Although the histological finding of prominent necro-inflammation in zone 3 of the liver parenchyma is considered not to be completely specific for AIH, this pathological change has been indicated to be a unique feature of some AIH patients[[5, 6]]. This change, called ‘CZN’, has tended to be given a broad interpretation because necro-inflammatory change of the liver parenchyma in AIH cases has shown greater intensity in zone 3 than in the other zones. Actually, small- to medium-size necrosis has been reported as not infrequent in zone 3 of typical AIH cases[].
Therefore, the inarticulate definition of CZN may obscure the significance of CZN in medical care of AIH. In the present study, we used a strict definition of CZN ࣧ that being, broad necro-inflammatory lesions systematically spreading through the hepatic parenchymal tissue. Although one research group has speculated that CZN is a histological feature of early-stage AIH[], we previously found that CZN-AIH is clinically and immunogenetically different from the majority of AIH (non-CZN-AIH) cases. However, consensus on the significance of CZN-AIH remains elusive, presumably due at least in part to the rarity of this type of AIH. To address this controversy, we collected 32 cases of CZN-AIH, and the clinicopathological features of these patients were studied in comparison to cases of non-CZN-AIH.
Distinguishing features of CZN-AIH from non-CZN-AIH have been studied previously by us and others[[8, 9, 12]]. The findings from the current study that CZN-AIH tended to develop similar to acute hepatitis and had low IgG, ANA titer and AIH score (Table 1) are in good agreement with findings from our previous study[] but different from those of Miyake et al[]. This discrepancy is probably due to the difference in histological definition of CZN between the studies. Our current findings also strengthen the previous findings[[8, 9]] that the characteristics of typical AIH were poor in CZN-AIH. In addition, we have newly determined that ALT/GGT is higher in CZN-AIH; this finding may correspond to relatively mild portal inflammation in CZN-AIH that may affect elevation of biliary enzymes.
Another novel finding from the current study was the higher co-existent rate of other autoimmune diseases in CZN-AIH (Table 1). We also showed that response to first-line immunosuppressive therapy was better for the CZN-AIH cases. Immunogenetically, in comparison with non-CZN-AIH, we found low frequency of HLA-DR4 and high frequency of HLA-DR9 (Table 2). While the observed frequencies of HLA-DR4 and HLA-DR9 in CZN-AIH are not distinct from those in the healthy Japanese population, the increase of HLA-DR4 and decrease of HLA-DR9 in non-CZN-AIH is distinct from healthy Japanese. These findings strongly suggest that disease susceptibility for CZN-AIH is not defined by HLA-DR phenotype.
It has been reported that some AIH cases develop similar to acute hepatitis, a situation prompting the name of ‘acute-onset AIH’[]. We found in this study that CZN is frequently associated with acute-onset AIH, though a small portion of non-CZN-AIH cases also developed similar to acute hepatitis as well (Table 1). When the clinical presentations of acute-onset CZN-AIH and acute-onset non-CZN-AIH were compared, the results were partially different from those obtained by the comparison between the entire CZN-AIH group and the entire non-CZN-AIH group (Table 1–3). In acute-onset AIH, ANA titer was not different between the CZN-AIH group and the non-CZN-AIH group; thus, the AIH score excluding the pathological score is similar between the two groups (Table 3). In the acute-onset non-CZN-AIH group, low ANA titer, low amount of IgG, and less advanced stage were the distinctive features of acute onset compared to entire CZN-AIH. However, no distinctive features of acute-onset CZN-AIH were found in comparison to the entire CZN-AIH group.
Although Miyake et al[] have previously described acute AIH in comparison with chronic AIH, they did not sub-classify the acute AIH according to CZN and non-CZN. In a previous study by Abe et al[], acute AIH cases were divided into two groups based on the presence or absence of central necrosis, for investigation of the clinicopathological differences among them. Those findings are partially discordant with ours, especially regarding the frequency of ANA negativity, serum ALP level, and presence of interface hepatitis. It is important to note that the other study included both a considerable number of cases that showed exacerbation in the chronic phase of AIH and patients with inconspicuous ALT elevation (5 X < maximum ALT < 10 X upper normal limit). Our comparative analysis of acute-onset CZN and acute-onset non-CZN, performed under the strict definition of both acute onset and CZN, was novel. Our findings of differences in laboratory data between acute-onset CZN-AIH and acute-onset non-CZN-AIH were serum levels of ALP, GGT, IgG and IgM. Tendency of elderly onset in acute CZN-AIH was noted. Histologically, acute-onset non-CZN-AIH had lower activity and tendency of less advanced fibrosis stage. Moreover, our data suggested that the difference between CZN-AIH and non-CZN-AIH could become more apparent as they evolve to a chronic state. In our previous study, we pointed out that the clinical feature of early fibrotic stage CZN-AIH was clearly different from that of early fibrotic stage non-CZN-AIH[]. When that finding is taken into consideration, our current findings strongly suggest that the manner of clinical and histological progression in CZN-AIH is distinctive from that of typical non-CZN-AIH.
Finally, we examined significance of interface hepatitis in CZN-AIH (Table 4), because interface hepatitis has been considered as the most important pathological feature of AIH[]. Although the severity of interface hepatitis is generally slight in CZN-AIH, we found significant interface hepatitis in 12 of our 32 patients. However, we did not find any distinctive clinical feature of these mixed-type CZN-AIH cases, except for increase of IgM, compared to pure-type CZN-AIH. Immunogenetically, distribution of the HLA-DR phenotype was similar between the pure-type CZN-AIH and mixed-type CZN-AIH. These findings suggest that existence of interface hepatitis in CZN-AIH is a part of the pathogenic evolution of CZN-AIH, manifesting at any time during the clinical course of CZN-AIH. The fate of untreated CZN-AIH may be acute hepatic failure or decompensated lever cirrhosis. We experienced one patient who died by chronic hepatic failure. However, the course of progression in CZN-AIH is not clearly understood, because liver architecture is severely distorted in advanced stage of disease that made it difficult to distinguish CZN-AIH from non-CZN-AIH.
The current study has some limitations that must be considered when interpreting or seeking to generalize our findings. First, this was not a prospective study; however, as CZN is a rare histological finding, it is extremely difficult to conduct a prospective study. Second, there was a small number of cases in the CZN-AIH group, which may have affected our sub-analyses; in order to verify our results, a larger group of CZN-AIH cases, identified based on the same strict definition of CZN we used, is needed. We will collect and examine more cases of CZN-AIH in the future.