Hytiroglou P, Snover DC, Alves V, Balabaud C, Bhathal PS, Bioulac-Sage P, et al. Beyond “cirrhosis”: a proposal from the International Liver Pathology Study Group. Am J Clin Pathol 2012;137:5-9. (Reprinted with permission.)
“Cirrhosis” is a morphologic term that has been used for almost 200 years to denote the end stage of a variety of chronic liver diseases. The term implies a condition with adverse prognosis due to the well-known complications of portal hypertension, hepatocellular carcinoma, and liver failure. However, recent advances in the diagnosis and treatment of chronic liver diseases have changed the natural history of cirrhosis significantly. This consensus, document by the International Liver Pathology Study Group, challenges the usefulness of the word cirrhosis in modern medicine and suggests that this is an appropriate time to consider discontinuing the use of this term. The role of pathologists should evolve to the diagnosis of advanced stage of chronic liver disease, with emphasis on etiology, grade of activity, features suggestive of progression or regression, presence of other diseases, and risk factors for malignancy, within the perspective of an integrated clinicopathologic assessment. (HEPATOLOGY 2012;)
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“Cirrhosis” is a morphologic term that has been used for almost 200 years to denote the end stage of a variety of chronic liver diseases. The term implies a condition with adverse prognosis due to the well-known complications of portal hypertension, hepatocellular carcinoma, and liver failure. However, recent advances in the diagnosis and treatment of chronic liver diseases have changed the natural history of cirrhosis significantly. This consensus document by the International Liver Pathology Study Group challenges the usefulness of the word cirrhosis in modern medicine and suggests that this is an appropriate time to consider discontinuing the use of this term. The role of pathologists should evolve to the diagnosis of advanced stage of chronic liver disease, with emphasis on etiology, grade of activity, features suggestive of progression or regression, presence of other diseases, and risk factors for malignancy, within the perspective of an integrated clinicopathologic assessment.
The last 30 years have witnessed profound changes in the understanding and interpretation of chronic liver diseases (CLD). Although the birth of hepatology in the 1950s corresponds with the identification of defined clinical syndromes and with the increasing adoption of liver biopsy as a key diagnostic tool, the development of this area of medicine has reached maturity only with the progressive identification of hepatitis viruses, immune- and toxicity-mediated mechanisms, genetic mutations, and the relative pathophysiological events leading to chronic damage, inflammation, fibrogenesis, and carcinogenesis. In spite of these major advancements, the term cirrhosis, introduced almost 200 years ago, to highlight the presence of profoundly abnormal structure of the liver in current clinical usage indicates an irreversible end-stage condition. However, it is increasingly evident that the term cirrhosis does not reflect accurately the modern understanding of chronic fibrogenic liver diseases, which demands an integrated clinical-pathological assessment; a readjustment of perspective is urgently required. This necessity is clearly expressed in the well-timed article by the International Liver Pathology Study Group.1 The key suggestion of this article is to abolish the term cirrhosis and to introduce a more rational and clinically useful approach to identify different stages of the evolution of advanced-stage CLD. This is in complete agreement with the increasing awareness of the hepatology community concerning the need for a pathophysiological classification of cirrhosis.2 In any case, it is remarkable that this suggestion comes from pathologists at the same time that clinicians have increasing difficulties in categorizing advanced liver disease after realizing that fibrosis in a cirrhotic liver (and even early cirrhosis itself) is at least partially reversible following appropriate treatment. In addition, the term cirrhosis is generally sensed as absolutely fatal by patients and many physicians, whereas by modern standards, all cases of cirrhosis do not inevitably result in clinically significant portal hypertension and hepatocellular failure leading to liver transplantation or death.
In addition to these considerations, in their article this group of pathologists make a vibrant analysis of several morphological, clinical, and pathophysiological matters strictly connected with the overall concept of cirrhosis. A first important issue is related to the contrast between the definition of cirrhotic liver as the morphological end stage common to all types of chronic liver disease, regardless of the different patterns and mechanisms of fibrogenesis or the culpable fibrogenic cell types (ie, portal myofibroblasts vs hepatic stellate cells) relevant to different etiologies of chronic liver disease.3 In other words, the natural history of disease associated with a cirrhotic liver caused by chronic alcohol abuse could be markedly different when compared to a cirrhotic liver caused by chronic viral hepatitis. In addition, the potential for disease progression and regression following abstinence and treatment will also be different. Along these lines, the results of a recently published study4 analyzing fibrosis distribution in explanted cirrhotic liver indicated that a case of alcoholic cirrhosis requiring liver transplantation is characterized by a collagen content, assessed with recently introduced collagen proportionate area (CPA) method,5 which is on average double that of a case of hepatitis C virus cirrhosis. These observations affirm the idea that cirrhosis, or more precisely advanced-stage CLD, should be primarily framed according to etiology. It is indeed rare in modern medicine to find a term equivalent to cirrhosis that serves as a blanket term to denote end-stage fibrous disease of other organs.
The evaluation of CPA as well as of other morphological aspects, such as nodule size and thickness of fibrous septa,6, 7 may help in establishing a pathophysiological link, possibly etiology driven, with the progression of portal hypertension particularly in the stage of advanced CLD known as compensated cirrhosis, which should be accordingly renamed advanced-stage CLD without clinically evident complications. Overall, the considerations made in this article apply mainly if not exclusively to this stage of CLD. Along these lines, measurement of hepatic venous pressure gradient (HVPG) associated with transjugular liver biopsy could be proposed at this clinical juncture, although these procedures are available only in highly specialized centers. More importantly, studies investigating the relationship between liver morphology, CPA, HVPG, and some of the available noninvasive methodologies, particularly liver stiffness, could increase the possibility for noninvasive monitoring of disease progression within a phase of the disease currently interpreted as end stage but not yet characterized by clinical complications.
As suggested by the authors, a more insightful morphological analysis of the liver of patients with advanced-stage CLD may also add important information on key pathophysiological aspects that are currently neglected, such as the degree of necroinflammation (still representing the main profibrogenic stimulus), the extent of neoangiogenesis in fibrous septa, the characteristics of liver regeneration (particularly the contribution of mature hepatocytes versus hepatocyte precursor cells), and the occurrence of preneoplastic features and features of neoplasia risk (such as small and large cell changes). As further stressed in the article, all of these features, and particularly the predictors of hepatocellular carcinoma, may be significantly different according to different etiologies.
Certainly, the definition of these morphological aspects would have a positive impact in the interpretation of fibrosis regression and architectural improvement following etiological and/or antifibrotic therapy, especially if linked with significant changes in portal pressure and in parameters obtained with noninvasive methodologies.8 In addition, considering that 1 of the most highly anticipated revolutions in medicine is the introduction of bioimaging techniques able to link cellular and molecular mechanisms with changes in tissue structure and clinical manifestations, a more precise definition of these aspects will help to set morphological standards of disease progression and regression to be targeted by new imaging technologies.
Although the content and the spirit of the proposal formulated in this article by the International Liver Pathology Study Group are innovative and represent a solid base for a constructive debate among hepatologists, the plan proposed to put these concepts into clinical practice is complex and of uncertain success. The main difficulty for the clinician is the central role of liver biopsy in this process of reclassifying advanced-stage CLD in times when the utility and the accuracy of liver biopsy are being continuously challenged even for initial and intermediate stages of disease progression. In other words, although this may be applicable in major specialized centers, it will be difficult to convince the hepatology community to introduce liver biopsy as a routine procedure in patients with advanced-stage CLD, who will still be seen as cirrhotics and therefore as subjects bearing a high risk of postbiopsy complications. In any case, Figure 1 proposes a working scheme complementing the outline provided in the article by Hytiroglou and colleagues1 that may represent the basis for future work aimed at a more detailed investigation of the relationships between pathological aspects and clinical data in the setting of advanced CLD without clinically evident complications.
In conclusion, what is the real impact of the International Liver Pathology Study Group proposal? The answer is that it is time to change our mentality and professional approach toward cirrhosis. The message of these pathologists converges with that of clinicians and scientists and calls for a new classification of advanced-stage CLD (not just cirrhosis!) incorporating etiology, prevalent cellular and molecular mechanisms, specific changes in tissue architecture and biology, and invasive (HVPG) and noninvasive diagnostic approaches, bearing in mind that fibrosis and even early cirrhosis could be reversible. At the same time, it becomes clear that we should look also at earlier stages with new eyes, because the traditional histopathological systems for staging CLD become more and more obsolete with the progress in understanding fibrogenesis. On the other hand, it is clinically crucial to know which patients will progress to cirrhosis. Therefore, the article by the International Liver Pathology Study Group is a stimulus to an overall rethink of the systems we use to assess the risk of progression of CLD. In other words, exploring beyond cirrhosis but also toward cirrhosis could create a platform for a future rich in noninvasive diagnostic and prognostic methods and advanced bioimaging.