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Abstract
Since the original description of the effectiveness of -blockers in lowering the portal pressure
and therefore the risk of variceal bleeding, more than 500 articles in the English literature on the
use of non selective -blockers (NSBB) in cirrhosis have been published. The use of NSBB in
pre-primary prophylaxis of variceal bleeding is currently not indicated. In primary prophylaxis,
patients with high risk small varices or large/medium varices should receive primary prophylaxis
either with NSBB or with endoscopic band ligation if there are contraindications to NSBB. For
secondary prophylaxis the current recommendation is to receive a combination of NSBB and
endoscopic variceal ligation. In addition to lowering portal pressure, NSBB can also reduce
bacterial translocation, potentially exerting multiple beneficial effects which go beyond the
reduction of bleeding risk. Carvedilol is a NSBB with intrinsic anti-(1)-adrenergic activity,
possibly more effective than propranolol in lowering portal hypertension. A potential harmful
effect of propranolol in patients with cirrhosis with refractory ascites deserves further confirmation. NSBB remain the cornerstone of therapy in cirrhotic patients with portal hypertension.
Keywords -Blockers; portal hypertension, propranolol; nadolol; carvedilol; cirrhosis;
Introduction
In 1981, Lebrec et al performed the first randomized clinical
trial involving 74 cirrhotic patients with a history of variceal
bleeding. This study documented a significant reduction in
rebleeding in patients on propranolol as compared to placebo
[1,2]. Since then, there has been a growing interest among
hepatologists regarding the role of non-selective -blockers
(NSBB) in decreasing portal hypertension and preventing
its complications.
2 V. Giannelli et al
The use of NSBB might also be beneficial for other outcomes, such as ascites, spontaneous bacterial peritonitis
(SBP), hepatorenal syndrome (HRS), hepatic encephalopathy
and overall survival. A landmark study by Abraldes et al
documented a positive effect of NSBB in the prevention of
the development of ascites, SBP and hepatic encephalopathy
[45]. Likewise, Hernandez-Gea and colleagues demonstrated
that in patients with compensated cirrhosis and large varices
treated with NSBB, even an HVPG decrease >10% was able to
significantly reduce the risk of developing ascites and other
complications such as refractory ascites and HRS [46]. These
findings may suggest that NSBB, in addition to their protective
role for variceal bleeding, might also be beneficial for other
complications of portal hypertension.
During recent years there has been increasing attention
towards the role of infections in cirrhotic patients [47-49].
Episodes of infection represent a frequent and severe burden
in this group. Up to 40% of hospitalized patients with cirrhosis
have infections and this is associated with longer hospital
stay and a higher risk of death. Infection related mortality
is reported to be between 15% and 19% [50,51]. Bacterial
infections have also been found to be associated with upper
gastrointestinal bleeding [52,53], failure to control variceal
bleeding [54] and early variceal rebleeding [55]. Moreover, the
occurrence of bacterial infections marks an important point in
the natural history of patients with cirrhosis, carrying a 30%
mortality at one month and a 60% mortality at one year [56].
A substantial number of infections in cirrhotic patients
is likely to be linked to bacterial translocation (BT), defined
as the migration of microorganisms or microbial products
from the intestinal lumen to the mesenteric lymph nodes or
other extra-intestinal sites [57,58]. Mechanisms contributing
to this phenomenon are small intestinal bacterial overgrowth
(SIBO) and structural and functional alterations of the intestinal mucosa, together with an impaired immunity [58,59].
The advanced stages of cirrhosis are characterized by an
elevated activity of the sympathetic nervous system whose
fibers terminate in blood vessels, gut-associated lymphatic
tissue and in the intestinal mucosa. The increased level of
norepinephrine promotes the development of SIBO by decreasing the intestinal transit time, impairing the mucosal barrier
function and inhibiting local chemotaxis and phagocytosis [60].
Two in-vitro studies also suggest that in the intestinal lumen, norepinephrine is absorbed by Escherichia coli and other
gram-negative gut bacteria resulting in an increase in growth,
virulence and ability to adhere to the gut mucosa [61,62].
Portal hypertension leads to an increase in intestinal permeability by reducing velocity of mucosal blood flow, causing
Annals of Gastroenterology 27
4 V. Giannelli et al
Hemodynamic responders
and non-responders: utility of assessing
HVPG response
Advantages of NSBB include not only their low cost and
ease of administration, but also the fact that further endoscopic
follow up is not necessary once treatment has been started.
On the other hand, the main inconvenience of NSBB is that
15% of patients may have absolute or relative contraindications to this treatment and another 15% may present side
effects requiring dose reduction or discontinuation [87,88].
The need for assessing hemodynamic response to NSBB is
not clear. As already mentioned, longitudinal studies in patients
treated with NSBB both in primary and secondary prophylaxis
have suggested a very low residual risk of bleeding if there is
a decrease of HVPG by at least 20% of baseline or to values
12 mmHg [19,45,67,89,90]. Patients achieving such a target
reduction in portal pressure have been defined hemodynamic
responders. However, concerns have been raised in relation to
the feasibility, the clinical appropriateness, the risks and the
costs of repeated HVPG measurement [91]. Also, a substantial
number of patients rebleed before their hemodynamic response
can be assessed [91]. This problem could partially be solved
by re-measuring the HVPG after a shorter interval (even
less than 1 month) [92]. Some studies investigated the role
of acute HVPG response to i.v. propranolol in predicting the
risk of bleeding and survival [46,93,94]. It is possible that the
assessment of such an acute hemodynamic response may have
clinical utility, possibly even with a lower threshold (HVPG
reduction of 9-12%). However, further studies are needed.
In addition, there are a substantial number of patients who
find themselves in what has been termed a grey area, in which
clinical benefit from NSBB is not explained by changes in portal
pressure. This could be explained by the non hemodynamic
mechanisms of NSBB described earlier. The protective effect
of -blockers may not only be due to a reduction in portal
pressure but also to a reduction in bacterial infections and,
through this, to a reduction in the risk of bleeding [59,72,95].
Indeed, even hemodynamic non responders to NSBB may
benefit from some of these beneficial effects [72].
As a result, it currently seems reasonable to aim for the
maximum tolerated dose of NSBB in all patients who have
no contraindications to this treatment, without the need
for routine assessment of hemodynamic response through
HVPG measurement.
Concluding remarks
Despite some debate about the relative benefit of NSBB
in patients with refractory ascites, they are still considered
the aspirin of hepatologists [96], both due to their hemodynamic and non-hemodynamic effects. The distinction of
hemodynamic responders and non-responders does not fully
take into account the complexity of the effects of this class of
drugs, which represents one of the most frequently used in
patients with cirrhosis over the last thirty years.
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