Journal of Hepatology
Volume 40, Issue 5 , Pages 860-867, May 2004

Cirrhosis reversal: a duel between dogma and myth

Department of Pathology, K.U. Leuven, Leuven, Belgium

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1. Introduction 

The 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]; 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]. There was controversy for many more years [3] whether cirrhosis is a uniform process or develops over several different pathways [4]; 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 [5], [6] 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]. Moreover, the term cirrhosis has met the test of time [7] and is deeply entrenched in the medical literature.

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2. Definition of cirrhosis 

In 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]. 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 [9], [10]. The vascular shunts are determined by the topography of the vascularized fibrotic septa and represent an essential feature of cirrhosis [11].

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]. 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.

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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 [7], [11] 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.

  • View full-size image.
  • Fig. 1. 

    Liver Biopsy of a patient with hepatitis C infection in the cirrhotic stage, showing a portal-central vascularized septum. Sirius Red stain, original magnification×100.

Shunting of blood causes striking changes in fluid dynamics [13], [14]. In advanced cirrhosis, most of the hepatic blood supply appears to pass through the liver via these channels [15]. 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]. 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], 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].

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 [18], [19]. Alterations in blood flow contribute in a fundamental way to the transformation of the damaged liver into a scarred nodular organ [20].

Perisinusoidal fibrosis consists in the development of neomatrix in the space of Disse, resulting in ‘capillarization of the sinusoids’ [21]. 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], contributes to the decreased functional reserve of the cirrhotic liver [23].

Further vascular changes in developing and established liver cirrhosis are due to vascular thrombosis. Wanless et al. [24], [25] 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 [24], [26].

In this sense, cirrhosis is indeed basically a vascular disease of the liver [7], [11], [25], [27], [28]. 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].

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].

Investigations on neo-angiogenesis in cirrhosis have focussed attention on hypoxia of liver tissue [19]. Hypoxia may result from several mechanisms: impairment in sinusoidal permeability and perfusion [14], intrahepatic shunts [31], vasoconstriction and thrombosis [24], capillarisation of sinusoids [22], [32]. 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 [19], [33], with its lower degree of hepatocellular metabolic regulation [34], [35].

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4. Irreversibility of cirrhosis. A dogma?1 

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].

Especially the vascular component of intrahepatic porto-systemic anastomoses [37] 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].

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 

Over the years [39], 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]. 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 [41], [42], [43], [44], [45], including the role of hepatic stellate cell apoptosis in the resolution of fibrosis [46], [47].

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], possibly due to corresponding differences in mesenchymal cell types [49].

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 myth3 

Several papers, some from years ago (summarized in Ref. [38]), others becoming more numerous in later years (mentioned in Ref. [48]), completed with some very recent additions (referred to in Ref. [50]) 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].

These papers showed that fibrosis may decrease with time in some cirrhotic livers [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60]. 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 [50], [51], [52], [53], [54], or a morphometric technique [55].

Two cases have been more extensively documented. [48], [56] However, in one instance [56], the ‘cirrhosis’ is admitted to be a biliary type fibrosis, which is not true cirrhosis [57], [58], [59], and in the other case [48] the author later reports that the clinical signs persist [60].

The conclusion is that all studies until now have demonstrated variable reversal of fibrosis in cirrhosis, and not complete reversal of cirrhosis. This statement also applies for one of the largest series of patients studied with so-called ‘reversal of cirrhosis’ in 49% of 153 patients with hepatitis C virus positive cirrhosis on the baseline biopsy and treated with pegylated interferon alfa-2b and ribavirin [50]. Also these authors underestimate that cirrhosis is morphologically defined as a diffuse liver disease, characterized not only by fibrosis, but in addition by architectural disturbance with parenchymal nodulation, and abnormalities of the intrahepatic vasculature [61].

Cirrhosis appears in a broad spectrum of variants: early cirrhosis, fully developed cirrhosis, active and inactive cirrhosis, micronodular, macronodular and mixed micro-macronodular cirrhosis, and incomplete septal cirrhosis [62], [63]. More than one study has documented the conversion of micronodular into macronodular cirrhosis, especially when the causative agent could be eliminated and the necro-inflammatory parenchymal damage reduced [29], [64] Wanless et al. [48] published an extensive (and controversial: see editorials [65], [66], [67], [68]) study on the regression of human cirrhosis. They conclude that the repair process of cirrhosis may possibly even evolve into the stage of incomplete septal cirrhosis, the variant of macronodular cirrhosis which is particularly difficult to diagnose on needle biopsy specimens [62].

In spite of advanced repair with extensive resolution of fibrosis, abnormalities in architecture and intrahepatic circulation remain. So-called veno-portal adhesions persist even in late regression stages, and streamlines of ‘arterialized’ sinusoids (lined by CD34 positive endothelial cells) appear to remain part of intrahepatic arterio-venous shunts [48].

In short, substantial improvement, both functionally and structurally, may occur in the cirrhotic liver, but it is unlikely that complete regression of all anatomic features ever occurs [69]. For this reason, ‘reversal’ or ‘regression’ of cirrhosis remains a myth today, since the average reader understands by the terms reversal or regression full reversal or complete regression.

The terms reversal and regression are intrinsically ambiguous: minimal reversal, partial reversal, extensive reversal, total reversal… This is a first problem today: confusing terminology. More precision is needed and closer clinico-pathological cooperation in the reporting of therapeutic trials and in studies on reversal of fibrosis and hopefully also other parameters in human cirrhosis. Scientific writing requires writing in such a way that what is written can only be understood in the way it is meant to be understood. Therefore, the terms reversal and regression should be specified, and the terms fibrosis and cirrhosis should not be used interchangeably, as pointed out already by a consensus meeting in 1956 [12].

Further problems include: sampling error in needle biopsies, imperfection and inadequate interpretation of semiquantitative scoring systems, and the difficulty in recognizing the ‘fully developed’ stage of cirrhosis in needle biopsy specimens.

Sampling error in needle liver biopsies of cirrhotic livers is a problem well-known since several decades [70], [71]. The diagnosis of macronodular cirrhosis in needle biopsy specimens is far more difficult than that of micronodular cirrhosis, because the pathologist can mostly not rely on the demonstrable presence of the clear-cut criteria of parenchymal nodules surrounded by fibrous septa in the tissue specimen. In such instance, evidence for cirrhosis of variable degree of convincing power is sought in the presence of more relative parameters, like fragmentation of the specimen, alterations in the orientation of reticulin fibres resulting from different patterns and rates of growth in different areas, approximation of portal tracts and central veins; excess numbers of draining veins in relation to the number of portal tracts, and hepatocellular changes including regenerative hyperplasia with thickening of liver cell plates, presence of adjacent hepatocyte populations with different outlook and zones of large-cell and small-cell dysplasia [72].

During the last quarter century, additional problems arose in the interpretation of semiquantitative scoring systems for staging of fibrosis [73]. All scoring systems for staging of liver fibrosis use cirrhosis as the highest score, like fibrosis score F4 in the Metavir system [74] or score 6 according to Ishak et al. [75], because cirrhosis corresponds to the end stage of chronic fibrosing liver disease. A Metavir fibrosis score F4 requires evidence for obvious cirrhosis, that is: nodules and septa. This implies that a Metavir score F4 equals obvious cirrhosis and that suggestive evidence (only relative parameters) for macronodular cirrhosis does not qualify for the stage F4 for lack of sufficient fibrosis in the specimen. The corollary is that a lower score does not exclude less obvious cirrhosis of the macronodular or incomplete septal type. In this respect, the definition of Metavir score F3 is unfortunate, as it reads ‘numerous septa without cirrhosis’, which actually must be intended to mean ‘numerous septa without obvious cirrhosis’. The latest report on post-treatment ‘resolution of cirrhosis’ in chronic hepatitis C (Pol et al. Hum Pathol 35, 107–118, 2004), includes the study of two cases based on hepatectomy specimens. However, also in the latter two, cirrhosis resolution is not complete and unfortunately described as Metavir fibrosis stages 3 and 2, instead of a more informative descriptive report on patterns of fibrosis (any ‘portal–central adhesions’ according to Wanless et al. [48]?), deviations in lobular architecture, and vascular anomalies. There is a fundamental difference between a DIAGNOSIS of cirrhosis and a SCORE of cirrhosis. Diagnosis of cirrhosis may have different levels of certainty, expressed in the biopsy report: suggestive, strongly suggestive or convincing evidence for cirrhosis; the first two modalities may rest on very little fibrosis, but mainly on architectural patterns of liver tissue and vascular abnormalities. More simple scoring systems with a lower number of categories, like the Metavir scoring system [74], allow less fine tuning as they oblige to force a case into a broader category than complex scoring systems providing a higher number of categories and hence a finer tuning: scoring according to Ishak [75] allows to put a case in the pre-cirrhotic niche of incomplete cirrhosis score 5. For semiquantitative scoring of fibrosis, two general rules need to be considered. The first is that the simpler the scoring system, the less information is provided, and the broader the categories of subdivision. The second is that histological semiquantitative scoring of fibrosis on needle biopsy specimens does not and cannot allow a conclusion of cure, nor of total disappearance or complete regression of cirrhosis [73].

A final, difficult problem is recognizing the borderline between pre-cirrhotic (or early cirrhotic) and truly cirrhotic stages of liver fibrosis, especially in smaller needle biopsy specimens. It has been recognized since the first half of the previous century, in studies on experimentally induced carbon tetrachloride-induced cirrhosis in the rat that there are two stages in the development of cirrhosis: 1° a pre-cirrhotic reversible stage, ‘with histological features indistinguishable from actual cirrhosis’, and (2) a cirrhotic stage ‘with a finely or coarsely granular liver’. ‘Once this stage is reached, the condition is no longer reversible’ [76].

Such category of ‘reversible cirrhosis’ has been indicated under various terms, including ‘precirrhotic liver’ [76], the ‘lesion preceding the committed precursor stage’ [7], or ‘early minimal cirrhosis’ by Galambos who also insisted on the usefulness of staging of cirrhosis [27].

The Ishak scoring sytem [75], although imperfect as any scoring system, has the advantage of awareness of this problem. Its score F5 allows to categorize a pre-cirrhotic (close to cirrhosis) stage, and the highest score F6 is defined as ‘cirrhosis, probable or definite’, thus recognizing that there is a problematic grey zone between something looking like cirrhosis on needle biopsy and true, fully established cirrhosis. Admittedly, although the Ishak score may help avoiding an untoward conclusion of reversal of cirrhosis, it does not solve the fundamental problem. The need persists of defining more precisely and reliably the borderline between authentic cirrhosis and its mimicking more readily reversible precursor stages [77].

Because of this possible error in histological diagnosis of cirrhosis in needle specimens, it is advisable to compare the histological data with macroscopical liver changes, either the appearance of the liver surface at laparoscopy [78] or at abdominal ultrasound investigation [79].

Although finer definition of the ‘point of no (or extremely slow?) return’ remains a task for the future, it is useful to consider suggestions and proven facts from the past. Early investigators noted that thin reticulin fibers, as evidenced by silver impregnation techniques, are more readily reversible than coarse collagen stained by classical connective tissue stains, such as Masson's trichrome, Van Gieson’ stain, Mallory's aniline blue or chromotrope 2R stain [80]. A difference is noted between more reversible young fibrosis versus older slowly reversible or nearly irreversible fibrosis. This may reflect a longer period of cross-linking of collagen, as reported in several papers [42], [43], [81], [82], rendering it less sensitive to degradation enzymes [41], [43]. Dense acellular or paucicellular connective tissue is less reversible than cellular or inflammatory infiltrated matrix [29], due to different amounts and availability of metalloproteinases secreted by the cells present. This may partly explain the difference in reversibility between loose connective matrix organisation (LCMO) versus dense connective matrix organisation [83]. Slender connective tissue septa disappear more readily than extensive postnecrotic scars [48]. Especially broad portal–central fibrotic connections and ‘portal–central adhesions’ due to extensive parenchymal extinctions are extremely slowly reversible or not reversible at all [48].

One may conclude that fibrosis varies in reversibility according to nature and cross-linking of collagen fibres, density and cellularity of the connective tissue, topography of septa (portal–central septa carrying vascular shunts in contrast to portal–portal or central–central septa), and total content of collagen and other scar molecules eventually creating a large mass inaccessible to degrading enzymes.

It is further important to note that disappearance of scar does not equal return to normal [60], that parenchymal nodules and architectural changes are also of poor reversibility [84], and that vascular shunts until now remain virtually irreversible [48].

4.2.1. How to estimate extent of reversal of cirrhosis? 

The extent of cirrhosis reversal or regression is a topic of considerable interest, as well for its clinical importance as for better insight in basic biological phenomena.

Estimating the extent of regression requires repeated morphological investigation, on at least two occasions. To increase the chance of observing noticeable changes, it is useful that the time-span between the two observations is of long enough duration.

Since the repair process of cirrhosis appears to involve conversion of micronodular into macronodular and even incomplete septal forms of cirrhosis [48], it is clear that a needle biopsy of the liver can hardly serve for the second or later control observation, since even a sizeable needle specimen of liver tissue may not allow to definitely exclude the latter types. Even control of the liver surface at laparoscopy or ultrasound may be insufficient. Older workers in experimentally induced murine cirrhosis were aware of this problem, stating that only observation of the whole liver (at necropsy) produced reliable data [71]. Morphological investigation of the entire human liver, previously only performed at autopsy, became more readily possible by the introduction of liver transplantation. Careful comparison of the morphological changes of the recipient's hepatectomy specimen with the histological changes in his/her previous biopsy (or biopsies), allows reliable conclusions to be made. Until now, very few studies of his sort have been published, but with most encouraging results [48] This field deserves further exploration.

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5. Need for a change in paradigma? 

From a conceptual point of view, apparently time has come for a change in paradigma. Over the last 20 years, the tenet was echoed in dozens of papers that the hepatic stellate cell is the cell responsible for progressive fibrosis and development of cirrhosis in the liver.

Much of the submitted evidence for the primordial role of the hepatic stellate cell (HSC) is based on in vitro work with isolated HSC's. However, critical studies indicate that many results of in vitro studies performed until now may not be applicable ‘ne varietur’ in vivo [85]. It was shown that distinction can be made between at least two distinct lineages of extracellular matrix-producing cells: hepatic stellate cells and septal myofibroblasts, the latter being derived from the portal myofibroblast-like cells [86], [87], [89]. A recent study on human cirrhotic livers added a third candidate of matrix-producing cell: the interface myofibroblast [49].

It is conceivable that reversibility of fibrosis in cirrhosis may be related to the matrix-producing cell type.

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6. Conclusions and future perspectives 

Liver fibrosis is reversible, including liver fibrosis in cirrhosis. The speed of regression of fibrosis may vary according to the nature of matrix components, cellularity, topography and duration of fibrosis. Cirrhosis implies more than just diffuse septal fibrosis of the liver. Further essential components of cirrhosis are architectural distortion (nodular parenchymal regeneration) and vascular derangements, including intrahepatic porto-systemic shunts [88]. According to present available evidence, cirrhosis is not completely reversible. In contrast to the fibrosis component, of which at least part is reasonably fast reversible, architectural distortion and even more the vascular shunts in portal–central septa and in larger fibrous scars of multinodular parenchymal extinction, are of such slow reversibility that—from the point of view of expected remaining life span of the patient—these lesions are for all practical purposes irreversible. Partial reversal of cirrhosis is associated with (variable) resorption of fibrosis and conversion of the cirrhotic pattern into a hyperregenerative, macronodular and possibly even incomplete septal variety. It remains for the future to find out whether, or to what extent, also established abnormal vascular shunts in cirrhosis are subject to remodulation or breakdown, in view of the emerging concepts of plasticity and remodulation of vascular structures [90]. ‘Panta rhei, ouden menei’ may perhaps become accelerated iatrogenically in the future.

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  • 1 Websters New Collegiate Dictionary (1977): ‘C. Dogma: a point of view or tenet put forth as authoritative without adequate grounds’.
  • 2 ‘panta rei, ouden menei’ Everything flows (changes), nothing remains (the same). Proposition ascribed to the philosopher Heraclitus of Ephesus, 540–480 BC.
  • 3 Websters New Collegiate Dictionary (1977) ‘b.: Myth: an ill-founded belief held uncritically especially by an interested group’.

PII: S0168-8278(04)00111-4

doi:10.1016/j.jhep.2004.03.007

Journal of Hepatology
Volume 40, Issue 5 , Pages 860-867, May 2004

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