When comparing the distribution of HLA-DR phenotypes between the NIC and the non-NIC groups, no significant differences were observed, except for a marginal decrease in the frequency of DR4 in the NIC group (Table 4).
Clinicopathological features of non-CZN patients compared with CZN patients with lower severity of fibrosis
In a further study including 27 non-CZN patients with mild fibrosis (F0–F1), a number of clinicopathological features differed between CZN and non-CZN patients with mild fibrosis. The frequencies of acute onset, ANA positivity, and high ANA titers were higher in non-CZN patients with mild fibrosis. Moreover, higher serum IgM levels, platelet counts, and %prothrombin time values were observed in non-CZN patients with mild fibrosis compared with CZN patients. Histologically, a marginal increase in the frequency of interface hepatitis and lymphoplasmacytic infiltration was observed in non-CZN patients with mild fibrosis. AIH scores were significantly higher in non-CZN AIH patients with mild fibrosis (Table 5).
Response to immunosuppressive therapy in CZN patients
In the 13 CZN patients, responses to prednisolone therapy were generally satisfactory without disease relapse, except for those in two patients. One patient was refractory to prednisolone following a considerable delay (>6 months) in the initiation of prednisolone therapy. The other patient relapsed following the interruption of a short duration (3 months) of prednisolone therapy. In both these patients, a definitive diagnosis of AIH was not confirmed despite the availability of histological findings.
In the present study, we assessed clinicopathological features and immunogenetic backgrounds in AIH patients with histological features of marked and extensive necrosis in zone 3, termed CZN.
The histological characteristics of CZN were first described by Pratt et al. 4 and Te et al. 5 as a prominent central zone (zone 3) necrosis with relative sparing of portal regions in liver biopsy specimens from patients with glucocorticoid-responsive chronic hepatitis. Subsequently, the clinicopathological features of CZN without classical histologic features of AIH were assessed and summarized 6,11. However, consensus on the histological features of CZN is still lacking. In addition, the natural clinical course of AIH with CZN is yet to be fully elucidated. However, Singh et al. 11 reported a case with a marked predominance of centrizonal injury in an initial liver biopsy that later transformed into a typical histological appearance over the course of several months. This finding may indicate that CZN represents a very early histologic phenotype of typical AIH.
Fulminant AIH, a severe form of CZN that progresses to pan-lobular necrosis, is considered distinct from other types of fulminant AIH with massive hepatic necrosis involving zone 3 12. However, the significance of typical CZN in nonfulminant AIH remains unclear. The frequency of significant necrosis in zone 3 has been reported to be 17.5–29% of all AIH cases 7,8 and 31.7% of all acute-onset AIH cases 13. However, the reported frequency of necrosis in zone 3 without obvious portal inflammation is relatively low, accounting for only 3.5% of all AIH cases 7.
A limitation of previous studies is the ambiguous histologic definition and clarification of necrosis in zone 3. In an earlier report, confluent necrosis and spotty necrosis in zone 3 were concomitantly abbreviated as CN 14. Although spotty or focal necrosis in zone 3 is often observed in AIH, marked confluent necrosis (typical CZN) is a relatively rare histological finding. Therefore, to clarify the significance of CZN, the distinction of typical CZN from other types of necrosis is necessary 15.
In the present study, we examined the significance of CZN after distinctive differentiation of typical CZN from other types of necrosis. As a result, we found that AIH patients with CZN had distinctive clinicopathological features such as a higher prevalence of acute-onset liver disease, lower frequency of ANA positivity, lower ANA titers, higher serum ALT levels, lower serum IgG levels, and a lower frequency of histological features of AIH compared with non-CZN patients. Accordingly, AIH scores were significantly lower in the CZN group.
Compared with previous reports, the prevalence of AIH with CZN was relatively low in the present study, accounting for only 13.3% of all AIH cases and 21.8% of acute-onset AIH cases. In addition, the observed clinicopathological features of CZN cases in the present study did not corroborate previous reports 7,8. Although the high frequency of acute-onset, higher serum ALT levels and less advanced fibrosis reported in previous studies were in agreement with the findings of the present study, other features differed markedly. In a previous European study 7, more severe portal and lobular inflammation was observed in cases of AIH with CN. Moreover, the proportion of definite AIH defined according to AIH was similar between AIH patients with CN and without CN. In a study of Japanese AIH patients 8, the reported clinical features associated with necrosis in zone 3 were lower serum albumin and higher serum total bilirubin levels; however, the observed frequency of cirrhosis was similar between AIH patients with and without necrosis in zone 3. In a further Japanese study of acute-onset AIH 13, AIH with CN was found to be characterized by lower serum IgG levels, lower prevalence of ANA, and less advanced fibrosis. The findings of the present study corroborate these reports. However, the frequencies of characteristic histological findings of AIH and ANA titers were reportedly similar between AIH patients with and without CN. The discordant clinicopathological features among previous reports and the findings of the present study are likely to be predominantly because of the different definitions of necrosis in zone 3 used.
The finding of less prominent portal inflammation in the CZN group was also reported by the original studies of CZN 4,5. We observed less prominent histological features of AIH with lower serum IgG levels, lower frequency of ANA, and lower ANA titers in the CZN group. Therefore, more importantly, AIH scores were significantly lower in the CZN group compared with other types of AIH. Thus, a definitive diagnosis of AIH was often challenging in these patients even after histological examination. In contrast to the CZN group, the clinicopathological features of AIH in the NIC group were similar to those of the non-NIC group (majority of AIH cases), except for lower serum IgM levels in the NIC group. Therefore, AIH with NIC does not appear to represent a separate subtype of AIH.
As discussed earlier, AIH with CZN may represent a very early histologic phenotype of typical AIH 11. However, the observed clinicopathological features of the CZN group in the present study differed markedly from those of the non-CZN group, with the observation of mild fibrosis in the CZN group strongly indicating that CZN was not a very early phenotype of typical AIH, but a specific phenotype of AIH that could be differentiated from the majority of the AIH cases. Although the consequence of AIH with CZN is currently unclear, we observed the presence of moderate to severe fibrosis in our series of CZN patients. Therefore, AIH with CZN may progress to advanced fibrosis and cirrhosis. Furthermore, even in cases of CZN with liver fibrosis progression, patients remained ANA negative with low titers 16.
Our proposal of CZN as a hallmark of a definite AIH subtype was further strengthened by the analysis of HLA-DR antigens. The prevalence of DR9 was significantly higher and the prevalence of DR4 was lower in the CZN group compared with the non-CZN group. The relative risk of HLA-DR9 in AIH with CZN was calculated to be 3.72 (95% confidence interval; 1.35–10.37) in a large-scale population study of healthy Japanese individuals by the HLA Laboratory (Kyoto, Japan) (http://www.hla.or.jp/). These findings indicate that HLA-DR9 is an immunogenetic factor associated specifically with AIH with CZN. However, there is an ethnic variation in the frequency of HLA-DR9 17. HLA-DR9 is very rare in the White population (1.5–2.4%), whereas it is ∼10 times more prevalent in the Asian population. Therefore, the association between HLA-DR9 and a histological finding pertaining to CZN may be limited to the Asian population. HLA-DR9 may play a role in the development of Japanese autoimmune fatigue syndrome 18. DR9 has been shown to contribute toward the acute onset and complete destruction of β-cells in Japanese patients with type 1 diabetes 19. Thus, HLA-DR9 may be involved in the acute onset and severity of immune-mediated diseases such as AIH, as indicated by the findings of the present study.
In contrast to HLA-DR9, HLA-DR4 was less frequent in the CZN group compared with the non-CZN group and marginally less frequent in the NIC group compared with the non-NIC group (majority of the AIH cases). HLA-DR4 is an established immunogenetic factor known to increase the susceptibility to type 1 AIH, particularly in Japanese patients 20. The findings of the present study indicate that HLA-DR4 may contribute toward the development of typical clinicopathological features of AIH.
To date, there has been a lack of consensus on the clinicopathological features and immunogenetic backgrounds of AIH with CZN. AIH is a relatively rare disease and the frequency of typical CZN is low. Thus, the size of our study may have been inadequate in conclusively elucidating the significance of CZN. Larger studies are required to validate our assertion that AIH with CZN is a distinctive subtype of AIH.
In conclusion, the clinicopathological features and immunogenetic background of AIH with typical CZN represent a distinct type of AIH. CZN is an unusual histological finding of AIH. Although the existence of this particular type of AIH should be recognized, its precise diagnosis and prompt treatment tend to be delayed because of the lack of typical features of AIH and a low AIH score in this specific subtype of AIH.
The authors thank all the staff of the Department of Pathology at the Jikei University Katsushika Medical Center and Tokyo Metropolitan Bokutoh Hospital for the preparation and staining of the liver biopsy samples.
This study was financially aided by Bristol-Myers KK, Japan.
Conflicts of interest
There are no conflicts of interest.
1. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM. American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis
. Hepatology 2010; 51:2193–2213.
2. Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, et al.. Review article: autoimmune hepatitis
– current management and challenges. Aliment Pharmacol Ther 2013; 38:887–913.
3. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al.. International Autoimmune Hepatitis
Group Report: review of criteria for diagnosis of autoimmune hepatitis
. J Hepatol 1999; 31:929–938.
4. Pratt DS, Fawaz KA, Rabson A, Dellelis R, Kaplan MM. A novel histological lesion in glucocorticoid-responsive chronic hepatitis. Gastroenterology 1997; 113:664–668.
5. Te HS, Koukoulis G, Ganger DR. Autoimmune hepatitis
: a histological variant associated with prominent centrilobular necrosis. Gut 1997; 41:269–271.
6. Zen Y, Notsumata K, Tanaka N, Nakanuma Y. Hepatic centrilobular zonal necrosis
with positive antinuclear antibody
: a unique subtype or early disease of autoimmune hepatitis
? Hum Pathol 2007; 38:1669–1675.
7. Hofer H, Oesterreicher C, Wrba F, Ferenci P, Penner E. Centrilobular necrosis in autoimmune hepatitis
: a histological feature associated with acute clinical presentation. J Clin Pathol 2006; 59:246–249.
8. Miyake Y, Iwasaki Y, Terada R, Onishi T, Okamoto R, Takaguchi K, et al.. Clinical features of Japanese type 1 autoimmune hepatitis
patients with zone III necrosis. Hepatol Res 2007; 37:801–805.
9. Miyake Y, Iwasaki Y, Kobashi H, Yasunaka T, Ikeda F, Takaki A, Yamamoto K. Autoimmune hepatitis
with acute presentation in Japan. Dig Liver Dis 2010; 42:51–54.
10. Herbut B, Woodman R, Kowalick L, Malkki M, Petersdorf EW, McKenna R. Identification of a novel HLA-B*07 allele – HLA-B*0726. Tissue Antigens 2002; 59:60–62.
11. Singh R, Nair S, Farr G, Mason A, Perrillo R. Acute autoimmune hepatitis
presenting with centrizonal liver disease: case report and review of the literature. Am J Gastroenterol 2002; 97:2670–2673.
12. Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, et al.. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011; 53:517–526.
13. Abe K, Kanno Y, Okai K, Katsushima F, Monoe K, Saito H, et al.. Centrilobular necrosis in acute presentation of Japanese patients with type 1 autoimmune hepatitis
. World J Hepatol 2012; 4:262–267.
14. Misdraji J, Thiim M, Graeme-Cook FM. Autoimmune hepatitis
with centrilobular necrosis. Am J Surg Pathol 2004; 28:471–478.
15. Yasui S, Fujiwara K, Yonemitsu Y, Oda S, Nakano M, Yokosuka O. Clinicopathological features of severe and fulminant forms of autoimmune hepatitis
. J Gastroenterol 2011; 46:378–390.
16. Miyake Y, Iwasaki Y, Kobashi H, Yasunaka T, Ikeda F, Takaki A, et al.. Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis
. Hepatol Res 2009; 39:241–246.
17. Brown J, Poles A, Brown CJ, Contreras M, Navarrete CV. HLA-A, -B and -DR antigen frequencies of the London Cord Blood Bank units differ from those found in established bone marrow donor registries. Bone Marrow Transplant 2000; 25:475–481.
18. Itoh Y, Igarashi T, Tatsuma N, Imai T, Yoshida J, Tsuchiya M, et al.. Immunogenetic background of patients with autoimmune fatigue syndrome. Autoimmunity 2000; 32:193–197.
19. Nakanishi K, Inoko H. Combination of HLA-A24, -DQA1*03, and -DR9 contributes to acute-onset and early complete beta-cell destruction in type 1 diabetes: longitudinal study of residual beta-cell function. Diabetes 2006; 55:1862–1868.
20. Zeniya M, Watanabe F, Aizawa Y, Toda G. Immunogenetic background of hepatitis B virus infection and autoimmune hepatitis
in Japan. Gastroenterol Jpn 1993; 28 (Suppl 4):69–75.
Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
antinuclear antibody; autoimmune hepatitis; centrilobular zonal necrosis; HLA-DR antigen