Cirrhosis reversal: a duel between dogma and myth
2004; Elsevier BV; Volume: 40; Issue: 5 Linguagem: Inglês
10.1016/j.jhep.2004.03.007
ISSN1600-0641
Autores Tópico(s)Liver Disease and Transplantation
Resumo1. IntroductionThe term cirrhosis itself and the liver pathology it indicates, have been a source of confusion and debate at the beginning of the 20th century, and apparently remains so at the start of the third millenium.It was Laennec who in 1819 rather casually introduced the term cirrhosis in a footnote in his ‘Traité de l'Auscultation’ [[1]Laennec R.T.H Traité de l'Auscultation Médiate, et des Maladies des Poumons et du Coeur. Chaude, Paris1819Google Scholar]; he regarded the granulations as neoformations, and because of their colour he called the condition in the liver ‘cirrhosis’, since ‘kirros’ in Greek means yellow or tawny. At the turn of the 20th century, a confusing plurality of types and classifications existed [[2]Schaffner F Sieratzki J.S The early history of cirrhosis.in: Boyer J.L Bianchi L Liver cirrhosis. MTP Press, Lancaster1987: 57-72Google Scholar]. There was controversy for many more years [[3]Popper H Zak F.G Pathologic aspects of cirrhosis.Am J Med. 1958; 24: 593-619Abstract Full Text PDF PubMed Scopus (18) Google Scholar] whether cirrhosis is a uniform process or develops over several different pathways [[4]Popper H Elias H Histogenesis of hepatic cirrhosis studied by the three-dimensional approach.Am J Pathol. 1955; 31: 405-441PubMed Google Scholar]; whether cirrhosis is a primary disturbance of the hepatic cells with reactive connective tissue formation, or a primary mesenchymal inflammatory lesion in which the epithelial alterations are secondary to the mesenchymal scarring. The latter concept would identify cirrhosis with a chronic hepatitis, reflected in Himsworth's suggestion [5Himsworth H.P The liver and its diseases. Harvard University Press, Cambridge, MA1947Google Scholar, 6Mallory F.B Cirrhosis of the liver. Five different types of lesions from which it may arise.Bull John Hopkins Hosp. 1911; 22: 69-75Google Scholar] to discard the term cirrhosis and designate the sclerosed appearance of the liver as fibrosis. However, such morphologic approach fails to do justice to the functional problem of cirrhosis which is characterized by cardinal features not necessarily found in chronic hepatitis, namely, reduced hepatic function, portal hypertension, ascites, and tendency to progression [[3]Popper H Zak F.G Pathologic aspects of cirrhosis.Am J Med. 1958; 24: 593-619Abstract Full Text PDF PubMed Scopus (18) Google Scholar]. Moreover, the term cirrhosis has met the test of time [[7]Popper H Pathologic aspects of cirrhosis.Am J Pathol. 1977; 87: 228-264PubMed Google Scholar] and is deeply entrenched in the medical literature.2. Definition of cirrhosisIn 1978, a working group sponsored by the World Health Organization defined cirrhosis as a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules [[8]Anthony P.P Ishak K.G Nayak N.C Poulsen H Scheuer P.J Sobin L.H The morphology of cirrhosis: definition, nomenclature and classification.Bull World Health Organ. 1977; 55: 521-540PubMed Google Scholar]. Implicit in this morphological definition is a most important hemodynamic alteration, consisting in the establishment of intrahepatic vascular shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) vessels of the liver [9Millward-Sadler G.H Hahn E.G Wright R Cirrhosis: an appraisal.in: Wright R Millward-Sadler G.H Alberti K.G.M.M Karran S Liver and biliary disease. 2nd ed. Baillière Tindall WB Saunders, London1985: 821-860Google Scholar, 10Desmet V.J Sciot R Van Eyken P Differential diagnosis and prognosis of cirrhosis: role of liver biopsy.Acta Gastroenterol Belg. 1990; 53: 198-208PubMed Google Scholar]. The vascular shunts are determined by the topography of the vascularized fibrotic septa and represent an essential feature of cirrhosis [[11]Rappaport A.M McPhee P.J Fisher M.M Phillips M.J The scarring of the liver acini (cirrhosis). Tridimensional and microcirculatory considerations.Virchows Arch [A]. 1983; 402: 107-137Crossref Scopus (132) Google Scholar].It took more than one consensus meeting to recognize that cirrhosis is more than just widespread liver fibrosis. The ‘Board for classification and nomenclature of cirrhosis’ of the Fifth Pan-American Congress of Gastroenterology, which met in La Habana, Cuba in 1956, provided a definition of cirrhosis which was the base for the present concept, and stated explicitly: “Fibrosis should not be used synonymously for cirrhosis” [[12]Fifth Pan American Congress of GastroenterologyReport of the Board for Classification and Nomenclature of Cirrhosis of the Liver.Gastroenterology. 1956; 31 (La Habana, Cuba): 213-219Google Scholar]. Thus cirrhosis corresponds to end-stage disease, characterized—like in any organ—by diffuse fibrosis. But unique to the liver and its cirrhotic stage is the occurrence of septal fibrosis, including portal–central septa carrying shunting vessels, and nodular parenchymal regeneration resulting in distorted architecture.3. Vascular changes in cirrhosis. ‘A bridge too far’Alterations in the hepatic vasculature are a crucial component in the development of the cirrhotic state [7Popper H Pathologic aspects of cirrhosis.Am J Pathol. 1977; 87: 228-264PubMed Google Scholar, 11Rappaport A.M McPhee P.J Fisher M.M Phillips M.J The scarring of the liver acini (cirrhosis). Tridimensional and microcirculatory considerations.Virchows Arch [A]. 1983; 402: 107-137Crossref Scopus (132) Google Scholar] and accompany the basic pathogenetic processes at play in the development of cirrhosis. These include: parenchymal cell damage and death, fibrogenesis and hepatocellular regeneration. Important forms of fibrosis during cirrhogenesis include septal and perisinusoidal fibrosis.Septal fibrosis refers to the development of three-dimensional vascularized connective tissue sheets which interrupt the parenchymal continuity. Septa may develop from portal tracts or central and subhepatic veins and extend over variable distance in different directions.Fibrous septa which extend into the lobular parenchyma without reaching other vascular anatomical landmarks (portal tract or central vein) are termed incomplete, ‘blind-ending’ septa.Complete septa may link central veins to central veins, resulting from long-lasting centrolobular liver cell damage and creating anastomoses between two or more draining vessels.Septa linking adjacent portal tracts create vascular anastomoses between afferent vessels of the portal tracts involved. Portal–portal linking septa typically occur in chronic hepatitis as a result of long-standing interface hepatitis and in chronic biliary disease (e.g. PBC, PSC).Vascular structures in central–central and portal–portal septa are not the major determinants of a detrimental change in intrahepatic circulation. The key phenomenon in the emergence of a truely cirrhotic state is the development of fibrous vascularized septa linking portal tracts and central veins (Fig. 1) . Therefore portal–central bridging fibrosis is ‘a bridge too far’. It creates direct anastomoses between the afferent (hepatic artery, portal vein) and efferent (centrolobular veins) vessels of the liver, allowing a fraction of the blood to bypass the lobular parenchyma, without functionally contacting a metabolically active parenchyma.Shunting of blood causes striking changes in fluid dynamics [13Picchiotti R Mingazzini P.L Scucchi L Bressan M Di Stefano D Donnetti M Feroci L Correlations between sinusoidal pressure and liver morphology in cirrhosis.J Hepatol. 1994; 20: 364-369Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 14Varin F Huet P.M Hepatic microcirculation in the perfused cirrhotic rat liver.J Clin Invest. 1985; 76: 1904-1912Crossref PubMed Scopus (121) Google Scholar]. In advanced cirrhosis, most of the hepatic blood supply appears to pass through the liver via these channels [[15]Sherman I.A Pappas S.C Fisher M.M Hepatic microvascular changes associated with the development of liver fibrosis and cirrhosis.Am J Physiol. 1990; 258: H460-H4H5PubMed Google Scholar]. Most of these shunts are microscopic, but in about 1 in 4 cirrhotic patients shunts measuring 1–2 mm in diameter can be demonstrated on transhepatic portography [[16]Ohnishi K Chin N Saito M Tanaka H Terabayashi H Nakayama T et al.Portographic opacification of hepatic veins and (anomalous) anastomoses between the portal and hepatic veins in cirrhosis—indication of extensive intrahepatic shunts.Am J Gastroenterol. 1986; 81: 975-978PubMed Google Scholar]. Shunted blood flow through the ‘fast’ vascular channels (porto-venous and arterio-venous shunts) leaves the remainder of the parenchyma nearly bereft of blood supply [[15]Sherman I.A Pappas S.C Fisher M.M Hepatic microvascular changes associated with the development of liver fibrosis and cirrhosis.Am J Physiol. 1990; 258: H460-H4H5PubMed Google Scholar], explaining the increased flow observed in sinusoids of the cirrhotic liver as well as the relative underperfusion of the liver parenchyma as a whole [[17]Vollmar B Siegmund S Menger M.D An intravital fuorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in rats.Hepatology. 1998; 27: 1544-1553Crossref PubMed Scopus (89) Google Scholar].Portal–central bridging fibrosis results from extensive and/or repetitive damage to the lobular parenchyma: portal–central bridging necrosis, panlobular necrosis and multilobular necrosis. The former may lead to slender portal–central septa, whereas multilobular necrosis creates more extensive areas of parenchymal extinction and fibrous scars, which link several original portal tracts and central veins interconnected by the vascular networks of the developing neomatrix.Vascular structures in cirrhotic connective tissue septa may develop in two ways. Some vessels derive from sinusoids which persist in areas of postnecrotic collapse of the connective tissue framework. Other vessels derive from angiogenesis associated with fibrogenesis. Hypoxia, possibly induced by vascular shunts and capillarization of sinusoids, induces angiogenesis at an early stage of cirrhosis development [18Rosmorduc 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 cirrhosis.Am J Pathol. 1999; 155: 1065-1073Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 19Corpechot 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: 1010-1021Crossref PubMed Scopus (402) Google Scholar]. Alterations in blood flow contribute in a fundamental way to the transformation of the damaged liver into a scarred nodular organ [[20]Crawford J.M Liver cirrhosis.in: MacSween R.N.M Burt A.D Portmann B.C Ishak K.G Scheuer P.J Anthony P.P Pathology of the liver. 4th ed. Churchill Livingstone, London2002: 575-619Google Scholar].Perisinusoidal fibrosis consists in the development of neomatrix in the space of Disse, resulting in ‘capillarization of the sinusoids’ [[21]Schaffner F Popper H Capillarization of hepatic sinusoids in man.Gastroenterology. 1963; 44: 239-242Abstract Full Text PDF PubMed Scopus (503) Google Scholar]. Hindrance to the metabolic exchange between blood and hepatocytes of that fraction of the blood flow that is not shunted directly from afferent to efferent vessels in the cirrhotic liver [[22]Reichen J Egger B Ohara N Zeltner T.B Zysset T Zimmermann A Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.J Clin Invest. 1988; 82: 2069-2076Crossref PubMed Scopus (97) Google Scholar], contributes to the decreased functional reserve of the cirrhotic liver [[23]Popper H Schaffner F Liver: structure and function. McGraw-Hill, New York1957Google Scholar].Further vascular changes in developing and established liver cirrhosis are due to vascular thrombosis. Wanless et al. [24Wanless I.R Wong F Blendis L.M Greig P Heathcote E.J Levy G Hepatic and portal vein thrombosis in cirhosis: possible role in development of parenchymal extinction and portal hypertension.Hepatology. 1995; 21: 1238-1247PubMed Google Scholar, 25Wanless I.R Vascular disorders.in: MacSween R.N.M Burt A.D Portmann B.C Ishak K.G Scheuer P.J Anthony P.P Pathology of the liver. 4th ed. Churchill Livingstone, London2002: 539-573Google Scholar] found obliterative lesions in portal veins and in hepatic veins of all sizes in at least 36 and 70%, respectively, of cirrhotic livers removed at liver transplantation. They concluded that thrombosis of medium and large portal veins and hepatic veins is a common occurrence in cirrhosis, and that these lesions are important in causing progression of cirrhosis [24Wanless I.R Wong F Blendis L.M Greig P Heathcote E.J Levy G Hepatic and portal vein thrombosis in cirhosis: possible role in development of parenchymal extinction and portal hypertension.Hepatology. 1995; 21: 1238-1247PubMed Google Scholar, 26Tanaka M Wanless I.R Pathology of the liver in Budd–Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules.Hepatology. 1998; 27: 488-496Crossref PubMed Scopus (192) Google Scholar].In this sense, cirrhosis is indeed basically a vascular disease of the liver [7Popper H Pathologic aspects of cirrhosis.Am J Pathol. 1977; 87: 228-264PubMed Google Scholar, 11Rappaport A.M McPhee P.J Fisher M.M Phillips M.J The scarring of the liver acini (cirrhosis). Tridimensional and microcirculatory considerations.Virchows Arch [A]. 1983; 402: 107-137Crossref Scopus (132) Google Scholar, 25Wanless I.R Vascular disorders.in: MacSween R.N.M Burt A.D Portmann B.C Ishak K.G Scheuer P.J Anthony P.P Pathology of the liver. 4th ed. Churchill Livingstone, London2002: 539-573Google Scholar, 27Galambos J.T Cirrhosis.in: Smith L.H.J Volume XVII in the series Major problems in internal medicine. WB Saunders, Philadelphia, PA1979Google Scholar, 28Baggenstoss A.H Postnecrotic cirrhosis: morphology, etiology and pathogenesis.in: Popper H Schaffner F Progress in liver diseases. vol. 1. Grune and Stratton, New York1961: 14-38Google Scholar]. As formulated by Popper: “The retention of the quaint term cirrhosis, which is etymologically meaningless, is accounted for by its connotation of disturbed hepatic circulation” [[29]Popper H What are the major types of hepatic cirrhosis?.in: Ingelfinger F Relman A Finland M Controversy in internal medicine. WB Saunders, Philadelphia, PA1966: 233-243Google Scholar].The fibrotic lesions of the cirrhotic liver together with the vascular changes represent the mechanical component of vascular obstruction in the pathogenesis of portal hypertension, which together with other mechanisms contributes to increased intrahepatic vascular resistance [[30]Grossman H.J Grossman V.L Bhathal P.S Intrahepatic vascular resistance in cirrhosis.in: Bosch J Grozmann R.J Portal hypertension. Pathophysiology and treatment. Blackwell Scientific Publications, Oxford1994: 1-16Google Scholar].Investigations on neo-angiogenesis in cirrhosis have focussed attention on hypoxia of liver tissue [[19]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: 1010-1021Crossref PubMed Scopus (402) Google Scholar]. Hypoxia may result from several mechanisms: impairment in sinusoidal permeability and perfusion [[14]Varin F Huet P.M Hepatic microcirculation in the perfused cirrhotic rat liver.J Clin Invest. 1985; 76: 1904-1912Crossref PubMed Scopus (121) Google Scholar], intrahepatic shunts [[31]Gaudio E Pannarale L Onori P Riggio O A scanning electron microscopic study of liver microcirculation disarrangement in experimental rat cirrhosis.Hepatology. 1993; 17: 477-485Crossref PubMed Scopus (35) Google Scholar], vasoconstriction and thrombosis [[24]Wanless I.R Wong F Blendis L.M Greig P Heathcote E.J Levy G Hepatic and portal vein thrombosis in cirhosis: possible role in development of parenchymal extinction and portal hypertension.Hepatology. 1995; 21: 1238-1247PubMed Google Scholar], capillarisation of sinusoids [22Reichen J Egger B Ohara N Zeltner T.B Zysset T Zimmermann A Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.J Clin Invest. 1988; 82: 2069-2076Crossref PubMed Scopus (97) Google Scholar, 32Onori P Morini S Franchitto A Sferra R Alvaro D Gaudio E Hepatic microvascular features in experimental cirrhosis: a structural and morphometrical study in CCL4-treated rats.J Hepatol. 2000; 33: 555-563Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. Liver tissue hypoxia aggravates fibrosis progression, so that fibrosis and hypoxia may aggravate each other in the presence of persistent parenchymal injury, leading to a vicious circle, which disrupts the normal tissue repair and hereby promotes the development and progression of cirrhosis [19Corpechot 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: 1010-1021Crossref PubMed Scopus (402) Google Scholar, 33Yancopoulos G Davis S Gale N Rudge J Wiegand S Holash J Vascular-specific growth factors and blood vessel formation.Nature. 2000; 407: 242-248Crossref PubMed Scopus (3253) Google Scholar], with its lower degree of hepatocellular metabolic regulation [34Berasain C Herroro J.-I Garcia-Trevijano E.R Avila M.A Esteban J.I Mato J.M et al.Expression of Wilms’ tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function.Hepatology. 2003; 38: 148-157Crossref PubMed Scopus (53) Google Scholar, 35Watt A.J Garrison W.D Duncan S.A Editorial. HNF4: a central regulator of hepatocyte differentiation and function.Hepatology. 2003; 37: 1249-1253Crossref PubMed Scopus (224) Google Scholar].4. Irreversibility of cirrhosis. A dogma? 1Websters New Collegiate Dictionary (1977): ‘C. Dogma: a point of view or tenet put forth as authoritative without adequate grounds’.1Websters New Collegiate Dictionary (1977): ‘C. Dogma: a point of view or tenet put forth as authoritative without adequate grounds’.Up to the 1970s of the previous century, cirrhosis was considered an irreversible endstage of liver disease. With the exception of abstinence in alcohol induced liver disease and venesection in hereditary iron overload, a therapeutic armamentarium for treatment of chronic liver diseases was virtually non-existent. As a result, many patients with diverse forms of chronic liver disease progressed to the cirrhotic endstage, including its complications, explaining the concept that real cirrhosis remains progressive ‘usque ad finem vitae (seu hepatis)’ (until the end of life or of the liver itself) [[36]Lauda E Die Leberzirrhosen.Wien Klin Wochenschr. 1956; 68: 73-80PubMed Google Scholar].Especially the vascular component of intrahepatic porto-systemic anastomoses [[37]Popper H Elias H Petty D.E Vascular patterns of the cirrhotic liver.Am J Clin Pathol. 1952; 22: 717-729PubMed Google Scholar] is considered a determinant of no return, the major factor causing ‘irreversibility’, thus explaining why the cirrhotic state is reported as ‘for all practical purposes irreversible’ in most textbooks and papers on liver pathology.‘For all practical purposes’ implies a reference to the present state of affairs, awaiting new developments, and hence not really dogmatic. The dogmatic nature of the tenet of irreversibility of cirrhosis was voiced most explicitly by Perez-Tamayo [[38]Perez Tamayo R Cirrhosis of the liver: a reversible disease?.Pathol Annu. 1979; 14: 183-213PubMed Google Scholar].He mentions three personal observations of ‘cirrhosis reversal’, but admits that the three patients did not present themselves as advanced cases of cirrhosis of the liver. “Indeed, it is quite possible that other pathologists would classify them as precirrhosis or simply as fibrosis of the liver. But the point is that, whatever the label finally accepted for their disease, it was characterized by an excess of fibrous tissue which eventually disappeared”.From his own notes it is clear that Perez-Tamayo wrote a flamboyant plea in favour of reversibility of fibrosis in cirrhosis, not on reversibility of cirrhosis as such.4.1 Reversibility of fibrosis. ‘Panta rhei, ouden menei’ 2‘panta rei, ouden menei’ Everything flows (changes), nothing remains (the same). Proposition ascribed to the philosopher Heraclitus of Ephesus, 540–480 BC.2‘panta rei, ouden menei’ Everything flows (changes), nothing remains (the same). Proposition ascribed to the philosopher Heraclitus of Ephesus, 540–480 BC.Over the years [[39]Popper H Introduction to the problem. Hepatic fibrosis and collagen metabolism in the liver.in: Popper H Becker K Collagen metabolism in the liver. Stratton Intercontinental Medical Book Corporation, New York1975: 1-14Google Scholar], evidence emerged on the dynamic aspects of fibrosis, including synthesis, deposition and degradation of matrix components, rendering the ‘fossil’ stability (sic!) of fibrosis obsolete [[40]Gressner A.M Major topics of fibrosis research: 1990 update.in: Wisse E Knook D.L McCuskey R.S Cells of the hepatic sinusoid. vol. 3. Kupffer Cell Foundation, Leiden1991: 136-144Google Scholar]. Investigations focussed on the cells of origin, and their mechanisms of matrix formation and degradation, revealing a remarkably complex network of interacting cells, cytokines and chemokines.Today, there is no doubt at all that liver fibrosis is reversible. Several recent reviews give brilliant synopses of the progress in this field [41Friedman S.L Liver fibrosis—from bench to bedside.J Hepatol. 2003; 38: S38-S53Abstract Full Text Full Text PDF PubMed Google Scholar, 42Chevallier M Paradis V Bedossa P Fibroses hépatiques.Ann Pathol. 1995; 15: 372-379PubMed Google Scholar, 43Greenwel P Geerts A Ogata I Solis-Herruzo J.A Rojkind M Liver fibrosis.in: Arias I.M Boyer J.L Fausto N Jakoby W.B Schachter D.A Shafritz D.A The liver: biology and pathobiology. 3rd ed. Raven Press, New York1994Google Scholar, 44Friedman S.L Arthur M.J Reversing hepatic fibrosis.Sci Med. 2002; 8: 194-205Google Scholar, 45Friedman S.L Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem. 2000; 275: 2247-2250Crossref PubMed Scopus (1877) Google Scholar], including the role of hepatic stellate cell apoptosis in the resolution of fibrosis [46Iredale J.P Benyon R.C Pickering J et al.Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.J Clin Invest. 1998; 102: 538-549Crossref PubMed Scopus (931) Google Scholar, 47Issa R Williams E Trim N Kenally T Arthur M.J.P Reichen J et al.Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors.Gut. 2001; 48: 548-557Crossref PubMed Scopus (276) Google Scholar].This does not mean that all fibrosis is equally reversible. It is quite possible that intralobular perisinusoidal fibrosis is more reversible than septal fibrosis [[48]Wanless I.R Nakashima E Sherman M Regression of human cirrhosis: morphologic features and the genesis of incomplete septal cirrhosis.Arch Pathol Lab Med. 2000; 124: 1599-1607PubMed Google Scholar], possibly due to corresponding differences in mesenchymal cell types [[49]Cassiman D Libbrecht L Desmet V Aertsen P Denef C Roskams T Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers.J Hepatol. 2002; 36: 200-209Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar].However slow or fast, there is no reason any more to doubt the dynamic nature of fibrosis as a net result of active deposition and removal. Panta rhei, ouden menei.4.2 Reversibility of cirrhosis. A myth 3Websters New Collegiate Dictionary (1977) ‘b.: Myth: an ill-founded belief held uncritically especially by an interested group’.3Websters New Collegiate Dictionary (1977) ‘b.: Myth: an ill-founded belief held uncritically especially by an interested group’.Several papers, some from years ago (summarized in Ref. [[38]Perez Tamayo R Cirrhosis of the liver: a reversible disease?.Pathol Annu. 1979; 14: 183-213PubMed Google Scholar]), others becoming more numerous in later years (mentioned in Ref. [[48]Wanless I.R Nakashima E Sherman M Regression of human cirrhosis: morphologic features and the genesis of incomplete septal cirrhosis.Arch Pathol Lab Med. 2000; 124: 1599-1607PubMed Google Scholar]), completed with some very recent additions (referred to in Ref. [[50]Poynard T McHutchison J Manns M Trepo C Lindsay K Goodman Z for the PEG-FIBROSIS Project Group et al.Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C.Gastroenterology. 2002; 122: 1303-1313Abstract Full Text Full Text PDF PubMed Scopus (984) Google Scholar]) tend to prove that hepatic fibrosis and even cirrhosis in some cases is reversible, thus refuting the old ‘dogma’ of irreversibility of human cirrhosis [[41]Friedman S.L Liver fibrosis—from bench to bedside.J Hepatol. 2003; 38: S38-S53Abstract Full Text Full Text PDF PubMed Google Scholar].These papers showed that fibrosis may decrease with time in some cirrhotic livers [50Poynard T McHutchison J Manns M Trepo C Lindsay K Goodman Z for the PEG-FIBROSIS Project Group et al.Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C.Gastroenterology. 2002; 122: 1303-1313Abstract Full Text Full Text PDF PubMed Scopus (984) Google Scholar, 51Kaplan M.M De Lellis R.A Wolfe H.J Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment.Ann Int Med. 1997; 126: 682-688Crossref PubMed Scopus (123) Google Scholar, 52Sobesky R Mathurin P Charlotte F Modeling the impact of interferon alpha treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view.Gastroenterology. 1999; 116: 378-386Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 53Dufour J.F De Lellis R Kaplan M.M Reversibility of hepatic fibrosis in autoimmune hepatitis.Ann Int Med. 1997; 127: 981-985Crossref PubMed Scopus (268) Google Scholar, 54Dufour J.F De Lellis R Kaplan M.M Regression of hepatic fibrosis in hepatitis C with long-term interferon treatment.Dig Dis Sci. 1998; 43: 2573-2576Crossref PubMed Scopus (117) Google Scholar, 55Guerret S Long-term administration of interferon-alpha in non-responder patients with chronic hepatitis C: follow-up of liver fibrosis over 5 years.J Viral Hep. 1999; 6: 125-133Crossref PubMed Scopus (51) Google Scholar, 56Lewis D.R Burbige E.J French S.W Reversal of cirrhosis in hemochromatosis following long-term phlebotomy.Gastroenterology. 1983; 34: 1382Google Scholar, 57Foulk W.T Baggenstoss A.H Biliary cirrhosis.in: Schiff L Diseases of the liver. 4th ed. J B Lippincott, Philadelphia, PA1975: 940Google Scholar, 58Desmet V.J Cirrhosis: aetiology and pathogenesis: cholestasis.in: Boyer J.L Bianchi L Liver cirrhosis. Falk Symposium 44. MTP Press, Lancaster1987: 101-118Google Scholar, 59Weinbren K Hadjis N.S Blumgart L.H Structural aspects of the liver in patients with biliary disease and portal hypertension.J Clin Pathol. 1985; 38: 1013-1020Crossref PubMed Scopus (23) Google Scholar, 60Wanless I.R Regression of human cirrhosis: in reply.Arch Pathol Lab Med. 2000; 124: 1592-1593Google Scholar]. Such regression of fibrosis has been documented in diseases in which (necro-inflammatory) progression could be arrested by therapy, as for instance in alcohol-induced liver damage, chronic biliary obstruction, hemochromatosis, Wilson disease, Indian childhood cirrhosis, intestinal bypass-related cirrhosis, autoimmune hepatitis, primary biliary cirrhosis and chronic viral hepatitis B, C and D. In most published studies, histologic changes have been reported as a decrease in fibrosis scores on needle biopsy specimens using semiquantitative scoring [50Poynard T McHutchison J Manns M Trepo C Lindsay K Goodman Z for the PEG-FIBROSIS Project Group et al.Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C.Gastroenterology. 2002; 122: 1303-1313Abstract Full Text Full Text PDF PubMed Scopus (984) Google Scholar, 51Kaplan M.M De Lellis R.A Wolfe H.J Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment.Ann Int Med. 1997; 126: 682-688Crossref PubMed Scopus (123) Google Scholar, 52Sobesky R Mathurin P Charlotte F Modeling the impact of interferon alpha treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view.Gastroenterology. 1999; 116: 378-386Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 53Dufour J.F De Lellis R Kaplan M.M Reversibility of hepatic fibrosis in autoimmune hepatitis.Ann Int Med. 1997; 127: 981-985Crossref PubMed Scopus (268) Google Scholar, 54Dufour J.F De Lellis R Kaplan M.M Regression of hepatic fibrosis in hepatitis C with long-term interferon treatment.Dig Dis Sci. 1998; 43: 2573-2576Crossref PubMed Scopus (117) Google Scholar], or a morphometric technique [[55]Guerret S Long-term administration of interferon-alpha in non-responder patients with chronic hepatitis C: follow-up of liver fibrosis over 5 years.J Viral Hep. 1999; 6: 125-133Crossref PubMed Scopus (51) Google Scholar].Two cases have been more extensi
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