Most authors find more support for a differential diagnosis among variables which point to EHC (Table 3). Very few histopathological variables indicate IHC and, according to some (14,19,21), no variable suggests this group of diseases. However, in our study there was a relationship between the presence of myeloid metaplasia and the existence of IHC. According to Desmet (22), myeloid metaplasia is a nonspecific finding. However, this author found that in cases of early severe BA, i.e., 1/4 of the cases of BA, myeloid metaplasia or gigantocyte proliferation is not found. In the study by Zerbini (19), a severe degree of myeloid metaplasia was only found in the extrahepatic cholestasis group between 2 and 4 months of age. Before this time, myeloid metaplasia was milder and occurred in both intra- and extrahepatic cholestasis. The author found no histological parameter for the diagnosis of intrahepatic cholestasis. Our finding is consistent with the observations by Allagille (1), which include extramedullary hematopoiesis among those variables which characterize IHC. Recently, Romero (23), analyzing the histopathological variables which are useful in the discrimination among different causes of neonatal cholestasis, included foci of extramedullary hematopoiesis among those which characterize idiopathic neonatal hepatitis. In our study and in Zerbini's study (19), giant cell transformation was a nonspecific finding. Giant cell transformation originates from a syncytial fusion of several hepatocytes (22) and its biological meaning is unknown. In contrast to data reported by Craig and Landing (6), it is a histopathological variable which is more specific for age than for causal disease, thus not serving as an IHC marker.
According to several authors, the changes which indicate EHC more often are portal ductal proliferation, cholestasis in neoductules and portal fibrosis (Table 3). In our study, we found that portal ductal proliferation and cholestasis in neoductules were discriminatory variables between IHC and EHC. Concerning portal fibrosis, we should clarify that it is one of the elements which characterize portal expansion, in addition to edema and ductal portal proliferation (18,19). Chandra (24) found portal expansion in all cases of BA, with distribution in all portal triads and with a varying extent of fibrosis. Kasai et al. (25) presented it as a feature of BA. Bennett (26) differentiates the fibrosis pattern of both groups of disease as being predominantly portal in EHC and lobular in IHC. However, in the present study the most important indicator of EHC was periportal ductal proliferation, whose importance had already been demonstrated by Brough and Bernstein in 1974 (14). Portal ductal proliferation originates from the mitotic proliferation of the preexisting ducts (particularly in complete mechanical biliary obstruction) and from ductular metaplasia of hepatocytes of zone 1 of the Rappaport acinus (mainly in cases of incomplete obstruction of the biliary flow) (22). The study by Cocjin et al. (27) seems to confirm the idea that in BA there is a coexistence of an important ductular metaplasia with mitotic proliferation of the biliary ductules on a smaller scale. According to Tan et al. (28), the portal ductal proliferation, at least on the hilar hepatic area, would be a reactive phenomenon to the progressive obstruction of the biliary flow due to fibrosis.
Cholestasis in neoductules is considered by Brough and Bernstein (14) to be a nonspecific finding, and by Shiraki et al. (21) as the most specific discriminatory element between EHC and IHC. Desmet (22) calls this variable "ductular bilirubinostasis", placing it among those findings characteristic of BA in the histopathological test. The fifth variable selected in the present study, portal cholestasis, is directly correlated to cholestasis in neoductules.
The seventh selected variable, portal-portal bridges, originates from what Desmet (22) calls "fibrosing piecemeal necrosis", i.e., the periportal fibrosis process which leads to the formation of fibrous septa amid portal spaces, which are still potentially reversible lesions, since the intrahepatic vascular relationships are preserved. In our study, as in Zerbini's (19), this finding favored the EHC diagnosis. In Zerbini's work there was no IHC case in patients younger than 2 months. According to Cocjin's study (27), the fibrogenesis process seems to be due to the proliferation of Ito cells for the formation of the periductular stroma surrounding the neoductules at the periphery of the portal spaces.
By comparing the present findings with Zerbini's indicating and guiding variables (19), we can see an agreement relative to the portal ductal proliferation and portal cholestasis in neoductules in the group of the indicating variables. Portal fibrosis, assigned by Zerbini to this group, was included in the portal expansion variable found by us. Among the guiding variables, our findings agree in terms of portal-portal bridges and myeloid metaplasia. In the present study, the two latter variables had the lowest canonical discriminant function coefficients among the variables selected (Table 1), which seems to agree with Zerbini's study, in which they were placed in the group with less discriminatory capacity between IHC and EHC.
Romero (23) includes among the histopathological variables which characterize BA the proliferation of bile ducts, portal expansion, fibrosis in portal tracts, the presence of biliary cylinders, the disarray of hepatic parenchyma and the absence of a marked proliferation of giant cells. Among the characteristics of INH, the author points to the loss of parenchyma organization, the existence of important giant cell proliferation, the bilirubinic pigmentation of the hepatocytes, the presence of biliary cylinders to a lesser extent and foci of myeloid metaplasia. As previously discussed, this theoretical description does not reflect the complexity of the differential diagnosis of neonatal cholestasis by histopathology, since there is a broad overlap of the findings for the intra- and extrahepatic cholestasis groups. Elements such as disarray of the hepatic parenchyma, proliferation of giant cells and the presence of biliary cylinders have been found to be nonspecific.
A criterion the pathologist has to take into account in this diagnostic differentiation is the age of onset of these histopathological changes in both IHC and EHC. The proliferation of ducts in portal spaces is a later finding in INH than in BA (19). However, even in children with BA portal ductal proliferation may be absent in patients younger than 4 weeks (18). The histopathological variables which indicate EHC, but which may be present in cases of IHC, usually appear later and in a more focal way in this second group of diseases. In our study, only 6 patients underwent biopsy before the age of two months, a fact that did not permit the use of this criterion as an adjuvant in the differential diagnosis between IHC and EHC. These data stress the need for early investigation of patients with neonatal cholestasis through a liver biopsy to provide a more adequate diagnosis (29). The histopathological changes in neonatal cholestasis reflect a dynamic process, with different characteristics in distinct age groups, a fact which should be taken into account by the pathologist who is investigating it.
To conclude, in this study seven histopathological variables indicated EHC, namely, periportal ductal proliferation, portal ductal proliferation, portal expansion, cholestasis in neoductules, portal cholestasis and portal-portal bridges. Only myeloid metaplasia pointed to a diagnosis of IHC.
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