Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis†

Abstract

For more than a century and a half, the description of a liver as "cirrhotic" was sufficient to connote both a pathological and clinical status, and to assign the prognosis of a patient with liver disease. However, as our interventions to treat advanced liver disease have progressed (e.g., antiviral therapies), the inadequacy of a simple one-stage description for advanced fibrotic liver disease has become increasingly evident. Until recently, refining the diagnosis of cirrhosis into more than one stage hardly seemed necessary when there were no interventions available to arrest its progression. Now, however, understanding the range of potential outcomes based on the severity of cirrhosis is essential in order to predict outcomes and individualize therapy. This position paper, rather than providing clinical guidelines, attempts to catalyze a reformulation of the concept of cirrhosis from a static to a dynamic one, creating a template for further refinement of this concept in the future. We already make the clinical distinction between compensated and decompensated cirrhosis, and are incrementally linking these clinical entities to quantitative variables such as portal pressure measurements and emerging noninvasive diagnostics. Moreover, mounting evidence suggests that cirrhosis encompasses a pathological spectrum which is neither static nor relentlessly progressive, but rather dynamic and bidirectional, at least in some patients. Thus, there is a pressing need to redefine cirrhosis in a manner that better recognizes its underlying relationship to portal hypertension and related circulatory changes, and more faithfully reflects its progression, reversibility and prognosis, ultimately linking these parameters to clinically relevant outcomes and therapeutic strategies. The Child-Pugh and Model for End-Stage Liver Disease (MELD) scores are currently deployed to define prognosis by modeling hepatic dysfunction, but do not provide direct evidence of the stage or dynamic state of cirrhosis. The need for more refined cirrhosis staging is especially germane given the increasing use of effective antiviral treatments in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) cirrhosis and the emergence of effective antifibrotic agents, wherein we must define favorable or unfavorable endpoints that correlate with a discrete clinical outcome in patients with cirrhosis. The normal liver has only a small amount of fibrous tissue in relation to its size. As a result of continued liver injury, however, there is progressive accumulation of extracellular matrix, or scar. Although different chronic liver diseases are characterized by distinct patterns of fibrosis deposition,1 the development of cirrhosis represents a common outcome leading to similar clinical consequences that impose an increasing burden in clinical practice. Cirrhosis is defined histologically as a diffuse process in which the normal anatomical lobules are replaced by architecturally abnormal nodules separated by fibrous tissue.2 Progressive histological stages have been defined in the process leading to the development of cirrhosis. Among the more common staging systems, the METAVIR scale is distinguished by four stages, with stage F0 representing lack of fibrosis; stage F1, portal fibrosis; stage F2, periportal fibrosis; stage F3, bridging fibrosis; and, finally, stage F4 representing cirrhosis.3 Similarly, the Ishak4 and Scheuer scoring systems5, 6 attempt to semiquantitatively define progressive fibrosis based on the pattern and relative amounts of scar within a liver biopsy specimen. In this context, once fibrosis reaches the final stages, the diagnosis of cirrhosis is established and the process is considered "end-stage" from a pathological perspective. HVPG, hepatic venous pressure gradient; LSM, liver stiffness measurement. Cirrhosis has also been increasingly defined by clinical outcomes. In this context, cirrhosis is distinguished between compensated and decompensated stages, with different features, prognoses and predictors of death.7 Within the compensated stage, two subpopulations have been identified based on the absence or presence of varices, each of which confers a distinct prognosis. Decompensated cirrhosis is defined by the development of clinically evident complications of portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy) or liver insufficiency (jaundice). The decompensated stage can be subclassified further into a more severe stage defined by the development of recurrent variceal hemorrhage, refractory ascites, hyponatremia and/or hepatorenal syndrome. Portal hypertension is the earliest and most important consequence of cirrhosis and underlies most of the clinical complications of the disease. 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 distortio