Interpreting Disease Progression in Chronic Liver Disease
Interpreting Disease Progression in Chronic Liver Disease
It is increasingly clear that different CLDs are characterised by different predominant profibrogenic mechanisms and, while cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrosis development in different and even within the same CLD (figure 1). For example, portal-portal septa surrounding liver nodules with preserved connection between central vein and portal tract are found in primary and secondary biliary cirrhosis and primary sclerosing cholangitis. Portal-central septa and interface hepatitis are characteristic of chronic viral hepatitis. Capillarisation of sinusoids and intercellular fibrosis (chicken-wire fibrosis) are typical of alcoholic and non-alcoholic steatohepatitis and hemocromatosis. Central-central septa and 'reversed' lobulation are a characteristic feature of advanced fibrosis secondary to venous outflow obstruction. These aetiology-related patterns are linked to the relative prevalence of different profibrogenic mechanisms, such as the activation of a chronic wound healing reaction, oxidative stress and derangement of the epithelial-stromal equilibrium around bile ducts. The knowledge of these aspects of the pathophysiology of CLD provides important insights on the correlation between time of progression of liver disease, the aetiological agents, the dynamics of the necroinflammatory infiltrate, the distribution of fibrosis and the onset and progression of portal hypertension (PH), depending on the aetiological agent leading to cirrhosis.
(Enlarge Image)
Figure 1.
Different patterns of aetiology-driven fibrosis. (A) Biliary fibrosis. Low magnification picture of a section of liver from a patient with primary sclerosing cholangitis (chromotrope aniline blue stain). Collagen is stained blue. Inflamed, expanded portal tracts are linked by fibrous tissue. A rounded scar (arrow) is present at the site of a destroyed bile duct, and there is fibrous thickening of the adjacent blood vessel wall. (B) Postnecrotic fibrosis. Low magnification picture of a section of liver from a patient with chronic HBV infection (chromotrope aniline blue stain). Collagen is stained blue. Inflamed, expanded portal tracts are linked by fibrous tissue (short arrows). A slender fibrous bridge connects a portal tract and an outflow venule in the middle of the picture (long arrow). (C) Pericellular fibrosis. High magnification picture of a section of liver from a patient with alcoholic hepatitis (chromotrope aniline blue stain). Collagen is stained blue. A fibrous lattice surrounds individual and small groups of hepatocytes. Pale blue intracytoplasmic Mallory material and associated inflammation can also be seen. (Courtesy of Professor A Paul Dhillon, Liver Pathology Service, Royal Free Hospital, London, UK).
A proof of concept of these considerations derives from a recent study aimed at quantifying the amount of fibrosis present in cirrhotic livers of different aetiologies explanted from patients undergoing liver transplantation presenting with compatible Model for End-Stage Liver Disease (MELD) scores. Remarkably, the amount of fibrosis, determined by means of the collagen-proportionate area (CPA) method in cirrhotic liver due to chronic alcohol intake is, on average, double that observed in cirrhotic liver due to chronic HCV or HBV infection. In this context, it is important to stress that the path leading to cirrhosis is not simply characterised by accumulation of fibrillar extracellular matrix (ECM), but is associated with neo-angiogenesis and hepatocellular regeneration as part of a chronic wound healing reaction. Along these lines, it is increasingly clear that the association between fibrogenesis, angiogenesis and regeneration is different in different CLDs, and this may have profound consequences on the rate of disease progression to cirrhosis, on the features of cirrhosis and on its complications. Additionally, these differences likely represent a key determinant affecting disease regression.
The Aetiology of Chronic Liver Disease Has a Profound Impact on the Pattern of Fibrotic Evolution and on the Relative Predominant Mechanism
It is increasingly clear that different CLDs are characterised by different predominant profibrogenic mechanisms and, while cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrosis development in different and even within the same CLD (figure 1). For example, portal-portal septa surrounding liver nodules with preserved connection between central vein and portal tract are found in primary and secondary biliary cirrhosis and primary sclerosing cholangitis. Portal-central septa and interface hepatitis are characteristic of chronic viral hepatitis. Capillarisation of sinusoids and intercellular fibrosis (chicken-wire fibrosis) are typical of alcoholic and non-alcoholic steatohepatitis and hemocromatosis. Central-central septa and 'reversed' lobulation are a characteristic feature of advanced fibrosis secondary to venous outflow obstruction. These aetiology-related patterns are linked to the relative prevalence of different profibrogenic mechanisms, such as the activation of a chronic wound healing reaction, oxidative stress and derangement of the epithelial-stromal equilibrium around bile ducts. The knowledge of these aspects of the pathophysiology of CLD provides important insights on the correlation between time of progression of liver disease, the aetiological agents, the dynamics of the necroinflammatory infiltrate, the distribution of fibrosis and the onset and progression of portal hypertension (PH), depending on the aetiological agent leading to cirrhosis.
(Enlarge Image)
Figure 1.
Different patterns of aetiology-driven fibrosis. (A) Biliary fibrosis. Low magnification picture of a section of liver from a patient with primary sclerosing cholangitis (chromotrope aniline blue stain). Collagen is stained blue. Inflamed, expanded portal tracts are linked by fibrous tissue. A rounded scar (arrow) is present at the site of a destroyed bile duct, and there is fibrous thickening of the adjacent blood vessel wall. (B) Postnecrotic fibrosis. Low magnification picture of a section of liver from a patient with chronic HBV infection (chromotrope aniline blue stain). Collagen is stained blue. Inflamed, expanded portal tracts are linked by fibrous tissue (short arrows). A slender fibrous bridge connects a portal tract and an outflow venule in the middle of the picture (long arrow). (C) Pericellular fibrosis. High magnification picture of a section of liver from a patient with alcoholic hepatitis (chromotrope aniline blue stain). Collagen is stained blue. A fibrous lattice surrounds individual and small groups of hepatocytes. Pale blue intracytoplasmic Mallory material and associated inflammation can also be seen. (Courtesy of Professor A Paul Dhillon, Liver Pathology Service, Royal Free Hospital, London, UK).
A proof of concept of these considerations derives from a recent study aimed at quantifying the amount of fibrosis present in cirrhotic livers of different aetiologies explanted from patients undergoing liver transplantation presenting with compatible Model for End-Stage Liver Disease (MELD) scores. Remarkably, the amount of fibrosis, determined by means of the collagen-proportionate area (CPA) method in cirrhotic liver due to chronic alcohol intake is, on average, double that observed in cirrhotic liver due to chronic HCV or HBV infection. In this context, it is important to stress that the path leading to cirrhosis is not simply characterised by accumulation of fibrillar extracellular matrix (ECM), but is associated with neo-angiogenesis and hepatocellular regeneration as part of a chronic wound healing reaction. Along these lines, it is increasingly clear that the association between fibrogenesis, angiogenesis and regeneration is different in different CLDs, and this may have profound consequences on the rate of disease progression to cirrhosis, on the features of cirrhosis and on its complications. Additionally, these differences likely represent a key determinant affecting disease regression.
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