with cirrhosis, but have not been widely validated as a marker of PBT [17,18].In this study, the systemic expression of hBD-1 expression was investigated via peripheral vein sampling with a subset of patients undergoing hepatic vein sampling. Real-time PCR of the DEFB1 gene (which encodes hBD-1) and other antimicrobial peptide genes from terminal ileal and colonic biopsies were obtained. Th ree cohorts of patients were compared; cirrhosis, non-cirrhotic chronic viral hepatitis and healthy controls who were age- and gender-matched. Th e cirrhosis group comprised 51  patients of various etiologies and was defi ned by the presence of clinical decompensation, or in the four patients who had compensated disease, either a consistent liver biopsy or a liver stiff ness measurement of greater than 12kPa. In contrast, where biopsies were available for the chronic viral hepatitis group, patients had minimal liver fi brosis (Ishak Stage 0-1).Kaltsa et al found higher plasma concentrations of hBD-1 in cirrhotic patients compared to both other groups, a diff erence that was sustained when cirrhotic viral hepatitis patients were compared to non-cirrhotic viral hepatitis patients. Levels of sCD14 signifi cantly correlated with hBD-1 in the hepatic venous blood of cirrhotic patients resulting in a Spearman r of 0.6 (P=0.0045) but not in the peripheral blood (P=0.0528); however this could be due to a type  II error. Interestingly, LBP correlated well with sCD14 in peripheral blood (r=0.5, Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UKConfl ict of Interest: NoneCorrespondence to: Dr Avik Majumdar, Royal Free Hospital, Pond St, London NW3 2QG, United Kingdom, Tel.: +44 7941638842, e-mail: avik.majumdar@nhs.netReceived 13 August 2015; accepted 17 August 20152 A. Majumdar and E. TsochatzisAnnals of Gastroenterology 29 P=0.0021), however this was in an undefi ned subset of cirrhotic patients. Conversely, there was no increased mucosal expression of antimicrobial peptide genes, including DEFB1, in the cirrhotic group compared with healthy controls. Th is could be due to a number of confounding issues such as variable intestinal sites of expression of hBD-1 or extraintestinal expression, as has been described in monocytes and platelets.Although the study by Kaltsa et al has a number of limitations, including the non-robust defi nitions of study cohorts, the lack of consistency of tests performed amongst all recruited patients and the heterogeneous group of cirrhotic patients with an under-representation of non-alcoholic fatty liver disease, the authors should be commended in aiming to identify a much needed surrogate of PBT. Th e pursuit of an endogenous antimicrobial peptide expressed in plasma is a valid concept. However, the strength of association of hBD-1 expression with PBT is hard to justify without bacterial DNA levels. Th e absence of a defi ned reference standard for PBT in patients with ACLD is a major challenge, however, measuring bacterial DNA appears to be the best available at present. Future research could include correlating hBD-1 levels with hepatic venous pressure gradient, infl ammatory cytokines and hard clinical endpoints including decompensation and mortality.Th e potential applications for a reproducible and reliable peripheral biomarker of PBT in ACLD are immense. Similar to the advent of non-invasive markers for pre-cirrhotic fi brosis, the early identifi cation of those who are at risk of developing complications of advanced chronic liver disease will allow better risk-stratifi cation and earlier treatment, which ideally will translate to better clinical outcomes. Finding these elusive biomarkers of PBT may just be the key to unlocking a new era in the management of patients with chronic liver disease.References1. Tsochatzis EA, Bosch J, Burroughs AK. New therapeutic paradigm for patients with cirrhosis. Hepatology 2012;56:1983-1992.2. Rosselli M, MacNaughtan J, Jalan R, Pinzani M. Beyond scoring: a modern interpretation of disease progression in chronic liver disease. Gut 2013;62:1234-1241.3. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet 2014;383:1749-1761.4. de Franchis R. Expanding consensus in portal hypertension. Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J  Hepatol 2015;63:743 752.5. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217-231.6. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classifi cation of cirrhosis. Hepatology 2010;51:1445-1449.7. Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014;60:197-209.8. Arvaniti V, D’Amico G, Fede G, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139:1246-1256, 56 e1-e5.9. Jalan R, Fernandez J, Wiest R, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014;60:1310-1324.10. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513-1524.11. Vlachogiannakos J, Daikos G, Th alheimer U, Burroughs AK, Ladas SD. Is bacterial DNA a better marker than endotoxin of bacterial translocation in decompensated cirrhosis? Hepatology 2011;53:2140-2141; author reply 41-42.12. Such J, Frances R, Munoz C, et al. Detection and identifi cation of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 2002;36:135-141.13. Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 1988;8:232-236.14. Trebicka J, Krag A, Gansweid S, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. Eur J Gastroenterol Hepatol 2011;23:1218-1225.15. Mortensen C, Karlsen S, Grønbaek H, et al. No diff erence in portal and hepatic venous bacterial DNA in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt insertion. Liver Int 2013;33:1309-1315.16. Kaltsa G, Bamias G, Siakavellas S, et al. Systemic levels of human β-defensin 1 are elevated in patients with cirrhosis. Ann Gastroenterol 2016;29:63-70.17. Ogawa Y, Imajo K, Yoneda M, et al. Soluble CD14 levels refl ect liver infl ammation in patients with nonalcoholic steatohepatitis. PLoS One 2013;8:e65211.18. Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011;141:1220-1230, e1-e3.

Biomarkers of bacterial translocation in advanced chronic liver disease: the key to individualizing prognosis.

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Biomarkers of bacterial translocation in advanced chronic liver disease: the key to individualizing prognosis.

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