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Cirrhosis: What else?
Gastroentérologie Clinique et Biologique (2010) 34, 252—254
COMMENTARY
Cirrhosis: What else? Cirrhose, quoi d’autre ? C. Balabaud a,∗,b, P. Bioulac-Sage b,c a
Service d’hépatologie, hôpital St-André, CHU de Bordeaux, 33075 Bordeaux, France Inserm, U889, université Bordeaux-2, 33076 Bordeaux, France c Service d’anatomie-pathologique, hôpital Pellegrin, CHU de Bordeaux, 33076 Bordeaux, France b
Available online 27 May 2010
Summary When the term cirrhosis was coined two centuries ago by Laennec, it designates by definition an end stage irreversible liver disease. Nowadays this word encompasses a whole range of disorders including some degree of reversibility for the early stage. It is therefore of prime importance to define the stages of the fibrotic process, based on the integration of knowledge about liver structure and function. In addition to morphological data, modern imaging techniques coupled to non-invasive biomarkers will probably help to better define and denominate this heterogeneous entity. © 2010 Elsevier Masson SAS. All rights reserved.
René Théophile Hyacinthe Laennec (1781—1826) gave cirrhosis its name from the greek ‘‘kirrhos’’, meaning tawny yellow. Cirrhosis is defined histologically as a diffuse process in which the normal anatomical lobules are replaced by architectural abnormal nodules separated by fibrous tissue. The elements in the definition of cirrhosis are used by pathologists to recognize cirrhosis, but the definition does not rely on understanding its pathogenesis. The two next paragraphs are quotes from Ian Wanless interpretation of cirrhosis pathogenesis [1]. ‘‘Liver cirrhosis is not, strictly, the end stage of hepatic scarring; it is a dynamic, biphasic process dominated on the one hand by progressive parenchymal fibrosis and on the other by severe disruption of vascular architecture
∗
Corresponding author. E-mail address: [email protected] (C. Balabaud).
and distortion of the normal lobular architecture. The main anatomic elements include deposition of collagen in the parenchyma and portal tracts, arterialization of parenchymal sinusoids, obliteration of small hepatic and portal veins with resultant loss of hepatocytes through a process called parenchymal extinction, abnormal vascular physiology, and regeneration of hepatocytes. Parenchymal extinction is defined as a focal loss of contiguous hepatocytes. Hepatocyte apoptosis and necrosis occur in all types of liver diseases that progress to cirrhosis. Progressive disease occurs when these injuries are accompanied by a stromal reaction that includes deposition of extracellular matrix, increased sinusoidal vascular resistance, and obstruction of blood flow. These extinction lesions may involve a small portion of an acinus, larger units of one or more adjacent acini, or even a whole lobe. The concept of parenchymal extinction is important [1] because it indicates that: parenchymal extinction is not directly caused by the initial hepatocellular injury but is
0399-8320/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.gcb.2010.03.007
Cirrhosis: What else? an epiphenomenon caused by innocent bystander injury of the local vessels; each parenchymal extinction lesion has its own natural history and may be in an early or late stage of healing; cirrhosis develops simultaneous with the accumulation of numerous independent and discrete parenchymal extinction lesions throughout the liver, and the form of cirrhosis is largely determined by the distribution of the vascular injury. Parenchymal extinction may progress long after cirrhosis is already established, leading to slow conversion of a marginally functional liver into liver failure. After parenchymal extinction, the formation of bridging fibrous septa between portal tracts and terminal hepatic veins enables portovenous and arteriovenous shunting through de novo vascular channels, effectively bypassing the parenchymal nodules. The histologic appearance of cirrhosis depends on the age of the accumulated extinction lesions. Parenchymal extinction, usually accompanied by inflammation, constitutes ‘‘activity’’; an ‘‘active’’ cirrhosis is a cirrhotic liver with continued destruction of residual tissue. Conversely, if the causative injury is remote at the time of examination, the liver will contain only lesions in late stages of repair and the cirrhosis is considered quiescent, or ‘‘inactive.’’ Cirrhotic livers may appear in different forms that can be traced to a small number of potential variables. These include the specific location within the liver microvasculature of the etiologic injury, the tempo and duration of the disease, and the presence or absence of an inactive period prior to histologic sampling. In the last instance, substantial remodeling of fibrous tissue may occur over time, which can obscure the architectural pattern of the initial injury. The progression of chronic liver disease is highly variable. In fact, the point at which a liver becomes cirrhotic is rather subjective and is a frequent source of interobserver disagreement. Cirrhosis is frequently viewed as an end stage in the evolution of many types of chronic liver diseases. However, in recent years, clinical reports indicate that on
253 cessation of the injurious process, cirrhosis may reverse, or at least improve, ‘‘histologically’’. Cirrhosis has also been increasingly defined by clinical outcomes. In this context, cirrhosis is distinguished between compensated and decompensated stages, with different features, prognoses and predictors of death. Portal hypertension is the earliest and most important consequence of cirrhosis and underlies most of the clinical complications of the disease. Portal hypertension results from an increased intrahepatic resistance combined with increased portal (and hepatic arterial) blood flow. The increased intrahepatic resistance is the result of architectural distortion. The hepatic venous pressure gradient (HVPG), an indirect measure of portal pressure, is the best predictor of the development of varices, and is also a harbinger of decompensation (e.g., ascites, variceal hemorrhage and encephalopathy). Both HVPG and semiquantitative features of histology do indeed predict hemodynamic and clinical features of chronic liver disease and cirrhosis [2]. It is obvious that the word cirrhosis as defined by Laennec represents the end of the spectrum (autopsy material). Nowadays this word encompasses a whole range of disorders. It is therefore of prime importance to define the stages of the disorder [3] (Fig. 1). Biopsy, a long time goal standard in the diagnosis of cirrhosis, has definitely lost its main role for three major reasons (invasiveness, sampling error, absence of different steps in stage F4 (cirrhosis) of the widely used METAVIR scoring system) [4]. The hepatic venous pressure gradient (HVPG), an excellent semi-invasive approach is unfortunately not widely available. Non invasive tests are becoming widely used as a screening test to classify patients into two broad categories: absence or presence of significant fibrosis which includes cirrhosis. A major issue today is to assess the capability of non invasive tests to stage cirrhosis. It is anticipated that the combination of different approaches combining blood tests [4], elastometry [5] and US Doppler [6] would give the best results. Ultrasonographic
Figure 1 Staging cirrhosis. VH: variceal hemorrhage. Laennec scoring identifies so far three stages depending on the thickness of the scars (4A, 4B, 4C) [1]; small nodularity and thick septa are independent predictors of the presence of clinically significant portal hypertension [2]. *HVPG: in decompensated cirrhosis, an HVPG > 20 mmHg is an important predictor of a poor outcome in the setting of acute variceal bleeding. It is likely that additional criteria will implement staging: imaging [8,9]: doppler US (detection of varices/shunts, ascitis, flow direction, dysmorphy, etc.); CT-based texture analysis; diverse MR imaging-based techniques (Conventional contrast material-enhanced MR imaging, MR elastography, diffusion-weighted imaging, MR perfusion imaging); Non invavive tests: Blood tests (fibrotest). Cirrhosis ≥ 0.75 and up to 1; Transient elastometry: cirrhosis > 12—17 kPa (depending on the etiology) and up to 75 kPa. Figure is modified from Garcia-Tsao et al. [3]
254 elastometry (transient, real time) is an invaluable tool to measure rapidly liver elasticity, to detect cirrhosis and anticipate the occurrence of complications [7,8]. Unfortunately elasticity does not reflect — as too often forgotten — the amount of fibrosis and when it is so, it does not assess the whole liver. In that sense new imaging techniques could be in the future the most promising approach to assess cirrhotic stage [9,10]. We have to think of cirrhosis as a series of critical steps that, if left unchecked, culminate in hepatic decompensation. A better classification of cirrhosis will require integration of knowledge about liver structure and function [3]. Unfortunately the word cirrhosis masks the complexity of still poorly defined entities, as a consequence, staging of chronic liver diseases with significant fibrosis is required. Ultimately one may ask whether the term cirrhosis coined two centuries ago by Laennec to designate an end stage liver disease is still appropriate for the early steps of a process of still uncertain future.
Conflicts of interest The authors have not declared any conflict of interest.
References [1] Wanless IR, Crawford JM. Cirrhosis in Surgical pathology of the GI tract, liver, biliary tract, and pancreas. In: Odze RD, Goldblum JR editors. 2nd ed. Philadelphia: Saunders Elsevier; 2009, p. 1115—1145 [section V part 3: liver].
C. Balabaud, P. Bioulac-Sage [2] Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histologicalhemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 2006;44: 111—7. [3] Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 2010;51:1445—9. [4] Poynard T, Benhamou Y, Thabut D, Ratziu V. Liver biopsy: the best standard. . . when everything else fails. J Hepatol 2009;50:1267—8. [5] Castéra L, Sebastiani G, Le Bail B, de Lédinghen V, Couzigou P, Alberti A. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. Hepatol 2010;52:191—8. [6] Goyal N, Jain N, Rachapalli V, Cochlin DL, Robinson M. Noninvasive evaluation of liver cirrhosis using ultrasound. Clin Radiol 2009;64:1056—66. [7] Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55: 403—8. [8] Castéra L, Le Bail B, Roudot-Thoraval F, Bernard PH, Foucher J, Merrouche W, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009;50:59—68. [9] Faria SC, Ganesan K, Mwangi I, Shiehmorteza M, Viamonte B, Mazhar S, et al. MR imaging of liver fibrosis: current state of the art. Radiographics 2009;29:1615—35. [10] Hussain SM, Reinhold C, Mitchell DG. Cirrhosis and lesion characterization at MR imaging. Radiographics 2009;29: 1637—52.
COMMENTARY
Cirrhosis: What else? Cirrhose, quoi d’autre ? C. Balabaud a,∗,b, P. Bioulac-Sage b,c a
Service d’hépatologie, hôpital St-André, CHU de Bordeaux, 33075 Bordeaux, France Inserm, U889, université Bordeaux-2, 33076 Bordeaux, France c Service d’anatomie-pathologique, hôpital Pellegrin, CHU de Bordeaux, 33076 Bordeaux, France b
Available online 27 May 2010
Summary When the term cirrhosis was coined two centuries ago by Laennec, it designates by definition an end stage irreversible liver disease. Nowadays this word encompasses a whole range of disorders including some degree of reversibility for the early stage. It is therefore of prime importance to define the stages of the fibrotic process, based on the integration of knowledge about liver structure and function. In addition to morphological data, modern imaging techniques coupled to non-invasive biomarkers will probably help to better define and denominate this heterogeneous entity. © 2010 Elsevier Masson SAS. All rights reserved.
René Théophile Hyacinthe Laennec (1781—1826) gave cirrhosis its name from the greek ‘‘kirrhos’’, meaning tawny yellow. Cirrhosis is defined histologically as a diffuse process in which the normal anatomical lobules are replaced by architectural abnormal nodules separated by fibrous tissue. The elements in the definition of cirrhosis are used by pathologists to recognize cirrhosis, but the definition does not rely on understanding its pathogenesis. The two next paragraphs are quotes from Ian Wanless interpretation of cirrhosis pathogenesis [1]. ‘‘Liver cirrhosis is not, strictly, the end stage of hepatic scarring; it is a dynamic, biphasic process dominated on the one hand by progressive parenchymal fibrosis and on the other by severe disruption of vascular architecture
∗
Corresponding author. E-mail address: [email protected] (C. Balabaud).
and distortion of the normal lobular architecture. The main anatomic elements include deposition of collagen in the parenchyma and portal tracts, arterialization of parenchymal sinusoids, obliteration of small hepatic and portal veins with resultant loss of hepatocytes through a process called parenchymal extinction, abnormal vascular physiology, and regeneration of hepatocytes. Parenchymal extinction is defined as a focal loss of contiguous hepatocytes. Hepatocyte apoptosis and necrosis occur in all types of liver diseases that progress to cirrhosis. Progressive disease occurs when these injuries are accompanied by a stromal reaction that includes deposition of extracellular matrix, increased sinusoidal vascular resistance, and obstruction of blood flow. These extinction lesions may involve a small portion of an acinus, larger units of one or more adjacent acini, or even a whole lobe. The concept of parenchymal extinction is important [1] because it indicates that: parenchymal extinction is not directly caused by the initial hepatocellular injury but is
0399-8320/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.gcb.2010.03.007
Cirrhosis: What else? an epiphenomenon caused by innocent bystander injury of the local vessels; each parenchymal extinction lesion has its own natural history and may be in an early or late stage of healing; cirrhosis develops simultaneous with the accumulation of numerous independent and discrete parenchymal extinction lesions throughout the liver, and the form of cirrhosis is largely determined by the distribution of the vascular injury. Parenchymal extinction may progress long after cirrhosis is already established, leading to slow conversion of a marginally functional liver into liver failure. After parenchymal extinction, the formation of bridging fibrous septa between portal tracts and terminal hepatic veins enables portovenous and arteriovenous shunting through de novo vascular channels, effectively bypassing the parenchymal nodules. The histologic appearance of cirrhosis depends on the age of the accumulated extinction lesions. Parenchymal extinction, usually accompanied by inflammation, constitutes ‘‘activity’’; an ‘‘active’’ cirrhosis is a cirrhotic liver with continued destruction of residual tissue. Conversely, if the causative injury is remote at the time of examination, the liver will contain only lesions in late stages of repair and the cirrhosis is considered quiescent, or ‘‘inactive.’’ Cirrhotic livers may appear in different forms that can be traced to a small number of potential variables. These include the specific location within the liver microvasculature of the etiologic injury, the tempo and duration of the disease, and the presence or absence of an inactive period prior to histologic sampling. In the last instance, substantial remodeling of fibrous tissue may occur over time, which can obscure the architectural pattern of the initial injury. The progression of chronic liver disease is highly variable. In fact, the point at which a liver becomes cirrhotic is rather subjective and is a frequent source of interobserver disagreement. Cirrhosis is frequently viewed as an end stage in the evolution of many types of chronic liver diseases. However, in recent years, clinical reports indicate that on
253 cessation of the injurious process, cirrhosis may reverse, or at least improve, ‘‘histologically’’. Cirrhosis has also been increasingly defined by clinical outcomes. In this context, cirrhosis is distinguished between compensated and decompensated stages, with different features, prognoses and predictors of death. Portal hypertension is the earliest and most important consequence of cirrhosis and underlies most of the clinical complications of the disease. Portal hypertension results from an increased intrahepatic resistance combined with increased portal (and hepatic arterial) blood flow. The increased intrahepatic resistance is the result of architectural distortion. The hepatic venous pressure gradient (HVPG), an indirect measure of portal pressure, is the best predictor of the development of varices, and is also a harbinger of decompensation (e.g., ascites, variceal hemorrhage and encephalopathy). Both HVPG and semiquantitative features of histology do indeed predict hemodynamic and clinical features of chronic liver disease and cirrhosis [2]. It is obvious that the word cirrhosis as defined by Laennec represents the end of the spectrum (autopsy material). Nowadays this word encompasses a whole range of disorders. It is therefore of prime importance to define the stages of the disorder [3] (Fig. 1). Biopsy, a long time goal standard in the diagnosis of cirrhosis, has definitely lost its main role for three major reasons (invasiveness, sampling error, absence of different steps in stage F4 (cirrhosis) of the widely used METAVIR scoring system) [4]. The hepatic venous pressure gradient (HVPG), an excellent semi-invasive approach is unfortunately not widely available. Non invasive tests are becoming widely used as a screening test to classify patients into two broad categories: absence or presence of significant fibrosis which includes cirrhosis. A major issue today is to assess the capability of non invasive tests to stage cirrhosis. It is anticipated that the combination of different approaches combining blood tests [4], elastometry [5] and US Doppler [6] would give the best results. Ultrasonographic
Figure 1 Staging cirrhosis. VH: variceal hemorrhage. Laennec scoring identifies so far three stages depending on the thickness of the scars (4A, 4B, 4C) [1]; small nodularity and thick septa are independent predictors of the presence of clinically significant portal hypertension [2]. *HVPG: in decompensated cirrhosis, an HVPG > 20 mmHg is an important predictor of a poor outcome in the setting of acute variceal bleeding. It is likely that additional criteria will implement staging: imaging [8,9]: doppler US (detection of varices/shunts, ascitis, flow direction, dysmorphy, etc.); CT-based texture analysis; diverse MR imaging-based techniques (Conventional contrast material-enhanced MR imaging, MR elastography, diffusion-weighted imaging, MR perfusion imaging); Non invavive tests: Blood tests (fibrotest). Cirrhosis ≥ 0.75 and up to 1; Transient elastometry: cirrhosis > 12—17 kPa (depending on the etiology) and up to 75 kPa. Figure is modified from Garcia-Tsao et al. [3]
254 elastometry (transient, real time) is an invaluable tool to measure rapidly liver elasticity, to detect cirrhosis and anticipate the occurrence of complications [7,8]. Unfortunately elasticity does not reflect — as too often forgotten — the amount of fibrosis and when it is so, it does not assess the whole liver. In that sense new imaging techniques could be in the future the most promising approach to assess cirrhotic stage [9,10]. We have to think of cirrhosis as a series of critical steps that, if left unchecked, culminate in hepatic decompensation. A better classification of cirrhosis will require integration of knowledge about liver structure and function [3]. Unfortunately the word cirrhosis masks the complexity of still poorly defined entities, as a consequence, staging of chronic liver diseases with significant fibrosis is required. Ultimately one may ask whether the term cirrhosis coined two centuries ago by Laennec to designate an end stage liver disease is still appropriate for the early steps of a process of still uncertain future.
Conflicts of interest The authors have not declared any conflict of interest.
References [1] Wanless IR, Crawford JM. Cirrhosis in Surgical pathology of the GI tract, liver, biliary tract, and pancreas. In: Odze RD, Goldblum JR editors. 2nd ed. Philadelphia: Saunders Elsevier; 2009, p. 1115—1145 [section V part 3: liver].
C. Balabaud, P. Bioulac-Sage [2] Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histologicalhemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 2006;44: 111—7. [3] Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 2010;51:1445—9. [4] Poynard T, Benhamou Y, Thabut D, Ratziu V. Liver biopsy: the best standard. . . when everything else fails. J Hepatol 2009;50:1267—8. [5] Castéra L, Sebastiani G, Le Bail B, de Lédinghen V, Couzigou P, Alberti A. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. Hepatol 2010;52:191—8. [6] Goyal N, Jain N, Rachapalli V, Cochlin DL, Robinson M. Noninvasive evaluation of liver cirrhosis using ultrasound. Clin Radiol 2009;64:1056—66. [7] Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55: 403—8. [8] Castéra L, Le Bail B, Roudot-Thoraval F, Bernard PH, Foucher J, Merrouche W, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009;50:59—68. [9] Faria SC, Ganesan K, Mwangi I, Shiehmorteza M, Viamonte B, Mazhar S, et al. MR imaging of liver fibrosis: current state of the art. Radiographics 2009;29:1615—35. [10] Hussain SM, Reinhold C, Mitchell DG. Cirrhosis and lesion characterization at MR imaging. Radiographics 2009;29: 1637—52.