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Keywords:

  • cholangitis;
  • fibrosis;
  • hepatitis;
  • primary biliary cirrhosis;
  • staging and grading

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1–3; stage 3, score 4–6; and stage 4, score 7–9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0–3, and HA0–3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease that predominantly affects middle-aged–old women.1,2 Serologically, anti-mitochondrial antibodies (AMA) are frequently detectable and serum IgM levels are usually elevated in PBC patients.3 Histologically, intrahepatic small bile ducts (interlobular bile ducts) are selectively affected, presenting characteristic findings such as chronic non-suppurative destructive cholangitis (CNSDC), and the affected bile ducts eventually disappear from the liver and chronic cholestatic features develop gradually.4–6 At the same time, hepatitis activity (HA) of varying degrees is not infrequently superimposed on the liver. Chronic cholangitis activity (CA) and HA in variable combination may be responsible for progressive hepatocellular damage and fibrosis, and liver cirrhosis and hepatic failure finally develop.7,8

For evaluating the progression of PBC, histological staging systems have been proposed by Rubin et al.,9 Scheuer and Lefkowitch,10 Scheuer, 11 Popper and Schaffner,12 and Ludwig et al.13 These histological stages reflect the progression of the disease from destruction of the intrahepatic bile ducts or portal inflammation to cirrhosis. Although the classical systems appear simple and seem to be applicable, the staging process itself is subjective. In addition, there are reports that histological changes are heterogeneous in a whole PBC liver, and sampling errors occur in needle liver biopsies of PBC; histological features characterizing different stages can be seen in the same liver biopsy specimen and the staging is not infrequently different in tissue specimens obtained from different parts at the same time.5,8,14 Furthermore, the grading of necroinflammatory activity to reflect the autoimmune-mediated pathogenesis of PBC is not reflected in these classical staging systems.

Since publication of the latest staging method, that of Ludwig et al. in 1978,13 much progress has been made in clinical areas, particularly in therapeutic fields.15–18 There are now a number of treatments for PBC such as ursodeoxycholic acid (UDCA) and also combined UDCA and corticosteroid therapy for overlapping syndrome (hepatitic form of PBC).16,18 The effects of such therapies should be evaluated according to histological aspects, in addition to laboratory and clinical effects.

We recently proposed a new histological staging and grading system of PBC, for the comprehensive analysis of the histological progression of PBC (staging) toward extensive duct loss, chronic cholestasis and cirrhosis, and also of the immune-mediated necroinflammatory activity of small bile duct (chronic cholangitis) and of hepatocytes (interface and lobular hepatitis).5 The original description, however, is very detailed and practical application seems not easy.5 Herein we have proposed a practical and convenient version of this new histological staging and grading system.

First, we concisely described the convenient version of our new staging and grading system of PBC. Then, we assessed the system using interobserver agreement among a total of 28 liver pathologists, using 62 needle liver biopsy specimens.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Classification of the intrahepatic biliary tree

The intrahepatic biliary tree is classified into the intrahepatic large and small bile ducts according to their size and distributions in the liver.6,19 Intrahepatic small bile ducts, which are recognizable on microscopy, run parallel with hepatic arterial branch(es) and portal vein branch within portal tracts. They are classifiable into septal and interlobular bile ducts: the former has its own fibrous wall and its size is >80 µm, while the latter's size is <80 µm. Bile ductules are located at the periphery of portal tracts. In the present study the interlobular bile ducts, which are selectively damaged in PBC, are mainly examined.

New convenient version for the staging and grading of PBC

Staging

Three items (fibrosis, bile duct loss and deposition of orcein-positive granules) were used for staging. Fibrosis reflects a progression of chronic liver disease leading to cirrhosis (Fig. 1a) and is used for the histological staging of chronic hepatitis and non-alcoholic steatohepatitis (NASH).20–22 Bile duct loss is characteristic of PBC and a result of immune-mediated progressive bile damage (Fig. 1b).4,6,23 Orcein-positive granules are copper-binding proteins in lysosomes and their deposition reflects chronic cholestasis.5,24 These granules are detectable in the relatively early stages of PBC, and their deposition becomes more severe and extensive with the progression of the disease (Fig. 1c). These three items constitute the basis of this staging system.

image

Figure 1. Three histological items for evaluation of staging of primary biliary cirrhosis. (a) Portal tracts are fibrously enlarged with complete fibrous septa formation. Score 2 of fibrosis (Azan-Mallory staining, original magnification ×80. (b) Well-formed interlobular bile duct is lost in this portal tract (HE, original magnification ×200). (c) Orcein-positive granules are deposited in the periseptal hepatocytes of regenerative nodules (R). Score of 3 for deposition of orcein-positive granules. P, enlarged portal tract. (Orcein stain, original magnification ×200).

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The three items are scored as shown in Table 1. For fibrosis (F), a score of 0 means that there is almost no fibrosis or the fibrosis is confined to the portal tracts. A score of 1 means that the fibrosis extends beyond the portal area occasionally with incomplete septal fibrosis; a score of 2, that there is completely connecting septal fibrosis or bridging fibrosis with variable lobular distortion, and a score of 3, cirrhosis (extensive fibrosis with regenerative nodules). For bile duct loss (B), interlobular bile ducts were evaluated in well-formed portal tracts with evident hepatic arterial branches and portal vein branches.6,19,25 A score of 0 means interlobular bile ducts were discernible in all portal tracts in the specimens. A score of 1 and 2 means that bile duct loss is evident in <1/3 and in 1/3–2/3 of portal tracts, respectively. A score of 3 indicates that bile ducts were absent in >2/3 of portal tracts. For chronic cholestasis assessed base on the deposition of orcein-positive granules (C), a score of 0 means no deposition in periportal hepatocytes. A score of 1 indicates deposition in <1/3 of periportal hepatocytes of at least one portal tract, and a score of 3, deposition in >2/3 of periportal hepatocytes of all the portal tracts or fibrous septa. Anything between score 1 and score 3 is assigned a score of 2. After each of these items is scored, a total is obtained: a total score of 0 is stage 1 (no or minimum progression), 1–3 is stage 2 (mild progression), 4–6 is stage 3 (moderate progression), and 7–9 is stage 4 (advanced progression) (Table 2; first half ). If orcein staining is not available for the evaluation, the sum of the scores for fibrosis and bile duct loss is also applicable, as shown in Table 2 (second half) .

Table 1.  Scoring of primary biliary cirrhosis
 Scoring of fibrosis
Score 0No portal fibrosis, or fibrosis limited to portal tracts
Score 1Portal fibrosis with periportal fibrosis or incomplete septal fibrosis
Score 2Bridging fibrosis with variable lobular disarray
Score 3Liver cirrhosis with regenerative nodules and extensive fibrosis
 Scoring of bile duct loss
Score 0No bile duct loss
Score 1Bile duct loss in <1/3 of portal tracts
Score 2Bile duct loss in 1/3–2/3 of portal tracts
Score 3Bile duct loss in >2/3 of portal tracts
 Scoring of deposition of orcein-positive granules
Score 0No deposition of granules
Score 1Deposition of granules in several periportal hepatocytes in <1/3 of portal tracts
Score 2Deposition of granules in variable periportal hepatocytes in 1/3–2/3 of portal tracts
Score 3Deposition of granules in many hepatocytes in >2/3 of portal tracts
Table 2.  Staging of primary biliary cirrhosis
StageSum of score: fibrosis, bile duct loss and deposition of orcein-positive granules
Stage 1 (no progression)0
Stage 2 (mild progression)1–3
Stage 3 (moderate progression)4–6
Stage 4 (advanced progression)7–9
StageSum of score: bile duct loss and fibrosis
Stage 1 (no progression)0
Stage 2 (mild progression)1–2
Stage 3 (moderate progression)3–4
Stage 4 (advanced progression)5–6
Grading of necroinflammatory activity

Chronic cholangitis including CNSDC and chronic active hepatitis-like change are two essential and representative necroinflammatory and immune-mediated lesions of PBC (Table 3). In this system, chronic cholangitis including CNSDC typical to PBC (Fig. 2a) and also evident chronic cholangitis with mild periductal lymphoplasmacytic infiltration (Fig. 2b) was categorized into four grades according to the degree and distribution of cholangitis in the liver specimen. In contrast, interface hepatitis and lobular hepatitis were chosen for evaluation of HA (Fig. 2b,3) and their combined activity was categorized into four grades, respectively. Portal inflammation itself was not counted in the evaluation of HA.

Table 3.  Grading of necroinflammatory activities of primary biliary cirrhosis (original)
  1. CA, cholangitis activity; CNSDC, chronic non-suppurative destructive cholangitis; HA, hepatitis activity.

 Cholangitis activitys
CA 0 (no activity)No cholangitis, but mild duct epithelial damage may be present
CA 1 (mild activity)Chronic cholangitis in <1/3 of portal tracts
CA 2 (moderate activity)Chronic cholangitis in 1/3–2/3 of portal tracts
CA 3 (marked activity)Chronic cholangitis in >2/3 of portal tracts
 Hepatitis activity
HA 0 (no activity)No interface hepatitis, and no or minimum lobular hepatitis
HA 1 (mild activity)Focal interface hepatitis in a few portal tract(s), and focal necrosis in the parenchyma
HA 2 (moderate activity)Moderate interface hepatitis in several portal tracts, and variable lobular hepatitis
HA 3 (marked activity)Moderate–marked interface hepatitis in many portal tracts, or bridging or zonal necrosis, or both
image

Figure 2. (a) Chronic non-suppurative destructive cholangitis, typical to primary biliary cirrhosis (*) (HE, original magnification ×200). (b) Evident chronic cholangitis with mild–moderate periductal lymphocytic infiltration (*). Part of the limiting plate shows interface hepatitis affecting approximately 10 hepatocytes (arrow; HE, original magnification ×200.

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image

Figure 3. Interface hepatitis affecting approximately 20 hepatocytes at the interface in primary biliary cirrhosis. Grade 3 hepatitic activity (HE, original magnification ×100).

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Chronic cholangitis activity.  Grade 0 means absent or ambiguous bile duct damage. Mild biliary epithelial damage can also be found in grade 0. In grades 1–3, evident cholangitis including CNSDC is seen in <1/3, 1/3–2/3, and >2/3 of portal tracts in liver biopsy specimens, respectively (Table 3).

Analysis of interobserver agreement showed that the kappa of CA was low (0.110, slight agreement). This means that more instruction and guidance were recommended, and the grading of CA was revised as follows (Table 4). In grade 3, at least one damaged bile duct showing CNSDC is found in the liver biopsy specimen, irrespective of other types of bile duct damages in the liver specimen. CNSDC shows marked biliary epithelial damaged bile ducts surrounded entirely by marked duct-oriented lymphoplasmacytic infiltration (Fig. 2a). The damaged bile ducts partly or entirely surrounded by epithelioid granuloma (granulomatous cholangitis) are also included. In grade 1, one damaged bile duct showing evident chronic cholangitis is found in the liver biopsy specimen. Evident chronic cholangitis involves damaged bile duct entirely surrounded by mild–moderate, duct-oriented lymphoplasmacytes (Fig. 2b), and this type of cholangitis is also occasionally encountered in chronic viral hepatitis.26,27 Interlobular bile ducts surrounded by a small number of lymphoplasmacytes or adjacent to lymphoid cell infiltration in the portal tract are not regarded as evident chronic cholangitis. In grade 2, more than two bile ducts showing evident chronic cholangitis are present in the liver specimen, irrespective of other types of bile duct damage.

Table 4.  Grading of necroinflammatory activity of primary biliary cirrhosis (revised after analysis of interobserver agreement)
  1. CA, cholangitis activity; CNSDC, chronic non-suppurative destructive cholangitis; HA, hepatitis activity.

 Cholangitis activity
CA 0 (no activity)No cholangitis, but mild duct epithelial damage may be present
CA 1 (mild activity)One evident chronic cholangitis in the specimen
CA 2 (moderate activity)More than two bile ducts with evident chronic cholangitis
CA 3 (marked activity)At least one CNSDC in the specimen
 Hepatitis activity
HA 0 (no activity)No interface hepatitis, and no or minimum lobular hepatitis
HA 1 (mild activity)Interface hepatitis affecting 10 continuous hepatocytes in one portal tract or fibrous septa, and mild–moderate lobular hepatitis
HA 2 (moderate activity)Interface hepatitis affecting 10 continuous hepatocytes in more than two portal tracts or fibrous septa, and mild–moderate lobular hepatitis
HA 3 (marked activity)Interface hepatitis affecting 20 continuous hepatocytes in more than half of the portal tracts, and moderate lobular hepatitis, or bridging or zonal necrosis

Hepatitis activity.  Grade 0 means no interface hepatitis. Grades 1–3 mean the presence of interface hepatitis in <1/3, 1/3–2/3, and >2/3 of portal tracts, respectively. No or minimum lobular hepatitis is found in grade 0, mild–moderate lobular hepatitis may also be found in grade 1 or 2, and moderate lobular hepatitis with occasional zonal necrosis and/or bridging necrosis may also be found in grade 3. The combined activity of interface hepatitis with or without lobular hepatitis is categorized into four grades (Table 2).

Analysis of interobserver agreement showed that the kappa of HA was found to be low (0.197, slight agreement). More instruction and guidance were therefore recommended, and the grading of HA was revised as follows (Table 4). Grade 0 means no interface hepatitis. Grade 1 and grade 2 mean the presence of interface hepatitis affecting approximately 10 continuous hepatocytes at the interface (Fig. 2a) of one portal tract or fibrous septa, and of more than two portal tracts or fibrous septa in the specimen, respectively. Grade 3 means the presence of interface hepatitis affecting >20 continuous hepatocytes at the limiting plate (Fig. 3) of many portal tracts or fibrous septa in the specimen. Entrapment of hepatocytes in the widened portal tract is also found in grade 3 HA. No or minimum lobular hepatitis is found in grade 0, mild–moderate lobular hepatitis may also be found in grade 1 or 2, and moderate lobular hepatitis in grade 3. Occasional zonal necrosis and/or bridging necrosis is regarded as grade 3.

Enrollment of observers

The observers were composed of 28 doctors (KH, MS, AN, TU, KS, FK, TF, KT, MI, KW, MN, HM, HH, MK, HY, JH, SA, TM, HA, AMH, TM, HS, HO, TCC, EU, JHK, YNP, WT). Four of them were pathologists based overseas, while the remainder were Japanese pathologists including internists with a special interest in liver biopsy diagnosis. Two pathologists (YN and YZ) acted as controllers in the present study, and were not enrolled in the panel of observers.

Case selection and liver specimens

A total of 62 needle liver biopsy specimens from 62 patients with PBC who fulfilled clinical, serological or histological criteria,1,2 were evaluated (58 women, four men, aged 45–76 years; mean, 62 years). Patients with known causes of liver disease such as NASH were excluded. None of the PBC patients had serological markers for HCV or HBV. The 62 cases were selected consecutively from the files of Kanazawa University Hospital and Department of Human Pathology, Kanazawa, Japan, covering 1993–2002. These patients were not receiving specific therapy, such as UDCA, corticosteroids or d-penicillamine. More than five portal tracts were identifiable in all of the liver biopsies. All PBC patients were serologically positive for AMA. The specimens were immediately fixed in formalin and embedded in paraffin, and >10 sections 3 µm thick were cut from each block for HE, reticulin and orcein staining. The orcein staining was used to evaluate the deposition of copper-binding proteins in hepatocytes.24 The availability of histological sections in these cases for detailed histological observations was checked by YZ and YN.

All specimens were scanned to make virtual slides using VASSALO (Claro, Yokohama, Japan). Scanning was performed using a 20× field lens. DVD-ROMs containing all virtual slides were sent to a panel of 28 pathologists with a questionnaire covering the following items. No clinical history or laboratory data were available to the observers.

Data analysis

Interobserver agreement was estimated regarding the score of fibrosis, bile duct loss and deposition of copper-binding protein, and that of chronic CA and HA. The former three are regarded to reflect staging and the latter two, necroinflammatory activity.5 This interobserver agreement was evaluated according to the concordance rate (%) and kappa. Interpretations for kappa have been described previously, that is, <0.00, poor agreement; 0.00–0.20, slight agreement, 0.21–0.40; fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; and 0.81–0.10, almost perfect agreement.28

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Applicability of this version

All participants were able to apply this version in all 62 needle liver biopsies of PBC.

Two examples of the staging and grading of PBC

All of the histopathological items were examined in 62 needle biopsy specimens. The scores of three histological items for staging (fibrosis, bile duct loss and deposition of orcein-positive granules) and scores of grading of cholangitis and hepatitis for 62 cases of PBC evaluated by two pathologists are shown in Table 5. For staging, the majority of the cases examined here were of stage 2, and the majority of fibrosis, bile duct loss and the deposition of copper binding proteins were scored as 0 or 1. For grading, the majority of CA and HA were either grade 1 or 2.

Table 5.  Example of staging and grading of 62 needle liver biopsy specimens of PBC by two examiners
  1. CA, cholangitis activity; HA, hepatitis activity; PBC, primary biliary cirrhosis.

Examiner A
 Score 0Score 1Score 2Score 3
CA (no. cases)10281410
HA (no. cases)931148
StagingStage 1Stage 2Stage 3Stage 4
No. cases73898
 Score 0Score 1Score 2Score 3
Bile duct loss (no. cases)13231610
Fibrosis (no. cases)262484
Deposition of orcein positive granules (no. cases)43838
Examiner B
 Score 0Score 1Score 2Score 3
CA (no. cases)1252511
HA (no. cases)841112
StagingStage 1Stage 2Stage 3Stage 4
No. cases64268
 Score 0Score 1Score 2Score 3
Bile duct loss (no. cases)113867
Fibrosis (no. cases)1728116
Deposition of orcein positive granules (no. cases)411227

Interobserver agreement for staging of PBC

As shown in Table 6, in the assessment of staging as a whole, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. Among the four stages, kappa was lowest in stage 3. As for the individual items used for the staging, kappa was 0.353 (fair agreement) and the concordance rate was 55.6% for fibrosis. For bile duct loss, kappa was 0.228 (fair agreement) and concordance rate was 44.3%. For deposition of copper-binding protein granules, kappa was 0.409 (moderate agreement) and concordance rate was 67.1%. Among the four scores, kappa was also lowest in score 2 for all three items: 0.090 for bile duct loss, 0.077 for deposition of orcein positive granules, and 0.172 for fibrosis.

Table 6.  Interobserver agreement for staging of PBC (kappa)
StagingStage 1 (total score 0)Stage 2 (1–3)Stage 3 (4–6)Stage 4 (7–9)Total
 0.1740.3500.1340.2700.385
Grading (activity)Score 
 CACA 0CA 1CA 2CA 3Total
0.1090.1720.0520.1090.110
 HAHA 0HA 1HA 2HA 3Total
0.1980.2110.1100.140.197
Histologic findings used for stagingScore 0Score 1Score 2Score 3Total
  1. CA, cholangitis activity; HA, hepatitis activity; PBC, primary biliary cirrhosis.

Bile duct loss0.2250.2020.0900.1890.228
Deposition of orcein-positive granules0.4450.1700.0770.2790.409
Fibrosis0.3360.2650.1720.2270.353

Interobserver agreement for grading of necroinflammatory activity of PBC

As shown in Table 6, in the assessment of CA, kappa was 0.110 (slight agreement) and concordance rate was 36.9%. For the assessment of HA, kappa was 0.197 (slight agreement) and concordance rate was 47.0%. Among the four grades, kappa was lowest in grade 2 in CA and also HA.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the present study we have proposed a concise version of our new histological staging and grading system for PBC,5 and this version was intended to apply to needle liver biopsies. We then conducted an analysis of interobserver agreement. The results obtained can be summarized as follows: (i) all participants were able to apply this version in all needle biopsies of PBC distributed; (ii) Interobserver agreement over the degree of staging was ‘fair’, and (iii) interobserver agreement for CA and HA was ‘slight’, less than our expectation.

For the staging of PBC, Scheuer's system is used worldwide.10,11 In this system, PBC is histologically classified into four stages using characteristic histological features: stage 1 is characterized by florid duct lesions or CNSDC, and in stage 2 there is a characteristic proliferation of bile ductules. Stage 3 is characterized by fibrosis or scarring, and stage 4, by cirrhosis. In our experience, however, these characteristic features occur variably and heterogeneously in the liver during the long course of PBC, and stage 1 and/or stage 2 lesions and stage 3 and/or stage 4 lesions are found in the same liver. In Ludwig's system,13 the histological features used for the staging of chronic active hepatitis are applied to the staging of PBC: portal hepatitis, periportal interface hepatitis, bridging necrosis or bridging fibrosis, and cirrhosis. Unfortunately, bile ductal lesions and cholestatic changes, which are very important and characteristic features of PBC, are not evaluated at all.

Different from other chronic liver diseases such as chronic hepatitis and NASH,20–22,29 PBC has at least two features characterizing disease progression: bile duct loss and its consequences and hepatocellular damage and its consequences.5,8,30–33 These two factors should be included in a staging system for PBC. Accordingly, we adopted three features reflecting the progression of PBC in our system: fibrosis, bile duct loss and the deposition of copper-binding proteins. In PBC, fibrosis reflects continuing hepatocellular damage due to diverse mechanisms such chronic cholestasis and hepatitis-related hepatocellular necrosis, bile duct loss is the result of chronic immune mediated cholangitis, and the deposition of copper binding proteins reflects chronic cholestasis due to bile duct loss.24 These three lesions are very important pathological features reflecting the progression of PBC.

The degree of fibrosis seems to constitute a basis for the staging of various chronic liver diseases such as chronic hepatitis and NASH.20–22,29 In PBC, however, there are many reports that histological changes including fibrosis are heterogeneous in a whole liver, and sampling errors have been noted in staging using needle liver biopsies. Use of multiple and heterogeneous histological features for disease progression might prevent or reduce sampling errors in the histological evaluation of PBC. Although the kappa of the new staging version proposed here was 0.385 (fair agreement), it seems plausible that this version combining three histological items to minimize the sampling errors inherent in PBC liver histology is superior to other staging systems reported so far, and this version reflects both the progression of bile duct destruction and the progression of fibrosis to cirrhosis resulting from hepatocellular damage due to chronic CA and HA. By becoming more familiar with this new version of staging, the kappa of staging would become higher, although it was lower than that for deposition of orcein-positive granules (0.409) and was comparable to that for fibrosis (0.353) in the present study.

In the evaluation of chronic progressive liver diseases, the grade of necroinflammatory activity inherent to these diseases should be carefully assessed. The concept of necroinflammatory activity reflecting the autoimmune-mediated pathology of PBC is, however, lacking or insufficient in classical staging systems available.9–14 In PBC, CA, reflecting bile duct damage, and HA, reflecting hepatocellular damage, are regarded as fundamental immunopathological and necroinflammatory processes. CA was evaluated according to the degree and character of chronic cholangitis, and the degree and extent of two histological features, interface hepatitis and lobular hepatitis, were assessed for the grading (activity) of HA. It was found in this analysis of interobserver agreement that kappa was unexpectedly low in CA (0.110) and also in HA (0.197). This suggests that the assessment process of necroinflammatory activity may be different in different institutions and also among pathologists. We therefore added more instruction and guidance for the grading of necroinflammatory activity of CA and HA, and in Table 2 (revised after analysis of interobserver agreement). Although this revision would be more easily applicable in the assessment of grading of CA and HA, more practice and experience are mandatory to polish this staging and grading system.

In conclusion, this new staging and grading system of PBC can be applied to routine histological sections of liver biopsies. Although it may be a little burdensome for pathologists, we believe that this method will provide more objective information from liver biopsy specimens of PBC to clinicians, and this grading and staging system could be applicable to the evaluation of therapeutic approaches in PBC.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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