Review Article: The Reversibility of Cirrhosis

Abstract

Background Cirrhosis is the end result of many types of chronic liver diseases. Recent developments in the understanding of the process of hepatic fibrogenesis have revealed that the process is a dynamic one and a capacity for recovery from any degree of fibrosis including those associated with cirrhosis is plausible.

Aim To review current evidence of histopathological reversibility following drug therapy of more common aetiologies of cirrhosis.

Methods A PubMed search was performed and the evidence for histopathological regression of advanced fibrosis/cirrhosis following drug therapy was reviewed as of the end of February 2012.

Results There is abundant clinical evidence in support of the idea of the reversibility of cirrhosis in patients with different aetiologies of advanced hepatic disease including viral, autoimmune and metabolic/infiltrative liver disease.

Conclusions The concept of cirrhosis has changed from being a form of static and irreversible entity to a dynamic and reversible diseases stage. Novel therapeutic strategies are under investigation to target specific steps in the process of fibrogenesis with the aim of reversing advanced fibrosis/cirrhosis.

Introduction

Cirrhosis is an important cause of morbidity and mortality. It is the morphological result of many different types of chronic insult to the liver. It may develop rapidly over a period of months, but most often it is a product of many years of chronic injury. In industrialised countries, chronic hepatitis C and heavy alcohol consumption represent the most common causes of cirrhosis. In developing countries like Iran, Chronic hepatitis B is the most common cause of cirrhosis.[1, 2] Due to pandemic of obesity and metabolic syndrome, non-alcoholic steatohepatitis (NASH) is becoming a common cause of chronic liver disease leading to cirrhosis all over the world.[3] Other common causes of cirrhosis include autoimmune hepatitis, metabolic liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis.[2]

Cirrhosis is defined by the presence of certain anatomical abnormalities of liver structure. However, a presumptive diagnosis of cirrhosis can often be made when certain clinical consequences of cirrhosis are found. Portal hypertension is the earliest and most important consequence of cirrhosis and is indeed the principal mechanism leading to the death of cirrhotic patients. It results from an increased intrahepatic resistance combined with increased portal (and hepatic arterial) blood flow. Many of the clinical effects of cirrhosis are found in other organs. Renal and pulmonary failure may occur secondary to the systemic haemodynamic response to cirrhosis. Haemorrhage may occur because of platelet dysfunction, platelet sequestration in the spleen and decreased synthesis of proteins of the coagulation cascade.

Due to advances in science and practice of hepatology and the ability to treat most common chronic liver diseases, the concept of cirrhosis has changed from being a form of static, irreversible entity to a dynamic and reversible diseases stage.[4] A recently published American Association for study of Liver Diseases (AASLD) position paper suggested that we should 'move beyond the simple characterisation of cirrhosis as a single stage and instead begin thinking of cirrhosis as a series of critical steps that, if left unchecked, culminate in hepatic decompensation'.[4] According to the report, we had better defined chronic liver disease not only by pathological finding of late-stage fibrosis as a single entity called cirrhosis, but rather on the basis of histopathology, functional and clinical data to at least four stages as shown in the following table.[4] This type of staging in chronic liver disease is necessary to be able to find and treat a subgroup of patients whose liver fibrosis or 'cirrhosis' is still reversible (Figure 1).




Figure 1.

Cirrhosis might be classified as sub-stages. The chance for reversibility declines as the liver goes through more advanced disease.4

In the past decade, researchers have focused more on the progressive substitution of the functioning hepatic parenchyma with fibrotic tissue. Our knowledge of cellular and molecular mechanisms of hepatic fibrogenesis has greatly increased and major efforts are now directed at translating these acquisitions in fruitful clinical applications.

Overview of Hepatic Fibrogenesis

Hepatic fibrosis is an outcome of many chronic liver diseases.[5]Development of liver fibrosis entails major alterations in both the quantity and quality of hepatic extracellular matrix (ECM) proteins. In all clinical and experimental models of liver fibrosis, myofibroblasts are the source of the ECM constituting the fibrous scar. Myofibroblasts (MFs) are only found in the injured, but not the normal, liver. Thus, activation and proliferation of hepatic myofibroblasts is a key mechanism in development of liver cirrhosis.

The origin of hepatic MFs is still incompletely understood. Current literature suggests that hepatic MFs mainly originate from hepatic stellate cells (HSCs)[6] or from fibroblasts of portal areas[7] through a process of activation and trans-differentiation. It has been reported that hepatic MFs may originate also from bone marrow-derived stem cells, including mesenchymal stem cells or circulating fibrocytes,[8] or through a process of epithelial to mesenchymal transition involving either hepatocytes or cholangiocytes.[9]

Hepatic MFs are highly proliferative and contractile cells and actively contribute to the process of fibrogenesis through excess deposition of ECM components and its altered remodelling; as well as synthesis and release (paracrine/autocrine) of several critical growth factors able to sustain and perpetuate not only fibrogenesis but also chronic inflammatory responses and neo-angiogenesis.

A key discovery in understanding fibrosis has been that the hepatic stellate cell (HSC) is the primary effector cell, orchestrating the deposition of ECM in normal and fibrotic liver. HSCs are resident perisinusoidal cells in the subendothelial space between hepatocytes and sinusoidal endothelial cells. They are strategically positioned to intimately interact with hepatocytes, endothelial cells and nerve endings through their numerous processes extending across the space of Disse.[10] In addition, the HSC plays a pivotal role in activating the immune response through secretion of cytokines and chemokines and interacting with immune cells. HSCs also contribute to angiogenesis and the regulation of oxidant stress.[11]

Recent genomic research in the field of hepatic fibrogenesis has placed focus on unravelling the genetic basis of disease susceptibility. It seems that in the precirrhotic stage, the aetiology and primary site of injury is of relevance to liver fibrogenesis.[12] In addition to activated HSCs representing a key and well-characterised reservoir for fibrogenic myofibroblasts (MFB), other cell populations such as portal fibroblasts or bone marrow-derived cells provide a context-specific substrate for modulation of hepatic fibrogenesis. The clinical appreciation of individual variation in fibrogenesis dynamics and cirrhosis risk has indicated a strong host genetic modulation in liver fibrosis independent of other appreciable environmental factors (concept of 'slow vs. rapid fibrosers').[13]

The increasing knowledge on the biological mechanisms of fibrogenesis, angiogenesis and extra-hepatic involvement typical of cirrhosis suggests that the evolution of cirrhosis cannot be described as a simple one-step phenomenon.

Assessing Hepatic Fibrosis

Liver biopsy is traditionally the most specific test to assess the nature and severity of liver diseases.[14] Due to the invasive nature of this procedure and the potential for sampling error, non-invasive methodologies of assessing hepatic fibrosis are under investigation.[15]

The accuracy of liver biopsy in assessing hepatic fibrosis has been debated by some researchers due to potential sampling error as well as intra- and inter-observer variability. It has been argued that a small sample measuring 10–30 mm in length and less than 2 mm in diameter might not represent the histopathological arrangement of the whole liver tissue and thus can be a source of substantial sampling error. A single blind liver biopsy may miss the diagnosis of cirrhosis in up to 30% of cases.[16]The experience of the reporting pathologist has an influence on inter-observer agreement.[17]

An ideal marker should be sensitive, specific and respond quickly to changes in liver fibrosis.[18]Currently available non-invasive methods can be placed into two distinct categories: (i) analysis of serum biomarkers of hepatic fibrosis; and (ii) measuring liver stiffness using transient elastography (TE).

Although liver fibrosis is a local reaction of the liver to chronic injury, serum levels of fibrogenic cytokines, extracellular matrix proteins and degradation products are markedly increased in cases of advanced fibrosis (bridging fibrosis or cirrhosis).[19, 20] A panel of multiple serum biomarkers consisting of hyaluronic acid, amino-terminal propeptide of type III collagen and tissue inhibitor of matrix metalloproteinase 1 can detect absence of fibrosis or presence of cirrhosis with high degrees of accuracy.[21] Fibrotest is a commercially available test to assess liver fibrosis; however, its diagnostic accuracy has been debated in some external validations studies.[22] These biomarkers are not liver-specific and can detect fibrogenesis in organs other than the liver and some are affected by renal or liver failure. Also, the available biomarkers are not highly accurate in intermediate stages of liver fibrosis.[23]

Transient elastography (TE) has been proposed for measuring liver stiffness.[24, 25] Both inter-observer and intra-observer agreement of this technique are excellent,[26] although they are significantly reduced in patients with lower degrees of hepatic fibrosis and with high body mass index.[27]

New image-based methods in current practice and in development to assess liver fibrosis include magnetic resonance (MR) spectroscopy, diffusion weighted MR and MR elastography.[28, 29] The MRI-based techniques can assess the whole liver to detect liver fibrosis; however, these methods are more expensive and time-consuming.[18]

Is Hepatic Fibrosis Reversible?

Liver fibrosis and cirrhosis result from the majority of chronic liver insults and represent a common and difficult clinical challenge of worldwide importance. There is a considerable imperative to develop antifibrotic strategies that are applicable to liver fibrosis. Such an approach is attractive precisely because it is aimed at the final common pathological pathway of chronic liver disease, regardless of aetiology. However, because fibrotic liver disease may not present clinically until an advanced or cirrhotic stage, the possibility of reversing the fibrosis is an essential issue for developing therapeutic approaches.

In clinical circumstances where an effective treatment for the underlying insult is available, remodelling of the scar tissue can occur and a return towards architectural normality has been documented even in advanced fibrosis and cirrhosis.

These observations are highly encouraging and suggest that the liver has a capacity to remodel scar tissue, which, if harnessed and manipulated, would offer a novel therapeutic approach to the treatment of liver fibrosis. As the mechanism of fibrogenesis varies by aetiology, the evidence for reversibility of fibrosis is addressed here according to the underlying liver disease.

Clinical Evidence of Reversibility

Hepatitis B

In chronic HBV infection, liver damage appears to be immune-mediated, with HBV-specific T cells playing a key role both in disease pathogenesis and viral clearance. CD4-positive T cells tend to predominate CD8-positive T cells in chronic hepatitis B.[30] When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology.[31]Inflammation is minimal in the immune-tolerant and inactive carrier phases, but is prominent in the immune-reactive phase. It is typically associated with scarring, which can vary from a mild portal expansion to periportal fibrous strands, bridging fibrosis and cirrhosis.[32]

Histological studies based on paired biopsies obtained before and after HBeAg seroconversion have consistently demonstrated that seroconversion of antibody to HBeAg (anti-HBe) is followed by a significant improvement or even disappearance of disease activity, and this improvement seems to be irrespective of the extent of the liver damage in the baseline biopsy.[33] When sustained, these changes are associated with excellent long-term prognosis.[34]

Five different oral nucleoside and nucleotide analogues have been approved. Such therapy can not only retard the progression of fibrosis and reverse both fibrosis and cirrhosis,[35–38] but also salvage patients with decompensated chronic hepatitis B[39] and prevent hepatic decompensation in patients with advanced fibrosis and cirrhosis.[40]

The most extensive evidence is in favour of lamivudine, the first oral agent licensed for treatment of hepatitis B. Clinical trials indicate that lamivudine can retard the progression of fibrosis, reduce progression to cirrhosis and also reverse cirrhosis.[39–42] In studies where lamivudine was compared with telbivudine or entecavir, Ishak fibrosis scores were improved by 35–73% in HBeAg-positive patients and by 38–46% in HBeAg-negative patients taking lamivudine.[41, 43–46] With extended therapy, patients are at an increasing risk of developing lamivudine-resistant variants, leading to increased viral replication prior to clinical relapse.

Long-term treatment (over 3 years) with entecavir has been associated with histological improvement including at least 1-point reduction in the Ishak fibrosis score in 88% of patients with chronic hepatitis B.[47] In another recent study, 10 patients with advanced fibrosis or cirrhosis (Ishak fibrosis score ≥4) were followed during 6 years of cumulative entecavir therapy. All showed improvement in Ishak fibrosis score (mean: −2.2). A reduction in Ishak fibrosis score to 4 or less was observed for all four patients who had cirrhosis at baseline.[48] Among patients with advanced liver fibrosis or cirrhosis treated with entecavir for 1 year, improvement in Ishak scores after 1 year was observed in 57% of HBeAg-positive patients, 59% of HBeAg-negative patients and 43% of lamivudine-refractory patients.[44, 46, 49]

In a long-term study of adefovir in which 15 patients had liver biopsies before treatment and after 5 years, seven of 12 patients (58%) with pre-treatment bridging fibrosis or cirrhosis improved their Ishak scores by at least 2 points, and three of the four patients with cirrhosis improved by 4 points, demonstrating that 5 years of adefovir therapy can reverse fibrosis (including cirrhosis) in most patients.[50]

In a large randomised, controlled trial in patients with chronic hepatitis B, after 1 year of telbivudine therapy, among the patients with marked pre-treatment bridging fibrosis or cirrhosis and Ishak fibrosis scores of 4–6, the Ishak scores improved to between 0 and 3 in 68% of HBeAg-positive and 56% of HBeAg-negative patients.[44]

A recent 5-year follow-up of patients treated with tenofovir was presented in the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), in November 2011. A total of 641 patients had baseline liver biopsies, 154 of which (24%) had cirrhosis (Ishak score ≥5). Of the 96 cirrhotic patients who had paired baseline and 5-year biopsies, 71 patients (74%) had decreases of ≥2 points at year 5.[51] Reversibility of HBV-related compensated cirrhosis has also been reported with the use of interferon alpha;[38] however, treatment of HBV-related cirrhosis with interferon alpha is currently not recommended because of the risk of hepatic decompensation associated with interferon-related flares of hepatitis.[52]

Hepatitis C

Several studies have demonstrated that regression of fibrosis in patients with chronic hepatitis C is associated with sustained virological response to therapy.[53–57] Poynard et al. pooled the data from four randomised trials including 3010 naïve patients with hepatitis C who had pre-treatment and posttreatment biopsies. The reversal of cirrhosis was observed in 49% of patients with baseline cirrhosis.[58]


To better define the long-term benefits of anti-viral therapy, we must take into account the likelihood of progression to cirrhosis in treated patients. Together with the amelioration of the necroinflammatory activity, the improvement in the stage of fibrosis may explain the portal haemodynamic improvement that are detected in sustained responders, changes that in turn might explain the decreased number of decompensation events observed in these patients.[59, 60]

It is notable that the currently available peginterferon-based therapies cannot be administered in most patients with advanced decompensated HCV-cirrhosis.[61] The development of novel interferon-free drug regimens for the treatment of chronic hepatitis C may hold promise for the treatment of patients with advanced HCV-related cirrhosis in the future.[62]

Autoimmune Liver Disease
Autoimmune hepatitis is a chronic disease of unknown cause, characterised by continuing hepatocellular inflammation and necrosis and tending to progress to cirrhosis. Immune serum markers frequently are present. Rapid institution of treatment with high-dose corticosteroids may rescue patients whose autoimmune hepatitis ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Cirrhosis is observed in one-fourth of patients at initial diagnosis.[63] Patients with AIH usually respond rapidly to corticosteroid treatment and follow-up biopsies show varying degrees of resolution of the necroinflammatory process. Fibrosis and other structural changes may also improve.


Dufour and colleagues reported a series of eight patients with autoimmune hepatitis and cirrhosis, treated with glucocorticoids and/or immunosuppressive drugs, with a second liver biopsy taken years after starting treatment. The median (Knodell) fibrosis score decreased from 3.3 to 0.8.[64] There is a case report of an autoimmune hepatitis patient with documented liver cirrhosis who attained a biochemical response to immunosuppressive therapy and a repeat liver biopsy after 14 years revealed normal liver histology.[65] There are several reports of reduced fibrosis score in patients with autoimmune hepatitis treated with corticosteroids and/or immunosuppressive agents.[63, 66–68]

Metabolic/Infiltrative Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to inflammatory steatohepatitis (NASH) and cirrhosis. Of those who develop NASH, about 20% of patients will develop cirrhosis during their lifetime.[69] Interestingly, some serial liver biopsy studies have shown that liver fibrosis in NAFLD might improve. In a cohort of 39 Japanese subjects with NAFLD, liver fibrosis improved in 12 patients (31%), progressed in 11 patients (28%) and remained unchanged in 16 patients (41%) after a median follow-up of 2.4 years. This small study indicated that better glycaemic control rather than losing weight might be a predictor of improvement of liver fibrosis in patients with NAFLD.[70] In another prospective study of 52 NAFLD patients with paired liver biopsies, after 36 months, 14 (27%) NAFLD patients had fibrosis progression, 25 (48%) had static disease and 13 (25%) had fibrosis regression. Reduction in BMI and waist circumference was associated with histological improvement or static disease. No data were provided specifically for the subset of patients with regressed fibrosis.[71]


To our knowledge, no treatment modality has resulted in the regression of human cirrhosis related to NASH. Treatment with pioglitazone[72] or vitamin E[73] has been shown to reverse steatosis and inflammation, but not liver fibrosis in NASH. Bariatric surgery may clear perisinusoidal fibrosis at least in some morbidly obese patients.[74] The regression of fibrosis is most commonly reported in restrictive bariatric surgeries (Laparoscopic Gastric Banding), but progression of fibrosis is reported in some patients undergoing malabsorbtive surgeries (Biliopancreatic diversion).[75] Future large scale studies are needed to assess the impact of bariatric surgery on the natural history of NASH.

Regarding alcoholic cirrhosis, achieving and maintaining abstinence has led to significant regression of fibrosis and possibly early cirrhosis.[76] In a retrospective French study, complete abstinence from alcohol for at least 6 months was associated with regression of cirrhosis in 8% of patients.[77]

Falize et al., studied the paired liver biopsies for 36 patients with hereditary haemochromatosis who had undergone weekly phlebotomies to achieve low body iron stores (serum ferritin <50 ng/mL) and then placed on maintenance therapy on the basis of 3–12 phlebotomies per year. They documented hepatic fibrosis regression along venesection therapy in approximately half the patients with GH initially complicated with either severe fibrosis or cirrhosis.[78]

Novel Therapeutic Strategies

Effective treatment of the underlying liver disease is the only available therapy for human liver fibrosis. However, no specific antifibrotic drug has been identified in human.

During resolution of liver fibrosis, activated HSCs undergo either apoptosis or reversion to inactive phenotype.[79] The occurrence of both phenomena has been confirmed in animal models of liver fibrosis.[80]

TGF-β1 plays a critical role in activation of myofibroblasts. Although inhibitors of TGF- β1 are effective in short-term animal models,[81, 82] they are not suitable for long-term therapy because of the significant role of TGF-β1 in homoeostasis and repair.[83]

The renin angiotensin pathway in hepatic stellate cells induces reactive oxygen species and accelerates hepatic fibrosis. Stimulation of AT1 receptor by angiotensin II results in proliferation of HSCs and extracellular matrix deposition. In concordance, several experimental models of liver fibrosis in rodents have demonstrated that prolonged administration of angiotensin II directly causes HSC activation.[84]Disruption of RAS pathway by RAS inhibitors may potentially be effective to attenuate liver fibrosis.

Clinical evidence demonstrates elevated LPS levels in the systemic and portal circulation in patients with cirrhosis.[85] Bacteria and LPS signal via Toll-like receptor pathway. It is postulated that TLR4 and gut microflora-derived LPS contribute to the progression of liver fibrosis. Indeed, systemic plasma levels of LPS are elevated in experimental animal models of liver fibrosis.[86] Consistently, mice with deficiencies in CD14, LPS binding protein (LBP) or TLR4 have impaired TLR signaling and are not susceptible to liver fibrosis.[87] Administration of TLR4 antagonists, LPS neutralising agents or prolonged antibiotic intake are of major consideration for clinical trials of patients with liver fibrosis.

Extensive neovascularisation is usually observed around dense scar tissue in cirrhotic liver. Moreover, administration of vascular endothelial growth factor (VEGF)-receptor 1 and 2 neutralising antibodies results in significant inhibition of liver fibrosis in mice.[88] Inhibition of angiogenesis by several drugs has been also shown to be effective in suppression of liver fibrosis.[89]

Some studies demonstrated that bone marrow cells contribute to myofibroblasts population in the injured liver. This raises concern that bone marrow may contribute to liver fibrosis.[90] However, several animal studies have shown that infusion of bone marrow cells reduces liver fibrosis. This appears to be mediated by matrix metalloproteinase-9 expressing bone marrow-derived cells.[91–94] Studies of mesenchymal and haematopoietic stem cell transplantation seem to be feasible. This technique might be effective for short-term improvement of liver function tests in human cirrhosis; however, its long-term beneficial effects or its role in regression of human fibrosis is not clear at present.[95–97]

The cannabinoid receptor 1 (CB1) is induced in activated HSCs. It is shown that CB1 receptor antagonist SR141716A inhibits progression of experimental liver fibrosis.[98] However, the use of rimonabant, a CB1 antagonist in human leads to severe depression as an undesirable side effect.[6, 99]

Enzyme Lysil oxidase-like-2 (LOXL2) promotes cross-linking of collagen 1 in liver fibrosis.[100] It has been shown that LOXL2 has essential role for creation of pathological stroma and a LOXL2 inhibitory antibody effectively reduces animal liver fibrosis.[101]

In summary, despite significant progress in treating animal models of liver fibrosis, there has not been a proof-of-concept trial in human demonstrating the value of treating liver fibrosis despite ongoing liver disease.[6]

Conclusion

Here, we reviewed the available evidence for the potential reversibility of cirrhosis in various types of liver disorders. In summary, we emphasise the following points:

1. Currently, the most reliable strategy for reversal of cirrhosis is the treatment of the underlying aetiology. However, treatment of the underlying cause is not feasible in all the patients with cirrhosis.
   
   
2. Reversal of human cirrhosis is probably a slow process and may take several years.
   
   
3. Not all patients with cirrhosis have a reversible disease. Patients with cirrhosis can be categorised into different stages. Patients in the earlier stages of cirrhosis are more likely to witness the reversal of cirrhosis. Although the point at which cirrhosis is irreversible is not established, it appears that cirrhosis becomes irreversible once septal neovascularisation happens and portal pressure increases significantly.[4]

Source

 

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