Histological reassessment of the role of bridging fibrosis in the angioarchitectural features associated with lobular distortion of the liver in chronic viral hepatitis.

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Hepatology Research 2016; 46: E70–E78

doi: 10.1111/hepr.12531

Original Article

Histological reassessment of the role of bridging fibrosis in the angioarchitectural features associated with lobular distortion of the liver in chronic viral hepatitis Hiroshi Hano,1,2 Satoshi Takasaki,1 Yasuhiko Endo,3 Tohru Harada,1 Kazumasa Komine2 and Yujin Koike3,4 1

Department of Pathology, 2Division of Pathology Clinical Service, Jikei University School of Medicine, Tokyo, Japan, Division of Diagnostic Pathology, Itabashi Chuo Medical Center, Tokyo, and 3Clinical Pathology, Fuji City General Hospital, Fuji, Japan

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Aim: To reassess the role of bridging fibrosis in the lobular distortion of the liver from an angioarchitectural aspect. Methods: Two tissue samples obtained from surgically resected livers with chronic hepatitis and one obtained from an autopsy case with chronic hepatitis were used for the threedimensional observation of angioarchitecture by histological reconstruction. Results: Samples showed bridging fibrosis with various degrees of severity, without cirrhotic changes. Two different types of portal–portal bridging fibrosis were found. In our samples, the type that developed in the bifurcation region of the portal tracts was more common than the type observed between the distal portions originating from different parent portal tracts. The angioarchitecture tended to be generally maintained in these lesions. Concerning portal–central bridging fibrosis, two types were observed. One type developed in the lesion with partial paucity of the third-step portal branches in

INTRODUCTION

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INCE THE INTRODUCTION of liver biopsy, the architectural distortion of the liver lobule has been discussed in terms of the progression of chronic hepatitis (CH) to liver cirrhosis (LC).1–3 Its histological hallmarks involve fibrosis, such as periportal fibrosis, or fibrous septa or bridging fibrosis (BF), which are used in semiquantitative scoring systems for CH.4–7 We previously reported that the lobular angioarchitecture, which provides the basic framework of the lobule, showed various pathological changes at different foci, which were closely related to Correspondence: Professor Hiroshi Hano, Department of Pathology, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. Email: [email protected] Received 6 January 2015; revision 16 April 2015; accepted 20 April 2015.

© 2015 The Japan Society of Hepatology

the portal tract at a relatively early stage of chronic hepatitis. The other type developed in an advanced lesion with a complete loss of the normal angioarchitecture of the parenchymal portion of the portal veins. The former was likely developed after largescale necrosis, such as bridging necrosis, while the latter was presumed to be attributable to portal vein damage associated with long standing chronic inflammation.

Conclusion: As has been previously noted regarding lobular angioarchitecture, portal–central bridging fibrosis clearly affects the lobular structure of the liver more than portal–portal bridging fibrosis. Therefore, portal vein damage may be a critical event in the eventual distortion of the lobular structure. Key words: angioarchitecture, bridging fibrosis, chronic viral hepatitis, liver cirrhosis, lobular distortion, three-dimensional observation

lobular architectural distortion in a case with CH.8 In particular, these changes with porta–portal BF (PP-BF) and portal–central BF (PC-BF) were indicated to directly cause various degrees of lobular angioarchitectural framework distortion of the lobule. These findings once again highlighted the key role of BF in the process of lobular distortion. However, an examination of BF in various states would be necessary in order to further elucidate the process of lobular distortion leading to LC. Therefore, we investigated the angioarchitectural changes of BF lesions three-dimensionally in cases with CH in both the relatively early and advanced stages, and discussed the effects of BF on lobular architecture on the basis of the results obtained. The reason why we employed the method of histological graphic reconstruction was because it was necessary to observe tissue samples three-

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dimensionally in order to accurately grasp the changes of the lobule having a three-dimensional structure. Twodimensional histological examination is limited on this point. Additionally, study results were also expected to contribute to the accurate histological assessment and staging of CH.

METHODS

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WO SAMPLES OF surgically resected livers diagnosed as hepatocellular carcinoma with chronic viral hepatitis and one autopsy liver tissue sample diagnosed as CH were examined. The tissue blocks from the surgical cases were taken from a portion of the liver deemed to be sufficiently distant from the tumor. Also, we used these samples which were at different stages of the disease and showed common histological features to reduce sample selection bias as much as possible. The tissue blocks were fixed in 10% formalin and embedded in paraffin. Sections were stained with hematoxylin–eosin, Masson-trichrome and silver impregnation for histopathological evaluation. In addition, serial sections were cut at 4 μm and stained with Massontrichrome for three-dimensional observation using the tissue reconstruction method. For tissue reconstruction, microscopic images captured using a Nikon Digital Sight DS-Fis camera and NIS Elements 4.00 (Nikon, Japan) were printed, and the outlines of the essential architectural elements were drawn serially by hand on sheets of tracing paper. The reconstruction was completed via step-by-step overlapping of the outlines. As we focused mainly on the portal vein and venous drainage systems in the current study, the arterial and biliary systems, especially the latter, were simplified or omitted if necessary. Henceforth, we use the terminology and concepts defined by Matsumoto et al. with reference to the angioarchitecture of a normal liver.9,10 Briefly, the portal system is divided into conducting and parenchymal portions. The portal veins of the latter are distinguished by three steps referred to as the first-, second- and thirdstep branches, and provide the angioarchitectural framework of the classic hexagonal liver lobule. The central vein and its small branches are situated within the lobule. The lobule is made up of six to eight primary lobules. The current study was approved by the ethics committee of the Jikei University School of Medicine.

RESULTS

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LINICAL DATA AND histological staging following Scheuer’s system5 are shown in Table 1. The first case

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Table 1 Clinical data and histological staging following Scheuer’s system Case (IU/L) 1 2 3

Age/sex

CD

AST/ALT

Scoring

56/M 59/M 63/M

NBCH, HT, SD CH-C, HCC CH-C, HCC

40/36 29/34 Uncertain

Stage 2 Stage 2 Stage 2

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CD, clinical diagnosis; CH-C, chronic hepatitis C; HCC, hepatocellular carcinoma; NBCH, non-B chronic hepatitis, HT, hypertension; Scoring, a scoring system for fibrosis and cirrhosis according to Scheuer’s scoring system.

was a 56-year-old Japanese man with CH under observation who suddenly died of cardiac arrest. Autopsy was performed 40 min after death and revealed severe cardiomegaly (510 g) due to unknown etiology and chronic active hepatitis. The liver tissue sample showed a general preservation of the fundamental lobular structure, although BF was occasionally observed. The portal tracts were slightly enlarged with fibrosis and inflammatory cell infiltration, sometimes associated with lymphoid aggregates and mild interface hepatitis. Focal necrosis was sparsely distributed in the lobule (Fig. 1a). CH with mild activity was assumed to be compatible histologically with chronic hepatitis C (CH-C), as neither hepatitis B surface antigen nor core antigen was detected immunohistochemically. The histological reconstruction at a low magnification was 348 μm in thickness (a total of 87 sections) and covered the range from the terminal branches of the conducting portion to the second-step branches of the parenchymal portion of the portal vein and the corresponding hepatic vein (Fig. 1b). Figure 1(a) corresponds approximately to the reconstructed area. The spatial arrangement of the first- and second-step branches of the portal veins and corresponding hepatic veins tended to be well preserved (representative ranked branches are indicated by symbols in Fig. 1b and subsequent figures). However, PP-BF and PC-BF were observed to have developed quite often and beyond our expectations based on the histological features of a single section (Fig. 1b). In addition, the histological graphic reconstruction suggested that it was always not easy to accurately identify PP-BF and PCBF by two-dimensional morphology. The lesions with BF suggested that lobular distortion had already begun. The enlarged histological reconstruction of a part of Figure 1(b) (336-μm thick [a total of 84 sections]) is shown in Figure 2(a). Although a PC-BF lesion with the portal veins in a disordered fashion was observed in the upper-right quadrant, attention was focused on the two types of PP-BF


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Figure 1 Histology and histological reconstruction of the first case. (a) Photomicrograph at a low magnification shows that the basic lobular architecture is generally preserved. BF is occasionally observed (Masson-trichrome). (b) Histological reconstruction at a low magnification. The spatial arrangements of the first- and second-step branches of the portal vein and the corresponding hepatic veins are well preserved. However, PP- and PC-BF have developed in some places. 1, first-step branch; 2, second-step branch; BF, bridging fibrosis; CP, conducting portion of the portal vein; PC, portal–central bridging fibrosis; PP, portal–portal bridging fibrosis.

Figure 2 Histology and histological reconstruction of PP-BF of the first case. (a) Histological reconstruction at a medium magnification shows two types of PP-BF. The BF indicated as PPa develops in the bifurcation portion of the portal tracts. PPb indicates the BF developing between the distal portions derived from different portal tracts. Angioarchitecture of the portal vein shows a tendency to be preserved in these lesions at this magnification. In the right-upper quadrant with PC-BF, portal trees demonstrate a distorted spatial arrangement. (b) Histological features of PPa show the BF with liver cells left behind between the upper and lower portal tracts (Masson-trichrome). (c,d) Serial histological features of PPb show that portal tracts X and Y are connected by a delicate fibrous band (Masson-trichrome). 1, first-step branch; 2, second-step branch; 3, third-step branch; BF, bridging fibrosis; CP, conducting portion of the portal vein; PC, portal–central bridging fibrosis; PPa and PPb, portal–portal bridging fibrosis; X and Y, portal tracts.



lesions present and the differences in their morphogenetic processes. One of the lesions was developing in a bifurcation portion of the portal tracts (PPa in Fig. 2a) and the other was in the region between the distal portions originating from different parent portal tracts (PPb in Fig. 2a). As the former PP-BF was obscured in the graphic reconstruction in Figure 2(a) due to the direction of its appearance, we show a histological picture from one of the serial sections demonstrating two dividing portal tracts connected by fibrosis with liver cells left behind (Fig. 2b; see also Fig. 4c). The latter (PPb in Fig. 2a) showed delicate BF, as demonstrated in serial histological sections in Figure 2(c,d). The branching pattern of the portal vein was generally preserved in these lesions. Histological reconstructions of the two different regions with PC-BF were conducted. The first reconstruction at a moderate magnification was 260 μm in depth (a total of 65 sections; Fig. 3a). PC-BF was observed in the center of Figure 3(a) (arrow). The angioarchitecture of the parenchymal portion of the portal vein was well preserved as a whole throughout the figure (note the

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preserved branching pattern). This represented good preservation of the lobular structure in general. In contrast to the abundant third-step branches present in most parts of the specimens, the PC-BF lesion showed a paucity of third-step branches (asterisk in Fig. 3a). The central veins showed localized positional deviation in places, but their branching pattern tended to be almost completely maintained. The second reconstruction at a high magnification was 336 μm in thickness (a total of 84 sections; Fig. 3b). Figure 3(c) corresponds to the second reconstructed area. Similar histological features to those seen in Figure 3(a) were also found in this reconstruction. In particular, a paucity of the third-step branches was noted in the PC-BF lesion (asterisk in Fig. 3b). On the other hand, the central vein was thought to be almost completely intact. Therefore, the paucity of the third-step branches was thought to be closely related to the development of PC-BF. The second case was a 59-year-old Japanese man with CH-C who underwent hepatectomy for hepatocellular carcinoma. He was also positive for hepatitis B surface

Figure 3 Histology and histological reconstruction of PC-BF of the first case. (a) Histological reconstruction with PC-BF observed in the center. Note a paucity of third-step branches (asterisk) in the PC-BF lesion. With the exception of this lesion, the number and branching pattern of third-step branches are well preserved in the portal tracts. (b) Histological reconstruction with PC-BF in a different area from (a) at a high magnification. As in the previous reconstructed area, the PC-BF lesion lacks third-step branches of the portal vein (asterisk), contrasting sharply with the abundant third-step branches in other portions. (c) Photomicrograph of the reconstructed area shown in (b) (Masson-trichrome). 1, first-step branch; 2, second-step branch; 3, third-step branch; BF, bridging fibrosis; HV, hepatic vein; PC, portal–central bridging fibrosis; PV, portal vein.


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antibodies. The histology of the liver sample showed the mild-to-moderate fibrously enlarged portal tracts with relatively dense infiltration of lymphocytes and occasional PP- or PC-BF, which suggested the beginning of lobular distortion. Necroinflammatory lesions such as interface hepatitis and focal necrosis were mild (Fig. 4a). Two lesions with BF were selected for histological reconstruction. The first histological reconstruction at a moderate magnification was 212 μm in thickness (a total of 53 sections), covered the range from the distal part of the conducting portion to the third-step branch of the parenchymal portion of the portal veins (Fig. 4b), and contained PP-BF lesions (PPa and PPb in Fig. 4b). The histological features of PPa are shown in Figure 4(c), where fibrosis replaced the hepatocytes and expanded in the forked portion formed by a bifurcation of the portal tracts. The PP-BF indicated by PPb was obscured in the graphic reconstruction depicted in Figure 4(b) for the same reason as the PP-BF in Figure 2(a). Although the branching pattern of the thirdstep branches was distorted by the loss of the normal spatial arrangement in the distal part of the PPb lesion (Fig. 4b;


compare with Fig. 3a,b), many branches, except for a few buried in fibrosis, ran into the sinusoids to maintain the parenchymal tissue. Furthermore, the arteries were relatively developed and were located around the portal veins. No PC-BF was found in this area. Additionally, the central vein was almost completely preserved in the lower-right quadrant of Figure 4(b), although its distal branch was partially involved in PC-BF (arrow). The second histological reconstruction of the second case at a moderate magnification was 148μm thick (a total of 37 sections) and is shown in Figure 5(a). The severely damaged portal veins and PC-BF were noted in the graphic reconstruction (PC with arrow in Fig. 5a). The first-step and second-step branches of the portal veins demonstrated segmental stenosis (black arrows in Fig. 5a), and the two second-step branches finally disappeared on their path through the portal tract (red arrows in Fig. 5a). Additionally, the central vein located in the lower-left part of the figure was preserved and almost intact. Figure 5(b) is the enlarged reconstruction of the central lower part (80μm thick [a total of 20 sections]) showing the disappearance

Figure 4 Histology and histological reconstruction of the second case. (a) Photomicrograph at a low magnification shows mild-tomoderate fibrously enlarged portal tracts with relatively dense infiltration of lymphocytes and PP-BF. (b) Histological reconstruction at a medium magnification containing the conducting portion and its dividing portal vein branches. Two PP-BF, as indicated by PPa and PPb, are seen. Both BF are located in the bifurcation portion of the portal tracts. Although the portal angioarchitecture is distorted to some extent in the distal part of the portal tracts in the lower-left quadrant, many third-step branches run into sinusoids. Arteries develop and run around the portal veins. Although the distal branch is involved in PC-BF, the branching pattern of the central vein was preserved in the lower-right quadrant. (c) Photomicrograph of PPa shows that fibrosis evolves in the forked area formed by dividing portal tracts (Masson-trichrome). 1, first-step branch; 2, second-step branch; 3, third-step branch; BF, bridging fibrosis; CP, conducting portion of the portal vein; PC, portal–central bridging fibrosis; PPa and PPb, portal–portal bridging fibrosis.


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Figure 5 Histological reconstructions of the second case. (a) Histological reconstruction of the lesion with PC-BF (PC with arrow) at a medium magnification. First- and second-step branches show stenosis (short black arrows) and two second-step branches are disrupted (red arrows). (b) Histological reconstruction at a high magnification (enlarged reconstruction of the lower part of [a]). The portal vein is abruptly disrupted (red arrow). Third-step branches are not found. Unidentified vessels are seen (Vsl). (c) Histological reconstruction at a high magnification of the central left part of Figure 5(a). The portal vein is apparently disrupted shortly after branching (red arrow). Third-step branches are not found in the PC-BF lesion (asterisk). Arteries are relatively developed. 1, first-step branch; 2, second-step branch; 3, third-step branch; BF, bridging fibrosis; PC, portal–central bridging fibrosis; Vsl, unidentified vessel.

of the portal veins. It was evident that the portal vein was moderately dilated following stenosis and disappeared in the stroma without any branching. An absence of PC-BF in this area indicated that a certain mechanism operated to compensate for the loss of the portal flow to the parenchyma. Two vessels are drawn with a dotted line (Vsl in Fig. 5b). Although they were suspected to be severely damaged portal veins that had lost their connections to the proximal portion, evidence to support this assertion was lacking. The enlarged histological reconstruction for the PC-BF lesion (160μm thick [a total of 40 sections]) is shown in Figure 5(c). Just as in the previous lesion, the portal vein was disrupted on the path (red arrow in Fig. 5c), resulting in the loss of abundant third-step branches. Close approximation and delicate fibrous connections developed between the central vein and the portal tract in the area with a paucity of portal veins. In addition, a complicated network of arteries developed in this lesion. The third case was a 46-year-old Japanese man with CHC who underwent an operation for hepatocellular carcinoma. Although this case has been previously reported with regard to the alteration of lobular architecture in CH,8 the liver tissue sample was further examined to focus on BF. Histological features showed the portal tracts with moderate-to-marked fibrous expansion and dense lymphoid cell aggregation, and moderate parenchymal necroinflammatory lesions. PP- and PC-BF were relatively frequent. The basic lobular architecture was presumed to

be distorted to some extent (Fig. 6a). One complicated lesion with BF representative of an advanced lesion in CH was selected for histological reconstruction as a representative advanced lesion in CH (628μm thick [a total of 157 sections]; Fig. 6b). In the portal tracts X and Z, the branching pattern of the parenchymal portion of the portal vein was generally preserved, although some branches ran parallel and a few third-step branches were buried in the stroma. In this situation, the parallel traveling course of the portal veins was thought to be an abnormal spatial arrangement as a consequence of portal inflammation and fibrosis. These portal veins without stenosis were considered not to have great effect on the portal flow. PP-BF was recognizable between portal tracts Y and Z. Portal tract Y showed the most striking features in that the parenchymal portion of the portal vein completely lost its normal branching pattern, ran randomly and disappeared into the stroma. The third-step branches running into sinusoids were difficult to locate. Thus, the portal tracts with severely damaged portal trees also caused PC-BF.

DISCUSSION

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N THE CURRENT study, we focused on and reassessed the BF lesions that are considered to play a critical role in the process of lobular distortion, and investigated them from the angioarchitectural perspective. BF is generally classified into PP-, PC- and central–central-BF.4–7,11 It


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Figure 6 Histology and histological reconstruction of the third case. (a) Photomicrograph at a low magnification shows the portal tracts with moderate-to-marked expansion and dense lymphoid cell aggregation. Localized BF indicates lobular distortion to some extent (Masson-trichrome). (b) Histological reconstruction at a high magnification. PP-BF develops between portal tracts Y and Z. PC-BF develops in portal tract Y. Angioarchitecture is well preserved in portal tracts X and Z, although there is a mild abnormality of the course of the distal portal veins. In contrast, the parenchymal portion of the portal tree shows a severely distorted branching pattern and almost all distal branches have disappeared in the connective tissue in portal tract Y. 1, first-step branch; 2, second-step branch; 3, third-step branch; BF, bridging fibrosis; CP, conducting portion of the portal vein; PC, portal–central bridging fibrosis; X, Y and Z, portal tracts.

should be noted that central–central-BF was not found in the current study. However, two types of PP-BF were found. One of the types was BF that developed in a bifurcation portion (forked region) of the portal tracts, and the other developed in the region between the distal portions originating from different parent portal tracts. The former type seemed to be more common than the latter type, although not in the advanced stage. It is conceivable that PP-BF is caused by fibrosis following prolonged chronic necroinflammatory reactions, especially interface hepatitis.3,7,11 The portal branches of the parenchymal portion are thought to be much less damaged in relatively early PP-BF lesions. These fibrous bridging lesions are shown diagrammatically in Figure 7(b). Figure 7(a) shows the normal lobular angioarchitecture. It is conceivable that the influence of two types of PP-BF on the portal blood flow depends on the severity of damage of the portal veins involved in the lesion and there is little essential difference between them as to the portal blood flow disturbance. The diagram indicates that these BF lesions do not greatly affect the basic lobular structure at this stage.5,11,12 However, damage to the portal branches of the parenchymal portion may progress to the level of severity exemplified by the PCBF lesion of the third case. Two types of PC-BF were observed in the current study. One type was accompanied by a paucity of a group of


the third-step portal branches, as was seen in the first and second cases, and the other type was accompanied by the complete loss of a normal angioarchitecture of the parenchymal portal veins, as was seen in the third case. With regard to the morphogenesis of the former type, it is possible that relatively large-scale necrosis, such as bridging necrosis, occurs first, and that the necrotic lesion subsequently collapses along with the damaged third-step branches and close approximation of the central vein to the portal tract prior to the development of a fibrous connection (i. e. PC-BF).1,3,11 It has been suggested that bridging or multilobular hepatic necrosis is a significant histological factor leading to the development of LC, as LC develops frequently in patients with CH with such lesions.12–14 It is important to note the possibility that this type of PCBF occurs in the relatively early stages of CH. As regards the morphogenesis of the latter type, it is assumed that prolonged chronic inflammation damages portal veins so severely as to cause the loss of the normal portal angioarchitecture and simultaneous fibrosis expanding to the central vein. To be specific, the partial lobular parenchyma, which is irrigated by the damaged portal veins, is thought to be lost and replaced by fibrosis resulting in the development of PC-BF. A diagram of PC-BF using a case with a paucity of the distal portal branches as an example is shown in Figure 7(c). This diagram indicates that


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Figure 7 Schematic diagram of the influence of PP- and PC-BF on lobular structure. (a) Normal spatial arrangement of portal and hepatic central veins in the liver lobule. (b) PP-BF. PPa indicates PP-BF developing in a bifurcation portion of the portal tract. PPb indicates PP-BF developing between distal portions of different portal tracts. (c) PC-BF. The portal tract with a portal vein devoid of branches is fibrously connected to the hepatic vein. PC-BF affects the lobular structure more severely than PP-BF. BF, bridging fibrosis; PC, portal–central bridging fibrosis; PP, portal–portal bridging fibrosis; PPa and PPb, portal–portal bridging fibrosis.

PC-BF has a greater impact on the basic lobular structure than PP-BF.11 This is because of the following reasons. The classic hexagonal lobule (secondary lobule) is made up of six to eight primary lobules, the most elementary parenchymal units, each of which maintains a cone-shaped parenchyma with the unit inflow by the third-step branches and its corresponding venous pole.9,10 As PP-BF involves the periphery of the lobule, the angioarchitectural framework of the lobule is less likely to be damaged. In contrast, PC-BF is considered to give a great influence on the basic lobular structure because it occurs in association with parenchymal loss and fibrosis of the primary lobules. Although our description has been focused on the lobular distortion until now, we would like to summarize the damage to the portal vein here. They generally showed stenosis of various severity, a disruption, decrease in number, and abnormal running course in inflamed or fibrotic area. Some ran while increasing the degree of stenosis, and finally disappeared. Namely, it was impossible to trace them three-dimensionally. Fresh or organized thrombi were not seen in those lesions as well as vascular destructive changes with light microscopy. The pathogenesis of portal vein damage is still unknown. It is conceivable that segmental stenosis and the subsequent disruption of the portal vein more or less impede the portal flow. Although these changes are

supposed to be related to portal hypertension, the exact estimation related to portal hypertension is a future problem to be solved. As the disease progresses, it is conceivable that the lesions with PP- and PC-BF increase in number and connect with each other to form fibrous septa that are larger in size. This suggests that the lobular angioarchitecture progressively disintegrates due to the damage to the portal veins throughout the liver. On the other hand, the central and hepatic veins were generally intact and showed almost normal branching patterns in the cases in the current study. Furthermore, obstructions of the central and hepatic veins were not found. Therefore, it would seem that these veins are not easily damaged in the stage of chronic viral hepatitis without precirrhotic or cirrhotic changes. The findings from the current study, which focused on chronic viral hepatitis, are not consistent with the view of pathogenesis LC posited by Wanless et al., which asserts that the obstruction of the hepatic terminal venules and hepatic vein and accompanying congestion play an important role in parenchymal injury throughout the whole process from an early chronic liver disease to LC.15–17 The “parenchymal injury” described above are called parenchymal extinction lesions (PEL). While lesions with PEL expand and are replaced by fibrosis, surviving parenchymal tissue regenerates expansively with the consequence of regenerative nodule


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formation. However, actual structural changes of the lobule have not been made sufficiently clear in the process from chronic liver disease to LC, although the diagram is shown. In contrast, our results indicate basically that the parenchyma, which is irrigated by blood flow from the damaged portal veins, is difficult to survive and finally replaced by fibrosis in chronic viral hepatitis. In parallel with this, distortion of the angioarchitectural framework and lobular structure is considered to begin. However, Japanese researchers reported the pathological changes of the venous drainage system in LC.18,19 In a previous study, we also observed the changes to the hepatic and central veins in the localized, remarkably damaged lesion.8 Collectively, these observed changes indicate the occurrence of damage to pre-existing veins in the advanced stage. The results of the current study, which focused on the changes in angioarchitectural lobular framework, also support the results of prior studies that highlighted the importance of BF in the process of lobular distortion. We would again like to emphasize that portal vein damage is the most critical event in the process of lobular distortion and rebuilding. This indicates that vascular protection may be among the potential therapeutic strategies for CH. Additional investigation will be necessary in order to better understand histological variations of BF and elucidate the formal pathogenesis of LC, although we have clarified basic pathological changes of BF and the effect on the lobular architecture from an angioarchitectural perspective.


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ACKNOWLEDGMENTS

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E THANK THE staff members of the Department of Pathology, Jikei University School of Medicine, for their technical assistance.

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histological activity in asymptomatic chronic active hepatitis. Hepatology 1881 1: 431–5. Scheuer PJ. Classification of chronic hepatitis: a need for reassessment. J Hepatol 1991 13: 372–4. Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995 22: 696–9. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995 19: 1409–17. Hano H, Takasaki S. Three-dimensional observation on the alterations of lobular architecture in chronic hepatitis with special reference to its angioarchitecture for better understanding of the formal pathogenesis of liver cirrhosis. Virchows Arch 2003 443: 655–63. Matsumoto T, Komori R, Magara T et al. A study on the normal structure of the human liver, with special reference to angioarchitecture. Jikeikai Med J 1979 26: 1–40. Matsumoto T, Kawakami M. The unit concept of hepayic parenchyma-a reexamination based on angioarchitectural studies. Acta Pathol Jpn 1982 32: 285–314. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer P. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994 19: 1513–20. Cooksley WGE, Bradbear RA, Robinson W et al. The prognosis of chronic active hepatitis without cirrhosis in relation to bridging necrosis. Hepatology 1968 6: 345–8. Boyer JL, Klatskin G. Pattern of necrosis in acute viral hepatitis. N Engl J Med 1970 283: 1063–71. Baggenstoss AH, Soloway RD, Summerskill WHJ, Elveback LR, Schoenfield LJ. Chronic active liver disease. Hum Pathol 1972 3: 183–98. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995 21: 1238–47. Wanless IR. Physioanatomic considerations. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Disease of the Liver, vol. 1, 2nd edn. PhiladelphiaLippincott Williams & Wilkins, 2007; 181–212. Wanless IR, Huang W. Vascular disorders. In: Burt A, Portmann B, Ferrell L, eds. MacSween’s Pathology of the Liver, 6th edn. Edinburgh: Churchill Livingstone, 2012; 601–43. Magara T. Three-dimensional characteristic of B’ type cirrhosis, with special reference to its angioarchitecture. Jikeikai Med J 1986 101: 579–602. Hayashi H. Angioarchitectural changes in a mixed nodular cirrhotic liver. Acta Hepatologica Japonica 1989 30: 1687–97.

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