In Reply

I am delighted to have an opportunity to respond to the comments of my friends and colleagues. Five years ago I would have shared many of their opinions expressed in this issue of the Archives, so I understand their viewpoint. After looking at liver specimens for 20 years with no particular insight into the phenomenon of regression of fibrosis, a number of experimental studies from Kossakowska, Urbanski, Arthur, and Iredale, among others, began to penetrate my mind.1,2 I began to look at liver tissue differently and rather quickly realized that the histologic appearances commonly associated with progressive fibrosis were actually manifestations of healing. In the last few years, I have become more convinced of this viewpoint, as examples have demonstrated the full extent of reparability.3,4Dr Ray suggests my study material is too limited to allow the conclusions expressed here.5 On the contrary, my opinions are based on personal experience with several hundred excised cirrhotic livers with an average of 1 to 2 dozen blocks per liver, as well as thousands of liver biopsies. An impression gained from such a visual parade cannot be easily summarized. Hence, we have presented a small number of cases with a limited number of slides.Dr Ray raises the issue of whether the patients coming to transplant have inactive disease.5 Most patients coming to transplant either do not have active disease or have low-grade activity. Indeed, alcoholic patients are expected to be abstinent for 6 months and patients with hepatitis B virus must be hepatitis B virus DNA negative prior to transplantation. The indications for transplantation are seldom related to active disease, apart from fulminant hepatitis, and are usually related to the effects of portal hypertension with renal failure, intractable ascites, or uncontrollable bleeding varices. However, these effects of portal hypertension are irrelevant, in that repair goes on continually even while there is active disease, although the repair is easier to appreciate when new lesions are few or absent.See also pp 1585, 1587, 1589, 1591, and 1599.Our index patient unquestionably had cirrhosis, as a second biopsy confirmed the appearance illustrated. The patient had mild portal hypertension with minimal ascites, mild splenomegaly, and a platelet count of 131 × 109/L3. These parameters have not shown improvement with a further year of treatment and follow-up since the article was written. However, larger studies have documented clinical improvement of patients with cirrhosis, including increasing albumin values and improvement in Child-Pugh score.6The notion that fibrosis in the liver is at least partly reversible is supported by well-known histologic changes in many tissues. For example, the sclerotic glomeruli in chronic glomerulonephritis become less cellular, more compact, and finally disappear. Indeed, the total number of visible glomeruli, whether sclerotic or intact, is severely decreased in chronic glomerulonephritis. This change can only be explained by total resorption of the glomerular structures. The liver has more regenerative capacity than the kidney, but this observation should be a reminder that the disappearance of scar is not synonymous with return to normal anatomy and function.My accompanying article7 makes 3 points about the natural history of cirrhosis: (1) cirrhosis is a condition that is in a continual process of healing and therefore may show regression as well as progression; (2) the process of healing includes the resorption of collagen, creating a number of histologic features that have not hitherto been interpreted in this context; and (3) the transient nature of lesions requires a reexamination of the definition of cirrhosis. Implicit in this discussion is the fact that cirrhosis is defined as a morphologic entity with certain abnormalities that can be seen grossly, microscopically, and to some degree with imaging techniques. This point was driven home to me by Harold Conn, who insisted that there was no such thing as a cirrhotic patient, only patients with cirrhotic livers (oral communication, 1990).The Figure shows the time course of appearance and disappearance of various histologic features of cirrhosis. All features increase during injury and regress during periods of relative inactivity. Because the features regress at different rates, the histologic appearance of cirrhosis varies with time. If seen at time A, septa and sinusoidal fibrosis may be prominent and the diagnosis of cirrhosis is not difficult. At time B, most remaining septa are delicate or incomplete, but large scars and vascular lesions remain. It is at time B that the diagnosis of cirrhosis becomes difficult and will be missed by many techniques, including biopsy. In such cases, the pathologic diagnosis will usually be incomplete septal cirrhosis or macronodular cirrhosis, and the clinicopathologic diagnosis will often be noncirrhotic portal hypertension. However, understanding the ebb and flow of chronic liver disease will allow a more complete diagnosis of “regressed cirrhosis” to be made.Dr Chedid worries that the criteria we include in the hepatic repair complex have not been validated by other pathologists.8 Because our viewpoint is a relatively new one, this situation would appear to be inevitable. It is our opinion that if pathologists are forced to explain these features in a mechanistic fashion, they may find that our interpretation is logical and (hopefully) imperative. The purpose of this presentation is not to prove that cirrhosis is reversible, but to offer what we believe is the best explanation as to how fibrous lesions in the liver develop and evolve.

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