Transient elastography in acute hepatitis: All that's stiff is not fibrosis

Two papers in this issue of HEPATOLOGY examine the effect of inflammation on liver stiffness measurement (LSM), as assessed by transient elastography (Arena and Vizzutti et al.,1Sagir et al.2). These papers challenge the commonly held assumption that liver stiffness is determined solely by the severity of hepatic fibrosis. Such a view is underpinned by the clinical experience that, on palpation, a cirrhotic liver is hard, and experimentally, by the correlation of stiffness (elastic modulus) with the histopathological fibrosis score in ex vivo hepatic samples.3 However, in the proof-of-principle study by Yeh and colleagues,3 it was stressed that “biological tissue is a composite material and it is difficult to separate the influence of each component of the tissue on the total of modulus estimates”. Demonstration that biological variables other than fibrosis contribute to LSM, therefore comes as no surprise. The development of transient elastography was a leap forward, enabling the rapid acquisition of objective liver stiffness measurements in vivo.4 In the seminal work by Sandrin and colleagues,4 a cohort of patients with chronic hepatitis C was studied. This patient group is appropriate for study as the natural history of the disease and its histological classification is well established, the prevalence of the disease is high in many countries and effective treatment options are available.5-7 Multiple regression analysis in early studies demonstrated a relationship between elasticity measurements and fibrosis stage, but not to the disease activity (or necroinflammatory score), nor to the degree of steatosis.4,8 However, the observation that the range of liver stiffness values obtained in patients with cirrhosis was very large led to speculation that there may be a relationship between portal hypertension and liver stiffness.4 Subsequently, a number of well-conducted studies confirmed the correlation between liver stiffness and hepatic fibrosis in hepatitis C,8,9 and other chronic hepatic conditions.10-12 However, studies have also indicated the presence of co-existing factors that contribute to liver stiffness. Area under the receiver operator characteristic (AUROC) curves plot sensitivity and specificity for all possible cutoff values between two given states, giving a measure of diagnostic accuracy. Accordingly, quoted cutoff values vary between patient cohorts with the same disease, between cohorts of differing diseases and according to whether the operator requires a cutoff value which gives maximal sensitivity or specificity.10,11 While the prevalence of a disease in the population studied affects the diagnostic accuracy, the presence of disease-specific factors other than fibrosis stage alone may also contribute to differences in LSM. Substantial differences in cutoff values for cirrhosis have been observed between those with chronic hepatitis and those with alcohol-related chronic liver disease and non-alcoholic fatty liver disease (NAFLD). 11,12 While the inter-test and inter-rater reliability for LSM was found to be excellent (intraclass correlation of 0.98) in a cohort of 200 patients with chronic liver disease in Italy, the reliability of measurements in overweight individuals and those with NAFLD as assessed by the intraclass correlation coefficient is reduced.13 However, in that study cohort, the mean BMI was just 24.8 kg/m2, which is lower than that found in many populations. As such, it was under-powered to examine the effects of obesity and NAFLD on the reliability of LSM. On the basis of clinical experience, LSM is difficult to perform successfully and reliably in obese individuals. Current evidence does not demonstrate an independent effect of hepatic steatosis on LSM, but it remains to be seen whether steatosis per se systematically alters LSM in a study where patients are stratified primarily by a validated method for lipid quantitation, such as proton magnetic resonance spectroscopy.14 A number of studies have pointed to a relationship between portal hypertension and liver stiffness measureAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operator characteristic; HPVG, hepatic venous pressure gradient; LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease. JFLC holds the Centenary Fellowship from the Hammersmith Hospitals Trustees Research Committee. SDTR holds grants from Engineering, Physics and Science Research Council, Swindon, UK; Medical Research Council, London, UK; AMMF, Essex, UK; Broad Foundation, Los Angeles, USA; Pfizer Global Research and Development Inc, Sandwich, UK and GlaxoSmithKline, Ware, UK. Address reprint requests to: Professor S.D. Taylor-Robinson, M.D., FRCP, Department of Hepatology, Division of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS United Kingdom. E-mail: s.taylor-robinson@imperial.ac. uk and j.cobbold@imperial.ac. uk; fax: (44) 20 8383 3038. Copyright © 2008 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.22200 Potential conflict of interest: Nothing to report.