The Role of Vascular Injury and Congestion in the Pathogenesis of Cirrhosis: the Congestive Escalator and the Parenchymal Extinction Sequence

Abstract

Purpose of Review Current research into the pathogenesis of cirrhosis is largely dominated by investigations of hepatocellular injury and fibrogenesis, mostly in short-term experimental models. Cirrhosis in the human evolves for decades with histologic features that are very different from the models studied, dominated by hepatic vein obstruction and congestion. This is a clue that the mechanisms operating in the human are different from those in most animal models. Recent Findings This paper presents an updated "vascular hypothesis" with previously unpublished observations that provide a more complete understanding of the pathogenesis of chronic liver disease in the human: (1) a definition of parenchymal extinction emphasizing the importance of sinusoidal destruction, (2) analysis of the temporal evolution of parenchymal extinction lesions, (3) new data to quantify hepatic vein obstruction, (4) a "congestive escalator" hypothesis to explain how vascular obstruction occurs, beginning with sinusoidal endothelial cell injury, fluid translocation, and vascular compression by mechanics known as "compartment syndrome," (5) a "nested cone model" of hepatic vein anatomy that predisposes to compartment syndrome in the human, and (6) a proposal for the mechanism of collagen formation in response to congestion ("congestive fibrosis"). Summary The guiding principle in this model is that flow has to be vented to keep pressure gradients within the physiological range. Vascular obstruction causes tissue congestion which induces further vascular obstruction that drives a congestive escalator leading to progressive parenchymal extinction. This model may be applicable to all types of cirrhosis found in the human.

Congestive Hepatopathy

“…The new model incorporates the concept of a “congestive escalator”, whereby the initial damage is usually at the level of sinusoidal endothelial cells and progresses to parenchymal extinction by a sequence of events that involve vascular leak, transudation into vein walls and interstitium, ischemia, and hyperemia. This microvascular injury leads to the extension of venous obstruction to larger vessels perpetuating and aggravating the congestive injury [ 30 ]. A recent experimental study provided evidence of the mechanistic link between CH and liver fibrosis through some of these mechanisms [ 26 ].…”

Ameliorative effect of Mangosteen (Garcinia mangostana L.) peel infusion on the histopathological structures of the liver and kidney of rats (Rattus norvegicus Berkenhout, 1769) after H2O2 induction

“…These substances contain all of the metabolic results including toxic substances. In the cirrhotic liver, sinusoidal dilatation is found in stress areas [ 31 ]. Therefore, sinusoidal dilatation is an appropriate parameter to evaluate the liver injury, as the dilatation was caused by hepatic necrosis.…”

Parenchymal Extinction Mimicking Hepatocellular Carcinoma in a Patient with Chronic Hepatitis B-Related Liver Cirrhosis

“…We presented a case of parenchymal extinction mimicking HCC in a patient with chronic hepatitis B-related liver cirrhosis. Wanless et al defined parenchymal extinction as the irreversible loss of hepatocytes and their replacement by fibrous tissue [ 2 , 7 ]. The putative mechanism of parenchymal extinction is linked to hepatic necro-inflammation due to chronic injury, including viral hepatitis and alcoholic liver disease, which leads to micro-infarcts by occlusive thrombi [ 8 , 9 ].…”

“…Parenchymal extinction is defined as the loss of contiguous hepatocytes in a pathologic examination [ 1 ]. Considering that the loss of hepatocytes is related to adjacent tissue hypoxia, parenchymal extinction has been newly defined as a region of focal loss of hepatocytes with adjacent microvascular structures [ 2 ]. Hepatocellular carcinoma (HCC), one of the most common malignant tumors with the third-highest cancer-related mortality worldwide, is closely associated with liver cirrhosis caused by a variety of underlying etiologies, including chronic viral hepatitis B and C, and alcohol intake [ 3 , 4 ].…”