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Reversibility of hepatitis B virus cirrhosis after therapy: who and why?


The end point of liver fibrosis in almost all chronic liver diseases is cirrhosis. Whether HBV cirrhosis is reversible when the viral disease has been cured is a question that has emerged because of the major progress of antiviral treatments.

The purpose of this review is to prevent the evidence supporting the regression of cirrhosis after antiviral treatment and to discuss several clinically relevant questions that concerning this new concept.

Histological reminder: from normal liver architecture to cirrhosis
A normal liver has no significant fibrous tissue and a lobular organization with blood streaming from the portal tract to the central vein throughout the hepatocyte trabecula. The histological progression of chronic hepatitis B is characterized by increasing deposits of fibrous tissue around the portal tract then the formation of fibrous septa bridging the adjacent portal tract and central vein [1]. Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores are used in both clinical trials and for individual evaluation [2].

Fibrosis is a result of an unregulated wound healing response driven by repeated injury that shifts the balance of extracellular matrix (ECM) turnover towards net deposition. This mechanism leads to the progressive replacement of the functional hepatic parenchyma with fibrous tissue or the ECM, which is composed of many different molecules, including highly cross-linked collagen type I/III [3]. Cirrhosis (F4 according to METAVIR) is a major step forward characterized by the association of annular fibrosis and major architectural remodeling with a shift from a lobular to nodular organization [4]. In cirrhosis, a significant part of the blood is diverted from the hepatocyte and flows through shunting neovessels along fibrous septa. The switch from a lobular to a nodular organization is only one part of the morphological spectrum of cirrhosis because angiogenesis, vascular remodeling, sinusoidal capillarization, perisinusoidal fibrosis, and loss of metabolic zonation also develop with important functional consequences to the physiology of the liver such as portal hypertension and liver decompensation. Thus cirrhosis can only be considered reversible if three major events occur: fibrous tissue degrades, hepatocytes replace the vanished fibrosis and a normal lobular architecture is restored.

Evidence of the reversibility of cirrhosis
Until recently it was generally believed that fibrosis and even cirrhosis was irreversible and the best hope for treatment was to halt the progression of these conditions. There is now increasing evidence in animal models as well as in humans that fibrosis and even cirrhosis can regress or even completely revert to the normal architecture if there is no more liver injury. Once cirrhosis is established and injections are discontinued in the rodent model of cirrhosis induced by repeated injections of carbon tetrachloride, the architecture of the liver becomes nearly normal, fibrosis regresses significantly resulting in a lobular architecture as well as some focal nodular organization [5]. Similarly, bile duct drainage after bile duct ligation is also associated with the regression of fibrosis/cirrhosis in rats [6]. Although results obtained in rodents in the field of experimental liver fibrosis are not always applicable to humans, results clearly show that cessation of the source of injury is the major and probably only condition needed for the regression of cirrhosis. In humans, isolated reports have been published with biopsy-proven regression of cirrhosis of various origins [7]. There are now well-documented pivotal trials in HBV assessing the percentage of regression of fibrosis and cirrhosis with histological follow-up including pre-and post-treatment biopsy (see [8, 9], for review). All studies show that viral suppression has a significant effect on the regression of fibrosis independently of the antiviral regimen. Indeed, In patients achieving long-term suppression of HBV replication with nucleos(t)ide analogues, the regression of cirrhosis has been shown in more than 60% of patients who underwent a protocol liver biopsy after 3–6 years of treatment [10-14].
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What cirrhosis may reverse?
The reversal of cirrhosis relies on three different mechanisms: degradation of the ECM, replacement of vanishing fibrotic tissue by newly formed hepatocytes (regeneration) and restoration of a lobular architecture with a translobular blood flow. If any one of these three mechanisms fails, then cirrhosis will not reverse: this may give some clues to which cases of cirrhosis may reverse.

The degradation of fibrous septa is mainly related to enzymatic digestion by a specialized enzymatic family, the metalloproteases [15]. In parallel, activated hepatic stellate cells either reverse to a quiescent phenotype or die by apoptosis [16]. Metalloproteases can digest most ECM components. However, the presence of extensive collagen crosslinks or the accumulation of elastic fibers, which are both hallmarks of ancient fibrosis can impair enzymatic degradation [17]. Therefore, more recent cirrhosis is more easily reversible than older cirrhosis.

Hepatic regeneration is also needed for hepatocytes to replace fibrous tissue [18]. For regeneration to occur, inflammatory reaction must be halted. In viral hepatitis this is directly linked to viral suppression. Therefore sustained viral suppression is necessary for the regeneration of hepatocytes. However, even if inflammation regresses, potential regeneration is not the same for all cases of cirrhosis. Indeed both aging and of the number of cycles of necrosis and regeneration decrease the ability of hepatocytes to regenerate. Moreover in atrophic cirrhosis the potential of hepatocytes to duplicate is exhausted due to major telomere attrition. In this case, reversal of cirrhosis is unlikely [19].

Finally, the major limiting factor is the shift from nodular to lobular organization with restoration of the translobular bloodstream from the portal tract to central veins and restoration of parenchymal specialized functions. The portal tracts may emerge after resorption of fibrous septa in some but not all cirrhosis, a step that may be impaired because of portal or hepatic vein thrombosis. Finally, a large percentage of cirrhosis may not reverse even after effective antiviral therapy. Altogether and based on pathophysiological mechanisms, cirrhosis is more likely to regress if it is recent, if the cause is controlled, if there is an internal capacity to regenerate and no vascular thrombosis (Table 1).

Table 1. Reversion of cirrhosis. Mechanisms and molecular mechanisms
Necessary mechanism for regression Physiopathology molecular mechanisms
Potential reversion if:
1. Fresh cirrhosis
2. Control of etiology antiviral drugs
3.Young patient macronodular cirrhosis
4.No vascular thrombosis

Physiopathology molecular mechanisms
Enzymatic degradation
Halting inflammation
Internal capacity to regenarate
Persistent permeable portal and central veins

Necessary mechanism for regression
1. Thinning of fibrous septa
2. Hepatocyte regeneration
3. Restoration of lobular architecture
Avatar universal
How can the reversal of cirrhosis be assessed?
One major clinical issue for the reversal of cirrhosis is the reliability of methods to measure the long-term changes of fibrosis. Although the assessment of liver fibrosis by liver biopsy is the current standard of reference for quantifying fibrosis, it is an imperfect gold standard. Another issue for the evaluation of the regression of cirrhosis concerns existing fibrosis scores, which were developed before the notion of regression became an issue. The most common scores are not equipped to assess this aspect, which may include peculiar histological features. The Laennec scoring system of cirrhosis was recently proposed to take this issue into account. This histological scoring system subdivides cirrhosis into three substages (4a, 4b, 4c) according to the thickness of fibrous septa and nodule size [20] (Fig. 1). Regression is probably impossible in stage 4c with thick septa and small nodules, while potential regression is more probable in the other.
Nevertheless and based on the current limitations of liver biopsy, a key to the future assessment of the regression of cirrhosis is the development of reliable, accurate noninvasive biomarkers of liver fibrosis. Although these approaches have gradually gained acceptance for the diagnosis of cirrhosis, they have not been fully validated for assessing the dynamics of liver fibrosis, especially the long-term evaluation of the regression of fibrosis. Although transient elastography can identify a decrease in liver stiffness after the suppression of HBV, the role of confounding histological factors (regression of inflammation) cannot be excluded [21]. Unfortunately, no parallel methods to assess the regression of cirrhosis with non-invasive markers or histology have been developed.
What is the clinical relevance of the reversal of cirrhosis?
Viral suppression in patients with cirrhosis improves the clinical outcome. Indeed, the suppression of viral replication is associated with improved survival, the prevention of hepatic decompensation, less need for liver transplantation and a persistent but reduced risk of HCC [22-24]. Viral suppression is also associated with a significant reduction of fibrosis or the reversal of cirrhosis. In the long-term follow-up of a large cohort of 344 chronic hepatitis C patients, a sustained virological response was found to be present up to 18 years after treatment had stopped, in addition to stable/improved fibrosis (88%) and the regression of cirrhosis (64%) [25]. Unfortunately it is still unknown whether the reversal of cirrhosis is merely a surrogate marker of viral suppression or an independent predictive factor of a positive clinical outcome.

Only one study in HCV has shown a relationship between the regression of histologically-proven cirrhosis and fewer liver-related events (decompensation, hemorrhage, transplantation) [26]. This relationship is not known for HBV and it is particularly relevant for HCC. Indeed, it is well known that cirrhosis is a significant factor associated with a risk of HCC in patients with HBV in Western countries [27]. It is also well-known that there is a residual but significant risk of HCC in HBV cirrhosis after a viral cure. However, it is not known whether there is no reversal of cirrhosis in patients that develop HCC after HBV has been cured, or if the de novo development of HCC is independent of the reversal of cirrhosis.

In conclusion, there is now firm clinical evidence suggesting that complete viral suppression can result in the reversal of HBV cirrhosis, which is restricted to some but not all patients. How to clinically assess this reversal is still a subject of debate. However, even when the reversal of cirrhosis is strongly suspected, monitoring for HCC should be continued.
Avatar universal

according to your experience and of course just an opinion because all US and tests should be considered

i read that histological regression of cirrhosis requires no fibrosis and a shift from micronodular cirrhosis (the most advanced) to macronodular cirrhosis to nodules reabsorption.
so can we guess my enlargment of nodules under peginterferon could be an improvement?
there is very little data online and very little experience except in pisa on the regression of advanced cirrhosis regenerative nodules.according to pisa experience they will dissolve in about a decade but they could not say liver improved
Avatar universal
thank you very much in advance for your thoughts
Avatar universal
thank you stef
Avatar universal
my baseline cirrhosis was 4b or 4c, micronodular cirrhosis, well compensated, all blood tests normal except ast-alt very high
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