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 (fibrous tissue, regenerative nodules), endothelial dysfunction leading to intrahepatic vasoconstriction, and intrahepatic vascular shunts between afferent and efferent vessels of the liver [44, 45]. These portal-central anastomoses, although representing direct connections between the portal and the systemic circulation, follow irregular patterns and are embedded in a developing scar tissue characterized by the presence of contractile cells (i.e. activated HSC and myofibroblasts). In clinical practice, the hepatic venous pressure gradient (HVPG) , an indirect measure of portal pressure, is the best predictor of the development of PH [46–50]. Since all cirrhotic patients are identified by the highest value of the currently used scoring systems, the histological features of disease progression within the stage of cirrhosis have not been traditionally linked to clinical outcomes. However, progressive increases in HVPG correlate with increasing severity of liver disease (normal, chronic hepatitis, pre-cirrhosis and cirrhosis) both in alcoholic [51] and in non-alcoholic liver disease [52]. In addition, the analysis of gross histologic features may also have important prognostic implications in cirrhotic liver biopsies: the thickness of fibrous septa correlates with HVPG and is an independent predictor of both clinically significant portal hypertension (i.e. HVPG > 10 mmHg) [53] and clinical decompensation [54]. A more precise definition of the relationship between the fibrogenic evolution occurring within cirrhotic liver and the worsening of PH has been established with the use of a new histological marker, the collagen proportionate area (CPA), obtained by digital video imaging analysis [55]. Additional work by the same authors suggests that CPA is indeed a histological variable that scores cirrhosis with a continuous scale and is able to predict relevant clinical outcomes [56].

Although a regression has been shown in animal models of cirrhosis , this possibility is not yet fully substantiated in humans. Evidence of either fibrotic or cirrhotic regression has now been reported in CLD of different aetiologies, including viral hepatitis [57–63], autoimmune hepatitis [64], alcoholic and non-alcoholic steatohepatitis [65–67]. However, when these results were examined by experienced liver pathologists, there was agreement only for a variable degree of fibrosis regression in cirrhosis but not for a reversal of cirrhosis in most cases [68, 69]. Along these lines, there is no convincing evidence that the abnormalities of the intrahepatic vasculature revert in the human cirrhotic liver. Actually, the available evidence suggests that the so-called veno-portal adhesions persist even in cases of extensive fibrosis regression, and evident “arterialized” sinusoids appear in the context of intrahepatic arteriovenous shunts [70].

The most obvious problem when discussing the issue of fibrosis regression in cirrhosis or even cirrhosis reversal is the lack of a clear and common language in the precise distinction of advanced fibrosis (“pre-cirrhosis”) from true cirrhosis and the staging of cirrhosis. The problem is fundamentally based on the use of semi-quantitative scoring systems for staging fibrosis and the fact that cirrhosis is always represented by the highest score and is indeed considered as an end stage of CLD [69, 71]. Indeed, cirrhosis appears in a very broad spectrum of variants (early, fully developed, “active” and “inactive”) and more than one study has documented the transition from micronodular to macronodular cirrhosis following the discontinuation of the causative agent [72, 73]. While it is doubtful than an accurately defined cirrhosis is able to reverse to normal, there is sound evidence concerning the capacity of the healing liver to reabsorb scar tissue following an effective causative treatment (i.e. sustained viral response, abstinence from alcohol, etc.). However, scar tissue in the liver of patients with CLD lasting 30 or more years is likely characterized by different stages of biochemical and biological evolution. Indeed, fibrotic deposition related to recent disease and characterized by the presence of thin reticulin fibres, often in the presence of a diffuse inflammatory infiltrate, is likely fully reversible, whereas long-standing fibrosis, branded by extensive collagen cross-linking by tissue transglutaminase, presence of elastin, dense acellular/paucicellular ECM, and decreased expression and/or activity of specific metalloproteinases, is not [74, 75]. In other words, within the same liver there are different types of scar tissue with different potential and dynamics of reversibility once the etiology agent is eradicated and/or anti-fibrogenic strategy is established. In addition, substantial experimental evidence suggests that long-term fibrogenesis occurring in human CLD is characterized by a progressive resistance to apoptosis of hepatic stellate cells/myofibroblasts with the consequent immovability of a critical mass of pro-fibrogenic cells [76].

The different aspects of the fibrogenic evolution towards the advanced stage of CLD illustrated in this chapter should invite to an open discussion and most importantly, to active research to address the question: “cirrhosis or cirrhoses?” Indeed, at least in the clinical phase of cirrhosis , when there are no evident clinical manifestations, it is likely that the disease is sustained by different prevalent mechanisms depending on disease etiology. This potentially call for different morphological classifications, different non-invasive diagnostic and prognostic indicators, different etiology-driven and/or antifibrotic therapies and, most importantly, different expectations on the effective reversibility of fibrosis and cirrhosis.