] is an easy to perform, reproducible method for the rapid and objective evaluation of LS in clinical practice[2,16
] and it is proposed as a reliable, non-invasive, surrogate marker of fibrosis[3-7,17,18
]. In fact, LS is a physical parameter that correlates primarily with fibrosis, but it is influenced also by other factors that modify the elasticity of the liver, such as significant variations of inflammatory infiltrate, edema and vascular congestion of the liver[8-10,19
]. Accordingly, we showed that LS variations parallel ALT values during hepatitis exacerbations in the setting of both acute and chronic liver damage[8
]. This evidence has important implications in clinical practice since the interpretation of the LS measure has to take into account the concurrent biochemical profile of the patient[8
]. Thus, the interpretation of LS might be more difficult in the setting of CHB when major fluctuations of necrosis and inflammatory activity occur in a significant proportion of patients[11,12,18,19
]. On the other hand, the availability of an easy to perform, non-invasive measure for fibrosis might improve the management of the HBV carrier. In the HBV carrier, the repeated measures of LS might help to identify the candidates for liver biopsy and to define both the phase of HBV infection and stage of liver disease that are mandatory to warrant the most appropriate treatment strategy, and to monitor liver disease progression in the single patient[20,21
Addressing the issue of the clinical usefulness of LS in the management of the HBV carrier we found a highly significant correlation between transient elastography and fibrosis stages (P
< 0.001). Using 7.5 and 11.8 kPa as cut-off values for fibrosis ≥ S3 and cirrhosis, the FS specificities were 88.5% and 96.3%, sensitivities 93.9% and 86.5%, and diagnostic accuracies 90.1% and 94.2%. These results confirm that FS is a reliable method to assess fibrosis in carriers with chronic HBV infection and disease[8
Additional factors were independently associated with FS, such as active HBV infection (P < 0.001), HBV-DNA (P = 0.042) and ALT (P < 0.001) levels. In inactive HBV carriers, mean FS values were similar to normal controls and significantly lower than in CHB patients (4.3 ± 1.0 vs 4.6 ± 1.2 vs 11.2 ± 9 kPa; P < 0.001). These findings qualify LS as a promising tool to provide an important diagnostic assessment of the HBV carrier with inactive viral profile when the increased FS values suggest the presence of liver damage caused by factors other than HBV. In such cases, liver biopsy can be proposed for the precise characterization of liver disease. Indeed, in our study, 17 inactive carriers with metabolic liver disease had FS values higher (6.9 ± 2.3 kPa) than inactive carriers without liver disease.
In addition to the phase of HBV infection, only two other parameters, namely HBV DNA and ALT, were independently correlated with LS. Since both these parameters are linked with the extent of liver disease activity in the immune competent HBV carrier, our results further support the hypothesis that the extent of necrosis and inflammation influence LS significantly[20,22-24
]. Accordingly, in the 83 untreated patients without cirrhosis, multivariate analysis showed that intra-hepatic necrosis and inflammation scores and ALT values were the only factors influencing FS (P
= 0.035 and P
< 0.001 respectively), in addition to the stage of liver disease.
The LS values identified as cut-offs for histological stage ≥ S3 and cirrhosis are lower than those proposed for chronic hepatitis C. A slight variable difference between cut-offs would not be surprising when different cohorts of patients are compared, but FS values in CHB patients with cirrhosis (11.8 kPa) are consistently and persistently lower than in chronic hepatitis C (CHC) cirrhosis[4-6,8,16
]. Accordingly, lower values of LS cut-offs have been proposed in preliminary reports[25,26
]. These findings are consistent with the specific features of histopathology of hepatitis C, in which the combination of portal lymphoid follicles, bile duct damage, lobular activity and steatosis may contribute to the different LS, as compared to hepatitis B histopathology[27
In this prospective study of CHB patients, we observed 1.2 to 4.4-fold increases of FS values with ALT flares, and similarly, LS values fluctuated in parallel with ALT values in nine patients with acute hepatitis. Interestingly, the extent of FS fluctuations during the hepatitis exacerbations differed according to the biochemical patterns of CHB. The range of LS variations were significantly wider in patients with ALT flares intervened by complete biochemical remissions, as compared to patients with persistent ALT elevations between flares (FS variations ranged from 1.4 to 4.4-fold in the former and 1.2 to 1.6-fold in the latter group, P
= 0.019). Altogether these findings confirm our original observation and other more recent reports on the major influence of the biochemical profile on LS in the setting of both acute and chronic liver damage[8-10
]. Finally, we found that prolonged biochemical remissions were associated with progressive reductions of FS values. LS declined yearly at about 0.2-fold in treated patients followed-up prospectively for 48 mo, and a proportion of patients who maintained evidence of cirrhosis at US achieved values of FS < 11.8 kPa. This was responsible for the worse diagnostic performance of FS in treated patients in whom the sensitivity for detecting cirrhosis fell from 86.5% to 54.2% in untreated vs
treated patients with fibrosis ≥ S5 (Table ). Altogether, these data suggest a non-linear correlation between the overall kinetics of LS and histological staging during antiviral treatment. Future studies should be addressed to understand the relations among the reductions of LS, necrosis, inflammation and fibrosis in the separate settings of different fibrosis stages (i.e. ≥ S3/< S3 and presence/absence of cirrhosis) and liver disease etiology (i.e. HBV and HCV). In fact, much of the LS changes depend on the different elastic relations among fine blocks of the liver structure. Thus, the interplay between the extent and structure of the collagen septa within the fine liver block, and the different type and extent of liver inflammatory infiltrate within them, might account for both the different FS cut-offs between CHB and CHC patients and for the different kinetics of FS and fibrosis decline during antiviral therapy.
In conclusion, our study suggests that the LS provides a useful non-invasive tool to monitor liver disease in the chronic HBV carrier. In the inactive carrier, it helps to identify non-HBV-related causes of liver damage and transient reactivation of HBV liver disease. In the CHB patient, provided that the pattern of biochemical activity is taken into account, LS values < 7.5 exclude the presence of significant fibrosis (≥ S3) with a high NPV (97.3%) and low negative likelihood ratio (0.07). FS values ≥ 11.8 kPa are highly specific (96.3%) for cirrhosis and show good PPV (86.5%) and positive likelihood ratio (23.18). In the HBV carrier with LS values ranging from 7.5 to 11.8 kPa, which are indicative of significant liver disease, liver biopsy remains the gold standard for an accurate grading and staging of liver disease. Finally, in CHB patients the monitoring of LS appears useful to highlight major changes in intrahepatic liver disease and warrants a more appropriate timing for control liver biopsies.