Robic MA, Procopet B, Métivier S, Péron JM, Selves J, Vinel JP, Bureau C. Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study. J Hepatol 2011;55:1017-1024. (Reprinted with permission.)
The prognosis of patients with chronic liver disease is to a great extent determined by the presence and degree of portal hypertension (PHT). Hepatic venous pressure gradient (HVPG) has been shown to be an accurate prognostic index in patients with cirrhosis. Transient elastography is a non-invasive procedure that assesses liver fibrosis through the measurement of liver stiffness (LS). In several reports, LS was found to be correlated with HVPG. LS could therefore be useful to identify patients with significant PHT. The aim of the present study was to prospectively assess and to compare the prognostic performances of LS and HVPG in patients with chronic liver disease. One hundred patients with chronic liver disease underwent LS and HVPG measurements on the same day. Patients were thereafter followed-up for 2 years or until they experienced a complication related to their liver disease. Within the two-year follow-up, 41 patients developed, at least, one liver disease related complication. The performances of HVPG and LS for predicting the occurrence of these complications were not significantly different: AUROC 0.815 [0.727-0.903] and 0.837 [0.754-0.920], respectively. When considering only complications related to PHT, both methods were found to be similarly accurate: AUROC 0.830 [0.751-0.910] and 0.845 [0.767-0.823], for HVPG and LS, respectively. When patients were divided in two groups according to a LS value below or above 21.1kPa, actuarial rates of remaining free of any complication at 2 years were 85.4% vs. 29.5%, respectively. When only PHT related complications were considered, these rates were 100% vs. 47.5%, respectively. The performances of LS and HVPG were also similar in the subgroup of 65 patients with cirrhosis. LS proved as effective as HVPG in predicting clinical decompensation and PHT related complications in patients with chronic liver disease. Therefore, LS could be a valuable clinical tool to avoid invasive procedures.
The ability of formulating accurately the diagnosis, prognosis, and therapy of a disease constitutes a fundamental skill in clinical medicine. This is especially important in patients with chronic diseases, because a precise prognosis might allow tailoring treatment according to the individual risk of developing relevant complications. In cirrhosis, based on a different prognosis, a compensated phase, which is asymptomatic and with low mortality, and a decompensated phase, which is characterized by the clinical consequences of liver failure and portal hypertension (e.g., ascites, variceal bleeding, sepsis, jaundice, and hepatic encephalopathy), and by high mortality 1 are distinguished.
Hence, in compensated patients with cirrhosis, prognosis should address the risk of clinical decompensation. The development of either clinically significant portal hypertension (CSPH) (hepatic venous pressure gradient [HVPG] ≥10 mmHg) or gastroesophageal varices (clinical consequence of CSPH), carry an increased risk of decompensation in patients with compensated cirrhosis. 1 Therefore, correct risk stratification in these patients should include the measurement of HVPG and upper gastrointestinal endoscopy, in addition to routine clinical and laboratory evaluation. 2 The availability of noninvasive diagnostic tools, such as serum fibrosis markers, imaging methods, and transient elastography, have recently increased the proportion of patients diagnosed in a very well-compensated phase of cirrhosis, 3 who, being totally asymptomatic, might be reluctant to undergo invasive tests. Moreover, even if HVPG measurement gives very precise information and is currently the best surrogate of clinical endpoints in hepatology, it is expensive and not universally available. 4 Therefore, noninvasive alternatives to predict CSPH are highly needed.
Transient elastography (TE) (FibroScan®) allows an accurate, noninvasive estimation of liver stiffness (LS), which is directly related to the amount of fibrosis in the parenchyma. Because fibrosis is the main determinant of hepatic resistance (the major determinant of portal pressure in early stages of portal hypertension), TE has been tested in recent years as a novel way of obtaining numerical, objective, and operator-independent noninvasive surrogate data of HVPG. In the five studies published so far in nontransplanted patients with chronic liver disease (CLD) 5-9 (Fig. 1), LS showed a significant linear correlation with HVPG (R, 0.55-0.86) and a high accuracy in predicting CSPH (area under the receiver operating characteristic curve [AUROC], 0.77-0.99). The best cutoff for predicting CSPH varies across studies, mainly as a result of differences in the choice of sensitivity or specificity (Fig. 1). If one applies to the existing literature a pragmatic rule, namely, that, in medicine, decision is not binary (i.e., yes/no), but is composed of three arms (i.e., yes/no/indeterminate), it can be concluded that LS <13.6 kPa (a very sensitive cutoff) confidently rules out CSPH, whereas LS ≥21.1 kPa (a very specific cutoff) accurately diagnoses CSPH; on the other hand, patients with intermediate values (LS between 13.6 and 21.1 kPa) cannot be easily classified as having or not CSPH.
The article by Robic et al. 10 provides strong evidence confirming the validity of TE and, specifically, of the cutoff of 21.1 kPa in predicting CSPH, in this case identified by the risk of its clinical consequences. The investigators assessed the performance of previously established cutoffs of both HVPG (≥10 mmHg) and LS (≥21.1 kPa) for the prediction of the “hard endpoint” represented by clinical decompensation in 100 compensated patients with CLD followed up for 2 years or until orthotopic liver transplantation or death, finding that both were good predictors, with substantially equal prognostic discriminative ability (AUROC, 0.815 versus 0.837; not significant). Interestingly, none of the patients with LS <21.1 kPa developed decompensation. This study is the first that clearly and prospectively demonstrates that this noninvasive technique has the potential of being as informative as HVPG in stratifying the risk of decompensation in cirrhosis. Nonetheless, as pointed out by the editorial accompanying the original publication, 11 before generalizing these results, some limitations of the study should be considered. The first regards the number and kind of patients included; among them, only 65 of 100 had cirrhosis on histology, and (as could be expected) this was the real “at risk” population, in which 93% of events occurred in the follow-up; moreover, most cirrhosis patients already had varices (47 of 65; 72%), thus belonging to stage 2 according to D'Amico's classification, 1 indicating a higher risk of transition to the decompensated phase, as compared to stage 1 (no varices). Therefore, this study mixed two “extreme” populations of compensated patients, one with negligible risk of decompensation (i.e., patients without cirrhosis) and the other with a much higher probability of decompensation (i.e., patients with cirrhosis and varices; stage 2). This could have magnified the discriminative ability of TE; therefore, a validation of these findings in patients with compensated cirrhosis stratified in stage 1 and 2 is strongly desirable.
Another problem regards the rate of events in the follow-up, which was much higher than expected: 41 of 65 patients (63%) developed at least one clinical event (including sepsis) within 2 years, and 18 of 65 (28%) had portal-hypertension–related events (e.g., ascites or variceal bleeding), which is approximately double of what is reported in other recent series. 1
Finally, the investigators decided not to include in the multivariate analysis some parameters that are almost invariably associated with prognosis, namely, Child-Pugh or Model for End-Stage Liver Disease scores, and the presence of varices. Therefore, whether TE is able to discriminate between good and poor prognosis in patients with similar liver function and/or with similar collateral circulation remains to be demonstrated.
Independent of its limitations, this study has the merit of confirming that liver stiffness holds the potential of predicting the clinical course of CLD, even in advanced phases. Recent data suggest that this also holds true for the prediction of hepatocellular carcinoma. 11
Is it possible to ameliorate these results? Perhaps it is. As for the HVPG, it has been known for years that values above 10, 12, and 16 mmHg identify different thresholds of risk in patients with cirrhosis 4; however, when something changes (e.g., when beta-blockers are started 4) or when liver function deteriorates during beta-blocker therapy, only a dynamic evaluation with repeated HVPG measurements can give precise information on the risk of bleeding and other complications. Data obtained by ultrasound (US) suggest that the serial evaluation of parameters related with portal hypertension, such as spleen size or the presence of abdominal portocollateral circulation, 12 can predict the complications of portal hypertension, whereas a single examination of these parameters cannot 12; therefore, it is likely that a dynamic evaluation of LS over time could give more accurate information than a single measurement. Another potential improvement can derive from newer methods for estimating stiffness in parenchymas; though magnetic resonance imaging elastography seems accurate, but difficult to apply on a routine basis as a result of its cost, different US equipment manufacturers are currently developing their own technologies for measuring stiffness in real time and without the limitations of FibroScan. Among them, acoustic radiation force imaging has already been shown to hold a similar accuracy as TE in predicting significant fibrosis and cirrhosis. 13 These new methods also allow measuring stiffness not only within the liver, but also in the spleen, which may reflect more accurately portal hypertension. Even if data in this regard are still scarce, pilot evidence is promising. 14
Finally, as a result of the complex interaction of the multiple factors that determine the course of disease, I think that it is very unlikely that a single test may ever permit a correct prognostic stratification in the individual patient with compensated cirrhosis. In this regard, recent data suggest that the combination of different tests, such as liver stiffness (i.e., TE), platelet count (i.e., laboratory) and spleen diameter (i.e., US) improves the prediction of esophageal varices in patients with compensated hepatitis B virus–related cirrhosis. 15 Again, tests do not describe the full picture because other factors, such as obesity 16 or etiological treatment, can dramatically change the prognosis of patients with compensated cirrhosis independent of portal pressure and liver function. The patient's question of “will I do well, and for how long?” is still difficult to answer; luckily for us, a doctor, and not only a machine, is needed to integrate the large number of variables with prognostic significance in an individual patient. Nonetheless, I am convinced that some of the above-mentioned new tests will soon help us toward refining our clinical skills.