Page 19 - NON-INVASIVE TESTS FOR EVALUATION OF LIVER DISEASE SEVERITY AND PROGNOSIS
P. 19
Clinical Practice Guidelines previously proposed methods, i.e. the LS–spleen diameter to pla-
telet ratio score (LSPS) and platelet count to spleen diameter
Use of non-invasive tests for monitoring disease progression [303–305]. SS and LS were more accurate than other non-invasive
parameters in identifying patients with OV and different degrees
Portal hypertension of PH. Further validation is needed before the place of SS in clini-
There is substantial evidence indicating that TE can be quite effec- cal practice can be defined.
tive in detecting patients with a high risk of having (or not having)
developed clinically significant elevations of hepatic venous pres- Several biological parameters have been proposed for the
sure gradient (HVPG) or varices. Several studies have shown that non-invasive detection of CSPH including prothrombin time
there is a good correlation between LS values and HVPG in [287], a score combining platelet count and total bilirubin
patients with advanced liver diseases in both pre- and post-trans- [306], and FibroTestÒ [307]. In particular, a score combining pla-
plant settings [285–288]. According to a recent meta-analysis, the telet count with total bilirubin had an AUROC of 0.91 for predict-
diagnostic performance of TE for predicting clinically significant ing CSPH with 88% sensitivity and 86% specificity at a cut-off of
PH (CSPH, HVPG P10 mmHg) in the setting of patients with com- À1.0.
pensated chronic liver disease/cirrhosis is excellent, with an
AUROC of 0.93 [289]; a 90% sensitive cut-off for CSPH diagnosis Similarly, several non-invasive tools have been proposed for
is 13.6 kPa, and a 90% specific cut-off in this setting is 21 kPa. the detection of OV including routine biological parameters
These cut-offs have been shown to allow a correct stratification [308], FibroTestÒ [309], and combination of simple biological
of presence/absence of CSPH in patients with compensated cirrho- and ultrasound parameters [303]. In the largest study to date
sis and potentially resectable HCC, thus reducing the need for comparing retrospectively a panel of serum markers (platelet
invasive hemodynamic assessment [290]. However, while the count, AST/ALT ratio, APRI, Forns index, Lok index, FIB-4, and
correlation is excellent for HVPG values between 5 and 10– Fibroindex) in more than 500 patients with chronic liver diseases,
12 mmHg (typical of cirrhosis without evident clinical mani- the combination of Lok index (cut-off = 1.5) and Forns index (cut-
festations related to PH), it hardly reaches statistical significance off = 8.8) had the best diagnostic performance (AUROC of 0.80
for values above 12 mmHg [286]. This is because, with the pro- and negative predictive value of 90%) for predicting clinically
gression of cirrhosis, the mechanisms of PH become less and less relevant OV [308].
dependent on the intrahepatic resistance to portal flow due to tis-
sue fibrosis and progressively more dependent on extra-hepatic In conclusion, the evidence accumulated so far indicates that
factors (i.e. hyperdynamic circulation, splanchnic vasodilatation) both HVPG and upper GI endoscopy cannot be replaced by non-
[291]. This observation sets a key limitation to the use of LS mea- invasive methods, although an initial non-invasive approach
surements as a non-invasive surrogate of HVPG beyond the pre- may be helpful in selecting patients in whom these procedures
diction of clinically significant (HVPG P10 mmHg) and severe are indicated with a certain level of urgency.
(HVPG P12 mmHg) PH, and, accordingly, TE of the liver is unli-
kely to be useful in monitoring the hemodynamic response to Hepatocellular carcinoma
the administration of beta-blockers or disease progression in the To date, several cross-sectional studies [310–313] identified that
decompensated phase. Conversely, repeated LS measurements high LS value measured by TE is significantly associated with
could be useful during the first year after liver transplantation the risk of presence of HCC (Table 8). However, these cross-sec-
to identify patients with hepatitis C recurrence characterized by tional studies only describe the ‘static’ phenomenon that
a rapid progression towards cirrhosis [292]; in addition, a LS patients with HCC have high LS values than those without
P8.7 kPa one year after orthotopic liver transplantation is associ- HCC, not considering the ‘dynamic’ association between the pro-
ated to a worse prognosis in this setting [293]. gression or regression of liver fibrosis and the risk of future HCC
development. To overcome this limitation, several longitudinal
More uncertain and controversial is the possibility of predict- prospective studies [267,314–323] have recently been published
ing the presence and the size of oesophageal varices (OV) based (Table 8).
on LS values. A correlation between LS values and the presence
of OV has been reported in several studies [196,286–288,294–296] A large prospective cohort study with chronic hepatitis C (866
with AUROCs ranging from 0.74 to 0.85 and cut-offs from 13.9 patients) was conducted in Japan [317]. Along with age, male
to 21.5 kPa. Although the sensitivity for the prediction of the gender, and clinical cirrhosis, stratified LS values were identified
presence of OV was high (76–95%), specificity was in general as an independent risk factor for HCC development. Compared
not satisfactory (43–78%). Regardless, the general features of with patients with LS values 610 kPa, patients with higher LS val-
these studies, i.e. single-centre retrospective, heterogeneous ues were at significantly increased risk of developing HCC (LS val-
etiology of cirrhosis and stages of disease progression, subjective ues, 10.1–15 kPa, hazard ratio [HR], 16.7; LS values, 15.1–20 kPa,
assessment of OV size, do not allow any sound conclusion on the HR, 20.9; LS values, 20.1–25 kPa, HR, 25.6; and LS values, >25 kPa,
utility of LS assessment in predicting the presence of OV and to HR, 45.5). In addition, the cumulative incidence rates of HCC
screen cirrhotic patients without endoscopy [297]. showed a stepwise increase according to the stratified LS values
(p <0.001 by the log-rank test). In addition, Jung et al. [316] fur-
Recently, studies employing different technical approaches ther validated the usefulness of TE in prediction of HCC develop-
have highlighted the potential utility of spleen stiffness (SS) ment in patients with chronic hepatitis B (n = 1130). Compared
assessment for predicting the presence of OV and the degree of with patients with LS values 68 kPa, patients with higher LS val-
PH in cirrhotic patients [298–302]. In particular, the study by ues were at significantly increased risk of developing HCC (LS val-
Colecchia and co-workers [300] measured SS and LS by TE in ues, 8.1–13 kPa, HR, 3.07; LS values, 13.1–18 kPa, HR, 4.68; LS
100 consecutive patients with HCV–induced cirrhosis. All values, 18.1–23 kPa, HR, 5.55; and LS values, >23 kPa, HR, 6.60).
patients also underwent measurements of HVPG and upper GI Furthermore, changes in the risk of HCC development according
endoscopy. The ability of both SS and LS to predict clinically sig- to the pattern of changes in the measured LS was also shown in
nificant PH and the presence of OV was compared to that of the the study, suggesting a potential role for serial LS measurement
18 Journal of Hepatology 2015 vol. xxx j xxx–xxx
Please cite this article in press as: EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J
Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.04.006
telet ratio score (LSPS) and platelet count to spleen diameter
Use of non-invasive tests for monitoring disease progression [303–305]. SS and LS were more accurate than other non-invasive
parameters in identifying patients with OV and different degrees
Portal hypertension of PH. Further validation is needed before the place of SS in clini-
There is substantial evidence indicating that TE can be quite effec- cal practice can be defined.
tive in detecting patients with a high risk of having (or not having)
developed clinically significant elevations of hepatic venous pres- Several biological parameters have been proposed for the
sure gradient (HVPG) or varices. Several studies have shown that non-invasive detection of CSPH including prothrombin time
there is a good correlation between LS values and HVPG in [287], a score combining platelet count and total bilirubin
patients with advanced liver diseases in both pre- and post-trans- [306], and FibroTestÒ [307]. In particular, a score combining pla-
plant settings [285–288]. According to a recent meta-analysis, the telet count with total bilirubin had an AUROC of 0.91 for predict-
diagnostic performance of TE for predicting clinically significant ing CSPH with 88% sensitivity and 86% specificity at a cut-off of
PH (CSPH, HVPG P10 mmHg) in the setting of patients with com- À1.0.
pensated chronic liver disease/cirrhosis is excellent, with an
AUROC of 0.93 [289]; a 90% sensitive cut-off for CSPH diagnosis Similarly, several non-invasive tools have been proposed for
is 13.6 kPa, and a 90% specific cut-off in this setting is 21 kPa. the detection of OV including routine biological parameters
These cut-offs have been shown to allow a correct stratification [308], FibroTestÒ [309], and combination of simple biological
of presence/absence of CSPH in patients with compensated cirrho- and ultrasound parameters [303]. In the largest study to date
sis and potentially resectable HCC, thus reducing the need for comparing retrospectively a panel of serum markers (platelet
invasive hemodynamic assessment [290]. However, while the count, AST/ALT ratio, APRI, Forns index, Lok index, FIB-4, and
correlation is excellent for HVPG values between 5 and 10– Fibroindex) in more than 500 patients with chronic liver diseases,
12 mmHg (typical of cirrhosis without evident clinical mani- the combination of Lok index (cut-off = 1.5) and Forns index (cut-
festations related to PH), it hardly reaches statistical significance off = 8.8) had the best diagnostic performance (AUROC of 0.80
for values above 12 mmHg [286]. This is because, with the pro- and negative predictive value of 90%) for predicting clinically
gression of cirrhosis, the mechanisms of PH become less and less relevant OV [308].
dependent on the intrahepatic resistance to portal flow due to tis-
sue fibrosis and progressively more dependent on extra-hepatic In conclusion, the evidence accumulated so far indicates that
factors (i.e. hyperdynamic circulation, splanchnic vasodilatation) both HVPG and upper GI endoscopy cannot be replaced by non-
[291]. This observation sets a key limitation to the use of LS mea- invasive methods, although an initial non-invasive approach
surements as a non-invasive surrogate of HVPG beyond the pre- may be helpful in selecting patients in whom these procedures
diction of clinically significant (HVPG P10 mmHg) and severe are indicated with a certain level of urgency.
(HVPG P12 mmHg) PH, and, accordingly, TE of the liver is unli-
kely to be useful in monitoring the hemodynamic response to Hepatocellular carcinoma
the administration of beta-blockers or disease progression in the To date, several cross-sectional studies [310–313] identified that
decompensated phase. Conversely, repeated LS measurements high LS value measured by TE is significantly associated with
could be useful during the first year after liver transplantation the risk of presence of HCC (Table 8). However, these cross-sec-
to identify patients with hepatitis C recurrence characterized by tional studies only describe the ‘static’ phenomenon that
a rapid progression towards cirrhosis [292]; in addition, a LS patients with HCC have high LS values than those without
P8.7 kPa one year after orthotopic liver transplantation is associ- HCC, not considering the ‘dynamic’ association between the pro-
ated to a worse prognosis in this setting [293]. gression or regression of liver fibrosis and the risk of future HCC
development. To overcome this limitation, several longitudinal
More uncertain and controversial is the possibility of predict- prospective studies [267,314–323] have recently been published
ing the presence and the size of oesophageal varices (OV) based (Table 8).
on LS values. A correlation between LS values and the presence
of OV has been reported in several studies [196,286–288,294–296] A large prospective cohort study with chronic hepatitis C (866
with AUROCs ranging from 0.74 to 0.85 and cut-offs from 13.9 patients) was conducted in Japan [317]. Along with age, male
to 21.5 kPa. Although the sensitivity for the prediction of the gender, and clinical cirrhosis, stratified LS values were identified
presence of OV was high (76–95%), specificity was in general as an independent risk factor for HCC development. Compared
not satisfactory (43–78%). Regardless, the general features of with patients with LS values 610 kPa, patients with higher LS val-
these studies, i.e. single-centre retrospective, heterogeneous ues were at significantly increased risk of developing HCC (LS val-
etiology of cirrhosis and stages of disease progression, subjective ues, 10.1–15 kPa, hazard ratio [HR], 16.7; LS values, 15.1–20 kPa,
assessment of OV size, do not allow any sound conclusion on the HR, 20.9; LS values, 20.1–25 kPa, HR, 25.6; and LS values, >25 kPa,
utility of LS assessment in predicting the presence of OV and to HR, 45.5). In addition, the cumulative incidence rates of HCC
screen cirrhotic patients without endoscopy [297]. showed a stepwise increase according to the stratified LS values
(p <0.001 by the log-rank test). In addition, Jung et al. [316] fur-
Recently, studies employing different technical approaches ther validated the usefulness of TE in prediction of HCC develop-
have highlighted the potential utility of spleen stiffness (SS) ment in patients with chronic hepatitis B (n = 1130). Compared
assessment for predicting the presence of OV and the degree of with patients with LS values 68 kPa, patients with higher LS val-
PH in cirrhotic patients [298–302]. In particular, the study by ues were at significantly increased risk of developing HCC (LS val-
Colecchia and co-workers [300] measured SS and LS by TE in ues, 8.1–13 kPa, HR, 3.07; LS values, 13.1–18 kPa, HR, 4.68; LS
100 consecutive patients with HCV–induced cirrhosis. All values, 18.1–23 kPa, HR, 5.55; and LS values, >23 kPa, HR, 6.60).
patients also underwent measurements of HVPG and upper GI Furthermore, changes in the risk of HCC development according
endoscopy. The ability of both SS and LS to predict clinically sig- to the pattern of changes in the measured LS was also shown in
nificant PH and the presence of OV was compared to that of the the study, suggesting a potential role for serial LS measurement
18 Journal of Hepatology 2015 vol. xxx j xxx–xxx
Please cite this article in press as: EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J
Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.04.006
