V. Monti

The systemic inflammatory response syndrome in cirrhotic patients: Relationship with their in-hospital outcome ☆

BACKGROUND/AIMS Some evidence suggests that the systemic inflammatory response syndrome (SIRS) contributes to the poor outcome of cirrhotic patients. We studied 141 cirrhotic patients consecutively admitted to a tertiary referral centre assessing prevalence of SIRS and its relationship with in-hospital outcome. METHODS Presence of SIRS was assessed on admission and during hospital stay. Main clinical outcomes were death and development of portal hypertension-related complications. RESULTS Thirty-nine patients met SIRS criteria. SIRS was present on admission in 20 of 141 patients (14.1%), whereas it occurred during hospital stay in 19 of 121 (15.7%). SIRS was correlated with bacterial infection at admission (p=0.02), jaundice (p=0.011), high serum creatinine levels (p=0.04), high serum bilirubin levels (p=0.002), high international normalized ratio (p=0.046), high model of end-stage liver disease (MELD) score (p=0.001), and high SOFA score (p=0.003). During a follow-up of 14+/-8 days, 16 patients died (11%), 7 developed portal hypertension-related bleeding (5%), 16 hepatic encephalopathy (11%), and 5 hepatorenal syndrome type-1 (3.5%). SIRS was correlated both to death (p<0.001) and to portal hypertension-related complications (p<0.001). On multivariate analysis, SIRS and MELD were independently associated with death. CONCLUSIONS SIRS frequently occurs in patients with advanced cirrhosis and is associated with a poor outcome.

Proliferating cell nuclear antigen assessed by a computer-assisted image analysis system in patients with chronic viral hepatitis and cirrhosis

BACKGROUND Assessment of liver cell proliferation by immunodetection of proliferating cell nuclear antigen may predict regenerative potential and survival of liver and hepatocellular carcinoma risk in patients with chronic viral hepatitis. AIM To evaluate proliferating cell nuclear antigen status and its clinical significance in a large cohort of patients with chronic viral hepatitis and different degree of liver damage by a computer assisted imaging analysis system. MATERIALS Liver biopsies from 358 patients with chronic hepatitis (259 males, 49 years, 63% with hepatitis C infection, 27% with hepatitis B virus, 10% with multiple infections) were studied. METHODS Proliferating cell nuclear antigen was localised by immunoperoxidase on microwave oven pre-treated formalin-fixed, paraffin embedded sections using PC10 monoclonal antibody. Proliferating cell nuclear antigen labelling index was calculated by an automated imaging system (Immagini e Computers, Milan, Italy). RESULTS Mean proliferating cell nuclear antigen labelling index ranged from 0.1% for patients with minimal changes to 3.6% for those with cirrhosis and hepatocellular carcinoma. Overall, proliferating cell nuclear antigen labelling index was higher in males, in older patients, in multiple infections and in hepatitis C virus compared to hepatitis B virus related cases. By linear regression analysis, proliferating cell nuclear antigen labelling index correlated with older age, male gender; higher transaminase levels, hepatitis C virus, higher histological gradIng and staging: by multivariate analysis male gender, hepatitis C virus, higher grading and staging resulted as independent variables. Both hepatitis C virus or hepatitis B virus cirrhotics had similar liver cell proliferation rate but those with hepatitis B virus had higher prevalence of liver cell dysplasia with respect to those with hepatitis C virus. CONCLUSIONS Proliferating cell nuclear antigen labelling index was a reliable assay for assessing liver cell proliferation rate in patients with chronic viral hepatitis and correlated with liver disease severity

Hepatorenal syndrome type 1 and bacterial infection: A catastrophic association in patients with cirrhosis

T ype-1 hepatorenal syndrome (HRS) is a severe and frequently lethal complication of cirrhosis. It is characterized by a rapid deterioration of kidney function related to derangement of systemic hemodynamic with vasodilatation in the splanchnic bed, low blood pressure, insufficient cardiac output, and release of vasoconstrictors with renal ischemia. Patients at risk of developing HRS are those with decompensated cirrhosis and patients with compensated cirrhosis who develop a severe clinical deterioration, the so-called acute-on-chronic-liver-failure. In many cases a “trigger” can be identified such as gastrointestinal bleeding, alcohol, hepatotoxic drugs, or bacterial infections. Until recently, when a patient with cirrhosis developed renal dysfunction concomitant to a bacterial infection, the diagnostic work-up and treatment for HRS were postponed until antibiotic treatment was completed and only the renal failure persisted, despite resolution of infection, was called HRS. This strategy was based on the opinion that the pathogenesis of renal failure precipitated by bacterial infections was different from that of HRS precipitated by other triggers. This practice, however, delayed specific HRS treatment with vasopressin analogs. Accordingly, the International Ascites Club removed the recommendation and determined that the diagnosis (and treatment) of HRS could be made before the precipitating infection had resolved. We now know that bacterial infections are a frequent trigger of HRS, probably through a cytokine-mediated impairment of circulatory function, worsening effective hypovolemia. Accordingly, the administration of human albumin to patients with spontaneous bacterial peritonitis (SBP) was shown to decrease mortality from type-1 HRS. This result was not replicated in a trial performed in patients with cirrhosis with bacterial infections other than SBP, making it uncertain whether the recommendation to infuse albumin should be extended to all patients with bacterial infection. Therefore, a better understanding of the natural history of HRS associated with bacterial infections can lead to an improved therapeutic approach. Moreover, we need to ascertain whether the antibiotics empirically used to treat infections in patients with cirrhosis with normal renal function should be the same as that used in patients with infections associated with HRS. Finally, as the survival of patients with cirrhosis after infection-related HRS can be insufficient for liver transplantation, the new therapeutic strategies should ensure longer survivals. In this issue, Barreto et al. studied a cohort of 70 patients with cirrhosis with HRS associated with bacterial infections. Their study’s main objectives were to evaluate the renal response to antibiotic therapy, shortterm survival, and predictors of treatment failure and survival. The use of routinely recommended antibiotic therapy failed to resolve renal dysfunction in two-thirds of patients, suggesting that the mechanism of renal damage in such patients is more complex than that causing HRS in the absence of bacterial infections (Fig. 1), or that the efficacy of antibiotics is impaired by renal dysfunction. Unfortunately, the investigators did not report on whether doses and types of antibiotics were adjusted according to the loss of renal filtration capacity. The independent predictors of irreversible HRS were older age, Child-Pugh and Model for Endstage Liver Disease (MELD) scores, high bilirubin levels, and nosocomial infection. This confirms that the syndrome’s severity is predominantly due to the severity of the bacterial infection and to liver dysfunction, rather than to renal impairment. This suggests that the best results of treatment with terlipressin and albumin Abbreviations: HRS, hepatorenal syndrome; MELD, Model for Endstage Liver Disease; SBP, spontaneous bacterial peritonitis. Address reprint requests to: Francesco Salerno, M.D., Policlinico IRCCS San Donato, Via Morandi, 30, 20097 San Donato (MI), Italy. E-mail: francesco. salerno@unimi.it; fax: 10039-0252774462. Received August 16, 2013; accepted January 7, 2014. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27015 Potential conflict of interest: Nothing to report.