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Reversibility of hepatitis B virus cirrhosis after therapy: who and why?
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].
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].
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.
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.
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.
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.
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?
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
no the risk of cirrhosis starts from low values like 11.5-12.5kpa, maybe the article was about very sure cirrhosis
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
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
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