Liver cirrhosis

Article (PDF Available)inBest practice & research. Clinical gastroenterology 25(2):281-90 · April 2011with377 Reads
DOI: 10.1016/j.bpg.2011.02.009 · Source: PubMed
Abstract
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.
8
Liver cirrhosis
Massimo Pinzani, Professor
a
,
b
,
*
, Matteo Rosselli, Research Fellow
a
,
Michele Zuckermann, Consultant Surgeon
a
a
Dipartimento di Medicina Interna, Viale G.B. Morgagni, 85, 50134 Firenze, Italy
b
Center for Research, High Education and Transfer DENOThe, Università degli Studi di Firenze, Florence, Italy
Keywords:
Cirrhosis
Liver brosis
Portal hypertension
Hepatocellular carcinoma
Liver failure
Chronic liver diseases
Liver cirrhosis is a frequent consequence of the long clinical course
of all chronic liver diseases and is characterized by tissue brosis
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 ow. The brotic and
angio-architectural modications of liver tissue leading to
increased intrahepatic resistance and the degree of portal hyper-
tension seem to be highly correlated until HVPG values of
1012 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 1012 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 detoxication 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-inammatory 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 inammation and tissue
brosis, 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: m.pinzani@dmi.uni.it (M. Pinzani).
URL: http://www.denothe.uni.it
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Gastroenterology
1521-6918/$ see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpg.2011.02.009
Best Practice & Research Clinical Gastroenterology 25 (2011) 281290
signicant 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 brosis in pre-cirrhotic
disease, the determinants of brosis regression in cirrhosis are not
sufciently 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 antibrotic therapy in
cirrhotic patients should be the reduction of brosis in the context
of cirrhosis with a benecial impact on portal hypertension and
the emergence of HCC.
Ó 2011 Elsevier Ltd. All rights reserved.
Introduction
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 brotic process may differ in different CLD.
Cirrhosis is a diffuse process characterized by tissue brosis and the conversion of normal liver
architecture into structurally abnormal nodules [1]. Key morphological features of cirrhosis include:
diffuse brosis, 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 [2]. The vascular shunts are determined by the topography of the vascularized brotic septa
and represent an essential feature of cirrhosis [3]. Other relevant characteristics include: capillarization
of sinusoids and perisinusoidal brosis, 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 sufcient
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
brosis (e.g., stage 4 brosis 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 reecting 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 brogenesis, angiogenesis and extra-hepatic involvement typical of this
stage of evolution, suggest that a simple one-stage description for advanced brotic 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 specic 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-
brotic agents) for patients in the cirrhotic stage strongly call for the denition of favourable or
unfavourable end-points that correlate with a discrete clinical outcome in this clinical context. Thus,
there is a pressing need to redene cirrhosis in a manner that better recognizes its underlying rela-
tionship to portal hypertension and related circulatory changes, and more faithfully reects its
progression, reversibility and prognosis [6].
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281290282
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 signicant reduction of brosis is often dened 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
brosis is the consequence of a chronic wound healing reaction occurring in response to chronic
damage and chronic inammation in a biological context characterized by a limited repertoire of
responses. In other words, the deposition of brillar 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 brosis is the net result of
the continuous deposition of new brillar ECM associated with a continuous, but obviously not efcient,
attempt of degradation and remodelling. Although tissue brosis is an essential element in the cirrhotic
transformation of the liver, it is per se devoid of signicant functional (and clinically relevant) effects.
The different pattern of brosis development typical of different CLD [7] may have diverse conse-
quences on the development of PH. In general, brosis 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 dened 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 ow.
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 [79]. 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 brogenic 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-
b
1 (TGF-
b
1), broblast
growth factor (FGF) and vascular endothelial growth factor (VEGF) have been shown to exert a potent
pro-brogenic and pro-angiogenic role [1013]. Second, neo-angiogenesis is stimulated in hepatic
tissue by the progressive increase of tissue hypoxia. This mechanism is strictly linked to the anatomical
modications following the establishment of periportal brosis with an increased contribution of the
hepatic artery to the formation of sinusoidal blood. Accordingly, sinusoidal blood ow 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
[1418]. Practically, tissue hypoxia promotes angiogenesis and brogenesis and brosis and hypoxia
aggravate each other in the presence of persistent parenchymal injury.
The evidence so far accumulated suggests that the association of brogenesis 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 brogenic 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 brosis.
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 ow. The increased intrahepatic resistance
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281290 283
is the result of architectural distortion (brous 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 myobroblasts).
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 35 mm Hg. Patients with
brosis stages 3 or 4 almost uniformly have an HVPG of 6 mm Hg whereas HVPG > 10 mm Hg is
a threshold that identies patients at risk of developing varices, and/or clinical decompensation. Thus,
HVPG > 10 mm Hg denes the presence of clinically signicant 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
events [2125].
Since all cirrhotic patients are identied 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 [26] and in non-
alcoholic liver disease [27]. Importantly, recent evidence indicates that the analysis of gross histologic
features may also have important prognostic implications in cirrhotic liver biopsies: the thickness of
brous septa correlates with HVPG and is an independent predictor of both clinically signicant portal
hypertension (i.e. HVPG > 10 mm Hg) [28] and clinical decompensation [29]. A more precise denition
of the relationship between the brogenic 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 [30]. 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 [31].
The brotic and angio-architectural modications of liver tissue leading to increased intrahepatic
resistance and the degree of portal hypertension seem to be highly correlated until HVPG values of
1012 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
ow that maintains and aggravatethe portal
h
ypertensive state [20]. 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 ow [18]. The loosening of the
close relationship between the pathological conguration 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 brotic 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 1012 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 [34]. 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) 281290284
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 [35]. However, these homeostatic adjustments are not sufcient 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 inuenced 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 baroreex sensitivity and reduced heart rate variability which
correlate with the severity of disease, central hypovolemia and portal hypertension [36]. The hemo-
dynamic derangement is nally 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 detoxication 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 [37] . 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 deciencies 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 microora associated with deranged immunity and integrity of the mucosa causing bacterial
translocation [39]. 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 [40], with activation of pro-inam-
matory cytokines (particularly TNF-
a
) and excessive production of nitric oxide [39].
The establishment of a systemic pro-inammatory 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-inammatory state to a further worsening of brosis 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 brogenesis and tissue inammation [41]. 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
broblasts, myobroblasts 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 myobroblasts [42] .
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 signicant 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) 281290 285
common clinical event leading to patient death [43]. The biology of liver cirrhosis is characterized by
a constant stimulus for hepatocellular regeneration in a microenvironment characterized by chronic
inammation and altered ECM composition [44]. 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 inammatory activity and the brotic stage of the disease [45].
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 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 [46].
In an additional scenario, HPC may rst differentiate into apparently normal hepatocytes, as suggested
by a recent study demonstrating that a signicant percentage of cirrhotic regenerative nodules are
composed by HPC-derived hepatocytes [47], 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
brosis, angiogenesis and inammation will likely results in a reduced incidence of HCC, as suggested
by clinical evidence in cirrhotic patients treated with antivirals [48].
The reversibility of brosis 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-brotic
agent. Pioneer studies highlighted the notion that all experimental models of cirrhosis are reversible
providing that the causative agent is discontinued and sufcient time is allowed. In addition, they
remarked that cirrhosis developing in weeks rather than years is characterized by different features and,
particularly, increased reticulum bres 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 brotic or cirrhotic regression has now been reported in
CLD of different aetiologies, including viral hepatitis [5157], autoimmune hepatitis [58], alcoholic and
non-alcoholic steatohepatitis [5961]. However, when these results were examined by the experi-
enced liver pathologists, there was agreement only for a variable degree of brosis 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 brosis regression, and evident arterialized sinusoids appear in the context of
intrahepatic arterio-venous shunts [64]
.
The
most obvious problem when discussing the issue of brosis 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 brosis (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 brosis 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 [63]. 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 dened 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 brosis once the cause of hepatocellular damage is removed
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281290286
or an effective anti-brogenic agent is administered for a sufcient 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, brotic deposition related to recent disease and
characterized by the presence of thin reticulin bres, of ten in the presence of a diffuse inammatory
inltrate, is likely fully reversible, whereas long standing brosis, branded by extensive collagen cross-
linking by tissue transglutaminase, presence of elastin, dense acellular/paucicellular ECM and
decreased expression and/or activity of specic 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-brogenic strategy is established. In
addition, substantial experimental evidence suggests that long-term brogenesis occurring in human
CLD is characterized by a progressive resistance to apoptosis of hepatic stellate cells/myobroblasts
with the consequent immovability of a critical mass of pro-brogenic cells [70].
Antibrotic therapies: end-points for cirrhosis
The current knowledge on the potential efcacy of antibrotic agents is currently limited to animal
models of liver brosis but it is quite evident that several agents could be sufciently effective and safe
for long-term administration in patients with brogenic CLD. Considering that brosis 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 antibrotic 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 antibrotic agents should be the reduction of brosis in the
context of cirrhosis with a benecial impact on portal hypertension and the emergence of HCC. In other
words, should antibrotic therapies become available for clinical use, the challenges of therapeutically
regressing brosis 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 brosis in pre-cirrhotic
disease, the determinants of brosis regression in cirrhosis are not sufciently 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 brosis 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 antibrotic agents coupled with effective treatments to reduce
portal pressure and its hemodynamic consequences might be more rational.
Practice points
Currently, the diagnosis of cirrhosis relies primarily on histopathological evidence of late
stage brosis (e.g., stage 4 brosis 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
reecting 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 brosis is an essential element in the cirrhotic transformation of the liver, it is
per se devoid of signi cant 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 antibrotic 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 antibrotic strategies is the reduction of
brosis in the context of cirrhosis with a benecial impact on portal hypertension and the
development of HCC.
M. Pinzani et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 281290 287
Conict of interest
None.
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    • "Abnormalities can occur by the following ways: (1) loss or downregulation of miRNA expression due to mutation, epigenetic inactivation, transcriptional downregulation or abnormality processing [48], (2) overexpression of miRNA due to gene amplification or transcriptional upregulation may result in the suppressed production of its target proteins [49], (3) a mutation in 3 0 UTR of an mRNA may affect a miRNA binding site and the miRNA may no longer be able to bind [50], and (4) a mutation in 3 0 UTR of a gene may generate a new miRNA binding site. [51] A huge number of studies reported that miRNAs dysregulation associated to a wide spectrum of diseases such as chronic kidney disease [9], liver cirrhosis [14], systemic sclerosis [15], cardiac fibrosis [13], diabetes [11], pregnancy-related diseases [10] [52], and most notably cancer [12]. Recent studies have shown the regulation of miRNA in human diseases only understood and explained by genetic (deletions , mutations and translocation), epigenetic mechanisms (methylation) or abnormalities in the miRNA processing machinery . "
    [Show abstract] [Hide abstract] ABSTRACT: The central proteins for protection against tuberculosis are attributed to interferon-γ, tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, while IL-10 primarily suppresses anti-mycobacterial responses. Several studies found alteration of expression profile of genes involved in anti-mycobacterial responses in macrophages and natural killer (NK) cells from active and latent tuberculosis and from tuberculosis and healthy controls. This alteration of cellular composition might be regulated by microRNAs (miRNAs). Albeit only 1% of the genomic transcripts in mammalian cells encode miRNA, they are predicted to control the activity of more than 60% of all protein-coding genes and they have a huge influence in pathogenesis theory, diagnosis and treatment approach to some diseases. Several miRNAs have been found to regulate T cell differentiation and function and have critical role in regulating the innate function of macrophages, dendritic cells and NK cells. Here, we have reviewed the role of miRNAs implicated in tuberculosis infection, especially related to their new roles in the molecular pathology of tuberculosis immunology and as new targets for future tuberculosis diagnostics.
    Full-text · Article · Aug 2013
    • "These collaterals are observed no later than 10 h after arterial ligation [28], and neither hepatic necrosis nor death from hepatic ischemia was observed following hepatic artery ligation [26]. However, since infiltration of inflammatory cells, extensive hepatocyte necrosis and proliferation of fibrous tissue reduce liver reserve function in patients with CLD, including chronic hepatitis and cirrhosis [29]–[31], these patients are less tolerable of ischemia and hypoxia than patients without CLD. Thus, severing of the ALHA can easily induce liver dysfunction in patients with CLD. "
    [Show abstract] [Hide abstract] ABSTRACT: To evaluate the prevalence of the accessory left hepatic artery (ALHA; defined as a vessel arising from the left gastric artery, which, together with a typical left hepatic artery, supplies blood to the left lobe of the liver) and its short-term clinical implications in patients undergoing radical gastrectomy for gastric cancer. Clinical data of 1173 patients with gastric cancer who underwent laparoscopy-assisted radical gastrectomy were retrospectively analyzed. Groups of patients with and without ALHA were compared to identify differences in intraoperative and postoperative variables and changes in liver function. Of the 1173 patients, 135 (11.5%) had an ALHA and 1038 (88.5%) did not. There were no significant between-group differences in clinicopathological and intraoperative characteristics, postoperative recovery, and morbidity and mortality rates (P>0.05 each). None of the patients had postoperative symptoms associated with impaired liver function. Glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and total bilirubin (TBIL) concentrations were similar preoperatively. TBIL concentrations on postoperative days 1, 3, and 7 were similar (P>0.05), while GOT and GPT activities were higher in the ALHA than in the non-ALHA group on days 1 and 7 (P<0.05), with all three markers similar in the two groups on day 14. In patients without chronic liver disease (CLD), GOT, GPT and TBIL concentrations were similar in patients with and without ALHA; whereas, in patients with CLD, GOT and GPT concentrations on days 1 and 3 and GOT on day 7 were higher in patients with than without ALHA. ALHA is a common anomaly that was found in 11.5% of patients. It can be safely severed during radical gastrectomy in patients without CLD, but should be left intact in patients with CLD to prevent liver dysfunction. If severed in the latter, the patient should be monitored and liver-protecting therapy may be necessary.
    Full-text · Article · May 2013
    • "Complications of cirrhosis include jaundice, ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy, whose presence is indicative of decompensated disease.8-10 Other reported complications include edema,11 spontaneous bacterial peritonitis,12 and hepatopulmonary13 and hepatorenal syndromes.14 "
    [Show abstract] [Hide abstract] ABSTRACT: Liver cirrhosis is one of the major causes of hospitalization and mortality in children. A wide spectrum of disorders including developmental abnormalities, infections, metabolic and genetic disorders can lead to liver cirrhosis in pediatric patients. Determination of its etiology is important for treatment, prevention of progressive liver damage, family counseling and prioritizing liver transplantation. The aim of this study is to evaluate causes of liver cirrhosis in children in Southern Iran. We included all cirrhotic children aged less than 18 years who referred to an outpatient pediatric gastroenterology clinic affiliated with Shiraz University of Medical Sciences between March 2009 and September 2010 in this cross-sectional study. The etiology of cirrhosis was determined according to clinical findings, laboratory tests, imaging studies such as ultrasonography or computed tomography scan, hepatobiliary scintigraphy and histopathologic examination of the liver biopsy. Cirrhosis with unknown etiology was considered as cryptogenic. A total of 106 cirrhotic children aged between 5 months to 18 years with a mean age of 8.24 ± 6.12 years that included 60 boys (56.6%) and 46 girls (43.4%) were enrolled in the study. The most common causes of liver cirrhosis were Wilson disease (n=22; 20.7%), biliary atresia (n=19; 17.9%), and cryptogenic cirrhosis (n=14; 13.2%). Other causes were autoimmune hepatitis (n=12; 11.3%), idiopathic neonatal hepatitis (n=10; 9.4%), hepatorenal tyrosinemia (n=9; 8.5%), glycogen storage disease (n=6; 5.7%), and progressive familial intrahepatic cholestasis (n=4; 3.8%). Considering the most common etiology of liver cirrhosis in children in this part of Iran we suggest testing for Wilson disease in all cirrhotic children.
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