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

[stef2011]

http://onlinelibrary.wiley.com/doi/10.1111/liv.12710/full

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].

[studyforhope]

This is a human monoclonal antibody to neutralize a fibrogenesis factor, tested on several fibrosis models with moderate success.
There are places in the body where fibrosis formation is needed, a general shutdown is always somewhat problematic.
Success is hard to proof, since only de novo fibrogenesis can at best be halted and one has to wait until the turnover of existing collagen fibers removes the state of fibrosis.

At this time we can only await reports of results, with modest optimism.

The reduction of inflammation by suppression of virion production seems to work well to halt further hbv induced fibrogenesis, thus potent antivirals will mostly lead to a slow regression of fibrosis status in the liver.

[new_hepb]

Studyforhope,

What are your thoughts on Fibrogen - FG-3019?

https://www.clinicaltrials.gov/ct2/show/NCT01217632?term=3019-801&rank=1

Looks like it has been in Phase 2 clinical trial since 2010.

Thanks in advance

[stef2011]

thanks i will go with MRI then, it is free by healthcare and add pre and probiotics

thank you very much for your very valuable suggestions

[studyforhope]

Probiotics are a must, together with prebiotics, like inulin a branched polyfructose compound well researched for its positive effect on intestinal flora composition.
To further support intestinal health and prevent intestinal leakage, the extremely high demand for DNA synthesis of the intensely replicating  intestinal epithelium must be met. Glutamin  (Not glutamic acid!) supplies nitrogen to build DNA building blocks and of course vit b12 and folic acid are a must.

Intestinal leakage and intestinal  ammonia producing bacteria are of particular danger to persons with compromised and inflamed liver disorders.

[studyforhope]

MRI with contrast is definitely better, but quite expensive. US is very capable of discovering small HCCs.And it might be easier to ask for less expensive testing, so you actually get it done. 4 month interval would be very sufficient. 6 month is normally used.

If a new round lesion is discovered by US, then a follow up using MRI is rapidly needed, to differentiate harmless hemangiomas from small HCCs.

Small single HCCs can be killed by several methods, like Ethanol injection, percutaneous radio ablation and chemembolization. The prognosis at this early stage is excellent, so frequent monitoring is the key to survival.

[stef2011]

thank you very much for your suggestions.

i understand the best thing is: go for preventive immune therapies at this point, which i am already doing like gcmaf, alkaline diet with lots of vegetables, lemon/baking soda.i just need to add probiotics to this like gcmaf probiotic

as to monitoring would you go US every 4 months or MRI with contrast?

[studyforhope]

Here is an example of the results of anslysis of individual nodules:

The number of dysplastic nodules detected clinically has increased since patients with hepatitis virus-associated cirrhosis, who are at increased risk for hepatocellular carcinoma (HCC), began to undergo regular cancer surveillance. Although it is potentially important to determine which type(s) of nodule may be prone to progress to HCC, outcomes of dysplastic nodules have not been fully investigated. This prompted us to examine the outcomes of dysplastic nodules in cirrhotic patients clinicopathologically. We studied 33 dysplastic nodules of <20 mm in maximum diameter, diagnosed by fine needle aspiration biopsy under ultrasonography (US). These nodules were clinically followed, mainly by US examination, for up to 70 months. When the nodules enlarged or exhibited changes on US, they were histologically reexamined by second biopsy. Surprisingly, 15 of the 33 nodules (45.5%) disappeared, 14 nodules (42.4%) remained unchanged, and only 4 nodules (12.1%) progressed to HCC. The latter 4 nodules were all hyperechoic on US and were composed of clear cells with fatty change or small cells with increased nuclear density, and in all 4 patients serum was positive for hepatitis C virus antibody. Univariate analyses revealed that, although not significant, the hyperechoic nodules or nodules with small cell change showed a higher HCC progression rate in comparison with the hypoechoic nodules or the nodules without small cell change. In summary, most of the dysplastic nodules we followed disappeared or remained unchanged, but some progressed to HCC. Hyperechoic nodules in patients with hepatitis C virus-associated cirrhosis, which show small cell change with increased nuclear density, may be prone to progress to HCC.

[studyforhope]

Nodules are mostly clonal expansions of liver cells more ready to proliferate due to beginning chromatin alterations. Their tissue architecture is rarely optimal, with proper portal tracts, sinusoidal capillaries and central vein drainage. They will provide mainly functional hepatocyte mass, leading to good synthetic properties of the liver in terms of albumin, clotting factors and other  functional proteins. Due to the suboptimal architecture of the substance exchange between liver and portal capillary blood you expect moderately reduced clearance and homeostatic metabolic functionality.

The key problem is the increased propensity to develop into HCC and frequent US monitoring is essential.

The reduction in liver stiffness is a sure sign of decreased collagen and fibrosis content, with increased functional cell mass and the elimination of the diffusion barrier in the space of disse between capillaries and hepatocytes.
This a very good sign re regaining overall liver functionality, but vascular architecture rebuilding is more limited and might depend on age, length of the cirrhotic stage pre improvement, degree of thrombotic destruction and general health together with persistent stress factors like alcohol, improper food and intestinal health and remaining low grade hepatitis.

At this stage a liver biopsy might be helpful to clarify the tissue qualities of these nodules.

[flyinsky]

What do you think about reliability of fibroscan.i am afraid that it does t give a correct mesure.i remark that many patient include me done fibroscan but different reading during small period.should we go for biopsy to be sure about the liver conditions?

[stef2011]

I saw that the cutoff value for Cirrhosis is 17kpa.

no the risk of cirrhosis starts from low values like 11.5-12.5kpa, maybe the article was about very sure cirrhosis

[stef2011]

Stef, if your fibroscan is only 4.5kpa, isn't is clear sign that you improved?

of course but thats fibrosis, not nodules.the liver can work perfectly with nodules too but full reversion of cirrhosis is both fibrosis and histology (nodules).so i would call mine regression until nodules are not cleared

[Kamranbey]

Stef, if your fibroscan is only 4.5kpa, isn't is clear sign that you improved? I saw that the cutoff value for Cirrhosis is 17kpa. I mean does one need to do other tests to see cirrhosis improvement besides fibroscan?  

[stef2011]

my baseline cirrhosis was 4b or 4c, micronodular cirrhosis, well compensated, all blood tests normal except ast-alt very high

[SafiSifa]

thank you stef

[stef2011]

thank you very much in advance for your thoughts

[stef2011]

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

[stef2011]

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.

[stef2011]

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
Others