Saudi Journal of Gastroenterology
Home About us Instructions Submission Subscribe Advertise Contact Login    Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
Users Online: 265 


 
NEW HORIZON Table of Contents   
Year : 2009  |  Volume : 15  |  Issue : 1  |  Page : 72-79
Reversal of liver fibrosis


1 Department of Internal Medicine, Division of Gastroenterology at King Fahad Hospital of the University, Al-Khobar, Saudi Arabia
2 Dipartimento di Medicina Interna-Center for Research, High Education and Transfer "DENOThe"- UniversitÓ degli Studi di Firenze, Florence, Italy

Click here for correspondence address and email

Date of Submission16-Sep-2008
Date of Acceptance30-Sep-2008
 

   Abstract 

Hepatic fibrosis is a scarring process associated with an increased and altered deposition of extracellular matrix in the liver. It is caused by a variety of stimuli and if fibrosis continues unopposed, it would progress to cirrhosis which poses a significant health problem worldwide. At the cellular and molecular level, this progressive process is characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-β with its downstream cellular mediators. Liver biopsy has been the reference test for assessment of hepatic fibrosis, but because of its limitations, noninvasive markers of liver fibrosis were developed. Liver fibrosis or cirrhosis was considered irreversible in the past but progress of research on the molecular pathogenesis of liver fibrosis has shown that hepatic cellular recovery is possible. Currently, no acceptable therapeutic strategies exist, other than removal of the fibrogenic stimulus, to treat this potentially devastating disease.

Keywords: Antifibrotic, cirrhosis, fibrogenesis, liver fibrosis

How to cite this article:
Ismail MH, Pinzani M. Reversal of liver fibrosis. Saudi J Gastroenterol 2009;15:72-9

How to cite this URL:
Ismail MH, Pinzani M. Reversal of liver fibrosis. Saudi J Gastroenterol [serial online] 2009 [cited 2019 May 26];15:72-9. Available from: http://www.saudijgastro.com/text.asp?2009/15/1/72/45072


Liver fibrosis, or scarring, occurs as an attempt to limit tissue damage in response to chronic liver injury, regardless of the etiology. It is characterized by excessive deposition of extracellular matrix (ECM) proteins, especially alpha 1 collagen [1] and is associated with major alterations in the quantity and composition of ECM. Liver fibrosis is initiated by a cascade of events resulting in hepatocyte damage, recruitment of inflammatory cells to the injured liver, and activation of collagen-producing cells. Hepatic stellate cells (HSC) are a major source of collagen type 1. [2] The fibrogenic response is a complex process in which accumulation of ECM proteins, tissue contraction, and alteration in blood flow are prominent. Progressive scarring in response to a persisting liver insult eventually results in cirrhosis which is one of the leading causes of death worldwide and a major global health burden. Liver fibrosis was considered an irreversible process in the past, however, recent advances and understanding of hepatic cellular processes and molecular biology have resulted in accumulation of clinical and experimental evidence of hepatic cellular recovery with possible remodeling of scar tissue. [3]


   Definition of Fibrosis and Cirrhosis Top


Liver fibrosis results from perpetuation of the normal wound healing response, resulting in an abnormal continuation of fibrogenesis. It is characterized by an excessive deposition of ECM proteins which includes three large families of proteins - glycoproteins, collagens, and proteoglycans. [4] Fibrosis occurs as a result of repeated cycles of hepatocytes injury and repair. The cascade of events that establish hepatic fibrosis is complex, and is influenced by how different cell types in the liver interact in response to injury, and activation of HSC is the central event. [5] Liver fibrosis is a dynamic process; it is usually secondary to hepatic injury and inflammation, and progresses at different rates depending on the etiology of liver disease and is also influenced by environmental and genetic factors. [6],[7] If fibrosis continues unopposed, it would disrupt the normal architecture of the liver which alters the normal function of the organ, ultimately leading to pathophysiological damage of the liver. Cirrhosis represents the final stages of fibrosis. [8] It is characterized by fibrous septa which divide the parenchyma into regenerative nodules [9] which leads to vascular modifications and portal hypertension with its complications of variceal bleeding, hepatic encephalopathy, ascites, and hepatorenal syndrome. In addition, this condition is largely associated with hepatocellular carcinoma with a further increase in the relative mortality rate. [10]


   Pathogenesis of Liver Fibrosis Top


The mechanisms able to elicit and sustain liver fibrogenesis may be classified in three main groups: a) chronic activation of the wound healing reaction, b) oxidative stress, and c) Derangement of epithelial-mesenchymal interactions and epithelial-mesenchymal transition in cholangiopathies.

Chronic activation of the wound healing reaction

Similar to what was observed in other fibrogenic disorders affecting different organs and systems, the chronic activation of the wound-healing reaction is the most common and relevant mechanism in hepatic fibrogenesis. Overall, hepatic fibrogenesis due to the chronic activation of the wound healing reaction is characterized by the following key features: i) the persistence of hepatocellular/cholangiocellular damage with variable degree of necrosis and apoptosis; ii) a complex inflammatory infiltrate including mononuclear cells and cells of the immune system; iii) the activation of different types of ECM-producing cells (HSCs, portal myofibroblasts (MFs), etc.) with marked proliferative, synthetic, and contractile features; iv) marked changes in the quality and quantity of the hepatic ECM associated with very limited or absent possibilities of remodeling in the presence of a persistent attempt of hepatic regeneration. [11] Work performed in the past two decades have highlighted the role of several growth factors and cytokines involved in the chronic wound healing reaction and affecting the profibrogenic potential of HSC. At present, most of the research on soluble factors potentially affecting the development of liver fibrosis is focused on the role of adipokines and their possible involvement in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). [12] A possible interplay and/or association between fibrogenesis and angiogenesis in chronic liver disease (CLD) is suggested and supported by several findings: angiogenesis and upregulation of vascular endothelial growth factor (VEGF) expression has been documented in different models of acute and chronic liver injury as well as in specimens from human fibrotic/cirrhotic liver and hepatocellular carcinoma. [13],[14] From a mechanistic point of view, angiogenesis in fibrogenic CLD can be interpreted according to two main pathways. First , the process of chronic wound healing, typical of fibrogenic CLD, is characterized by an overexpression of several growth factors, cytokines, and metalloproteinases (MMPs) with an inherent proangiogenic action. [15] Second , neoangiogenesis is stimulated in hepatic tissue by the progressive increase of tissue hypoxia. This mechanism is strictly linked to the anatomical modifications following the establishment of periportal fibrosis with an increased contribution of the hepatic artery to the formation of sinusoidal blood. Accordingly, sinusoidal blood flow becomes increasingly arterialized with hepatocytes adjusting to an abnormally high oxygen concentration. Subsequently, the progressive capillarization of sinusoids leads to an impairment of oxygen diffusion from the sinusoids to hepatocytes with the consequent upregulation of proangiogenic pathways. [16],[17] An elegant and convincing demonstration of the interplay among inflammatory response, angiogenesis, and fibrogenesis has been recently provided by an experimental study in which all these features have been significantly reduced by the treatment with the multitargeted receptor tyrosine kinase inhibitor Sunitinib. [18]

Oxidative stress

Involvement of oxidative stress has been documented in all human major clinical conditions of CLD as well as in most experimental models of liver fibrogenesis, [19] but it is likely to represent the predominant profibrogenic mechanism mainly in NAFLD/NASH and alcoholic steatohepatitis (ASH). Oxidative stress in CLD, resulting from increased generation of reactive oxygen species (ROS) and other reactive intermediates as well as by decreased efficiency of antioxidant defenses, does not represent simply as a potentially toxic consequence of chronic liver injury but actively contributes to excessive tissue remodeling and fibrogenesis. ROS and other reactive mediators such as 4-hydroxynonenal (HNE) can be generated outside MFs, here considered as potential 'target' cells, being released either by activated inflammatory cells or deriving from hepatocytes, directly or indirectly, damaged by the specific etiological agent or conditions. Indeed, oxidative stress, presumably by favoring mitochondrial permeability transition, is able to promote hepatocyte death (necrotic and/or apoptotic). In some of clinically relevant conditions, generation of ROS within hepatocytes may represent a consequence of an altered metabolic state (like in NAFLD and NASH) or of ethanol metabolism (as in ASH), with ROS being generated mainly by mitochondrial electron transport chain or through the involvement of selected cytochrome P450 isoforms like cytochrome P2E1 (CYP2E1). [20] Oxidative-stress-related mediators released by damaged or activated neighboring cells can directly affect the behavior of human HSC/MFs: ROS or the reactive aldehyde HNE have been reported to upregulate expression of critical genes related to fibrogenesis including procollagen type I, monocyte chemoattractant protein 1 (MCP-1), and TIMP-1, possibly through activation of a number of critical signal transduction pathways and transcription factors, including activation of c- jun N-terminal kinases (JNKs), transcription factor AP-1 (AP-1) and for ROS, nuclear factor- kB (NF-kB). [21],[22] In addition to 'profibrogenic' extracellular release by neighboring cells, ROS generation within human and rat HSC/MFs has been reported to occur in response to several known profibrogenic mediators, including angiotensin II, platelets derived growth factor (PDGF), and the adipokine leptin. [23] A final concept to mention is the fact that oxidative stress may contribute to CLD progression also by affecting the immune response. Experimental studies (alcohol fed rodents) and clinical data (patients affected by alcoholic liver disease (ALD), chronic hepatitis C virus (HCV) infection or NAFLD) indicate that oxidative stress is associated with the development of circulating IgG antibodies directed against epitopes derived from proteins modified by lipid peroxidation products or against oxidized cardiolipin. Of relevance, titer of these antibodies correlates with disease severity and, as recently proposed for NAFLD patients, may serve as prognostic predictor of progression of NAFLD to advanced fibrosis. [24]

Derangement of epithelial-mesenchymal interactions and epithelial-mesenchymal transition in cholangiopathies

Cholangiopathies represent a group of progressive disorders and are considered a major cause of chronic cholestasis in adult and pediatric patients. They share a common scenario that involves coexistence of cholestasis, necrotic or apoptotic loss of cholangiocytes, cholangiocyte proliferation, as well as portal/periportal inflammation and fibrosis. The so-called 'ductular reaction' (i.e., proliferation of bile ductular cells or cholangiocytes) has been seen as the 'pace maker of portal fibrosis'; intense proliferation of these epithelial cells is associated with significant changes in the surrounding mesenchymal cells (first portal fibroblasts and then HSCs with parenchyma invasion) and ECM. [25] It has long been unclear whether the first event was represented by phenotypic changes in proliferating cholangiocytes or by changes in ECM leading to epithelial cell proliferation. However, an intense cross-talk between mesenchymal and epithelial (i.e., cholangiocytes) cells has been suggested to underlie the release of cytokines and proinflammatory mediators possibly responsible for the overall cholangiopathies. As a matter of fact, cholangiocytes are now considered as active 'actors' in pathological conditions by their ability to secrete chemokines (Interleukin-6 (IL-6), tumor necrosis factor α (TNF β), Interleukin-8 (IL-8), and MCP-1) and profibrogenic factors (Platelets derived growth factor (PDGF-BB), endothelin 1 (ET-1), connective tissue growth factor (CTGF), and transforming growth factor beta 2 (TGF β2). All these factors, which can also be produced by infiltrating immune, inflammatory, or mesenchymal cells, may affect, in turn, both epithelial cells and their intense cross-talk with mesenchymal cells, thus sustaining the fibrogenic response. [26] However, very recently different laboratories are accumulating preliminary evidence suggesting that the scenario of cholangiopathies may be initiated by a process of 'epithelial-mesenchymal transition' involving cholangiocytes and possibly driven by TGF β. [27]


   Diagnosis of Fibrosis Top


The complete evaluation of a patient with diffuse liver diseases requires clinical evaluation, laboratory tests, and pathological examination. The liver biopsy is regarded as the historical 'gold standard' for diagnosis and assessment of prognosis in CLD. [28],[29] At least three scoring methods are commonly used to stage liver fibrosis: the Knodell, Ishak, and METAVIR scores. [30],[31] The Knodell and METAVIR score fibrosis from stage 0-4, with stage 4 as cirrhosis, whereas Ishak scores fibrosis from 0-6 where 5 is incomplete or early cirrhosis and 6 indicates established cirrhosis. [32] These methods are semi-quantitative and the invasiveness of liver biopsies with its associated life-threatening risks and morbidity make it a poor choice when considering assessment of liver fibrosis progression or regression. Furthermore, there is the issue of sampling error, defined as variable levels of fibrosis throughout the liver, with biopsy only examining a small (1/50,000) portion of the liver. [33],[34] Liver biopsy has been shown to have significant inter and intraobserver variability among pathologists, with an average 20% error rate in the staging of fibrosis. [35] The minimum suitable length of liver tissue needed for assessing liver fibrosis reliably is 25 mm and the presence of an experienced hepatopatholgist is important. [34]

Over the past years, several noninvasive tests have become available to assess liver fibrosis, primary in patients with chronic hepatitis C infection. [36],[37] The currently available noninvasive tests, which are surrogate markers of liver fibrosis (direct markers of fibrosis), such as serum hyaluronate, Type IV collagen, matrix metalloproteinase 1 (MMP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), laminin, and TGF β, have limited accuracy for diagnosis of significant fibrosis (METAVIR ≥ F2 or Ishak >3). Other noninvasive tests (indirect markers of liver fibrosis) include FibroTest-ActiTest, [38] APRI, [39] Forns fibrosis index, [40] and enhanced liver fibrosis (ELF) score. [41],[42] The diagnostic performance of these indices is generally good, with a receiver operating characteristics (ROC) curve ranging from 0.77-0.88. Parkes et al . conducted a systematic review to assess the performance of panels of serum markers of hepatic fibrosis in chronic HCV infection, incorporating analyses placing markers in a clinical context. They concluded that serum markers can rule-in or rule-out fibrosis in up to 35% of patients, but cannot differentiate stages of fibrosis reliably and improvement of index and reference test is needed. [43]

FT-AT, from Biopredictive, Paris, France, is a noninvasive blood test that combines the quantitative results of six serum biochemical markers (alfa2-macroglobulin, haptoglobin, gamma glutamyl transpeptidase, total bilirubin, apolipoprotein A1, and alanine aminotransferase (ALT)) with patients' age and gender in a patented algorithm in order to generate a measure of fibrosis and necroinflammatory activity in the liver. [38],[44] FT-AT provides an accurate measurement of bridging fibrosis and/or moderate necroinflammatory activity with area under the receiver operating curve (AUROC) predictive value between 0.70 and 0.80, when compared to the liver biopsy. [45],[46]

Recently, transient elastography or Fibroscan (Echosens, Paris, France) has become available, which measures liver stiffness or elasticity to assess liver fibrosis. [47] The scan was developed on the principle that livers with increasing degrees of scarring or fibrosis have decreasing elasticity and that a shear wave propagating through stiffer material would progress faster than in one with more elastic material. [48] Transient elastography is painless, rapid, and easily performed at the bedside or in the outpatient clinic. A recent systemic review identified twelve studies, 9 for FibroTest ( N = 1,679) and 4 for Fibroscan ( N = 546) and the area under the curve (AUCs) for FibroTest and Fibroscan were 0.90 (95% CI not calculable) and 0.95 (95% CI 0.87-0.99), respectively. The authors concluded that FibroTest and Fibroscan have excellent diagnostic accuracy for the identification of HCV-related cirrhosis, but lesser utility for earlier stages of fibrosis. [49] The combined use of transient elastography and biochemical markers seems to be the most promising noninvasive techniques which can help the clinician decide whether a liver biopsy is necessary in some patients, and accordingly decide who to treat [37] [Table 1]


   Reversal of Fibrosis or Cirrhosis Top


The concept of reversibility of liver fibrosis and cirrhosis is not new. Popper and Udenfreind emphasized the importance of enzymatic processes to fibrosis regression in 1970. [50] Perez-Tamayo in 1979 wrote a review entitled "Cirrhosis of the liver: a reversible disease?" and enumerated evidence for reversibility of fibrosis and cirrhosis in both animal models and human disease provided the inciting agent is discontinued and sufficient time is allowed for the injured liver to recover. [51] Fibrosis usually requires at least several months to years of ongoing insult. However, not all patients exposed to a similar causal agent develop the same degree of liver fibrosis, that is, patients with similar risk factors have some variability in progression of liver fibrosis, which also may reflect host genotypic polymorphisms. [7] Evidence of fibrotic regression has now been documented in the entire spectrum of CLDs, including autoimmune hepatitis, biliary obstruction, iron overload, NASH, and viral hepatitis B and C. [52],[53],[54],[55],[56],[57],[58]

The issue of regression/reversibility of cirrhosis originates from evidence obtained in animal models upon the discontinuation of the cause of liver damage or following treatment with a putative antifibrotic agent. Although a regression has been shown in animal models of cirrhosis this possibility is not yet fully substantiated in humans. Evidence of either fibrotic or cirrhotic regression has now been reported in CLD of different etiologies, including viral hepatitis, [59],[60],[61],[62],[63],[64],[65] autoimmune hepatitis, [52] alcoholic, and nonalcoholic steatohepatitis. [55],[66],[67] However, when performing an accurate analysis of the results of these studies, the only prudent conclusion is that, in most cases, there was a variable degree of fibrosis regression in cirrhosis but not a reversal of cirrhosis. [25],[68] Along these lines, there is no convincing evidence that the abnormalities of the intrahepatic vasculature regress in human cirrhotic liver. Actually, the available evidence suggests that the so-called veno-portal adhesions persist even in cases of extensive fibrosis regression, and evident 'arterialized' sinusoids appear in the context of intrahepatic arterio-venous shunts. [69] The most obvious problem when discussing the issue of fibrosis regression in cirrhosis or even cirrhosis reversal is the lack of a clear and common language. Ultimately, what we need is a precise distinction of advanced fibrosis ('precirrhosis') from true cirrhosis and the possibility of staging cirrhosis. The problem is fundamentally based on the use of semi-quantitative scoring systems for staging fibrosis and, in particular, the fact that cirrhosis is always represented by the highest score and is indeed considered as an end-stage of CLD. [25],[70] In fact, cirrhosis appears in a very broad spectrum of variants (early, fully developed, 'active', and 'inactive') and more than one study has documented the transition from micronodular to macronodular cirrhosis following the discontinuation of the causative agent. [71],[72] Practically, as clearly stated by Desmet and Roskams, [25] there is a fundamental difference between a diagnosis of cirrhosis and a score of cirrhosis. For example, a low score does not exclude cirrhosis of the macronodular or incomplete septal type, which can be due to sampling error. From a clinical point of view, patients with cirrhosis can experience a widely variable clinical course and the cirrhotic stage defined as "compensated cirrhosis" includes anything from the initial histopathological demonstration of 'early cirrhosis' to the development of complications of portal hypertension. This oversight is mainly motivated by the fact that, until recently, it hardly mattered whether a patient had 'early' or 'late' cirrhosis since the only viable option was liver transplantation, and it is clearly reflected by clinical staging systems such as the mayo end stage liver disease (MELD) score. [73]

The increasing clinical awareness that cirrhosis represents a new dimension in the clinical course of CLD and not just the extreme stage of fibrosis, together with the more and more realistic possibility of reducing fibrosis even in a cirrhotic liver have led to the assumption that liver transplantation is no longer the only possible option to increase patient survival. Importantly, according to epidemiological data concerning two of the most common CLDs, i.e., HCV and NASH, and the relative estimates of disease progression, the number of patients with definite cirrhosis will increase exponentially in the next 10-15 years, thus representing the most frequent clinical entity in hepatology practice. [74],[75]

The possibility of monitoring fibrosis regression in cirrhosis faces the already mentioned lack of a system able to classify cirrhosis in different stages. A distinction should be made between 'compensated' (i.e., complication-free) and 'decompensated' (i.e., with clinically evident complications of portal hypertension) cirrhosis. In this context, a classification of compensated cirrhosis represents the major clinical need when analyzing the effect of a causative and/or antifibrotic therapy aimed at prolonging complication-free survival. Different approaches have been proposed in order to reach this goal. First, as suggested by Goodman et al. [76] morphometric image analysis may help quantify the extension of fibrosis in cirrhotic liver, thus overcoming the biases of the semi-quantitative scores and to provide staging of cirrhosis beyond an end-stage score. However, morphometric analysis of hepatic collagen content may be also limited by potential sampling variability and is not reliable when dealing with fragmented specimens. Second, the measurement of hepatic venous pressure gradient (HVPG), a validated, safe, and highly reproducible technique, has been proposed for monitoring the progression of the disease from the precirrhotic to advanced stages of cirrhosis. [77] In absence of significant fibrotic evolution, HVPG, as an expression of intrahepatic resistance, does not exceed 5 mm Hg, whereas a gradient of more than 5 mm Hg is always associated with significant fibrosis. Cross-sectional studies have shown that portal pressure (estimated by the HVPG) must reach certain thresholds for the development of complications of portal hypertension: 10 mm Hg for the development of varices and ascites ('clinically significant' portal hypertension) and 12 mm Hg for variceal bleeding ('clinically severe' portal hypertension). [78] Therefore, in broad terms, at least cirrhotic patients with a HVPG within the range 5-10 mm Hg should be complication-free, i.e., 'compensated'. Third, the majority of the so far proposed noninvasive methodologies for the evaluation of fibrosis progression in CLD, including serum biomarkers and transient elastography, [79] seem to have an adequate diagnostic accuracy for the prediction of advanced fibrosis and cirrhosis and could be further implemented for staging cirrhosis. Along these lines, a 3-variable algorithm consisting of hyaluronic acid, TIMP-1, and platelet count was recently shown to correlate with histopathological scores better than with the hepatic collagen content measured by morphometric analysis. [80] In addition, in patients with compensated HCV cirrhosis, with a HVPG in the range 5-12 mm Hg, liver stiffness measurement (LSM) by transient elastography shows an excellent correlation with HVPG values and may be a good predictor of significant and severe portal hypertension. [81] Therefore, it is imaginable that the use of noninvasive methodologies could represent a feasible way to complement traditional/morphometric histopathological analysis and the measurement of HVPG in the attempt of staging compensated cirrhosis and assessing response to treatment.


   Liver Fibrosis and Antifibrotic Therapy Top


Advances in understanding of the pathophysiologic basis of fibrogenesis are now leading to novel therapeutic approaches. [82],[83] Cure of the primary disease to prevent ongoing injury remains the most effective strategy to reverse fibrosis. Existing treatments, particularly those that treat the primary injury, can allow complete resolution. Although it is likely that newly synthesized collagen may be more susceptible to degradation than old collagen, there is abundant evidence in animal models that even advanced cirrhosis is reversible, and in humans, the data suggest that fibrosis is reversible. [52],[53],[62],[84],[85] Antifibrotic therapies would target different areas in the fibrogenic cascade, including inhibition of matrix deposition, collagen synthesis, modulation of stellate cell activation, enhancing matrix degradation, or stimulation of stellate cell death or apoptosis. Several drugs with specific 'antifibrotic activity' have been studied in human trials but were not proved to be clearly effective. The ideal antifibrotic agent which is safe, when used over a long time, specific to the liver and nontoxic to hepatocytes, potent, orally bioavailable, and inexpensive is not yet available. Many agents were shown to be effective in vitro and in animal models. Translation of this laboratory success into clinical trials is underway, paving the way for use in human liver disease. [86] Increasingly, multiple-agent strategies that work at different mechanistic levels are likely to be assessed (combination therapy) [Table 2]. Evidence of the long-term benefits of the reversal of fibrosis on clinical outcome, such as a reduction in portal hypertension or the rate of development of hepatocellular carcinoma, is needed. [87] Although there are no definite and effective antifibrogenic agents, possible candidates are antioxidants, [88],[89] interferons, [90] flavonoids, [91] renin-angiotensin system inhibitors, [92],[93],[94] endothelin receptor antagonists, [95] and peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists. [96],[97]


   Conclusions Top


Reversal of fibrosis is a reality and treatment of the primary cause of injury can allow complete resolution of fibrosis. Noninvasive approaches in diagnosis of fibrosis are still evolving but promising. Our understanding of the mechanism of liver fibrosis has changed dramatically over the last decade and is no longer viewed as either passive or permanent but as a dynamic process. Many mechanisms and potential therapies continue to be identified and more research is required. The number of potential therapeutic targets has exploded in recent years and the realization that fibrosis can regress lends new urgency to their investigation.


   Acknowledgement Top


We would like to thank Dr. Abdulmohsen Al-Elq for his editorial assistance and to Mr. Ramesh Kumar for secretarial assistance.



 
   References Top

1.Alcolado R, Arthur MJP, Iredale JP. Pathogenesis of liver fibrosis. Clin Sci 1997;92:103-12.  Back to cited text no. 1    
2.Friedman SL, Roll FJ, Boyles J, Bisslell DM. Hepatic lipocytes: The principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci 1985;82:8681-5.  Back to cited text no. 2    
3.Fallowfield JA, Kendall TJ, Iredale JP, Reversal of fibrosis: No longer a pipe dream? Clin Liver Dis 2006;10:481-97.  Back to cited text no. 3    
4.Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver: Collagens and glycoproteins. Semin Liver Dis 1990;10:1-10.  Back to cited text no. 4  [PUBMED]  
5.Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000;275:2247-50.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Friedman SL. Liver fibrosis-from bench to bedside. J Hepatol 2003;38:S38-53.  Back to cited text no. 6  [PUBMED]  
7.Bataller R, North KE, Brenner DA, Genetic polymorphisms and the progression of liver fibrosis: A critical appraisal. Hepatology 2003;37:493-503.  Back to cited text no. 7    
8.Wanless IR. Pathogenesis of cirrhosis. J Gastroenterol Hepatol 2004;19:S369-71.  Back to cited text no. 8    
9.Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis: Working group sponsored by the World Health Organization. J Clin Pathol 1978;31:395-414.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 2002;36:S74-83.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Pinzani M, Rombouts K. Liver fibrosis-from the bench to clinical targets. Dig Liver Dis 2004;36:231-42.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Bertolani C, Marra F. The role of adipokines in liver fibrosis. Pathophysiology 2008;15:91-101.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Medina J, Arroyo AG, Sanchez-Madrid F, Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease. Hepatology 2004;39:1185-95.  Back to cited text no. 13    
14.Novo E, Cannito S, Zamara E, Valfrθ di Bonzo L, Caligiuri A, Cravanzola C, et al . Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 2007;170:1942-53.  Back to cited text no. 14    
15.Pinzani M, Marra F. Cytokine receptors and signalling in hepatic stellate cells. Sem Liv Dis 2001;21:397-416.  Back to cited text no. 15    
16.Rosmorduc O, Wendum D, Corpechot C, Galy B, Sebbagh N, Raleigh J et al . Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary fibrosis. Am J Pathol 1999;155:1065-73  Back to cited text no. 16    
17.Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, et al . Hypoxia - induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 2002;35:1010-21.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Tugues S, Fernandez-Varo G, Muρoz-Luque J, Ros J, Arroyo V, Rodes J, et al . Antiangiogenic treatment with Sunitinib ameliorated inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007;46:1919-26.  Back to cited text no. 18    
19.Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol 2001;35:297-306.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: Cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology 2006;131:934-45.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:109-18.  Back to cited text no. 21    
22.Zamara E, Novo E, Marra F, Gentilini A, Romanelli RG, Caligiuri A, et al . 4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells. J Hepatol 2004;40:60-8.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.De Minicis S, Bataller R, Brenner DA. NADPH oxidase in the liver: Defensive, offensive, or fibrogenic? Gastroenterology 2006;131:272-5.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Albano E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 2006;65:278-90.  Back to cited text no. 24  [PUBMED]  
25.Desmet VJ, Roskams T. Cirrhosis reversal: A duel between dogma and myth. J Hepatol 2004;40:860-7.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Pinzani M, Rombouts K. Liver fibrosis-from the bench to clinical targets. Dig Liver Dis 2004;36:231-42.   Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Robertson H, Kirby JA, Yip WW, Jones DEJ, Burt AD. Biliary epithelial-mesenchymal transition in post transplantation recurrence of primary biliary cirrhosis. Hepatology 2007;45:977-81.  Back to cited text no. 27    
28.Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495-500.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Campbell MS, Reddy KR. Review article: The evolving role of liver biopsy. Aliment Pharmacol Ther 2004;20:249-59.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]
30.Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al . Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-5.  Back to cited text no. 30  [PUBMED]  
31.Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513-20.  Back to cited text no. 31  [PUBMED]  
32.Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: The Knodell histology activity index and beyond. Hepatology 2000;31:241-6.  Back to cited text no. 32  [PUBMED]  [FULLTEXT]
33.Dienstag JL. The role of liver biopsy in chronic hepatitis C. Hepatology 2002;36:S152-60.  Back to cited text no. 33  [PUBMED]  
34.Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449-57.  Back to cited text no. 34    
35.Regev A, Berho M, Jeffers LT, Milikowski C, Molina EG, Pyrsopoulos T, et al . Sampling error and intraobserver variability in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;15:945-51.  Back to cited text no. 35    
36.Afdhal NH. Diagnosing fibrosis in hepatitis C: Is the pendulum swinging from biopsy to blood tests? Hepatology 2003;37:972-4.  Back to cited text no. 36  [PUBMED]  [FULLTEXT]
37.Kotlyar D, Blonski W, Rustgi V. Noninvasive monitoring of hepatitis C fibrosis progression. Clin Liver Dis 2008;12:557-71.  Back to cited text no. 37    
38.Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T, et al . Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: A prospective study. Lancet 2001;357:1069-75.  Back to cited text no. 38    
39.Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al . A simple non-invasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatits C. Hepatology 2003;38:518-26.  Back to cited text no. 39  [PUBMED]  [FULLTEXT]
40.Forns X, Ampurdanes S, Llovet JM, Aponte J, Quinto L, Martinez-Bauer E, et al . Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002;36:986-92.  Back to cited text no. 40    
41.Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, et al . Serum markers detect the presence of liver fibrosis: A cohort study. Gastroenterology 2004;127:1704-13.  Back to cited text no. 41  [PUBMED]  [FULLTEXT]
42.Patel K, Gordon SC, Jacobson I, Hιzode C, Oh E, Smith KM, et al . Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol 2004;41:935-42.  Back to cited text no. 42    
43.Parkes J, Neil Guha I, Roderick P, Rosenberg W. Performance of serum marker panels for liver fibrosis in chronic hepatitis C. J Hepatol 2006;44:462-74.  Back to cited text no. 43    
44.Poynard T, Imbert-Bismut F, Ratziu V, Chevret S, Jardel C, Moussalli J, et al . Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: Longitudinal validation in a randomized trial. J Viral Hepat 2002;9:128-33.  Back to cited text no. 44  [PUBMED]  [FULLTEXT]
45.Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin. Hepatology 2003;38:481-92.   Back to cited text no. 45  [PUBMED]  [FULLTEXT]
46.Sporea I, Popescu A, Sirli R. Why, who and how should perform liver biopsy in chronic liver diseases. World J Gastroenterol 2008;14:3396-402.  Back to cited text no. 46  [PUBMED]  [FULLTEXT]
47.Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al . Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41:48-54.  Back to cited text no. 47  [PUBMED]  [FULLTEXT]
48.Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al . Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-13.  Back to cited text no. 48  [PUBMED]  [FULLTEXT]
49.Shaheen A, Wan A, Myers RP. Fibro-test and FibroScan for the prediction of hepatitis C-related fibrosis: A systematic review of diagnostic test accuracy. Am J Gastroenterol 2007;102:2589-600.  Back to cited text no. 49    
50.Popper H, Udenfriend S. Hepatic fibrosis: Correlation of biologic and morphologic investigations. Am J Med 1970;49:707-21.  Back to cited text no. 50    
51.Perez-Tamayo R. Cirrhosis of the liver: A reversible disease? Pathol Ann 1979;14:183-213.  Back to cited text no. 51    
52.Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med 1997;127:981-5.  Back to cited text no. 52  [PUBMED]  [FULLTEXT]
53.Hammel P, Couvelard A, O'Toole D, Ratouis A, Sauvanet A, Flejou JF, et al . Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 2001;344:418-23.   Back to cited text no. 53    
54.Muretto P, Angelucci E, Lucarelli G. Reversibility of cirrhosis in patients cured of thalassemia by bone marrow transplantation. Ann Intern Med 2002;136:667-72.   Back to cited text no. 54  [PUBMED]  [FULLTEXT]
55.Dixon JB, Bhathal PS, Hughes NR, O'Brien PE. Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss. Hepatology 2004;39:1647-54.  Back to cited text no. 55  [PUBMED]  [FULLTEXT]
56.Kral JG, Thung SN, Biron S, Hould FS, Lebel S, Marceau S, et al . Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery 2004;135:48-58.   Back to cited text no. 56  [PUBMED]  [FULLTEXT]
57.Kweon YO, Goodman ZD, Dienstag JL, Schiff ER, Brown NA, Burkhardt E, et al . Decreasing fibrogenesis: An immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001;35:749-55.  Back to cited text no. 57    
58.Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32.  Back to cited text no. 58    
59.Shiratori Y, Imazeki F, Moriyama M, Yano M, Arakawa Y, Yokosuka O, et al . Histological improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;132:517-24.  Back to cited text no. 59  [PUBMED]  [FULLTEXT]
60.Kweon YO, Goodman ZD, Dienstag JL, Shiff ER, Brown NA, Burkardt E, et al . Decreasing fibrogenesis: An immunoistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001;35:749-55.   Back to cited text no. 60    
61.Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al . Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-17.  Back to cited text no. 61  [PUBMED]  [FULLTEXT]
62.Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al . Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303-13.   Back to cited text no. 62  [PUBMED]  [FULLTEXT]
63.Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al . Long-term benefit of interferon alpha therapy of chronic hepatitis D: Regression of advanced hepatic fibrosis. Gastroenterology 2004;126:1740-9.   Back to cited text no. 63  [PUBMED]  [FULLTEXT]
64.Serpaggi J, Carnot F, Nalpas B, Canioni D, Guιchot J, Lebray P, et al . Direct and indirect evidence for the reversibility of cirrhosis. Hum Pathol 2006;37:1519-26.   Back to cited text no. 64    
65.Hui CK, Leung N, Shek TW, Yao H, Lee WK, Lai JY, et al . Hong Kong Liver Fibrosis Study. Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology 2007;46:690-8.   Back to cited text no. 65    
66.Wakim-Fleming J, Mullen KD. Long-term management of alcoholic liver disease. Clin Liver Dis 2005;9:135-49.   Back to cited text no. 66  [PUBMED]  [FULLTEXT]
67.Kral JG, Thung SN, Biron S, Hould FS, Lebel S, Marceau S, et al . Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery 2004;135:48-58.  Back to cited text no. 67  [PUBMED]  [FULLTEXT]
68.Desmet VJ, Roskams T. Reversal of cirrhosis: Evidence based medicine? Gastroenterology 2003;125:629-30.   Back to cited text no. 68  [PUBMED]  [FULLTEXT]
69.Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis: Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000;124:1599-607.  Back to cited text no. 69  [PUBMED]  [FULLTEXT]
70.Desmet VJ. Milestones in liver disease: Scoring chronic hepatitis. J Hepatol 2003;38:382-6.  Back to cited text no. 70  [PUBMED]  [FULLTEXT]
71.Popper H. What are the major types of hepatic cirrhosis? In: Ingelfinger F, Relman A, Finland M, editors. Controversies in internal medicine. Philadelphia, PA: WB Saunders; 1966. p. 233-43.  Back to cited text no. 71    
72.Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E. The Copenhagen study group for liver disease: Conversion of micronodular into macronodular cirrhosis. Hepatology 1983;3:928-31.  Back to cited text no. 72  [PUBMED]  
73.Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al . United network for organ sharing liver disease severity score committee: Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-6.  Back to cited text no. 73  [PUBMED]  [FULLTEXT]
74.Seef LB, Lie BA. Is cirrhosis an inevitable consequence of chronic hepatitis C infection? Clin Gastroenterol Hepatol 2005;3:840-2.   Back to cited text no. 74    
75.Angulo P. Non alcoholic fatty liver disease. N Engl J Med 2002;346:1221-31.  Back to cited text no. 75  [PUBMED]  [FULLTEXT]
76.Goodman ZD, Becker RL, Pockros PJ, Afdhal NH. Progression of fibrosis in advanced chronic hepatitis C: Evaluation by morphometric image analysis. Hepatology 2007;45:886-94.  Back to cited text no. 76    
77.Bosch J, Garcia-Pagan JC, Berzigotti A, Abraldes Jl. Measurement of portal pressure and its role in the management of chronic liver disease: Prognosis in Patients with Cirrhosis. Sem Liver Dis 2006;26:348-62.  Back to cited text no. 77    
78.Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419-24.  Back to cited text no. 78  [PUBMED]  
79.Pinzani M, Vizzutti M, Arena U, Marra F. Technology insight: Noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol 2008;5:95-106.  Back to cited text no. 79    
80.Fontana RJ, Goodman ZD, Dienstag J, Bonkowsky HL, Naishadham D, Sterling RK, et al . Relationship of serum markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology 2008;47:789-98.  Back to cited text no. 80    
81.Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al . Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007;45:1290-7.  Back to cited text no. 81  [PUBMED]  [FULLTEXT]
82.Friedman SL. The cellular basis of hepatic fibrosis: Mechanisms and treatment strategies. N Engl J Med 1993;328:1828-35.  Back to cited text no. 82  [PUBMED]  [FULLTEXT]
83.Rockey DC. New Therapies in hepatitis C virus and chronic liver disease: Antifibrotics. Clin Liver Dis 2006;10:881-900.  Back to cited text no. 83  [PUBMED]  [FULLTEXT]
84.Dufour JF, DeLellis R, Kaplan MM. Regression of hepatic fibrosis in hepatitis C with long term interferon treatment. Dig Dis Sci 1998;43:2573.  Back to cited text no. 84  [PUBMED]  [FULLTEXT]
85.Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al . Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-16.   Back to cited text no. 85  [PUBMED]  [FULLTEXT]
86.Pinzani M, Rombouts K. Liver fibrosis: From the bench to clinical targets. Dig Liver Dis 2004;36:231-42.  Back to cited text no. 86  [PUBMED]  [FULLTEXT]
87.Friedman SL, Maher JJ, Bissell DM. Mechanisms and therapy of hepatic fibrosis: Report of the AASLD single topic basic research conference. Hepatology 2000;32:1403-8.   Back to cited text no. 87  [PUBMED]  [FULLTEXT]
88.Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 1997;113:1069-73.  Back to cited text no. 88  [PUBMED]  [FULLTEXT]
89.Parola M, Leonarduzzi G, Biasi F, Albano E, Biocca ME, Poli G, et al . Vitamin E dietary supplementation protects against carbon tetrachloride-induced chronic liver damage and cirrhosis. Hepatology 1992;16:1014-21.  Back to cited text no. 89  [PUBMED]  
90.Rockey DC, Chung JJ. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: Implications for treatment of hepatic fibrosis. J Investig Med 1994;42:660-70.  Back to cited text no. 90  [PUBMED]  
91.Pavanato A, Tunon MJ, Sanchez-Campos S, Marroni CA, Llesuy S, Gonzalez-Gallego J, et al . Effects of quercetin on liver damage in rats with carbon tetrachloride-induced cirrhosis. Dig Dis Sci 2003;48:824-9.  Back to cited text no. 91    
92.Croquet V, Moal F, Veal N, Wang J, Oberti F, Roux J, et al . Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis and/or portal hypertension. J Hepatol 2002;37:773-80.   Back to cited text no. 92  [PUBMED]  [FULLTEXT]
93.Warner FJ, Lubel JS, McCaughan GW, Angus PW. Liver fibrosis: A balance of ACEs? Clin Sci (Lond) 2007;113:109-18   Back to cited text no. 93  [PUBMED]  [FULLTEXT]
94.Paizis G, Gilbert RE, Cooper ME, Murthi P, Schembri JM, Wu LL, et al . Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol 2001;35:376-85.  Back to cited text no. 94  [PUBMED]  [FULLTEXT]
95.Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG, et al. An oral endothelin: A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 2000;118:1169-78.  Back to cited text no. 95    
96.Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, et al . Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002;122:1924-40.  Back to cited text no. 96  [PUBMED]  [FULLTEXT]
97.Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, et al . Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 2000;119:466-78.  Back to cited text no. 97  [PUBMED]  [FULLTEXT]

Top
Correspondence Address:
Mona H Ismail
Department of Internal Medicine, Division of Gastroenterology, College of Medicine, King Faisal University-Dammam, King Fahad Hospital of the University, PO Box 40149, Al-Khobar 31952
Saudi Arabia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.45072

Rights and Permissions



 
 
    Tables

  [Table 1], [Table 2]

This article has been cited by
1 Establishment of a liver fibrosis model in cynomolgus monkeys
Ke Ding,Man-Rong Liu,Jianmin Li,Ke Huang,Yi Liang,Xiaobin Shang,Jiong Chen,Jian Mu,Huimei Liu
Experimental and Toxicologic Pathology. 2014; 66(5-6): 257
[Pubmed] | [DOI]
2 Effect of antioxidant therapy on hepatic fibrosis and liver iron concentrations in ╬▓-thalassemia major patients
Elalfy, M.S. and Adly, A.A.M. and Attia, A.A.M. and Ibrahim, F.A. and Mohammed, A.S. and Sayed, A.M.
Hemoglobin. 2013; 37(3): 257-276
[Pubmed]
3 Inhibition of hepatic fibrosis with artificial microRNA using ultrasound and cationic liposome-bearing microbubbles
D Yang,Y-H Gao,K-B Tan,Z-X Zuo,W-X Yang,X Hua,P-J Li,Y Zhang,G Wang
Gene Therapy. 2013;
[Pubmed] | [DOI]
4 Effect of Antioxidant Therapy on Hepatic Fibrosis and Liver Iron Concentrations in ▀-Thalassemia Major Patients
Mohsen S. Elalfy,Amira A.M. Adly,Atef A.M. Attia,Fatma A. Ibrahim,Amer S. Mohammed,Abdelbasset M. Sayed
Hemoglobin. 2013; 37(3): 257
[Pubmed] | [DOI]
5 Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis
Zeisberg, M. and Kalluri, R.
American Journal of Physiology - Cell Physiology. 2013; 304(3): C216-C225
[Pubmed]
6 Prospective non-invasive follow-up of liver fibrosis in patients with chronic hepatitis C
Crisan, D. and Radu, C. and Grigorescu, M.D. and Lupsor, M. and Feier, D. and Grigorescu, M.
Journal of Gastrointestinal and Liver Diseases. 2012; 21(4): 375-382
[Pubmed]
7 Antifibrotic potential of a selective COX-2 inhibitor (celecoxib) on liver fibrosis in rats
Mona M. Ftahy, Noha S. Abdl Latif, Essam F. Alalkamy, Fatma A. El-Batrawi, Ahmad H. Galal, Hany M. Khatab
Comparative Clinical Pathology. 2012;
[VIEW] | [DOI]
8 KangXian FuFang I inhibits acetaldehyde-stimulated extracellular matrix synthesis and cytokine secretion in cultured hepatic stellate cells
Lin, H., Huang, Y.-H., Li, Y.-L., Fu, B.-Y., Wang, B.-Y.
World Chinese Journal of Digestology. 2011; 19(17): 1826-1829
[Pubmed]
9 Pharmacological therapy of nonalcoholic steatohepatitis
Hojo, M. and Watanabe, S.
Hepatology Research. 2011; 41(3): 209-216
[Pubmed]
10 Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice
Rong Wang,Yue Nan,Wen Wu,Ling Kong,Fang Han,Su Zhao,Li Kong,Jun Yu
Lipids in Health and Disease. 2011; 10(1): 31
[Pubmed] | [DOI]
11 Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: The Hidden Epidemic
Mona H. Ismail
The American Journal of the Medical Sciences. 2011; 341(6): 485
[Pubmed] | [DOI]
12 Correlative research between leptin and TGF-╬▓1 and the recovery on CCl4 induced hepatic fibrosis in rats
Li, H. and Li, J. and Huang, C. and Huang, Y. and Zhang, L. and Li, Z.-T. and Zhang, S.-P. and Cheng, J.
Chinese Pharmacological Bulletin. 2011; 27(4): 473-477
[Pubmed]
13 Pharmacological therapy of nonalcoholic steatohepatitis
Mariko Hojo,Sumio Watanabe
Hepatology Research. 2011; 41(3): 209
[Pubmed] | [DOI]
14 Nonalcoholic fatty liver disease and type 2 diabetes mellitus: The hidden epidemic
Ismail, M.H.
American Journal of the Medical Sciences. 2011; 341(6): 485-492
[Pubmed]
15 Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice
Wang, R.Q., Nan, Y.M., Wu, W.J., Kong, L.B., Han, F., Zhao, S.X., Kong, L., Yu, J.
Lipids in Health and Disease. 2011; 10(art 31)
[Pubmed]
16 Advances in hepatic stellate cell-targeted treatment of hepatic fibrosis with bone marrow-derived mesenchymal stem cells
Hu, M.-D. and Guo, G.-H.
World Chinese Journal of Digestology. 2010; 18(24): 2558-2562
[Pubmed]
17 Liver fibrosis: A dynamic and potentially reversible process
Povero, D. and Busletta, C. and Novo, E. and Di Bonzo, L.V. and Cannito, S. and Paternostro, C. and Parola, M.
Histology and Histopathology. 2010; 25(8): 1075-1091
[Pubmed]



 

Top
 
  Search
 
  
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
    Definition of Fi...
    Pathogenesis of ...
    Diagnosis of Fib...
    Reversal of Fibr...
    Liver Fibrosis a...
    Conclusions
    Acknowledgement
    References
    Article Tables

 Article Access Statistics
    Viewed7340    
    Printed185    
    Emailed1    
    PDF Downloaded1204    
    Comments [Add]    
    Cited by others 17    

Recommend this journal