Towards the non-invasive diagnosis of cirrhosis: The nuts-cirrhosis connection
Authors: Jaime Bosch
Journal: Journal of Hepatology (2008)

Cirrhosis of the liver is characterized by a profound derangement of liver architecture caused by fibrosis and nodule formation, which confers to the liver the typical aspect of a bag filled with nuts (Fig. 1a and b). Its diagnosis requires pathological examination of a liver sample, usually obtained using a liver biopsy needle. Liver biopsy however is an invasive procedure, unpleasant for the patient, expensive, not free from severe complications, and prone to sampling errors due to the very small size of needle biopsy specimens [1Maharaj B. Maharaj R.J. Leary W.P. Cooppan R.M. Naran A.D. Pirie D. et al.Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver.Lancet. 1986; 1: 523-525Abstract PubMed Scopus (59) Google Scholar, 2Pagliaro L. Rinaldi F. Craxì A. Di Piazza S. Filippazzo G. Gatto G. et al.Percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis. A prospective, randomized trial.Dig Dis Sci. 1983; 28: 39-43Crossref PubMed Scopus (175) Google Scholar, 3Bravo A.A. Sheth S.G. Chopra S. Liver biopsy.N Engl J Med. 2001; 344: 495-500Crossref PubMed Scopus (1878) Google Scholar, 4Bruguera M. Bordas J.M. Mas P. Rodes J. A comparison of the accuracy of peritoneoscopy and liver biopsy in the diagnosis of cirrhosis.Gut. 1974; 15: 799-800Crossref PubMed Scopus (56) Google Scholar]. Because of this, a number of non-invasive tests have been proposed to identify the presence of cirrhosis. Identifying transition to cirrhosis is clinically relevant in many chronic liver diseases, from chronic hepatitis (viral or autoimmune) to alcoholic, genetic, metabolic liver disease (non-alcoholic fatty liver disease) and cholestatic disorders. This is due to the fact that once cirrhosis is present most patients will develop portal hypertension, which precedes clinical decompensation and that calls for specific investigations to institute appropriate therapy [5Groszmann R.J. Garcia-Tsao G. Bosch J. Grace N.D. Burroughs A.K. Planas R. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (755) Google Scholar, 6Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. et al.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.Gastroenterology. 2007; 133: 481-488Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar]. In recent years, the advent of transient elastography (TE) using Fibroscan has emerged as a very useful tool for the non-invasive diagnosis of significant fibrosis and cirrhosis in patients with chronic hepatitis C (CHC) virus infection. While in other causes of liver disease the potential of TE has not yet been well established, in patients with CHC there is strong evidence showing that TE is of real clinical utility and that its use may save a substantial number of liver biopsies. This is well illustrated by the findings presented in the article by Castera et al. [[7]Castéra L. Le Bail B. Roudot-Thoraval F. Bernard P.-H. Foucher J. Merrouche W. et al.Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.J Hepatol. 2009; 50: 59-68Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar] in the current issue of Journal of Hepatology, as well as by many previous studies by the same group and others [8Castera L. Forns X. Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography.J Hepatol. 2008; 48: 835-847Abstract Full Text Full Text PDF PubMed Scopus (1043) Google Scholar, 9Castera L. Vergniol J. Foucher J. Le Bail B. Chanteloup E. Haaser M. et al.Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.Gastroenterology. 2005; 128: 343-350Abstract Full Text Full Text PDF PubMed Scopus (2095) Google Scholar, 10Ziol M. Handra-Luca A. Kettaneh A. Christidis C. Mal F. Kazemi F. et al.Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C.Hepatology. 2005; 41: 48-54Crossref PubMed Scopus (1275) Google Scholar, 11Ganne-Carrié N. Ziol M. de Ledinghen V. Douvin C. Marcellin P. Castera L. et al.Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.Hepatology. 2006; 44: 1511-1517Crossref PubMed Scopus (436) Google Scholar, 12Carrion J.A. Navasa M. Bosch J. Bruguera M. Gilabert R. Forns X. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation.Liver Transpl. 2006; 12: 1791-1798Crossref PubMed Scopus (366) Google Scholar]. The only important limitation for the use TE is the impossibility of obtaining adequate measurements in a large fraction of obese patients and of those with ascites. Obviously, the one that counts the most in the evaluation of transition to cirrhosis is overweight since in most instances ascites is a sign of advanced cirrhosis. In this regard it is worth noting that in the study by Castera et al. [[7]Castéra L. Le Bail B. Roudot-Thoraval F. Bernard P.-H. Foucher J. Merrouche W. et al.Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.J Hepatol. 2009; 50: 59-68Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar] overweight precluded correct TE measurements in a very low number of patients (3%), much below what would be expected in a French population of (extremely) well nourished middle aged men and women. So some selection bias may have been present. In our own experience in Barcelona, where quality of food and wine is hopefully close to that in Paris (but probably not better), failure of TE due to overweight is of about 9%. Although this difference is rather small quantitatively, it will have a bigger impact on the figures of the “intention to treat” analysis, by increasing the number of subjects with indeterminate values. However, this will not detract from the validity of their observations. Another important aspect of the paper is the confirmation that TE is not a good method to obviate the need of endoscopy to screen for varices in patients with TE values above the cirrhosis threshold or higher cut-offs [13Nagata N. Miyachi H. Nakano A. Nanri K. Kobayashi H. Matsuzaki S. Sonographic evaluation of the anterior liver surface in chronic liver diseases using a 7.5-MHz annular-array transducer: correlation with laparoscopic and histopathologic findings.J Clin Ultrasound. 2003; 31: 393-400Crossref PubMed Scopus (11) Google Scholar, 14Bosch J. Predictions from a hard liver.J Hepatol. 2006; 45: 174-177Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. This is not surprising since despite an increased portal pressure being a requirement for the formation of varices [[6]Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. et al.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.Gastroenterology. 2007; 133: 481-488Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar], in itself the magnitude of the portal pressure elevation does not correlate with either the presence or size of varices. Thus, the fact that TE values in cirrhosis due to HCV correlate with HVPG values [12Carrion J.A. Navasa M. Bosch J. Bruguera M. Gilabert R. Forns X. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation.Liver Transpl. 2006; 12: 1791-1798Crossref PubMed Scopus (366) Google Scholar, 15Vizzutti F. Arena U. Romanelli R.G. Rega L. Foschi M. Colagrande S. et al.Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis.Hepatology. 2007; 45: 1290-1297Crossref PubMed Scopus (583) Google Scholar] it is not helpful in identifying patients with varices. Besides, when varices are detected by a non-endoscopic procedure (i.e. radiology), endoscopy should be performed to evaluate other important aspects that influence therapeutic decisions, independently of the varices being small or large such as presence of red colour signs, of gastric varices or of other concomitant lesions [[16]Garcia-Tsao G. Bosch J. Groszmann R.J. Portal hypertension and variceal bleeding – unresolved issues. Summary of an American Association for the study of liver diseases and European Association for the study of the liver single-topic conference.Hepatology. 2008; 47: 1764-1772Crossref PubMed Scopus (190) Google Scholar]. A negative aspect of the study is that the comparison with other non-invasive methods of diagnosing cirrhosis did not include any imaging technique. This takes us back to the bag full of nuts (Fig. 1b). TE senses the hardness of the nuts, but misses the nodules. It is important to remember that for many years cirrhosis was diagnosed at laparoscopy, precisely by seeing a nodular liver surface [4Bruguera M. Bordas J.M. Mas P. Rodes J. A comparison of the accuracy of peritoneoscopy and liver biopsy in the diagnosis of cirrhosis.Gut. 1974; 15: 799-800Crossref PubMed Scopus (56) Google Scholar, 2Pagliaro L. Rinaldi F. Craxì A. Di Piazza S. Filippazzo G. Gatto G. et al.Percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis. A prospective, randomized trial.Dig Dis Sci. 1983; 28: 39-43Crossref PubMed Scopus (175) Google Scholar] (Fig. 1c). A number of studies even showed that diagnosis of cirrhosis was more reliable by peritoneoscopy than by liver biopsy, since the latter may not demonstrate cirrhosis in an unequivocally cirrhotic liver, due to the small size of liver tissue obtained by needle biopsy [2Pagliaro L. Rinaldi F. Craxì A. Di Piazza S. Filippazzo G. Gatto G. et al.Percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis. A prospective, randomized trial.Dig Dis Sci. 1983; 28: 39-43Crossref PubMed Scopus (175) Google Scholar, 4Bruguera M. Bordas J.M. Mas P. Rodes J. A comparison of the accuracy of peritoneoscopy and liver biopsy in the diagnosis of cirrhosis.Gut. 1974; 15: 799-800Crossref PubMed Scopus (56) Google Scholar]. Current imaging techniques have such a resolution that it is hard to believe that they can not show a nodular liver surface [[13]Nagata N. Miyachi H. Nakano A. Nanri K. Kobayashi H. Matsuzaki S. Sonographic evaluation of the anterior liver surface in chronic liver diseases using a 7.5-MHz annular-array transducer: correlation with laparoscopic and histopathologic findings.J Clin Ultrasound. 2003; 31: 393-400Crossref PubMed Scopus (11) Google Scholar]. Even very simple techniques, like ultrasonography using a high frequency transducer have a very high resolution and should allow observation of nodules on the liver surface (Fig. 1d). It is likely therefore that the combination of TE and liver ultrasound (or another imaging technique) may have a greater accuracy in detecting cirrhosis than TE alone. As in many other circumstances, not only in science, seeing is believing! Finally, the study by Castera et al. [[7]Castéra L. Le Bail B. Roudot-Thoraval F. Bernard P.-H. Foucher J. Merrouche W. et al.Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores.J Hepatol. 2009; 50: 59-68Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar] clearly shows that the role of currently available non-imaging methods to diagnose cirrhosis, based on different combinations of serum markers of fibrosis and haematological or biochemical parameters, have very limited value if any. Clearly, these are not appropriate to validate any new non-invasive technique since its diagnostic yield is much below that afforded by TE, which is emerging as the test to be beaten by future developments. The author is grateful to Drs. J.M. Bordas and A. Berzigotti for the figures and to Ms. Clara Esteva for expert assistance in preparing the manuscript. The CIBERehd is an initiative of the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.