Liver stiffness and hepatocellular carcinoma: Liaisons dangereuses?
Authors: Laurent Castera
Journal: Hepatology (2009)

Hepatocellular carcinoma (HCC) is currently the leading cause of death among patients with cirrhosis and the sixth most common cancer worldwide.1 In Western countries and Japan, HCC mainly occurs in patients with chronic hepatitis C (CHC) and cirrhosis, with an annual incidence of 3%-5%.2 The prognosis is poor unless HCC is diagnosed and treated early. Cirrhosis is the strongest risk factor for HCC, and 80% of these tumors occur on a cirrhotic liver. CHC, chronic hepatitis C; HCC, hepatocellular carcinoma; HVPG, hepatic venous pressure gradient; LSM, liver stiffness measurement; TE, transient elastography. Until recently, liver biopsy was the reference method for diagnosing and staging liver fibrosis. However, this invasive procedure carries a risk of rare but potentially life-threatening complications and is prone to sampling errors. These limitations stimulated the search for new noninvasive approaches.3 A variety of methods have been proposed, including standard serum markers, complex algorithms based on marker panels, and liver stiffness measurement (LSM) by means of transient elastography (TE) (FibroScan; Echosens, Paris, France).4 Liver stiffness values are expressed in kilopascals and range from 2.5-75 kPa5; values around 5.5 kPa were recently shown to reflect normality.6 Liver stiffness correlates with hepatic fibrosis stages in patients with CHC7, 8 and has excellent diagnostic accuracy for cirrhosis.9, 10 When compared with current biomarkers and routine blood tests, TE emerges as the most accurate noninvasive method for early detection of cirrhosis.11 Another promising application of TE is for monitoring the progression of liver fibrosis. The clinical significance of the wide range of liver stiffness values observed in patients with cirrhosis (13-75 kPa) remains uncertain. Preliminary results suggested that liver stiffness values in patients with cirrhosis increased as the liver disease progressed.12 For instance, cutoff values of 27.5, 37.5, 49.1, 53.7, and 62.7 kPa, respectively, had >90% negative predictive value for the presence of stage 2/3 esophageal varices, Child-Pugh score B or C, and a past history of ascites, HCC, and esophageal bleeding. Although retrospective and conducted in a single center, this study provided the first "proof of concept" that liver stiffness values may have prognostic value in a context of cirrhosis. In addition, several studies13, 14 have shown a correlation between liver stiffness values and portal hypertension diagnosed by means of hepatic venous pressure gradient (HVPG) measurement, the gold standard for the diagnosis and staging of portal hypertension and a reliable predictor of clinical decompensation.15 A correlation between liver stiffness values and the presence of esophageal varices has also been reported.11, 14, 16 However, LSM cannot yet confidently predict the presence of esophageal varices in clinical practice and thus avoid the need for upper gastrointestinal endoscopic screening of patients with cirrhosis.11 Because TE is a user-friendly technique that can be performed rapidly (less than 5 minutes) at the bedside, with immediate results and high patient acceptance, it is gaining in popularity and is likely to become an important tool in clinical practice in the near future. However, there was a need for prospective follow-up studies designed to determine whether liver stiffness values can predict the occurrence of clinical events in patients with compensated cirrhosis. In this issue of HEPATOLOGY, Masuzaki et al.17 report on a large prospective cohort of 866 Japanese patients with CHC, 77 of whom developed HCC during mean follow-up of 3 years. Importantly, the cumulative incidence of HCC increased with baseline liver stiffness values, ranging from 0.4% at 3 years in patients with LSM ≤ 10 kPa to 38.5% in patients with LSM > 25 kPa. Cox proportional hazard models adjusted for age, male sex, and the presence of clinical cirrhosis showed that LSM was the strongest predictor of HCC onset, with relative risks of 16.7, 20.0, 25.6, and 45.5 for respective LSM values of 10-15 kPa, 15-20 kPa, 20-25 kPa, and >25 kPa. This important study is the first to show a correlation between liver stiffness values and the risk of HCC. The fact that liver stiffness is expressed as a continuous variable may represent an advantage over the traditional binary histological classification as cirrhosis/no cirrhosis, because the latter patients (particularly those with Metavir stage 3 fibrosis) are still at risk of HCC. However, the reader should be aware that the value of this large cohort study is undermined by the lack of histological information. For instance, 19 of the 77 patients who developed HCC had no clinical evidence of cirrhosis and, although the authors claim that LSM was suggestive of cirrhosis (>15 kPa), they provide no histological confirmation in eight of these 19 patients. In addition to fibrosis, parameters such as necroinflammatory activity may influence LSM.18 Also, it has been suggested12 that higher LSM values correlate with more advanced liver disease, reflected by a higher grade of esophageal varices, a higher Child-Pugh class (B or C), or a past history of ascites or bleeding esophageal varices. It would have been very interesting to have this information for the subgroup of 87 patients with LSM > 25 kPa. Finally, 139 (17.6%) of the 789 patients who did not develop HCC had clinical cirrhosis, but the authors did not report whether they had lower LSM values than the patients who developed HCC. It is conceivable that these 139 patients would have developed HCC during a longer follow-up period (5 years). Thus, the question remains as to whether increased liver stiffness is simply a surrogate marker of disease severity or rather a significant risk factor for HCC, independently of disease severity. Interestingly, subgroup analyses suggested that, even in patients who are traditionally considered to have a low risk of developing HCC (young women with low body mass index and low α-fetoprotein levels), elevated LSM values were associated with a significant risk of HCC. Further studies are needed to address this issue. Another potential limitation of this study is that liver stiffness was only measured once, at enrollment, and that 173 patients (20%) received interferon therapy during the study period, yielding a sustained virological response in 83 cases and likely affecting disease progression, hepatocarcinogenesis, and liver stiffness. Although TE is a reproducible method,19 little is known of LSM dynamics. Preliminary results suggest that liver stiffness values are stable over time in untreated patients with CHC, but that they fall significantly in patients who have a sustained virological response to treatment.20 Serial measurements, at 1-year intervals for instance, would have strengthened the results of this study and could have provided an excellent opportunity to show whether LSM can be used as a dynamic indicator of the risk of HCC. In conclusion, despite a number of shortcomings, this important study provides further support for the prognostic value of LSM in patients with cirrhosis and opens up new perspectives. Although these findings need to be confirmed in other cohorts (Caucasians or patients infected with HBV) and with longer follow-up, they suggest that TE could be used as a rapid screening tool to allocate patients with cirrhosis and CHC to specific risk categories.