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Digestive and Liver Disease xxx (xxxx) xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease
journal homepage: www.elsevier.com/locate/dld
The need of HVPG-guided beta-blocker therapy for NASH
cirrhosis with varices –Answer is still up in the air
Portal pressure (PP) is a key predictor of the development
of liver decompensation and mortality in patients with advanced
chronic liver disease (aCLD). Among the methods of portal pres-
sure assessment, hepatic venous pressure gradient (HVPG) mea-
surement is the gold-standard method to assess the presence of
clinically signiﬁcant portal hypertension (CSPH) which is deﬁned
as HVPG ≥10 mmHg  . The assessment of response to non-
selective beta-blockers (NSBB) therapy is another indication for
HVPG, which also helps in the prognostication of the patients
with aCLD [ 1 , 2 ]. We read the recently published original arti-
cle by Paternostro et al.  , analyzing the prognostic value of
HVPG-response to (NSBB) in patients with NASH-related cirrho-
sis and varices. The authors reported that 55.3% of the patients
achieved HVPG-response to NSBB. Presence of diabetes (adjusted
odds ratio (aOR) 0.16, p = 0.038) and baseline mean arterial pres-
sure (MAP) (aOR:1.07, p = 0.044) were independent predictors of
NSBB- response. Child-Pugh stage B/C, MELD ≥15, and HVPG ≥
20 mmHg but not HVPG response, predicted the composite end-
point of bleeding or decompensation at 90 days and 2 years. While
this study adds to the limited existing literature on eﬃcacy and
outcomes of NSBB induced HVPG-response in patients with NASH
cirrhosis, some issues need to be addressed.
First, the study has a small sample size, making it underpow-
ered to study decompensation and mortality. The retrospective na-
ture may also have led to selection bias. In cirrhotic patients with
obesity, a lifestyle change through diet and exercise reduces body
weight and HVPG  . The difference in the proportion of patients
adhering to lifestyle modiﬁcation practices and the difference in
the choice of NSBB in both groups may have led to a difference in
Second, the study included patients on NSBB for both primary
and secondary prophylaxis and HVPG response was deﬁned as re-
duction ≥10% or to < 12 mmHg. However, this cut-off is appli-
cable only for primary prophylaxis. For patients on secondary pro-
phylaxis, an HVPG reduction of ≥20% or to < 12 mmHg quali-
ﬁes as a response [ 1 , 2 ]. Hence, using the same criteria for both
the patient category leads to a higher proportion of patients on
secondary prophylaxis being labeled as responders, which further
makes the comparison diﬃcult.
✩ Letter to original article : Paternostro R, Becker J, Hofer BS, Panagl V, Schiffke H,
Simbrunner B, et al. The prognostic val ue of HVPG-response to non-selective beta-
blockers in patients with NASH cirrhosis and varices . Dig and Liv Dis. 2021 Nov 16.
DOI of original article: 10.1016/j.dld.2021.09.009
Third, details of the sedation protocol used for HVPG mea-
surement are missing from the study. In a previous study by Re-
verter et al.  , propofol and remifentanil-induced deep seda-
tion was found to be signiﬁcantly associated with variation in
levels of HVPG and portal pressure gradient (PPG) in patients
with TIPS. Half of the patients were incorrectly classiﬁed based
on the target of a 10% reduction in HVPG. Similar ﬁndings were
reported in a recent study  , showing propofol to reduce the
wedged hepatic vein pressure values (WHVP) measurement lead-
ing to alterations in HVPG readings. Hence, it is important to take
this into account when estimating prognosis or targeting HVPG
Fourth, the study reported that NSBB-response was neither pre-
dictive of the development of bleeding/decompensation at 90 days
( p = 0.172) nor at 2 years ( p = 0.993). Also, NSBB response did
not predict the 2-years transplant-free survival. So, whether HVPG-
guided therapy should be advocated for all patients with varices or
only high-risk patients, remains a question. The AASLD guidelines
also recommend against routine performance of HVPG for moni-
toring changes, outside clinical trials  .
Lastly, the levels of HVPG and WHVP in NASH patients are
lower than those in HCV patients at each stage of ﬁbrosis  . In
a recent study, patients with NASH-related cirrhosis had a higher
prevalence of decompensation than patients with HCV at any cut-
off level of HVPG ( < 10, 10 –12 or > 12 mmHg)  . Among those
with HVPG < 10 mmHg, around 9% of patients had decompensa-
tion. Hence, a cut-off HVPG of 20 mmHg for predicting adverse
outcomes in NASH-related cirrhosis as suggested by the present ar-
ticle is going to overlook a lot of patients who still remain at risk
While the technique of HVPG measurement is safe, feasible,
and reproducible, it is invasive. Additionally, HVPG has low ac-
ceptability among chronic liver disease patients and requires tech-
nical expertise typically only found in tertiary medical centers.
Hence, non-invasive methods of assessment are increasingly be-
coming popular. In a study of patients with biopsy-proven NASH,
APRI, FIB-4, and NAFLD ﬁbrosis scores were found to have sim-
ilar AUC as HVPG for prediction of decompensation or mortality
 . Dynamic change in splenic stiffness ( SS) was found to be a
good predictor of hemodynamic response to NSBB prophylaxis in
patients with high-risk esophageal varices  . In another subse-
quent study, SS with a reduction of ≥10% was found to be pre-
dictive of the hemodynamic response, similar to HVPG  .
To conclude, disease behavior and progression in patients with
NASH-related cirrhosis are different from other etiologies of cirrho-
sis. Further, well-designed prospective studies with larger popula-
tion are needed to deﬁne thresholds for HVPG for the prediction of
decompensation and long-term outcomes in patients with NASH-
related cirrhosis and to study the performance of non-invasive
methods for assessment of response to NSBB.
1590-8658/© 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
S. Giri Digestive and Liver Disease xxx (xxxx) xxx
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JID: YDLD [m5G; December 13, 2021;8:12 ]
Conﬂict of interest
All authors have participated in (a) conception and design, or
analysis and interpretation of the data; (b) drafting the article or
revising it critically for important intellectual content; and (c) ap-
proval of the ﬁnal version.
This manuscript has not been submitted to, nor is under review
at, another journal or other publishing venue.
The authors have no aﬃliation with any organization with a di-
rect or indirect ﬁnancial interest in the subject matter discussed in
The following authors have aﬃliations with organizations with
direct or indirect ﬁnancial interest in the subject matter discussed
in the manuscript: Dr. Suprabhat Giri, Seth GS Medical College and
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Department of Gastroenterology, Seth GS Medical College and KEM
Hospital, Mumbai, India
∗Corresponding author at: Department of Gastroenterology,
Seth GS Medical College and KEM Hospital, Acharya Donde
Marg, Parel, Mumbai, India-40 0 012.
E-mail address: email@example.com