Section 3 -

Role of Vascular Injury and "Congestive Hepatopathy" in the Pathogenesis of Cirrhosis Ian R. Wanless Department of Pathology Dalhousie University Halifax, Canada

It is well established that inflammatory injury in the liver leads to cirrhosis. The mechanism of this progression is not understood. This lecture will describe the vascular changes that occur in cirrhosis and present an hypothesis to explain how these lesions cause cirrhosis [1, 2, 3, 4, 5]. The mechanisms of vascular obstruction in the development of cirrhosis are multifactorial. In early chronic liver disease, inflammation in the primary chronic hepatitis leads to venous injury and venous obliteration. As disease becomes moderately advanced, the vascular obliteration and arterialization that have accumulated lead to widespread congestive and exudative lesions that accelerate the transition to end-stage cirrhosis. This process I call congestive and exudative hepatopathy (or congestive hepatopathy for short). Congestive hepatopathy may be recognized by the presence of congestive sinusoidal injury and congestive venopathy. These features are characterized histologically as endothelial lifting with edema or hemorrhage that evolves to fibrosis of the sinusoidal wall and venous intimal fibrosis and venous occlusion. As venous occlusion develops, especially hepatic vein obstruction, stasis leads to ischemic death of hepatocytes and septum formation (parenchymal extinction). Surviving parenchyma having favorable vascular supply and drainage becomes hypertrophied to form cirrhotic nodules. Once the parenchyma is replaced by cirrhotic nodules, one can see a progressive degeneration in the nodules leading to higher grades of cirrhosis characterized by transition from large nodules containing CD34 negative sinusoids to arterialized micronodules (entirely supplied by CD34 positive sinusoids), and, in severe cases, total necrosis of nodules, the remains of which are incorporated into septa resulting in a very broad septa. Thus, there is simultaneous transition from thin to broad septa. The characteristics of the transitions indicate congestive hepatopathy is the mechanism of progression. Fibrosis accumulates in septa as hepatocytes disappear from the stroma. Broad fibrous septa are complex mixtures of condensed parenchyma and include original structural collagen and true fibrosis. True fibrosis in late cirrhosis is largely the result of organized lymphedema and represents only recently deposited collagen, since most early fibrosis is resorbed before end-stage cirrhosis occurs. Thus, the pathogenesis of cirrhosis can be summarized as the gradual accumulation of obstructive lesions in small hepatic veins with reactive hyperemia and angiogenesis that together cause progressive elevation of the tissue pressure. The elevated tissue pressure leads to exudation that renders septa as non-healing and progressive wounds that are ultimately independent of the original causative disease. References Wanless IR. Vascular disorders. In MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC (eds). Pathology of the Liver, 4th (and upcoming 5th ) edition, Churchill Livingston, Edinburgh, 2002, 539-574. 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. Wanless IR. Structural changes leading to progression of cirrhosis and portal hypertension. In Portal Hypertension in the 21st Century. Groszmann, RJ, Tytgat, GNJ, Bosch J (Eds.) 2004. pp 47-53 O'Shea A-M, Wanless IR. Congestive hepatopathy: Possible role in the formation of tumour capsule in the liver (Poster). IAP congress, Montreal, 2006 Freitas J, Alves V, Freitas L, Andrade Z, and Wanless IR. Congestive hepatopathy in Schistosomiasis mansoni. Role in causing necrosis, fibrous septation, and fibrous obliteration of hepatic veins (Poster). IAP congress, Montreal, 2006