Journal of Hepatology
Volume 34, Issue 5 , Pages 764-767, May 2001

Progression of fibrosis in chronic liver diseases: time to tally the score

Dipartimento di Medicina Interna, Università di Firenze, Viale G.B. Morgagni 85, 50134 Florence, Italy

See Article, pages 730–739

Article Outline

 

The fibrogenic progression of liver diseases characterized by chronic tissue damage and inflammation represents a key issue in hepatology. Regardless of the etiology (viral, toxic, immune-mediated or related to inherited defects), most chronic liver diseases (CLD) progress, in a variable interval of time, to a stage defined ‘cirrhotic’, in which the disease becomes clinically significant. For many years the work of the clinical hepatologist has been limited to the monitoring and management of the complications of liver cirrhosis. In more recent years, the discovery of hepatitis viruses and of other potential causes responsible for chronic liver tissue damage has allowed a great advancement in the understanding of the mechanisms leading to liver cirrhosis, in the development of diagnostic tools, and ultimately, in the identification of potential treatments. In this context, the discovery and characterization of the hepatitis viruses and the introduction of antiviral and immunomodulatory therapies in the 80’s have constituted ‘revolutionary’ landmarks.

In spite of these important advancements, two main problems remain still incompletely resolved. The first is the possibility of monitoring the progression of chronic hepatitis in prognostic terms: once the patient with chronic liver disease and initial fibrosis has been identified, are there clinical and/or biochemical markers that can predict the rapidity of fibrosis progression? In other terms, how many years will be required before the patient becomes cirrhotic? It is becoming increasingly clear that the speed of this progression is not related to the commonly observed abnormalities of liver enzymes, and that information deriving from liver biopsy provides only a ‘static’ view of the process. In general terms, the extent of fibrosis detectable in liver biopsy (fibrosis stage), is the net result of active deposition of fibrillar extracellular matrix (ECM) and its active degradation. Both these processes are characterized by a complex regulation and are by definition ‘dynamic’ [1], [2]. Therefore, liver biopsy, although indispensable to document the stage of evolution of the disease (and in many instances useful to support the etiology), does not provide indications on its fibrogenic progression, unless frequently repeated. In addition, in HCV-related CLD, further interpretative problems arise from the non-homogeneous distribution of tissue damage/inflammation/fibrosis with increasing possibility of sampling error and reduced adequacy of comparing biopsies obtained from the same patient during follow-up [3], [4]. The second issue is strictly related to the previous and concerns the possibility of evaluating the real efficacy of the currently available treatments for CLD, and particularly those related to HCV and HBV. Indeed, an evaluation of the efficacy of antiviral drugs simply based on virological and biochemical parameters is indeed insufficient to establish the likelihood of long-term benefits. Consequently, more and more recent studies evaluating the efficacy of a given treatment schedule for CLD focus on the impact of the treatment on the fibrogenic evolution of the disease, and it would be fair to assume that there is no effective treatment of CLD without a demonstrable decrease in the progression rate towards cirrhosis.

After these general considerations the reader will conclude that this topic is reaching a degree of great complexity and, at the beginning of this new millennium, the hepatologist faces more questions than answers when dealing with the management of CLD. In this context, Poynard and his colleagues have directly and/or indirectly addressed several of these questions. The work of these investigators [5], [6], focused on HCV-related CLD, has highlighted the following points: (1) fibrosis is a time-dependent end-point and an estimate of fibrosis progression is an important surrogate for the evaluation of the vulnerability of an individual patient and for the assessment of the impact of a given treatment on the natural history of the disease. Although this assumption seems rather obvious, the clinical features of fibrosis progression in a large cohort of patients had not been described before; (2) in a population of 1157 patients with HCV-related CLD the fibrosis progression rate is not normally distributed and at least three different patterns of progression can be identified, referred to as ‘rapid’, ‘intermediate’ and ‘slow’; (3) three independent factors are associated with a faster rate of fibrosis progression: age at infection, male gender and alcohol consumption of 50 g or more per day; (4) the modality of infection, the viral genotype and the viral load are not independently associated with the extent and with the rate of fibrosis progression; (5) the extent of necrosis/inflammation detectable in liver biopsy (generally referred to as ‘activity’ and/or ‘grading’) is not a good predictor of fibrosis progression, whereas fibrosis alone is the best marker of ongoing fibrogenesis. In addition to these observations, the same group of investigators has published studies dealing with other aspects of this rather complex field, and in particular the progression of fibrosis in HCV-positive patients with persistently normal liver enzymes [7], in HCV/HIV-positive patients [8], and in patients with HCV-related CLD treated with IFNα associated or not with ribavirin [9], [10].

As these authors always acknowledge in their papers, these assumptions must be taken with caution. It is indeed difficult to use cross-sectional data to estimate longitudinal parameters, to employ mathematical modelling to adequately translate numbers into a complex biological and clinical reality, and to establish the actual date of infection based on patient history. On the other hand, in the absence of long-term prospective studies and because of the practical (and ethical) impossibility to follow a large representative sample of patients from infection to death, with repeated liver biopsies and without treatment, the results of these studies provide important basis for constructive discussion and for further analysis.

In the work published in the present issue of Journal of Hepatology [11], Poynard and colleagues have further refined their observations by performing a cross-sectional study in a larger cohort of patients with HCV-related CLD, in which information on HCV genotype and viral load was available together with an evaluation of the stage of fibrosis. In particular, the study addresses a main area of controversy emerging from the previous work of these authors as well as from other reports [12], [13]: the potential heterogeneity of fibrosis progression including the shape or rate of progression. In order to pursue this aim, the independent association of factors such as age, gender, alcohol consumption etc. with the shape or rate of fibrosis progression was analyzed for each stage of fibrosis (from F0=no fibrosis to F4=cirrhosis) evaluated according to the METAVIR scoring system. A first very important finding of this analysis is that, in the natural history of HCV-related CLD, there is no plateau in fibrosis progression and that, for all stages, there are four periods with a linear progression: very slow (the first 10 years after the estimated date of infection), slow (the following 15 years), intermediate (the following 10 years), and fast progression for the last 5 years. Furthermore, the results of the study confirm the independent association between age at infection, gender and alcohol consumption with the rate of fibrosis progression. However, the impact of these factors is in general very relevant only in the later stages of fibrosis progression, i.e. from F2 (few septa) to F3 (numerous septa without cirrhosis) and from F3 to F4. The study also confirms that fibrosis progression is not independently associated with the viral genotype, the viral load, the route of infection and the histological activity of the disease. The main conclusions of this study are the following: (A) there is a large time-frame for therapeutic intervention before chronic hepatitis evolves towards cirrhosis and (B) the patient should be treated as soon as possible during the natural history of the disease, particularly if over 50 years of age and/or of male gender and/or alcohol abuser.

In addition to these conclusions of clinical utility, these studies provide useful elements for a more practical interpretation of the cellular and molecular mechanisms of liver fibrogenesis elucidated in the past twenty years [1], [2]. The identification of these mechanisms has certainly highlighted the importance of the fibrogenic process in the evolution of CLD and has provided basis for designing appropriate pharmacological and biotechnological strategies. It is obvious that the value of these potential strategies, presently based on evidence obtained by studies performed in vitro and/or in animal models of hepatic fibrogenesis, will be greatly strengthened once confirmed in the clinical reality. Along these lines, some relevant considerations emerge from the work of Poynard and colleagues. First, the long latency period (10-15 years) occurring between HCV infection and the detection of a minimal stage of fibrosis, in the presence of an evident and consistent degree of necroinflammatory activity, suggest that, at least within this time-frame, the chronic activation of the wound-healing process may not be characterized by a great imbalance between the newly synthesized ECM and its effective degradation, as it is generally assumed when considering the general definition of fibrogenesis. In cellular and molecular terms this could indicate that the period of time required for achieving a population of activated hepatic stellate cells (HSC) and other ECM-producing cells within the damaged liver tissue sufficient to produce significant ECM deposition is rather prolonged. This could be explained by the concomitant presence of mechanisms negatively modulating the activation of these cell types and/or counteracting the pro-fibrogenic effects of their activation. It is indeed conceivable that, in the biological microenvironment of chronically damaged hepatic tissue, soluble factors characterized by potent antiinflammatory and antifibrogenic properties are present together with those stimulating the proliferation, migration and ECM synthesis by ECM-producing cells. In addition, in an initial period of time following their activation these cell types could be characterized by: (i) more efficient intrinsic mechanisms negatively regulating their proliferation and survival, and (ii) efficient regulation of the genes encoding for factors governing effective ECM degradation in the presence of increased ECM synthesis. According to the current in vitro evidence, it is possible to speculate that these ‘control’ mechanisms become progressively less efficient and are finally lost during the long-term activation of ECM-producing cells. In summary, the deposition of fibrillar ECM becomes biologically and clinically significant only when a ‘critical mass’ of ECM-producing cells largely defective in their ‘control’ mechanisms is present in a microenvironment rich in profibrogenic stimuli. At this stage the wound healing process has proceeded beyond its aim and fibrogenesis rapidly progresses. The observation that the stage of fibrosis detected in liver biopsy is a better predictor of fibrosis progression than the degree of necroinflammatory activity indirectly corroborates this still speculative view.

Another interesting finding is the impact of age at infection and the more rapid progression of fibrosis. It is well-established that lipid peroxidation, a free-radical-mediated process, plays a central role in the fibrogenic transformation of several organs, including the liver [14]. Moreover, the biological action of free-radicals is associated with the process of aging [15]. In the pathogenesis of liver fibrosis of CLD enhanced lipid peroxidation is related to the extensive oxidative breakdown of membrane lipids and is characterized by increased generation of both reactive oxygen intermediates (ROI) and organic radical intermediates. Both ROI and reactive aldehydic end products of lipid peroxidation have been shown to increase the expression of proinflammatory and profibrogenic cytokines and to enhance collagen type I synthesis by hepatic ECM-producing cells [16], [17], [18]. The increased rate of fibrosis progression observed in older subjects could be related to these effects associated with features that are typical of the process of aging such as an increased susceptibility towards oxidative stress and to a reduced availability and/or ability of anti-oxidant systems [15].

Analogous considerations on the pro-fibrogenic role of oxidative stress could be proposed to explain the increased susceptibility to develop hepatic fibrosis in alcohol abusers and in overweight patients [19] with or without steatosis or steatohepatitis. Importantly, these latter conditions are considered an independent risk factor of liver injury and might contribute to liver fibrosis either alone or in association with other liver diseases [20].

An additional issue that is worth discussing is the increased fibrosis progression in male patients with HCV-related CLD. This issue is, however, not limited to CLD and of potential interest for other chronic fibrogenic disorders. The predominance of atherosclerosis and the higher renal fibrosis progression rate in men [21] are excellent lines of evidence suggesting a role of sex hormones in the wound healing/fibrogenic process. A significant antifibrogenic effect of estrogens has been demonstrated in the dimethylnitrosamine rat model of liver fibrosis as well as in cultured rat HSC [22], [23]. Based on these and other more general experimental observations, the following mechanisms have been hypothesized to explain the antifibrogenic effect of estrogens [24], [25]: (A) a radical scavenging action, (B) a modulation of collagen synthesis, and (C) a modulation in the expression of pro- and anti-fibrogenic cytokines. However, the real importance of these mechanisms remains to be confirmed.

Since the results of studies analyzing fibrosis progression in large populations such as those of Poynard's and colleagues statistically evaluate an ‘average’ pattern, a last consideration is related to the possible ‘individual’ variability in fibrosis progression, regardless of the etiology of CLD. Indeed, a markedly different fibrosis progression rate among patients with identical clinical and pathological features is frequently observed in clinical practice. In this respect, several recent preliminary data tend to highlight the importance of polymorphisms of genes encoding for molecules known to play a key role in fibrogenesis (e.g. metalloproteinases and TGF-β). This evidence, once further substantiated and correlated with the natural history of CLD, will likely provide new tools for predicting the clinical outcome of CLD in individual patients. In addition, the introduction of fast, sensitive, reproducible, and easily available technologies for the measurement of a specific panel of serum markers of fibrogenesis/fibrolysis, currently under investigation [26], would greatly enhance this possibility.

In conclusion, several aspects of the fibrogenic progression of CLD appear now better delineated and represent an important area of discussion and further investigation. Hopefully, additional studies will help establishing whether or not the progression of fibrosis observed in HCV-related chronic hepatitis differs from that of other fibrogenic CLD. These studies, together with further knowledge on the basic mechanisms of liver fibrosis will improve our approach to this complex field of hepatology.

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PII: S0168-8278(01)00055-1

Journal of Hepatology
Volume 34, Issue 5 , Pages 764-767, May 2001

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