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This paper presents an updated “vascular hypothesis” with previously unpublished observations that provide a more complete understanding of the pathogenesis of chronic liver disease in the human: (1) a definition of parenchymal extinction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.
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Introduction
Cirrhosis is defined anatomically by the presence throughout the liver of hepatocellular nodules that are separated by septa. The principle clinical manifestations are related to portal hypertension. It is widely accepted that cirrhosis is caused by a primary injury that results in loss of hepatocytes followed by synthesis of collagen that accumulates in the septa. Portal hypertension is thought to result from vascular compromise in this distorted architecture [1]. Discussions of pathogenesis have usually concentrated on the mechanisms of liver cell injury and fibrogenesis [1,2,3,4,5,6]. The significance of vascular injury in the progression of liver disease is not widely appreciated, although there is new interest with evidence that anticoagulants, simvastatin, and VEGF modulation have protective effects on the liver [7, 8••, 9, 10••, 11, 12].
This paper presents an updated vascular hypothesis for the pathogenesis of cirrhosis. The original, proposed in 1994, suggested that regions of tissue loss and fibrosis (called parenchymal extinction) were secondary to vascular obstruction [13, 14••, 15]. New observations were incorporated sequentially in several textbooks and elsewhere [16, 17, 18•]. The current model includes previously unpublished observations that provide a more complete and detailed understanding of the pathogenesis of chronic liver disease and progression to cirrhosis. The definition of parenchymal extinction [14••] is modified to recognize the importance of sinusoidal destruction, including loss of sinusoidal endothelial cells (SEC). The temporal evolution of histologic features is incorporated into a “parenchymal extinction sequence”. New data to quantify hepatic vein (HV) obstruction is provided. The “congestive escalator” hypothesis [16, 19] is further elaborated to explain how vascular obstruction begins with onset of SEC injury, fluid translocation, and vascular compression by mechanics well-known in other organs as “compartment syndrome.” A “nested cone model” of hepatic vein anatomy is described that facilitates the development of a compartment syndrome effect. A mechanism of collagen formation in response to congestion (“congestive fibrosis”) is proposed. Arterialization (capillarization) is also discussed.
The Congestive Escalator
The pathogenesis of chronic liver disease can be summarized with the concept of a “congestive escalator,” whereby vascular injury causes vascular obstruction which causes more vascular injury which causes more vascular obstruction, in a positive feedback loop. This mechanism operates because vascular obstruction increases tissue pressure gradients which drive transudation of fluid into vessel walls and interstitial tissues to cause vascular obstruction. Vascular obstruction causes hepatocellular ischemia followed by parenchymal extinction lesions (PELs) with collapse of the architecture. Collapse and regeneration explain the tissue distortion found in cirrhosis. An important feature of the congestive escalator is that vascular injury progresses to cause obstructing lesions in ever larger branches of the hepatic and portal veins so that PELs become larger and eventually merge into confluent septa.
Although vascular injury is the central event in this paradigm, parenchymal extinction is more easily quantified in tissue sections. Therefore, the process of parenchymal extinction has been selected as the best focal point for analysis of the pathogenesis of cirrhosis and its regression.
Definition of Parenchymal Extinction
Parenchymal extinction lesion was originally defined as a region with loss of contiguous hepatocytes [14••]. While loss of hepatocytes is the most obvious feature, loss of the local microvasculature is probably more significant for the progression of disease. A revised definition is “a region with focal loss of contiguous hepatocytes and adjacent microvascular structures.” An important feature of PELs is that local vascular impairment delays repair so that tissue replacement from progenitor cells becomes the dominant pathway to repopulate regions of injury [20].
Vascular Obstruction in Chronic Liver Disease
Hepatic vein obstruction is a prominent histologic finding in cirrhosis, whether caused by alcohol, NASH, hepatitis B, or chronic biliary disease [14••, 21•, 22,23,24,25,26]. Obstruction is also found in early NASH [25•], alcoholic hepatitis, and in recurrent hepatitis C after transplantation [27, 28]. Small portal vein obstruction is found in biopsies with chronic viral hepatitis [26] and in all cirrhotic explant livers [24, 29].
In the present study, high-grade (> 50%) obstruction of HVs were found in 15.0% and 66.5% of recognizable HVs in mild cirrhosis and severe cirrhosis, respectively. After correction for collapse of tissue, patent HVs were decreased by 59% in mild cirrhosis and 94% in severe cirrhosis (Fig. 1a, b).
The involvement of small (20–100 μm) and larger HVs was also measured. In stage 4A cirrhosis, high-grade obstruction was found in 63.4% of small and 26.5% of larger HVs. Comparable figures in 4C cirrhosis were 83.9% and 47.3%. In a study of needle biopsies with NASH, small HVs (< 30 μm) showed increasing obstruction from stage F0 to F4 [25•]. Together, these data confirm that HV obstruction begins in small HVs and progresses to involve more HVs and larger HVs as disease advances in severity. The relocation of original hepatic veins to the septa is a useful observation that clarifies the origins of cirrhosis 4A (see legend to Fig. 1c).
Major obliteration of hepatic veins explains the prominent congestive features found in cirrhotic livers (Fig. 2). Many regenerative nodules have zones of sinusoidal congestion and collapse that lead to subdivision and remodeling of nodules into two or more smaller nodules. The congested zones also contain red blood cells that have dissected into vein walls, causing luminal compromise. These features indicate that congestion is a significant mechanism causing progression from mild to severe cirrhosis. Vascular obstruction in early stage disease is confined to terminal and small branches (Fig. 3b, e–l); in cirrhosis, larger vessels are involved (Figs. 2h, j, k and 3m). Vascular obstruction is largely confined to PELs (i.e., septal regions) where hepatocytes have been lost. Lesions in small hepatic veins are difficult to identify because vein walls are composed of separate small collagen bundles that are easily obscured by collapse and fibrosis.
The Parenchymal Extinction Sequence
Parenchymal extinction is a process that evolves with a spectrum of histological appearances (Figs. 2, 3 and 4). These findings were analyzed to create a temporal “parenchymal extinction sequence” that facilitates an understanding of the histologic transitions that eventuate in cirrhosis. Table 1 defines nine levels in the natural history of PELs, with some highlights described here. Because individual PELs develop over a prolonged period of time, a mixture of early, late, and regressed lesions can usually be seen in the same specimen.
Stress Zones (Level 1 and 2 Lesions)
These lesions are the precursors that may evolve into PELs (Figs. 2c–e and 3a–d). In early-stage disease, stress zones are subtle, caused by a mild degree of vascular derangement, described below. In cirrhosis, when most PELs have already aggregated into a network of septa (as level 5–7 PELs), there continue to be stress zones, as well as level 3 and 4 lesions, indicating ongoing congestive stress in the regenerative nodules.
In early-stage disease, stress zones and level 3 lesions may be initiated by the primary disease (generally accompanied by inflammation) but if inflammation is minimal or absent, the lesions likely progress because of added congestive features, including endothelial leak, fluid translocation, and vascular compression. In established cirrhosis, level 2–3 lesions often have no evidence of inflammation, suggesting these lesions are entirely congestive in nature with little dependence on primary disease activity.
Stress zones may be explained as a response to flow changes induced by the earliest obstructive lesions in portal and hepatic veins, some of which are accompanied by small shunts and reactive hyperemia. Shunts would cause local regions with higher outflow pressure (IOI, defined below), leading to sluggish flow, dilatation, as well as atrophy in level 2 lesions. Glycogen depletion may be caused by local diversion of insulin delivery.
Level 3 and 4 Lesions (Open- and Closed-PELs)
Open-PELs (level 3) are those in which the hepatocytes are lost and SEC are lifted or lost, but the residual tissue space contains blood because the lesion has not fully collapsed (Figs. 2f, g, 3b, h, i, and 4c, k, l). Closed-PELs (level 4) have collapsed, so that the area of tissue loss may be inapparent except for approximation of adjacent portal tracts and hepatic veins (Fig. 3c–g, j–l). Open-PELs may indicate recent necrosis, but may also be seen in late regressed disease, suggesting that they are open to afferent flow but have significant outflow obstruction.
Small level 3 PELs are often linear, distributed as a thin sleeve of necrotic hepatocytes surrounding a collapsed HV wall, and connecting to congested portal tracts that have splayed stromal fibers (Figs. 3h, n, and 4b). After the lesions have collapsed, the fibers of HV walls and PT stroma often remain splayed (see Fig. 4d–g). In level 4 PELs, the points of attachment of PT and HV are often arranged perpendicularly (Fig. 3a, b, i–l).
Both open- and closed-PELs often show arteries adjacent to the hepatic venule (Fig. 3c, g, h, l) or inside a hepatic vein lumen, representing an A-HV shunt. Shunts would allow local arterial flow to drain, thereby lowering intra-lesional tissue pressure. The recognition that there is an apparent evolution of stress zones, to open-PELs to closed-PELs allows creation of a coherent pathogenic model, as illustrated in Figs. 5 and 6.
This video demonstrates the vascular changes that contribute to the pathogenesis of cirrhosis, from the earliest events (described in Fig. 6) to late chronic liver disease (Laennec 4C). (The highest resolution (720P) is recommended if internet connection is optimal.)
PELs are constantly healing, especially after congested areas drain, presumably through A-HV shunts. Thus, in pre-cirrhotic and early cirrhotic chronic liver disease (F3/4A), most PELs are level 4–6. In F4B/4C, PELs are mostly level 7 aggregates seen as numerous and broad septa. As these later stages regress and aggregated PELs become separate, the PELs become more delicate and resemble those seen in F3/4A. The distinction can be made, if sufficient tissue is available, by the larger number of aggregated PELs (septa) in regressing cirrhosis, often with curved contours. In F3/4A, there are likely to be some portal tracts that are not linked. There will be overlap, so a previous biopsy with cirrhosis may be needed for confirmation.
Pressurized Common Channels (PCC) as Shunts that Transmit Tissue Pressure
Aggregated PELs may also be open or closed. Large aggregates of open-PELs are seen as congested septa. Congested septa can be understood as “pressurized common channels” (PCC) that formed when sinusoidal walls were destroyed and then incorporated into the septum. PCCs are interconnecting shunts that may be fed by arteries from many portal tracts throughout the septum, with drainage into available hepatic or portal veins. These channels can transmit elevated tissue pressure, potentially throughout large portions of the liver. This is the mechanism whereby the adventitia of large hepatic veins is exposed to high pressure, leading to congestive injury and luminal narrowing (Fig. 2k).
Regression of PELs
Level 7–8 PELs show regressed features. These lesions are invariably collapsed (closed) suggesting that any contained channels are not pressurized. Tissue pressure is likely to be low, consistent with successful outflow re-vascularization, and healthy parenchymal regeneration.
Congestive Vasculopathy and the Congestive Escalator
Function and survival of liver parenchyma require that flow and pressure remain within a physiological range. In the course of liver disease, there is vascular obstruction (resistance to flow) and local hyperemia that causes a departure from this range, summarized as “in-out-imbalance”(IOI). Congestive injury occurs in a vascular system when there is IOI, that is, when inflow (expressed as hepatic artery flow, HAF) exceeds the outflow capacity of the system (expressed as hepatic outflow capacity, HOC). HAF is taken as an approximation of the inflow load on the system, since portal vein flow is probably insignificant after early obstruction of small portal veins has occurred, mostly in stages F2–3. HOC can be defined as the maximum flow that can be carried without causing injury to the vascular bed.
In-out-imbalance provides a conceptual framework to summarize the causes and pathogenesis of congestive injury and the congestive escalator. Thus, HAF is increased by reactive hyperemia (in response to inflammation, ischemia, portal vein obstruction, or shunting). HOC is decreased by obstruction of hepatic veins or portal veins (by intimal thickening or external compression). In-out-imbalance causes an elevated transmural pressure gradient that causes endothelial injury, vascular leak, with transudation and edema. Expansion of tissue compresses adjacent tissues including veins (compartment syndrome effects), leading to more increase in IOI and more vascular injury. Thus, we can summarize the sequence of events: IOI causes congestive vasculopathy which leads to parenchymal extinction and cirrhosis (Table 1, Figs. 5 and 6). In overview, the physiological state of in-out-imbalance can explain, in large measure, the progression of chronic liver disease. A video of these events is available (Fig. 7).
Discussion
The Vascular Hypothesis Summary
Vascular obstruction, particularly involving sinusoids and hepatic veins, causes tissue congestion which itself induces further vascular obstruction leading to focal necrosis involving hepatocytes and sinusoidal endothelial cells, in a process called parenchymal extinction.
The PE Sequence
Parenchymal extinction proceeds through a sequence of tissue changes beginning with stress zones that progress to atrophy, necrosis, collapse, and ultimately, regression of PELs and septa. Parenchymal extinction progresses by increase in number and size of PELs until aggregated PELs form a continuous web of septa typical of cirrhosis. Regression involves repopulation of septa with progenitor-derived hepatocytes, detachment of adhesions, and resorption of residual collagen. The forces that drive the lesions are summarized above and illustrated in Fig. 6.
Value of the PE Sequence Model
PELs are larger than the minute vascular lesions that cause them. Therefore, PELs are easily visible histologically, especially with glutamine synthetase staining, making them a useful surrogate target for quantitative analysis of microvascular obliteration. PEL size correlates with the size of obstructed hepatic veins, so that sites of obstruction can be identified quickly at low magnification.
The levels within the PE sequence allow one to understand the process of tissue destruction from onset, to aggregation into septa, and regression towards normal. Examination of these transitions allows insight into the timing and quantity of collagen deposition and resorption, and to distinguish these parameters from increase in collagen concentration caused by simple collapse. The open and closed variants allow further evaluation of progressive and regressive states of the vasculature. Areas of parenchymal extinction may repopulate with new tissue that can be localized by EpCAM, CK7, and CK19 distribution. These stains allow evaluation of location and pace of regeneration in relation to regression of cirrhosis.
Laennec stages correlate with features of the PE sequence, potentially allowing new features to be incorporated into a revised Laennec system (Table 1). These would improve the precision of staging in early chronic liver disease. For example, stages 0–4A can be defined quantitatively by the percentage of portal tracts that are attached to adjacent hepatic veins by PELs (the VPA index). This exercise is facilitated with the glutamine synthetase stain.
Difficulty Identifying Destroyed Tissue Elements
The early events in chronic liver disease have been difficult to characterize, as we and others [34] have found, largely because the microvasculature is usually destroyed beyond recognition. Three approaches have allowed progress in this field. By recognizing that open-PELs are the precursor of closed-PELs, the small hepatic veins could be located and studied at level 3 before tissue collapse that masks the venous damage (Fig. 3b, h, i). A second approach was to examine level 3 and 4 lesions, with the help of the glutamine synthetase stain, to show in detail small PELs, small hepatic veins, and points of venous adhesion to portal tracts (Fig. 3e–g). A third approach was to examine early microvascular lesions in more acute diseases, where damaged terminal hepatic venules were easier to identify before tissue collapse and fibrosis.
Mechanism of Fibrosis (Inflammatory Vs Congestive)
Edema is an important clue that expansion of interstitial- and intravascular spaces contributes to luminal obstruction and the formation of pressure gradients [36]. Congestive fibrosis occurs at sites where translocation of fluid and blood components occurs. This is seen in the skin of the lower legs in patients with chronic heart failure, where “brawny edema” reflects the development of subcutaneous fibrosis. Fibrous capsular thickening of the liver and spleen is also seen in such patients and in cirrhosis [37, 38]. Exudation generates deposits of relatively static protein-rich fluid that activates fibroblasts as part of a granulation tissue response (Fig. 2j–l).
Mueller hypothesized that elevated sinusoidal pressure is a major factor in the synthesis of collagen in chronic liver disease. He proposed that collagen synthesis was caused by stretching of the hepatic stellate cells and activation of biomechanical signaling. This hypothesis was based on correlation with liver stiffness and pressure but without discussion of vascular lesions and other histologic evidence [39].
Role of Fibrosis in the Pathogenesis of Cirrhosis
Fibrosis occurs at many sites in the cirrhotic liver. Fibrosis within vascular channels would be the most potent to increase congestion and progression of parenchymal extinction. However, increased tissue stiffness caused by collagen deposition at any site would impair dilatation of the micro-vasculature in response to hyperemia. With this confinement, SEC injury, transudation, and parenchymal extinction would occur with lesser degrees of hyperemia.
Primary Injury Is Necessary to Drive Progression of Disease, Until a Tipping Point Is Reached
The severity of primary injury determines the clinical outcome in chronic disease. When primary disease is suppressed by spontaneous remission or therapy, most livers with mild to moderate cirrhosis regress substantially. In this population, the primary injury is required to initiate or maintain progression. Patients with severe cirrhosis may not regress, even with remission, and these patients (enriched in the transplant population) may have reached the tipping point where obstructed veins and destroyed sinusoids are sufficient to support progression (i.e., drive the congestive escalator). New onset of tense ascites, portal vein thrombosis, anemia and hypoxemia, and super-infection are factors that may tip the balance towards a congestive progression.
Histologic features of active viral disease or steatohepatitis, adjacent to PELs, suggest that a primary inflammatory mechanism may still be active in PEL formation. The presence of open-PELs or congested or edematous septa but without active inflammation suggests that the tipping point has been reached.
Role of Thrombus in Progression of Chronic Liver Disease
Thrombus may be a factor in progression of disease, as seen in Budd-Chiari syndrome and chronic congestive heart failure. In chronic viral and alcoholic disease, histological thrombosis of small hepatic and portal veins does occur but is rarely identified, in part because recent thrombus is rapidly replaced by less specific fibrous plugs. Sub-microscopic fibrin deposition could also have an effect. Detection of large portal vein thrombi, often achieved by clinical imaging, has been a major focus of attention. Patients with cirrhosis who received enoxaparin, had decreased rates portal vein thrombosis as well as less decompensation on follow-up [8••]. Portal vein thrombosis may be an important cause of decompensation. In severe cirrhosis, portal vein flow is often retrograde, indicating the importance of the portal vein as an outflow tract (see Fig. 4h, i).
Role of Endothelial Cell Injury
The vascular model presented here is focused on the potential of SEC injury to initiate chronic liver disease. This is supported by finding SEC injury in most primary diseases that can progress to cirrhosis. It is not surprising that hepatitis C is synergistic with toxic agents used in preparation for bone marrow transplantation [40] in causing liver decompensation. The same agents used alone can cause hepatic SOS/VOD. At doses of oxaliplatin used for colon carcinoma therapy, patients with advanced cirrhosis are at increased risk for hepatic decompensation [41].
The vascular model allows the rationale for various therapies to be understood in anatomic terms. Thus, any procedure that lowers intrahepatic pressure or outflow resistance might be of benefit. Simvastatin has hepatoprotective properties by several mechanisms, including protection of SEC [42, 43•].
Conclusion
The vascular model described here, provides an anatomic framework to understand the mechanisms that drive progression of chronic liver disease in the human.
Cirrhosis is the morphologic result of parenchymal extinction that leads to collapse of tissue to form septa. Parenchymal extinction is characterized by focal loss of hepatocytes as well as destruction of sinusoids and obstruction of small portal and hepatic veins.
Parenchymal extinction is initiated by a primary liver disease that causes vascular injury, usually at the level of sinusoidal endothelial cells. Sinusoidal injury progresses to parenchymal extinction by a sequence of events that involve vascular leak, transudation into vein walls and interstitium, ischemia, and hyperemia. The resultant microvascular obstruction causes further congestive injury and the extension of venous obstruction to larger vessels in a positive feedback loop called the “congestive escalator,”
The human liver is particularly vulnerable to this congestive escalator because the “nested cone” architecture, mandated by the long and branched hepatic vein tree, is susceptible to “compartment syndrome” effects. Animals used for most experimental models have a very short hepatic venous tree that is unlikely to produce the prominent congestive effects found in human liver disease. This difference suggests that the pathogenesis of cirrhosis in humans and animal models may be quite different.
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Wanless, I.R. The Role of Vascular Injury and Congestion in the Pathogenesis of Cirrhosis: the Congestive Escalator and the Parenchymal Extinction Sequence. Curr Hepatology Rep 19, 40–53 (2020). https://doi.org/10.1007/s11901-020-00508-y
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DOI: https://doi.org/10.1007/s11901-020-00508-y