Testing Beneficial Therapy in Human Cirrhosis Usin

Authors: John Carl Hoefs Timothy Morgan Bernard Joseph Ilagan

Publish Date: 2011/03/02

Volume: 56, Issue: 4, Pages: 929-930

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Abstract

The study by Minuk and colleagues entitled “Daily Ciprofloxacin Treatment for Patients with Advanced Liver Disease Awaiting Liver Transplantation Reduces Hospitalizations” 1 tested the hypothesis that patients on the liver transplant list may benefit from antibiotics as a method of enhancing hepatic regeneration and improving liver function The authors had previously shown in a rat model of acute and subacute liver failure that antibiotics improved survival 2 3 and that antibiotics appeared to also improve survival in a model of chronic liver injury 4 This benefit correlated in these animal models with improvement in markers of hepatic regeneration In the current study the authors asked whether the same benefit might be found in cirrhotic patients on the liver transplant waiting listThis singlesite prospective randomized doubleblind study measured routine markers of hepatic function albumin bilirubin and international normalized ratio for prothrombin time INR markers of hepatic inflammation aspartate aminotransferase AST and alanine aminotransferase ALT and clinical outcomes hospitalizations hepatic encephalopathy etc after 1 or 3 months of treatment with placebo or ciprofloxacin 250–500 mg twice daily Results showed no systematic benefit at 1 or 3 months in markers of hepatic function or inflammation and a significant improvement in albumin at 1 month was not confirmed at 3 months However it should be noted that more precise measurements of hepatic function 5 6 or markers of regeneration might have shown subclinical benefits that would have been encouraging for further studies Potential benefits in hospitalizations and clinical outcomes were also assessed There were fewer hospitalizations for hepatic encephalopathy among subjects receiving ciprofloxacin but little benefit for other clinical outcomes As the authors note antibiotics are helpful in treating encephalopathy and in prophylaxis against spontaneous bacterial peritonitis 7 8 9 10 The effect of antibiotics on improvement in survival among variceal bleeders has been profound 11 Thus the reduction in hospitalizations among patients receiving antibiotics in this study is not surprising and hepatic regeneration is not required to explain this improvement Thus the benefits of antibiotics in animal models of acute and chronic liver injury were not confirmed in this clinical trial among patients with advanced cirrhosis on the liver transplant waiting listAnimal models have been very useful in the evaluation of the pathophysiology of portal hypertension ascites and hepatic fibrosis 12 13 14 15 16 17 Why was so little benefit observed when antibiotics were used in humans with cirrhosis as compared with animal models The answer partially lies in the difference between changes in pathophysiology in animal models of acute liver injury and humans with cirrhosis who have dense hepatic fibrosis that develops over long periods of time and resolves slowly when the insult is stopped 18 19 By contrast animal models of cirrhosis generally require continued liver injury to produce cirrhosis and fibrosis resolves rapidly if the insult is stopped 12 13 14 15 16 17 Furthermore there is often a complex interaction of factors contributing to hepatic injury that includes bacterial products such as endotoxin from the gut that may be less important in man 12 13 14 Antibiotics markedly decrease injury in most animal models 12 13 14 Therefore study of the pathophysiology of liver injury and complications of liver disease in animal models has been very valuable but the regression of liver fibrosis differs between humans and animals Thus findings in animal models must be confirmed in clinical settings and we applaud the authors for testing their hypothesis in humans 1 Unfortunately this study shows that antibiotics do not enhance hepatic regeneration or improve clinical outcomes by means of regeneration in patients on the liver transplant listAccording to several recent studies there is no experimental model that completely reproduces human liver fibrosis 12 13 14 Since there are contraindications to serial liver biopsies in humans with liver disease studies of genetic and molecular aspects of liver injury and fibrosis should continue An initial approach should involve exploration of the molecular mechanisms of liver fibrosis in different diseases 20 This might elucidate areas of potential efficacy of ciprofloxacin and other fluoroquinolones Ultimately all benefits in animals must be confirmed by clinical trials in manThis article is published under an open access license Please check the Copyright Information section for details of this license and what reuse is permitted If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and reuse information please contact the Rights and Permissions team

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