Advances
and challenges in cirrhosis and portal hypertension
Annalisa Berzigotti
Abstract
Background:
Liver
cirrhosis is the fourth cause of death in adults in Western countries, with
complications of portal hypertension being responsible for most casualties. In
order to reduce mortality, development of accurate diagnostic methods for early
diagnosis, effective etiologic treatment, improved pharmacological therapy for
portal hypertension, and effective therapies for end-stage liver failure are
required.
Discussion:
Early
detection of cirrhosis and portal hypertension is now possible using simple
non-invasive methods, leading to the advancement of individualized risk
stratification in clinical practice. Despite previous assumptions, cirrhosis
can regress if its etiologic cause is effectively removed. Nevertheless, while
this is now possible for cirrhosis caused by chronic hepatitis C, the incidence
of cirrhosis due to non-alcoholic steatohepatitis has increased dramatically
and effective therapies are not yet available. New drugs acting on the dynamic
component of hepatic vascular resistance are being studied and will likely
improve the future management of portal hypertension.
Conclusion:
Cirrhosis
is now seen as a dynamic disease able to progress and regress between the compensated
and decompensated stages. This opinion article aims to provide the author’s
personal view of the current major advances and challenges in this field.
Keywords:
Hepatic
venous pressure gradient, Non-invasive methods, Liver stiffness, Therapy, Transjugular
intrahepatic portosystemic shunt
Background
Chronic
liver disease (CLD) affects more than 29 million people in Europe [1] and over
300 million people worldwide. The main causes of CLD are alcohol abuse, chronic
viral hepatitis, and metabolic factors (non-alcoholic fatty liver disease).
Over time, extracellular fibrotic tissue develops and accumulates in the liver
as a result of chronic injury, progressively leading to fibrous septa that
prevent normal oxygenation and blood exchange to the liver parenchyma. This
late stage, featuring marked liver anatomical changes, including hepatocyte
extinction, micro- and macrovascular remodeling, neoangiogenesis, nodule
formation, and development of portosystemic shunts, is termed ‘cirrhosis’ [2].
Mortality in CLD is primarily due to complications of liver cirrhosis and
hepatocellular carcinoma (HCC), which is considerably more prevalent in
patients with cirrhosis. The term ‘advanced chronic live disease’ (ACLD) has
been recently proposed to better mirror the
late stages of CLD, which should be considered within a continuum spectrum,
ranging from severe fibrosis to fully developed cirrhosis [3].
Compensated versus
decompensated cirrhosis: the burden of advanced chronic liver disease (ACLD)
According
to the largest study available thus far [4], cirrhosis represents the fourth cause
of death due to non-communicable diseases worldwide, with the total number of
deaths from cirrhosis and liver cancer having steadily risen by approximately
50 million per year over the last two decades. This large mortality rate is
due, to some extent, to a late diagnosis. A decades-long asymptomatic stage
during which no overt sign of the disease is noticed is characteristic of CLD.
Indeed, even after the onset of cirrhosis, the disease can remain asymptomatic,
or ‘compensated’, for a long time [5]. Nevertheless, during this time, portal
hypertension progressively develops, usually accompanied by a decline in
hepatocellular function. Portal hypertension is the major driver in the
transition
from
the compensated to the ‘decompensated’ stage of cirrhosis [5], defined by the
presence of clinical complications, including ascites [6], bleeding from
gastroesophageal varices [7], spontaneous bacterial peritonitis [8],
hepatorenal syndrome [6], and hepatic encephalopathy [9]. Further
decompensating episodes are often triggered
by
bacterial infections [10], and are associated with a very high mortality risk.
From a prognostic point of view, compensated and decompensated cirrhosis are dramatically
different, and can be considered as two separate diseases. Furthermore, within
these two major stages, several sub-stages with varying risk of further
decompensation and death can be identified [11] (Fig. 1).
Knowledge
of the pathophysiological mechanisms driving the transition within these stages
is key in the current management of cirrhosis [7]. Besides its negative impact
on life expectancy, cirrhosis implies several other burdens, including a marked
increase in healthcare costs due to hospitalization and treatment (estimated at
approximately $2.5 billion per year in the US) [12], loss of productivity
(estimated at $10.6 billion per year in the US) [12], and a marked reduction in
quality of life [13]. These burdens are almost exclusively caused by
complications during the decompensated stage. Given that chronic viral
hepatitis C (HCV) is a leading etiology of CLD [14], the recent availability of
direct, high efficacy oral antiviral agents against HCV represents a major
breakthrough towards achieving a reduction in mortality linked to CLD. Unfortunately,
despite the reduction in the incidence of HCV-related liver disease
complications already observed [15] and
the marked decrease further expected over the coming years, over 40% of HCV
infection
cases have not been identified and may be recognized at a late, decompensated
stage, when treatment of the viral infection may be futile [16]. In addition,
other etiologies of CLD are becoming more common or remaining steadily
frequent. Cirrhosis due to non-alcoholic steatohepatitis is markedly increasing
as a consequence of the obesity pandemic worldwide [17], already ranking second
among the etiologies of cirrhosis in patients on the
waiting
list for liver transplantation in the US [15].
Furthermore, liver disease associated
with alcohol use
disorders
is highly prevalent worldwide, and is particularly relevant in Europe, where it
accounts for the highest proportion of cirrhosis cases [18]. Of note, over the past
30 years, mortality due to cirrhosis in Europe increased in areas with the
highest alcohol consumption
(United
Kingdom, Eastern Europe, Ireland, and Finland) [19]. Nevertheless, in several
countries within the EU limiting alcohol use is not yet considered an absolute
priority for policy-makers [20].
Over
the last decades, new knowledge on the pathophysiology,
diagnostic
methods, and therapy of cirrhosis and portal hypertension have significantly
improved the management of this disease, with a marked reduction in mortality
related to some of its complications, particularly variceal bleeding [21].
However, in a recent analysis based on over 100,000 cases, 30-day mortality
following discharge for any decompensation of cirrhosis was equal to or even
higher than that observed 10 years prior, suggesting that the burden of
mortality was merely shifted to the immediate postdischarge period [22]. Among
the major determinants of mortality are inflammation in
acute-on-chronic
liver failure (associated with different complications of end-stage liver
disease) and HCC [23] (not discussed in the present paper), both of which have
been the subject of extensive research but remain unsatisfactorily resolved. To
achieve a substantial improvement in survival, every step of the management
process of patients with ACLD should be addressed and optimized (Fig. 2). An early
diagnosis of cirrhosis, i.e., within the compensated
stage,
and an accurate risk stratification are key to the
following
steps. Indeed, in the author’s opinion, the use of resources at this initial
step (e.g., initiation of HCC surveillance, endoscopic screening of varices
needing treatment in patients at high risk, prevention of decompensation by
appropriate non-pharmacological and pharmacological therapy) is largely
justified by the expected
survival
benefits.
Early
diagnosis and risk stratification: moving towards personalized medicine
The reference standard methods to
diagnose cirrhosis, portal hypertension, and esophageal varices are liver
biopsy, hepatic venous pressure gradient (HVPG) measurement, and endoscopy,
respectively [24]. All of these methods are invasive, and require expertise to
be correctly performed and interpreted. Undoubtedly, the availability of novel
non-invasive diagnostic methods, and ultrasound elastography in particular, has
enhanced the likelihood of early diagnosis of ACLD, facilitating the
identification of patients with compensated disease who are at high risk of complications,
prior to the occurrence of decompensation. Liver stiffness (and more recently
spleen stiffness) can be measured by various ultrasound elastography methods [25],
and mirrors the severity of liver disease and portal hypertension in patients
with compensated ACLD [26].
The diagnosis of clinically
significant portal hypertension
(CSPH;
HVPG ≥ 10 mmHg) is made possible by elastography, with an accuracy greater than
80% when using a binary cut-off approach [27]. As with all numerical variables holding
prognostic value, liver stiffness can be modeled and calibrated, and the risk
(probability) of CSPH can be calculated according to the measured values [28],
thus
Fig. 1 Clinical
stages of cirrhosis. The first major classification is based on the absence or
presence of complications. Cirrhosis is named ‘compensated’ in the absence of
complications, and ‘decompensated’ if complications are present or have been
present in the past. In patients with compensated cirrhosis, the presence of
clinically significant portal hypertension (HVPG ≥ 10 mmHg) identifies a
substage with higher risk of developing any complication (varices, decompensation).
The decompensated stage is characterized by a high risk of progression to
further decompensation, liver failure, and death. Evidence-based therapy has
been developed by targeting the pathophysiological mechanisms driving the
transition from a given step to the following one. The major advances in each
stage are indicated within the figure
leading
to personalized medical decision-making. The vast data available regarding the
relationship between liver stiffness, CSPH, and varices led the Baveno VI
consensus conference on portal hypertension, held in 2015 [29], to suggest a
simple combination of liver stiffness measured by transient elastography
(<20 kPa) and platelet count(>150 G/L) in order to identify patients at
low risk of varices needing treatment in whom endoscopic screening could be
safely avoided [29]. Since 2015, these noninvasive criteria have proven robust
and accurate, even if conservative (only approximately 20–25% of endoscopies spared).
Recent research has proposed expanded non-
Fig. 2
Logical steps in the clinical management of advanced chronic liver
disease/cirrhosis. Improved survival can be achieved through adequate diagnosis
and risk stratification, thus allowing a personalized approach to therapy. Some
examples of factors to be considered, as well as the major pathophysiological
factors driving the therapy of portal hypertension in patients with compensated
cirrhosis, are provided
invasive
criteria allowing a much larger proportion of endoscopies to be spared without
increasing the risk of false negative results [30, 31].Real-time, simple
diagnostic methods, such as ultrasound and elastography, are key to achieving
bedside screening and first risk stratification. However, in patients who
cannot be sufficiently characterized by these simple methods or in particularly
sensitive situations, such as in patients with compensated cirrhosis and
potentially resectable HCC [23, 32], HVPG measurement remains the best method
to accurately stage portal hypertension. Nevertheless, recent advances in
magnetic resonance imaging (magnetic resonance elastography [33],
multiparametric magnetic resonance imaging [34]) hold promise and should be
further investigated as surrogates of portal hypertension, particularly in
patients who are not appropriate candidates for ultrasound elastography. Despite
the use of diagnostic tests being of paramount importance to achieve a correct
risk stratification, the meaning of risk factors that are easily detected by
physical examination and clinical history should not be disregarded.
For instance, factors related to
nutrition, and which are therefore potentially modifiable, should be actively investigated.
Irrespective of the etiology leading to ACLD, overweight and obesity are increasingly
observed in compensated patients [35], and have been consistently associated
with an up to three-fold higher risk of clinical decompensation. Further,
sarcopenia [36] and vitamin D deficiency [37] are frequent in cirrhosis
(including in obese patients), almost invariably present in decompensated patients,
and associated with higher mortality. Research in the field of nutritional
factors modulating the natural history of cirrhosis is insufficient and
represents a field for future investigation. For example, while alcohol intake
is a well-known negative prognostic factor, coffee consumption has only
recently been proven protective [38, 39]. Future research should also focus on
providing accurate and individualized prediction of ‘hard’ endpoints, such as
clinical decompensation and death, by noninvasive diagnostic methods. In the
author’s opinion, the development of risk algorithms similar to those used in cardiovascular
medicine (e.g., Framingham risk score [40]) would be advisable and feasible in the
field of compensated cirrhosis to predict and stratify the risk of
complications of portal hypertension.
Advances in therapy
Several
studies have demonstrated that, in portal hypertensive patients, if portal
pressure is reduced enough (i.e., by at least 20%) by applying pharmacological
and/or non-pharmacological therapies, the risk of decompensation or further
decompensation and death is markedly reduced [7, 41–43] – this constitutes the
rationale of treatment of portal hypertension. To achieve the highest efficacy,
treatment should be aimed at correcting the main pathophysiological target in
each stage of cirrhosis. In the early, compensated stages of cirrhosis,
increased hepatic resistance plays a pivotal role in the development of portal
hypertension (Pressure = Resistance × Flow) [2]. Therefore, in compensated
cirrhosis, correction of increased intrahepatic resistance should be addressed
[7, 44].
This can be achieved by
ameliorating the mechanical component
of
resistance mostly represented by fibrosis and/or by acting on the functional
component represented by active vasoconstriction and sinusoidal endothelial dysfunction[45].
Etiologic treatments have been shown effective in improving
fibrosis
and can lead to cirrhosis regression in the long term [46]; thus, they should
be considered central at this stage of the disease. Short-term (4 months)
lifestyle changes consisting of diet and exercise combinations are able to
improve obesity in compensated cirrhosis and are associated with a significant
reduction in HVPG [47], likely mirroring a decrease in intrahepatic resistance
(e.g., mediated by a decrease in insulin resistance). While supplementing vitamin
D deficiency and correcting sarcopenia is likely to positively influence prognosis,
the mechanisms driving the interaction between nutritional factors and portal hypertension
remain to be elucidated.
Pure antifibrotic drugs are currently lacking
[48]. However, statins, which improve the phenotype of sinusoidal endothelial
cells by restoring nitric oxide production, are able to decrease intrahepatic
fibrogenesis and angiogenesis in experimental models [49] and ameliorate portal
hypertension by decreasing both the dynamic and structural components of
intrahepatic resistance [50]. Interestingly, this is accompanied by an amelioration
in hepatic function and perfusion in patients with cirrhosis [51]. Statins have
proven effective in preventing hepatic decompensation in large epidemiological
surveys in patients with HCV and hepatitis B virus cirrhosis [52, 53]. In
addition, their use has been associated with a decreased risk of HCC [54] and, most
recently, addition of simvastatin to standard medical and endoscopic therapy
has been shown to improve survival in a double-blind randomized multicenter
clinical trial
in
patients who survived an episode of bleeding from esophageal varices [55]. Thus, statins constitute the most promising
class of drugs to be added to the standard therapy armamentarium for ACLD and
portal hypertension. Once CSPH has developed, and even more so following the
formation of varices, the resulting hyperdynamic circulatory state leads to an increased
portocollateral flow, which aggravates portal hypertension [2, 56]. At this
stage, drugs acting to reduce blood flow are effective in reducing portal
pressure. Non-selective beta-blockers (NSBBs; propranolol, nadolol, or carvedilol)
are the mainstay of therapy in this clinical scenario [7], and recent data from
a
randomized
controlled trial (RCT) suggest that they
effectively
reduce the risk of ascites and clinical decompensation in patients with small
varices [57]. Given the abovementioned data, it has been suggested that NSBBs,
statins, and oral antibiotics (rifaximin [58] or norfloxacin) could be used in combination
to prevent clinical decompensation in patients with cirrhosis [59]. In a recent
study, patients treated with rifaximin added to propranolol showed a more
marked decreased in HVPG as compared to patients on propranolol alone [60]. A
further group of drugs showing promising results is
represented
by anticoagulants. Contrarily to what was previously thought, cirrhosis can be
considered a procoagulant state, and experimental data suggest that low
molecular weight heparin [61] and direct oral anticoagulants
[62]
inhibit fibrogenesis and decrease portal pressure in cirrhosis. A small RCT
using enoxaparin Mto prevent portal vein thrombosis in patients in the waiting
list for liver transplantation showed a reduction in mortality [63].
Given the increased
susceptibility to life-threatening bacterial infections observed in patients
with decompensated cirrhosis [8], the reduction of intestinal bacterial translocation
by antibiotic therapy is another potential treatment able to reduce the risk of
spontaneous bacterial peritonitis and mortality in patients with decompensated cirrhosis
and ascites. In a recent RCT [64], norfloxacin combined to standard medical
therapy improved survival compared with standard medical therapy alone in
patients with decompensated alcoholic cirrhosis and severe liver failure. In
addition, a further strategy aimed at improving effective intravascular volemia
by using weekly administration of intravenous albumin in addition to standard
medical therapy improved survival
in
patients with ascites versus standard medical therapy alone [65]. Nevertheless, these
results are not yet published in full and require validation. Transjugular
intrahepatic portosystemic shunt (TIPS) is a well-accepted therapy to prevent
rebleeding in patients experiencing more than one episode of variceal bleeding,
in patients with refractory ascites it demonstrated a survival benefit vs.
large volume paracentesis.Recent data suggest that TIPS may also be applied to other
clinical scenarios in cirrhosis to improve outcomes. In a RCT of TIPS versus
standard medical plus endoscopic therapy in patients presenting with variceal bleeding
and poor liver function (Child–Pugh score B9 to C12 points), the early use of
TIPS (within 72 hours with the aim of preventing early rebleeding) reduced From
mortality
by 25% [66]; these results have been validated in a second multicentric study
[67]. In the setting of patients with recurrent (not refractory) ascites, TIPS improved
survival by over 40% in comparison to standard medical therapy [68]. A major
gap remains regarding the ability to noninvasively monitor the effect of
therapy on portal pressure. None of the currently available non-invasive tests holds
sufficient accuracy in mirroring the HVPG response. A recent study suggested
that changes in spleen stiffness (measured by point shear wave elastography) might
parallel changes in HVPG and portal pressure gradient after NSBB and TIPS [69];
however, these results require validation. The development of other noninvasive tests,
such as subharmonic aided pressure estimation on contrast-enhanced ultrasound
[70], as well as non-invasive measurements derived by parameters from resonance
imaging
[34] are urgently needed in this field. Finally, a novel challenge has resulted
with regards to the population of patients with HCV cirrhosis in whom
the
virus was successfully cured by direct acting antivirals. A minority of these
patients will improve after treatment, but a substantial proportion (over 70%)
of
those
who had CSPH at the time of therapy remains at risk of developing complications
of portal hypertension [72]. Unfortunately, we currently lack non-invasive
surrogates of HVPG in this population, and it remains unknown
whether
cirrhosis will successfully revert in the long term. The ‘point of no return’
in the natural history of cirrhosis is currently unknown, and certainly
represents a major field for future research as well as a potential endpoint
for novel therapies.
