Liver cirrhosis is a frequent consequence of the long clinical course of all chronic liver diseases and is characterized by tissue fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. Portal hypertension is the earliest and most important consequence of cirrhosis and underlies most of the clinical complications of the disease. Portal hypertension results from an increased intrahepatic resistance combined with increased portal (and hepatic arterial) blood flow. The fibrotic and angio-architectural modifications of liver tissue leading to increased intrahepatic resistance and the degree of portal hypertension seem to be highly correlated until HVPG values of 10-12 mmHg are reached. At this stage, which broadly represents the turning point between 'compensated' and 'decompensated' cirrhosis, additional extra-hepatic factors condition the further worsening of PH. Indeed, a HVPG ≥10-12 mmHg represents a critical threshold beyond which chronic liver disease becomes a systemic disorder with the involvement of other organs and systems. The progressive failure of one of the fundamental functions of the liver, i.e. the detoxification of potentially harmful substances received from the splanchnic circulation and particularly bacterial end-products, is responsible for the establishment of a systemic pro-inflammatory state further accelerating disease progression. The biology of liver cirrhosis is characterized by a constant stimulus for hepatocellular regeneration in a microenvironment characterized by chronic inflammation and tissue fibrosis, thus representing an ideal condition predisposing to the development of hepatocellular carcinoma (HCC). In reason of the significant improvements in the management of the complications of cirrhosis occurred in the past 20 years, HCC is becoming the most common clinical event leading to patient death. Whereas evidence clearly indicates reversibility of fibrosis in pre-cirrhotic disease, the determinants of fibrosis regression in cirrhosis are not sufficiently clear, and the point at which cirrhosis is truly irreversible is not established, either in morphologic or functional terms. Accordingly, the primary end-point of antifibrotic therapy in cirrhotic patients should be the reduction of fibrosis in the context of cirrhosis with a beneficial impact on portal hypertension and the emergence of HCC.
Massimo Pinzani, Professor
, Matteo Rosselli, Research Fellow
Michele Zuckermann, Consultant Surgeon
Dipartimento di Medicina Interna, Viale G.B. Morgagni, 85, 50134 Firenze, Italy
Center for Research, High Education and Transfer “DENOThe”, Università degli Studi di Firenze, Florence, Italy
Chronic liver diseases
Liver cirrhosis is a frequent consequence of the long clinical course
of all chronic liver diseases and is characterized by tissue ﬁbrosis
and the conversion of normal liver architecture into structurally
abnormal nodules. Portal hypertension is the earliest and most
important consequence of cirrhosis and underlies most of the
clinical complications of the disease. Portal hypertension results
from an increased intrahepatic resistance combined with
increased portal (and hepatic arterial) blood ﬂow. The ﬁbrotic and
angio-architectural modiﬁcations of liver tissue leading to
increased intrahepatic resistance and the degree of portal hyper-
tension seem to be highly correlated until HVPG values of
10–12 mm Hg are reached. At this stage, which broadly represents
the turning point between ‘compensated’ and ‘decompensated’
cirrhosis, additional extra-hepatic factors condition the further
worsening of PH. Indeed, a HVPG 10–12 mm Hg represents
a critical threshold beyond which chronic liver disease becomes
a systemic disorder with the involvement of other organs and
systems. The progressive failure of one of the fundamental func-
tions of the liver, i.e. the detoxiﬁcation of potentially harmful
substances received from the splanchnic circulation and par ticu-
larly bacterial end-products, is responsible for the establishment of
a systemic pro-inﬂammatory state further accelerating disease
progression. The biology of liver cirrhosis is characterized by
a constant stimulus for hepatocellular regeneration in a microen-
vironment characterized by chronic inﬂammation and tissue
ﬁbrosis, thus representing an ideal condition predisposing to the
development of hepatocellular carcinoma (HCC). In reason of the
Corresponding author. Dipartimento di Medicina Interna, Viale G.B. Morgagni, 85, 50134 Firenze, Italy.
Tel.: þ39 055 4271084; fax: þ39 055 417123.
E-mail address: firstname.lastname@example.orgﬁ.it (M. Pinzani).
Contents lists available at ScienceDirect
Best Practice & Research Clinical
1521-6918/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290
signiﬁcant improvements in the management of the complications
of cirrhosis occurred in the past 20 years, HCC is becoming the
most common clinical event leading to patient death. Whereas
evidence clearly indicates reversibility of ﬁbrosis in pre-cirrhotic
disease, the determinants of ﬁbrosis regression in cirrhosis are not
sufﬁciently clear, and the point at which cirrhosis is truly irre-
versible is not established, either in morphologic or functional
terms. Accordingly, the primary end-point of antiﬁbrotic therapy in
cirrhotic patients should be the reduction of ﬁbrosis in the context
of cirrhosis with a beneﬁcial impact on portal hypertension and
the emergence of HCC.
Ó 2011 Elsevier Ltd. All rights reserved.
Liver cirrhosis is a frequent consequence of the long clinical course of all chronic liver diseases (CLD)
characterized by reiterated parenchymal damage. In industrialized Countries, chronic hepatitis C and
heavy alcohol consumption represent the most common causes of cirrhosis. Obesity, associated with
non-alcoholic steatohepatitis, is becoming a common cause of chronic liver disease leading to cirrhosis,
either as the sole cause or in combination with alcohol, hepatitis C, or both. Other common causes of
cirrhosis include hepatitis B, hepatitis D, primary biliary cirrhosis and autoimmune hepatitis. As
detailed in dedicated articles included this issue of Best Practise, the incidence of the evolution towards
cirrhosis as well as the relative patterns of evolution of the ﬁbrotic process may differ in different CLD.
Cirrhosis is a diffuse process characterized by tissue ﬁbrosis and the conversion of normal liver
architecture into structurally abnormal nodules . Key morphological features of cirrhosis include:
diffuse ﬁbrosis, regenerative nodules, altered lobular architecture and establishment of intrahepatic
vascular shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) vessels of
the liver . The vascular shunts are determined by the topography of the vascularized ﬁbrotic septa
and represent an essential feature of cirrhosis . Other relevant characteristics include: capillarization
of sinusoids and perisinusoidal ﬁbrosis, vascular thrombosis and obliterative lesions in portal tracts and
hepatic veins, under-perfusion of lobular parenchyma and consequent tissue hypoxia [4,5]. Altogether
these changes are responsible for the development of portal hypertension and relative complications.
Portal hypertension is indeed the principal mechanism leading to the death of cirrhotic patients.
Traditionally and still in everyday clinical practise, the description of a liver as ‘cirrhotic’ is sufﬁcient
to connote both a pathological and clinical status, and to assign the prognosis of a patient with liver
disease. Indeed, the diagnosis of cirrhosis relies primarily on histopathological evidence of late stage
ﬁbrosis (e.g., stage 4 ﬁbrosis using the METAVIR system, or stages 5 or 6 in the Ishak scoring system). In
these and related staging systems, however, ‘cirrhosis’ is a static diagnosis reﬂecting the end stage of
the wound healing process, without adequately signifying the complexity of its pathogenesis, or its
functional, hemodynamic and prognostic correlates. Along these lines, the increasing knowledge on
the biological mechanisms of ﬁbrogenesis, angiogenesis and extra-hepatic involvement typical of this
stage of evolution, suggest that a simple one-stage description for advanced ﬁbrotic liver disease is
inadequate. This in spite of the distinction between compensated and decompensated cirrhosis which
is based on the degree of portal pressure and the occurrence of clinical complications but not neces-
sarily to other potentially relevant biological events including altered tissue regeneration and the
progressive loss of speciﬁc liver functions. In addition, the emergence of feasible therapeutic options
(i.e. antiviral treatments in patients with HBV and HCV cirrhosis and the surfacing of effective anti-
ﬁbrotic agents) for patients in the cirrhotic stage strongly call for the deﬁnition of favourable or
unfavourable end-points that correlate with a discrete clinical outcome in this clinical context. Thus,
there is a pressing need to redeﬁne cirrhosis in a manner that better recognizes its underlying rela-
tionship to portal hypertension and related circulatory changes, and more faithfully reﬂects its
progression, reversibility and prognosis .
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290282
Fibrogenesis: the path to cirrhosis
Fibrosis and cirrhosis are often used as a synonym and this causes obvious confusion. In particular,
this problem of ten emerges in the description of the favourable effects of antiviral therapy when
a signiﬁcant reduction of ﬁbrosis is often deﬁned as ‘cirrhosis reversal’. This relevant clinical issue will
be dissected in detail in a dedicated section of this article.
As exhaustively detailed in the article by Lang and Friedman in this issue of Best Practise, tissue
ﬁbrosis is the consequence of a chronic wound healing reaction occurring in response to chronic
damage and chronic inﬂammation in a biological context characterized by a limited repertoire of
responses. In other words, the deposition of ﬁbrillar extracellular matrix (ECM) is the simplest, fastest
and only solution and it is, eventually, an ‘intention to treat’ process aimed at preserving tissue
continuity. In addition, it is important to stress that the detectable amount of ﬁbrosis is the net result of
the continuous deposition of new ﬁbrillar ECM associated with a continuous, but obviously not efﬁcient,
attempt of degradation and remodelling. Although tissue ﬁbrosis is an essential element in the cirrhotic
transformation of the liver, it is per se devoid of signiﬁcant functional (and clinically relevant) effects.
The different pattern of ﬁbrosis development typical of different CLD  may have diverse conse-
quences on the development of PH. In general, ﬁbrosis developing with portal to central septa, typical
of chronic viral hepatitis, is characterized by an earlier involvement of the centrolobular vein with the
establishment of neo-vascular shunts between the portal system and the systemic circulation thus
leading to what is deﬁned ‘sinusoidal PH’. Fibrosis secondary to cholestatic diseases, developing with
a portal to portal pattern, is instead characterized by a late involvement of the centrolobular vein with
a more evident development of pre-sinusoidal resistance to portal ﬂow.
Angiogenesis: towards the point-of-no-return
Vascular structures in cirrhotic septa originate either from pre-existing sinusoids, which persist in
areas of post-necrotic collapse of the connective tissue framework, or from pathological angiogenesis
which, irrespective of the aetiology, has been extensively described in CLD [7–9]. From a mechanistic
point of view, angiogenesis in CLD can be explained according two main pathways. First, the process of
liver chronic wound healing typical of ﬁbrogenic CLD is characterized by an over-expression of several
growth factors, cytokines and metalloproteinases (MMPs) with an inherent pro-angiogenic action. In
particular, platelet-derived growth factor (PDGF), transforming growth factor-
growth factor (FGF) and vascular endothelial growth factor (VEGF) have been shown to exert a potent
pro-ﬁbrogenic and pro-angiogenic role [10–13]. Second, neo-angiogenesis is stimulated in hepatic
tissue by the progressive increase of tissue hypoxia. This mechanism is strictly linked to the anatomical
modiﬁcations following the establishment of periportal ﬁbrosis with an increased contribution of the
hepatic artery to the formation of sinusoidal blood. Accordingly, sinusoidal blood ﬂow becomes
increasingly arterialized with hepatocytes adjusting to an abnormally high oxygen concentration.
Subsequently, the progressive capillarization of sinusoids leads to an impairment of oxygen diffusion
from the sinusoids to hepatocytes with the consequent up-regulation of pro-angiogenic pathways
[14–18]. Practically, tissue hypoxia promotes angiogenesis and ﬁbrogenesis and ﬁbrosis and hypoxia
aggravate each other in the presence of persistent parenchymal injury.
The evidence so far accumulated suggests that the association of ﬁbrogenesis and angiogenesis
should be regarded as crucial in the modern evaluation of disease progression and in the search of
therapeutic targets. In addition, depending on the different pattern of ﬁbrogenic evolution distinctive
of different CLD (i.e. post-necrotic, biliary, centrolobular, pericellular/perisinusoidal), the extent of neo-
angiogenesis may have profound consequences on the rate of disease progression to cirrhosis and
represents a key determinant affecting reversibility of ﬁbrosis.
Fibrosis and portal hypertension
Portal hypertension (PH) is the earliest and most important consequence of cirrhosis and underlies
most of the clinical complications of the disease. PH results from an increased intrahepatic resistance
combined with increased portal (and hepatic arterial) blood ﬂow. The increased intrahepatic resistance
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290 283
is the result of architectural distortion (ﬁbrous tissue, regenerative nodules), endothelial dysfunction
leading to intrahepatic vasoconstriction, and intrahepatic vascular shunts between afferent and
efferent vessels of the liver [19,20]. These portal-central anastomoses, although representing direct
connections between the portal and the systemic circulation, follow irregular patterns and are
embedded in a developing scar tissue characterized by the presence of contractile cells (i.e. activated
hepatic stellate cells and myoﬁbroblasts).
In clinical practise, the hepatic venous pressure gradient (HVPG), an indirect measure of portal
pressure, is the best predictor of the development of PH. Normal HVPG is 3–5 mm Hg. Patients with
ﬁbrosis stages 3 or 4 almost uniformly have an HVPG of 6 mm Hg whereas HVPG > 10 mm Hg is
a threshold that identiﬁes patients at risk of developing varices, and/or clinical decompensation. Thus,
HVPG > 10 mm Hg deﬁnes the presence of ‘clinically signiﬁcant portal hypertension’. Notably, variceal
hemorrhage and ascites do not occur when the HVPG is reduced to levels below 12 mm Hg (i.e.
clinically severe PH) and therefore this threshold is closely related to the presence of decompensating
Since all cirrhotic patients are identiﬁed by the highest value of the currently used scoring systems,
the histological features of disease progression within the stage of cirrhosis have not been traditionally
linked to clinical outcomes. However, there is recent evidence indicating that both HVPG and semi-
quantitative features of histology do indeed predict hemodynamic and clinical features of chronic liver
disease and cirrhosis. For example, progressive increases in HVPG correlate with increasing severity of
liver disease (normal, chronic hepatitis, pre-cirrhosis and cirrhosis) both in alcoholic  and in non-
alcoholic liver disease . Importantly, recent evidence indicates that the analysis of gross histologic
features may also have important prognostic implications in cirrhotic liver biopsies: the thickness of
ﬁbrous septa correlates with HVPG and is an independent predictor of both clinically signiﬁcant portal
hypertension (i.e. HVPG > 10 mm Hg)  and clinical decompensation . A more precise deﬁnition
of the relationship between the ﬁbrogenic evolution occurring within cirrhotic liver and the worsening
of PH has been established with the use of a new histological marker, the collagen proportionate area
(CPA), obtained by digital video imaging analysis . Additional work by the same authors suggests
that CPA is indeed a histological variable that scores cirrhosis with a continuous scale and is able to
predict relevant clinical outcomes .
The ﬁbrotic and angio-architectural modiﬁcations of liver tissue leading to increased intrahepatic
resistance and the degree of portal hypertension seem to be highly correlated until HVPG values of
10–12 mm Hg are reached. At this stage, which broadly represents the turning point between
‘compensated’ and ‘decompensated’ cirrhosis, additional extra-hepatic factors condition the further
worsening of PH. These include a decreased vascular resistance in the splanchnic and systemic
circulations leading to an increase in splanchnic blood ﬂ
ow that maintains and aggravatethe portal
ypertensive state . In addition, the progressive development of neo-angiogenesis, particularly
VEGF-dependent angiogenesis, in the splanchnic territory leads to an expansion of the splanchnic
vascular bed with consequent further increase of splanchnic blood ﬂow . The loosening of the
close relationship between the pathological conﬁguration of cirrhotic liver and PH beyond
HVPG > 12 mm Hg is also suggested by studies correlating liver stiffness values (as an expression of the
degree of ﬁbrotic transformation of liver tissue), obtained by transient elastography, with HVPG in
cirrhotic patients [32,33].
From ‘compensated’ to ‘decompensated’ cirrhosis: the evolution towards a systemic disease
From the clinical point of view it is well established that a HVPG 10–12 mm Hg represents
a critical threshold beyond which chronic liver disease becomes a systemic disorder with the
involvement of other organs and systems and the development of life threatening complications. At
this stage of evolution the presence of porto-systemic shunts together with the extra-hepatic collateral
circulation open the way to a gut-derived antigenic load that is therefore free to enter the systemic
circulation triggering and maintaining a constant and subclinical activation of the innate immune
system with production and release of vasoactive molecules, and particularly nitric oxide . These
mediators play a pivotal role in the hemodynamic derangement of liver cirrhosis, on the one hand by
reducing systemic resistances and, on the other hand, participating with a synergic effect on the
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290284
dilatation of splanchnic vessels. This progressively induces a compartmentalization of blood volume in
the splanchnic vascular bed with consequent ‘central hypovolemia’ that, in combination with low
blood pressure, triggers a baroceptor response with potent activation of the sympathetic nervous
system . However, these homeostatic adjustments are not sufﬁcient to counteract the over-
whelming action of systemic vasodilators with a progressive worsening of the hemodynamic condi-
tions. Moreover, the effective hypovolemia reduces kidney perfusion which is also inﬂuenced by the
detrimental effects of circulating catecholamines and other vasoconstrictors such as endothelin 1.
Activation of the renin-angiotensin-aldosterone system leads to sodium-water retention and vaso-
pressin secretion with increased circulating blood volume that is largely ‘captured’ in the splanchnic
district closing the vicious cycle. The consequence is the establishment of a hyperdynamic circulatory
syndrome characterized by low and hyporeactive vascular resistances, low blood pressure, high
circulating blood volume, high cardiac output and increased heart rate. The cardiovascular system of
patients with liver cirrhosis is also characterized by an autonomic dysfunction demonstrated by
abnormal tilting response, reduced baroreﬂex sensitivity and reduced heart rate variability which
correlate with the severity of disease, central hypovolemia and portal hypertension . The hemo-
dynamic derangement is ﬁnally characterized by hyperdynamic circulation and an unequal distribu-
tion of blood volume that accounts for a multiorgan syndrome in which the different perfusion state
paces the degree of organ dysfunction affecting kidneys, lungs, brain and muscles.
The progressive failure of one of the fundamental functions of the liver, i.e. the detoxiﬁcation of
potentially harmful substances received from the splanchnic circulation and particularly bacterial end-
products, has been classically regarded as a main determinant of the hemodynamic derangement
typical of decompensated cirrhosis  . This malfunction is secondary to the progressive reduction of
hepatocellular function and to the intra- and extra-hepatic shunting of portal blood into the systemic
circulation. In addition, the oxidative damage of the intestinal wall, the increased activity of the
sympathetic nervous system and the increased production of nitric oxide lead to marked intestinal
dysmotility causing bacterial overgrowth [37,38]. Furthermore, immune mechanisms in the mesenteric
lymph nodes are compromised and cirrhotic patients show deﬁciencies in their bacteriostatic and
serum chemotactic capacity, in neutrophil phagocytosis and in the effector functions of circulating
immune cells. The cooperation between these mechanisms lead to an altered composition of the
intestinal microﬂora associated with deranged immunity and integrity of the mucosa causing bacterial
translocation . Once in the systemic circulation, bacterial end-products, particularly lipopolysac-
charides (LPS), promote the hepatic synthesis of a bacterial lipopolysaccharide binding protein (LBP)
which favours the binding to the CD14 site of the LPS receptor , with activation of pro-inﬂam-
matory cytokines (particularly TNF-
) and excessive production of nitric oxide .
The establishment of a systemic pro-inﬂammatory state is therefore a key pathogenetic event in
advanced CLD although its manifestations are clinically evident only in patients with decompensated
cirrhosis. It is however likely that early signs of this state are subclinically present in compensated
cirrhosis and their detection could represent an useful tool for predicting the rate of progression
toward decompensation. An additional relevant issue is the potential contribution of the systemic
pro-inﬂammatory state to a further worsening of ﬁbrosis and portal hypertension in cirrhotic liver. This
possibility is supported by the increasingly established role of pathogen-associated molecular patterns
(PAMPs) in the induction of ﬁbrogenesis and tissue inﬂammation . PAMPs are pathogen byprod-
ucts, such as lipopolysaccharides, lipoproteins, bacterial DNA and double-stranded RNA, which are
recognized by pattern recognition receptors (PRRs). In this connection, it is particularly relevant that
ﬁbroblasts, myoﬁbroblasts and vascular pericytes express a variety of PRRs, including toll-like recep-
tors (TLRs), and that their ligands can directly activate these cell types and promote their differentiation
into collagen-producing myoﬁbroblasts  .
Fibrosis and hepatocellular carcinoma
Liver cirrhosis represents an ideal condition predisposing to the development of hepatocellular
carcinoma (HCC). Accordingly, HCC develops in approximately 80% of cirrhotic patients with an
increasing incidence worldwide. Importantly, in reason of the signiﬁcant improvements in the
management of the complications of cirrhosis occurred in the past 20 years, HCC is becoming the most
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290 285
common clinical event leading to patient death . The biology of liver cirrhosis is characterized by
a constant stimulus for hepatocellular regeneration in a microenvironment characterized by chronic
inﬂammation and altered ECM composition . Abnormal hepatocellular regeneration leading to HCC
can be secondary to a step-wise process in which external stimuli induce genetic alterations in mature
hepatocytes thus originating monoclonal populations that harbour dysplastic and subsequently
neoplastic hepatocytes. Alternatively or in addition, HCC may derive from the activation and the
abnormal differentiation of the hepatic progenitor cell (HPC) compartment. The degree of activation of
HPC is positively correlated with the inﬂammatory activity and the ﬁ brotic stage of the disease .
Indeed, the possible involvement of HPC in hepatocarcinogenesis is fully conceivable with the
progression of cirrhosis when the regenerative capability of mature hepatocytes become progressively
more limited. In this context, the relationship between tissue ﬁ brosis and HCC become even more
relevant in reason of the presence of a deranged stem cell niche conditioning the direct differentiation
of HPC into malignant hepatocytes. Along these lines, HCC expressing progenitor cell/ductular markers
such ascytokeratin 19 seem to be more aggressive, chemoresistant and more prone to metastasize .
In an additional scenario, HPC may ﬁrst differentiate into apparently normal hepatocytes, as suggested
by a recent study demonstrating that a signiﬁcant percentage of cirrhotic regenerative nodules are
composed by HPC-derived hepatocytes , with a subsequent neoplastic transformation.
In reason of the intimate relationship between cirrhotic liver and the emergence of HCC, it is
increasingly evident that any action able to reduce the key features of cirrhosis i.e. tissue damage and
ﬁbrosis, angiogenesis and inﬂammation will likely results in a reduced incidence of HCC, as suggested
by clinical evidence in cirrhotic patients treated with antivirals .
The reversibility of ﬁbrosis and cirrhosis
The issue of regression/reversibility of cirrhosis originates from evidence obtained in animal models
upon the discontinuation of the cause of liverdamage or following treatment with a putative anti-ﬁbrotic
agent. Pioneer studies highlighted the notion that all experimental models of cirrhosis are reversible
providing that the causative agent is discontinued and sufﬁcient time is allowed. In addition, they
remarked that cirrhosis developing in weeks rather than years is characterized by different features and,
particularly, ‘increased reticulum ﬁbres are more easily reabsorbed than thick collagen bundles’ [49,50].
Although a regression has been shown in animal models of cirrhosis, this possibility is not yet fully
substantiated in humans. Evidence of either ﬁbrotic or cirrhotic regression has now been reported in
CLD of different aetiologies, including viral hepatitis [51–57], autoimmune hepatitis , alcoholic and
non-alcoholic steatohepatitis [59–61]. However, when these results were examined by the experi-
enced liver pathologists, there was agreement only for a variable degree of ﬁbrosis regression in
cirrhosis but not for a reversal of cirrhosis in most cases [62,63]. Along these lines, there is no
convincing evidence that the abnormalities of the intrahepatic vasculature regress in human cirrhotic
liver. Actually, the available evidence suggests that the so-called veno-portal adhesions persist even in
cases of extensive ﬁbrosis regression, and evident ‘arterialized’ sinusoids appear in the context of
intrahepatic arterio-venous shunts 
most obvious problem when discussing the issue of ﬁbrosis regression in cirrhosis or even
cirrhosis reversal is the lack of a clear and common language and, ultimately, in: A. the precise
distinction of advanced ﬁbrosis (‘pre-cirrhosis’) from true cirrhosis and B. the possibility of staging
cirrhosis. The problem is fundamentally based on the use of semi-quantitative scoring systems for
staging ﬁbrosis and, in particular, in the fact that cirrhosis is always represented by the highest score
and is indeed considered as an end stage of CLD [63,65]. Indeed, cirrhosis appears in a very broad
spectrum of variants (early, fully developed, ‘active’ and ‘inactive’) and more than one study has
documented the transition from micronodular to macronodular cirrhosis following the discontinuation
of the causative agent [66,67]. Practically, there is a fundamental difference between a diagnosis of
cirrhosis and a score of cirrhosis . For example, mostly in reason of sampling error, a low score does
not exclude a cirrhosis of the macronodular or incomplete septal type.
While it is doubtful than an accurately deﬁned cirrhosis is able to reverse to normal, there is sound
evidence concerning the capacity of the healing liver to reabsorb scar tissue. This possibility is abso-
lutely unambiguous in animal models of ﬁbrosis once the cause of hepatocellular damage is removed
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290286
or an effective anti-ﬁbrogenic agent is administered for a sufﬁcient amount of time. However, scar
tissue in the liver of patients with CLD lasting 30 or more years is likely characterized by different
stages of biochemical and biological evolution. Indeed, ﬁbrotic deposition related to recent disease and
characterized by the presence of thin reticulin ﬁbres, of ten in the presence of a diffuse inﬂammatory
inﬁltrate, is likely fully reversible, whereas long standing ﬁbrosis, branded by extensive collagen cross-
linking by tissue transglutaminase, presence of elastin, dense acellular/paucicellular ECM and
decreased expression and/or activity of speciﬁc metalloproteinases, is not [68,69]. In other words,
within the same liver are present different types of scar tissue with different potential and dynamics of
reversibility once the etiological agent is eradicated and/or anti-ﬁbrogenic strategy is established. In
addition, substantial experimental evidence suggests that long-term ﬁbrogenesis occurring in human
CLD is characterized by a progressive resistance to apoptosis of hepatic stellate cells/myoﬁbroblasts
with the consequent immovability of a critical mass of pro-ﬁbrogenic cells .
Antiﬁbrotic therapies: end-points for cirrhosis
The current knowledge on the potential efﬁcacy of antiﬁbrotic agents is currently limited to animal
models of liver ﬁbrosis but it is quite evident that several agents could be sufﬁciently effective and safe
for long-term administration in patients with ﬁbrogenic CLD. Considering that ﬁbrosis is per se the best
solution available to ensure tissue continuity in a context of chronic tissue damage, it would be
detrimental to treat patients with antiﬁbrotic agents without treating the primary cause of damage.
However, this consideration has a strong rationale for the pre-cirrhotic stages of all CLD, where the
primary end-point is to prevent the evolution to cirrhosis, but not necessarily for cirrhosis. At this stage
of evolution, the primary end-point of antiﬁbrotic agents should be the reduction of ﬁbrosis in the
context of cirrhosis with a beneﬁcial impact on portal hypertension and the emergence of HCC. In other
words, should antiﬁbrotic therapies become available for clinical use, the challenges of therapeutically
regressing ﬁbrosis in a cirrhotic liver will be quite different from those of a non-cirrhotic liver for
several reasons. First, whereas evidence clearly indicates reversibility of ﬁbrosis in pre-cirrhotic
disease, the determinants of ﬁbrosis regression in cirrhosis are not sufﬁciently clear, and the point at
which cirrhosis is truly irreversible is not established, either in morphologic or functional terms.
Second, there is a heightened sense of urgency in attempting to regress ﬁbrosis in cirrhosis, since
continued progression might lead to imminent decompensation, while non-cirrhotic disease could be
decades away from clinical consequences. Therefore, in cirrhotic liver, where the ultimate goal is the
reduction of portal pressure, the use of antiﬁbrotic agents coupled with effective treatments to reduce
portal pressure and its hemodynamic consequences might be more rational.
Currently, the diagnosis of cirrhosis relies primarily on histopathological evidence of late
stage ﬁbrosis (e.g., stage 4 ﬁbrosis using the METAVIR system, or stages 5 or 6 in the Ishak
scoring system). In these and related staging systems, however, ‘cirrhosis’ is a static diagnosis
reﬂecting the end stage of the wound healing process, without adequately signifying the
complexity of its pathogenesis, or its functional, hemodynamic and prognostic correlates.
Although tissue ﬁ brosis is an essential element in the cirrhotic transformation of the liver, it is
per se devoid of signi ﬁcant functional (and clinically relevant) effects. Portal hypertension
with the relative hemodynamic complications and the emergence of HCC are the main
clinical and pathophysiological events leading to patient death.
In the pre-cirrhotic stages of all CLD, the primary end-point is to prevent the evolution to
cirrhosis. Consequently any antiﬁbrotic strategy should be applied in association with
strategies able to eliminate or reduce the primary cause of tissue damage (i.e. antivirals).
In cirrhotic patients, the primary end-point of antiﬁbrotic strategies is the reduction of
ﬁbrosis in the context of cirrhosis with a beneﬁcial impact on portal hypertension and the
development of HCC.
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281–290 287
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