Liver, 1990: 10, 209-216 Key words: extrahepatic portal vein; idiopathic portal hypertension; phlebosclerosis; portal trunk.
Pathomorphologc study on the extrahepatic portal vein in idiopathc portal hypertension MASAYOSHI KAGE, MASAHIRO ARAKAWA, KAZUNORI FUKUDA AND MASAMlCHl KOJIRO The First Department of Pathology, Kurume University School of Medicine, Kurume, Japan
Patients with idiopathic portal hypertension (IPH) are known to have sclerotic changes of the intrahepatic portal vein radicles. In order to elucidate the pathological changes in the extrahepatic portal venous system in IPH, studies were carried out on the portal trunk in 12 patients with IPH, 59 patients with liver cirrhosis including some with associated hepatocellular carcinoma, and 12 normal matched control subjects. Histological examinations including histomorphometry were performed on the transverse sections of the portal trunk taken at autopsy. Most of the patients with IPH showed severe phlebosclerosis which was more pronounced than seen in liver cirrhosis. Thrombosis was also frequently observed in IPH. In IPH, the portal trunk was characterized by fibrous thickening of the intima and media with a prominent increase of elastic fibers. The mean area and thickness of the intima and media were significantly greater than in patients with liver cirrhosis. Sclerosis extensively involving both the extrahepatic and intrahepatic ramifications of the portal vein appeared to be characteristic of IPH. ABSTRACT -
Acrepled for publication I December 1989
Idiopathic portal hypertension (IPH) is a new term replacing past synonyms for so-called Banti’s syndrome in Japan (1). Banti’s syndrome was previously a poorly defined clinical entity comprising various disorders featuring splenomegaly and portal hypertension, including splenomegalic liver cirrhosis. Similar conditions have been reported in India as non-cirrhotic portal fibrosis ( 2 4 ) , and in the United States as hepatoportal sclerosis (5). The syndrome has also been reported in other countries where it was less precisely identified. Although a number of excellent studies have elucidated various aspects of IPH, its etiology and pathogenesis have still not been fully clarified. The principal pathological changes of the liver in IPH are sclerosis of the entire intrahepatic portal
vein together with portal fibrosis and narrowing and obliteration of the peripheral portal veins. These changes play an important role in the genesis of obstruction of the portal flow (2, 3, 5 . 6). On the .basis of these findings, we have suggested that the primary lesion of IPH may originate in the portal venous system (6, 7). However, some investigators have pointed out that IPH may be caused by viral hepatitis, which primarily affects the hepatic parenchyma and is followed secondarily by changes of the intrahepatic portal venous system (8). Investigating the lesions of the extrahepatic portal vein therefore appeared likely to be helpful in understanding the pathogenesis of IPH, since the pathological changes of the extrahepatic portal vein have not yet been described
210
KAGE ET AL.
in detail. Our goal in this study was to elucidate the pathological changes of the portal trunk which occur in IPH.
logical findings were graded according to the severity as follows: abscnt (-), slight (+), modcrate ( + +) and marked (+ + +).
Histomorphometry
Material and methods The study material consisted of autopsied livers from 12 authentic patients with IPH (IPH subgroup), 20 patients with liver cirrhosis (LC subgroup), and 39 patients with liver cirrhosis associated with hepatocellular carcinoma (LC + HCC subgroup). These three subgroups were designated as the portal hypertension group. The diagnostic criteria of IPH adopted by the Japan Research Committee (9) were used in this study and are as follows: IPH is a disorder of unknown cause characterized by splenomegaly, anemia, and portal hypertension occurring in the absence of liver cirrhosis, blood disease, parasites, occlusion of the portal vein and hepatic vein, granulomatous liver disease, congenital hepatic fibrosis, and other known diseases. The mean (*SD) age of the patients with IPH was 58.9k9.1 years and that of those with cirrhosis was 57.8k9.5. There were 2 male and 10 female patients with IPH. Gastrointestinal hemorrhage from ruptured esophageal varices was the cause of death in 11 patients with IPH, and the remaining patient died of hepatic failure. Of the 59 cirrhotics with and without hepatocelMar carcinoma, 48 were male and I 1 were female. In 48 of them cirrhosis was post-hepatitic, in 7 it was alcoholic, and in the remaining 4 cryptogenic. Esophageal varices of varying severity were present in all patients of the portal hypertension group. Twelve patients, matched for age and sex with the IPH patients, and having no past or present history of liver disease, were used as the control group. The profiles of each group and brief clinical and pathological data of the IPH subgroup are shown in Table 1. Tissue specimens were taken transversely from each portal trunk and fixed in formalin. Paraffin sections were stained with hematoxylin-eosin. Azan-Mallory, and elastica van Gieson for microscopic observation. Histo-
Histomorphometry was performed as follows. A section of the portal trunk stained with elastica van Gieson was magnified and traced onto tracing paper using a projector. We then measured the area, thickness, and outer circumference of the intima, media, and adventitia using a computer image analyzer (Cosmozone 11, NEC, Japan). The following definitions of the intima, media, and adventitia were adapted from Li (10): the intima was all structures inside the internal elastic lamina; the media was the structures from the internal elastic lamina to the outer edge of the circular muscle: and the adventitia extended from the edge of the circular muscle to the outer edge of the longitudinal muscle.
Statistical analysis Student’s !-test for paired samples was used to evaluate the significance of difference between the groups in the
Table 1 Clinical and pathologic profiles of each group
Group IPH LC LC +HCC Control
No. of cases (M:F)
Age (years)
Liver weight (g)
Spleen weight (g)
12 (4:8) 58.9k9.1 20 (13:7) 57.8+ 13.3
848k223 630k304 1104k265 3 5 0 k 188
39 (35:4) 57.8k8.8 12 (4:8) 58.9k9.1
1674k327 303+167 I231 I89 126k42
~
M =number of male patients, F = number of female patients. Values represent meanskSD of age, liver weight, and spleen weight.
Fig. 1. Normal portal trunk in transverse section, showing a very thin intima and thin strands of muscle fibers in-the media and adventitia. Elastica van Gieson, x 20.
PHLEBOSCLEROSIS OF EXTRAHEPATIC PORTAL VEIN
mean values obtained from the histometrical measurements.
Results Histopathological findings in the portal trunk in control group The intima consisted of a layer of endothelial cells, a small amount of subendothelial connective tissue, and a definite internal elastic lamina. Not a single subject showed intimal thickening. The internal elastic lamina was composed of wavy and thin elastic fibers without defects. The media consisted of bundles of circular smooth muscle fibers with a small amount of intervening connective tissue containing elastic and collagen fibers. The adventitia was composed of bundles of closely packed longitudinal smooth muscle fibers and connective tissue. Elastic and collagen fibers were present between the muscle layers, but were less common in the adventitia than in the media. Elastic fibers were rare in some areas, and not present at all in others. The appearance of a portal trunk section from a control subject is shown in Fig. 1.
21 1
Histopathological findings in the portal trunk in portal hypertension group The pathological findings in the portal trunk were as follows. Fig. 5 shows the degree of elastic and collagen fibers in each coat of the portal vein wall. Zntima. Thickening of the intima was common in all subgroups. It was generalized but not uniform, being more marked in some regions than in others. In the thickened intima, the connective tissue showed marked proliferation and was mixed with varying amounts of elastic and collagen fibers. The most marked thickening of the intima was observed in the IPH subgroup (Fig. 2), followed by the LC+ HCC subgroup. A laminated appearance was prominent in severely thickened regions of the intima (Fig. 2 and 3). Lamination, thickening, and partial disappearance of the internal elastic lamina were found in all subgroups. The most striking changes of the internal elastic lamina were observed in the IPH subgroup (Fig. 3 and 4), where partial disappear-
Fig. 2. Portal trunk of a patient with IPH in transverse section, showing prominent sclerosis characterized by irregular intimal fibrous thickening with marked proliferation of elastic fibers. Elastica van Gieson. x 2.
212
KAGE ET AL.
ance of the internal elastic lamina was seen in 75.0% of the cases. In contrast, this was only seen in 15.0 and 30.8% of the LC and LCSHCC subgroups, respectively. Media. Thickening of the media was commonly found in the portal hypertension group. In this group, the circular muscle of the media was generally atrophied and there was an increase of the elastic and collagen fibers. There were no appreciable differences in the degree of fibrosis of the media between the subgroups, although an increase of the elastic fibers was prominent in many cases of IPH. The circular muscle was atrophic and partially replaced by fibrous tissue (Fig. 4)in 62.5% of the IPH subgroup as compared to 34.2% of the LC subgroup. In portal trunk sections showing severe changes of the media, marked intimal thickening was usually also present.
Fig. 3. Portal trunk of a patient with IPH in transverse
section. Marked fibrous thickening with a laminated appearance is seen. The internal elastic lamina disappears due to severe fibrosis. Elastica van Gieson, x 40.
Adventitiu. Adventitial thickening due to an increase of both elastic and collagen fibers was frequently found in the portal hypertension group. However, fibrosis was less marked in the adventitia than in the media. There were no marked differences in the degree of fibrosis among the subgroups. Collagen fibers were predominant and the degree of elastosis in the adventitia was generally milder than in the media, although elastic fibers were more prominent in the IPH subgroup than in the other subgroups. Atrophy and partial loss of the longitudinal muscle was observed in half of the IPH subgroup, while the longitudinal muscle remained intact in the LC and LC+HCC subgroups.
Fig. 4. Portal trunk of a patient with IPH in transverse section, showing partial loss of the internal elastic lamina (arrow) and thickening of the intima and media. Muscle fibers in the media are replaced by a dense proliferation of elastic fibers. Elastica van Gieson, x 40.
PHLEBOSCLEROSIS
Thrombosis in the portal trunk The frequency and features of the thrombi detected are shown in Table 3. Thrombosis was frequently found in eight of the IPH subgroup (66.7%), four patients (20.0%) of the LC subgroup, and nine patients (23.1%) of the LC+ HCC subgroup (six of whom had tumor thrombi). The thrombi varied from fresh to well-organized. Fresh red thrombi that were probably formed during the terminal stages were found in four subjects with IPH. Three of them had mural thrombi, and the remaining one had a thrombus which almost completely obstructed the portal trunk. Mural thrombi that were either partially or well-organized were also found in four other
OF EXTRAHEPATIC PORTAL VEIN
2 I3
subjects with IPH, but there was neither obstruction nor significant narrowing of the portal trunk in these cases.
Histomorphometry of the portal trunk The results are summarized in Fig. 6. 1) Area of the intima, media, and adventitia. The mean area of the intima in the IPH subgroup was significantly greater than those in the other subgroups and in the control group. The mean area of the media in the IPH subgroup was also significantly greater than in the LC HCC sub-
+
Table 2 Main pathological findings of the IPH subgroup Case Pathologic findings Liver wt (g) Spleen wt (g) Intruheputir portal vein Phlebosclerosis: Small Medium-sized Large Obliteration of small portal veins Portal trunk Intima: Thickening Lamination Elastosis Collagenosis Disappearance of elastica lamina
Media: Thickening Elastosis Collagenosis Disappearance of muscle fibers Adventitia: Thickening Elastosis Collagenosis Disappearance of muscle fibers ( ) = splenectomized,
1
2
3
4
5
6
7
8
730 320
870 550
660 360
930 1000
450 560
520 600
1070 720
1340
tt
+ +
ttt tt tt
tt tt tt
ttt tt tt
tt
+
tt
+
tt ttt ttt
tt
ttt
tt
+
tt
ttt
ttt* tt tt ttt
+ +
tt
+
-
ttt* ttt* ttt* tt + ttt + tt ttt ttt ttt ttt + tt ttt tt
+
+ + +
tt
tt
tt ttt tt
+ tt tt
t t + + tt tt tt ttt tt ttt
+ +
ttt tt
+
-
tt
+
tt
-
tt
tt tt ttt
-
tt tt
-
+
+
+
tt tt
+ - =absent,
+
tt
tt tt
-
tt tt
12
I050 850 (390) 700
'950 740
900 290
ttt ttt tt
ttt tt tt
ttt ttt ttt
tt tt
tt +
tt
+
tt
tt
tt
1200
+
+
tt* ttt* + tt ttt ttt tt ttt
tt
-
ttt
-
tt
tt
+
tt ttt tt
tt ttt tt
tt
+ +
tt ttt tt
tt ttt ttt
-
tt
-
ttt
tt
tt ttt ttt
-
-
tt
+
tt
tt ttt tt
+
+
+
tt
+
tt ttt
+
tt tt
tt + + t + + + =slight, tt =moderate, ttt =marked, * =irregular tt
10
ttt* tt* ttt* tt + tt tt tt ttt ttt ttt tt + ttt + tt
+
-
II
9
+
thickening.
214
KAGEETAL
Table 3 Frequency and types of thrombi in the portal trunk Group
Frequency
Fresh"
Partially organizedh
IPH LC LC + HCC Control
8/12 (66.7) 4/20 (20.0)
4 (33.3) 4 (20.0)
9*/39 ( I 5.6) 0/12 (0.0)
I (2.6) 0
2 (16.7) 0 2 (5.2) 0
Well organized' 2 (16.7) 0 0 0
( ) = YO,a = fresh red thrombus without organization, b = partially organized thrombus, c = well-organized thrombus, * = 6 patients had tumor thrombus
group and the control group. No significant differences were observed in the mean area of the adventitia among the groups.
2 ) Thickness of the intima, media, and adventitia. The mean thickness of the intima and media in the IPH subgroup was significantly greater than that in the other subgroups and the control group. No significant differences were found in the mean thickness of the adventitia among the subgroups.
3 ) Outer circumference of the intima, media, and adventitia. No statistically significant differences in the mean outer circumferences of the intima, media, and adventitia were present between the subgroups and the control group, or among the subgroups.
Discussion All of the IPH subgroups had severe portal hypertension and were clinically diagnosed as having IPH, Banti's syndrome, or liver cirrhosis with esophageal varices. In these patients, the liver showed phlebosclerosis of the intrahepatic portal vein associated with scarring and obliteration of its peripheral branches and portal fibrosis. These have been designated as the characteristic changes of IPH. In addition to this intrahepatic portal sclerosis, our study revealed the presence of severe sclerosis of the extrahepatic portal vein in IPH. Phlebosclerosis of the portal trunk in the portal hypertension group was histologically characterized by intimal thickening with changes of the internal elastica lamina, as well as by fibrosis and
Collagen fiber
Elastic fiber Intima
IPH
Media Advent i t ia
t
I
T
I
lntima
LC
Media Advent i t i a lntima
LC -I H C C Media Adventiria
Control
lntima Media Advent i t ia
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
(M)
(M)
moderate
0slight
or absence
Fig. 5 . The degree of proliferation of elastic and collagen fibers in the intima, media, and adventitia of the portal trunk in each group.
PHLEBOSCLEROSIS OF EXTRAHEPATIC PORTAL VEIN
atrophy of the muscle coats in the media and adventitia. Eccentric thickening of the portal vein wall, which Mikkelsen et al. ( 5 ) have described as a characteristic finding in hepatoportal sclerosis, was observed in both patients with IPH and patients with cirrhosis. There were no qualitative differences in the histological findings of portal sclerosis between the IPH subgroup and the other subgroups of the portal hypertension group, but sclerosis of the portal vein with frequent thrombosis was more prominent in the IPH subgroup than the other subgroups. The “end-stage of the portal vein” in Banti’s syndrome, a term which was previously used to describe a severely damaged portal vein (1 I), was almost always found in the IPH subgroup. This “end-stage change” is characterized by destruction of the portal vein due to marked fibrous thickening of the intima and media being composed mainly of elastic fibers. The marked sclerotic changes observed in the extrahepatic portal vein have also been described in some patients by Mikkelsen et al. ( 5 ) from the United States, Boyer et al. (3) and Nayak & Ramalingaswami (4)from India, and Nakanuma
215
et al. (12) from Japan. In those patients as well as ours, marked intimal thickening was striking enough to be regarded as a characteristic feature of IPH. As to the pathogenesis of the intimal thickening, Nayak has speculated that it might be the result of incorporation of mural thrombi into the intima, which over a considerable period of time then become completely organized. Complete intimal incorporation of mural thrombi that finally leads to fibrous thickening of the portal vein wall has been shown in both human and experimental animals (1 3). The frequently noted laminated appearance of the thickened intima in our patients might reflect the organization of numerous mural thrombi superimposed on the underlying lesions of the portal vein. Fresh thrombus formation would thus be a terminal event in the portal trunk. It may be reasonable to predict that such an obliterative thrombotic process in the intrahepatic portal vein system could extend to the extrahepatic portal vein, or that such lesions could occur simultaneously in the entire intrahepatic and extrahepatic portal venous system. The cause of such severe portal phlebosclerosis
A
1
INTIMA
MEDIA
ADVENTlTIA
T
Fig. 6 . Results of histomorphometry. The mean value and standard deviation of the area (A), thickness (B),
INTMA
MEDIA
ADVENTITIA
and outer circumference (C) of the intima, media and adventitia are shown for each group. * p
Pathomorphologc study on the extrahepatic portal vein in idiopathc portal hypertension MASAYOSHI KAGE, MASAHIRO ARAKAWA, KAZUNORI FUKUDA AND MASAMlCHl KOJIRO The First Department of Pathology, Kurume University School of Medicine, Kurume, Japan
Patients with idiopathic portal hypertension (IPH) are known to have sclerotic changes of the intrahepatic portal vein radicles. In order to elucidate the pathological changes in the extrahepatic portal venous system in IPH, studies were carried out on the portal trunk in 12 patients with IPH, 59 patients with liver cirrhosis including some with associated hepatocellular carcinoma, and 12 normal matched control subjects. Histological examinations including histomorphometry were performed on the transverse sections of the portal trunk taken at autopsy. Most of the patients with IPH showed severe phlebosclerosis which was more pronounced than seen in liver cirrhosis. Thrombosis was also frequently observed in IPH. In IPH, the portal trunk was characterized by fibrous thickening of the intima and media with a prominent increase of elastic fibers. The mean area and thickness of the intima and media were significantly greater than in patients with liver cirrhosis. Sclerosis extensively involving both the extrahepatic and intrahepatic ramifications of the portal vein appeared to be characteristic of IPH. ABSTRACT -
Acrepled for publication I December 1989
Idiopathic portal hypertension (IPH) is a new term replacing past synonyms for so-called Banti’s syndrome in Japan (1). Banti’s syndrome was previously a poorly defined clinical entity comprising various disorders featuring splenomegaly and portal hypertension, including splenomegalic liver cirrhosis. Similar conditions have been reported in India as non-cirrhotic portal fibrosis ( 2 4 ) , and in the United States as hepatoportal sclerosis (5). The syndrome has also been reported in other countries where it was less precisely identified. Although a number of excellent studies have elucidated various aspects of IPH, its etiology and pathogenesis have still not been fully clarified. The principal pathological changes of the liver in IPH are sclerosis of the entire intrahepatic portal
vein together with portal fibrosis and narrowing and obliteration of the peripheral portal veins. These changes play an important role in the genesis of obstruction of the portal flow (2, 3, 5 . 6). On the .basis of these findings, we have suggested that the primary lesion of IPH may originate in the portal venous system (6, 7). However, some investigators have pointed out that IPH may be caused by viral hepatitis, which primarily affects the hepatic parenchyma and is followed secondarily by changes of the intrahepatic portal venous system (8). Investigating the lesions of the extrahepatic portal vein therefore appeared likely to be helpful in understanding the pathogenesis of IPH, since the pathological changes of the extrahepatic portal vein have not yet been described
210
KAGE ET AL.
in detail. Our goal in this study was to elucidate the pathological changes of the portal trunk which occur in IPH.
logical findings were graded according to the severity as follows: abscnt (-), slight (+), modcrate ( + +) and marked (+ + +).
Histomorphometry
Material and methods The study material consisted of autopsied livers from 12 authentic patients with IPH (IPH subgroup), 20 patients with liver cirrhosis (LC subgroup), and 39 patients with liver cirrhosis associated with hepatocellular carcinoma (LC + HCC subgroup). These three subgroups were designated as the portal hypertension group. The diagnostic criteria of IPH adopted by the Japan Research Committee (9) were used in this study and are as follows: IPH is a disorder of unknown cause characterized by splenomegaly, anemia, and portal hypertension occurring in the absence of liver cirrhosis, blood disease, parasites, occlusion of the portal vein and hepatic vein, granulomatous liver disease, congenital hepatic fibrosis, and other known diseases. The mean (*SD) age of the patients with IPH was 58.9k9.1 years and that of those with cirrhosis was 57.8k9.5. There were 2 male and 10 female patients with IPH. Gastrointestinal hemorrhage from ruptured esophageal varices was the cause of death in 11 patients with IPH, and the remaining patient died of hepatic failure. Of the 59 cirrhotics with and without hepatocelMar carcinoma, 48 were male and I 1 were female. In 48 of them cirrhosis was post-hepatitic, in 7 it was alcoholic, and in the remaining 4 cryptogenic. Esophageal varices of varying severity were present in all patients of the portal hypertension group. Twelve patients, matched for age and sex with the IPH patients, and having no past or present history of liver disease, were used as the control group. The profiles of each group and brief clinical and pathological data of the IPH subgroup are shown in Table 1. Tissue specimens were taken transversely from each portal trunk and fixed in formalin. Paraffin sections were stained with hematoxylin-eosin. Azan-Mallory, and elastica van Gieson for microscopic observation. Histo-
Histomorphometry was performed as follows. A section of the portal trunk stained with elastica van Gieson was magnified and traced onto tracing paper using a projector. We then measured the area, thickness, and outer circumference of the intima, media, and adventitia using a computer image analyzer (Cosmozone 11, NEC, Japan). The following definitions of the intima, media, and adventitia were adapted from Li (10): the intima was all structures inside the internal elastic lamina; the media was the structures from the internal elastic lamina to the outer edge of the circular muscle: and the adventitia extended from the edge of the circular muscle to the outer edge of the longitudinal muscle.
Statistical analysis Student’s !-test for paired samples was used to evaluate the significance of difference between the groups in the
Table 1 Clinical and pathologic profiles of each group
Group IPH LC LC +HCC Control
No. of cases (M:F)
Age (years)
Liver weight (g)
Spleen weight (g)
12 (4:8) 58.9k9.1 20 (13:7) 57.8+ 13.3
848k223 630k304 1104k265 3 5 0 k 188
39 (35:4) 57.8k8.8 12 (4:8) 58.9k9.1
1674k327 303+167 I231 I89 126k42
~
M =number of male patients, F = number of female patients. Values represent meanskSD of age, liver weight, and spleen weight.
Fig. 1. Normal portal trunk in transverse section, showing a very thin intima and thin strands of muscle fibers in-the media and adventitia. Elastica van Gieson, x 20.
PHLEBOSCLEROSIS OF EXTRAHEPATIC PORTAL VEIN
mean values obtained from the histometrical measurements.
Results Histopathological findings in the portal trunk in control group The intima consisted of a layer of endothelial cells, a small amount of subendothelial connective tissue, and a definite internal elastic lamina. Not a single subject showed intimal thickening. The internal elastic lamina was composed of wavy and thin elastic fibers without defects. The media consisted of bundles of circular smooth muscle fibers with a small amount of intervening connective tissue containing elastic and collagen fibers. The adventitia was composed of bundles of closely packed longitudinal smooth muscle fibers and connective tissue. Elastic and collagen fibers were present between the muscle layers, but were less common in the adventitia than in the media. Elastic fibers were rare in some areas, and not present at all in others. The appearance of a portal trunk section from a control subject is shown in Fig. 1.
21 1
Histopathological findings in the portal trunk in portal hypertension group The pathological findings in the portal trunk were as follows. Fig. 5 shows the degree of elastic and collagen fibers in each coat of the portal vein wall. Zntima. Thickening of the intima was common in all subgroups. It was generalized but not uniform, being more marked in some regions than in others. In the thickened intima, the connective tissue showed marked proliferation and was mixed with varying amounts of elastic and collagen fibers. The most marked thickening of the intima was observed in the IPH subgroup (Fig. 2), followed by the LC+ HCC subgroup. A laminated appearance was prominent in severely thickened regions of the intima (Fig. 2 and 3). Lamination, thickening, and partial disappearance of the internal elastic lamina were found in all subgroups. The most striking changes of the internal elastic lamina were observed in the IPH subgroup (Fig. 3 and 4), where partial disappear-
Fig. 2. Portal trunk of a patient with IPH in transverse section, showing prominent sclerosis characterized by irregular intimal fibrous thickening with marked proliferation of elastic fibers. Elastica van Gieson. x 2.
212
KAGE ET AL.
ance of the internal elastic lamina was seen in 75.0% of the cases. In contrast, this was only seen in 15.0 and 30.8% of the LC and LCSHCC subgroups, respectively. Media. Thickening of the media was commonly found in the portal hypertension group. In this group, the circular muscle of the media was generally atrophied and there was an increase of the elastic and collagen fibers. There were no appreciable differences in the degree of fibrosis of the media between the subgroups, although an increase of the elastic fibers was prominent in many cases of IPH. The circular muscle was atrophic and partially replaced by fibrous tissue (Fig. 4)in 62.5% of the IPH subgroup as compared to 34.2% of the LC subgroup. In portal trunk sections showing severe changes of the media, marked intimal thickening was usually also present.
Fig. 3. Portal trunk of a patient with IPH in transverse
section. Marked fibrous thickening with a laminated appearance is seen. The internal elastic lamina disappears due to severe fibrosis. Elastica van Gieson, x 40.
Adventitiu. Adventitial thickening due to an increase of both elastic and collagen fibers was frequently found in the portal hypertension group. However, fibrosis was less marked in the adventitia than in the media. There were no marked differences in the degree of fibrosis among the subgroups. Collagen fibers were predominant and the degree of elastosis in the adventitia was generally milder than in the media, although elastic fibers were more prominent in the IPH subgroup than in the other subgroups. Atrophy and partial loss of the longitudinal muscle was observed in half of the IPH subgroup, while the longitudinal muscle remained intact in the LC and LC+HCC subgroups.
Fig. 4. Portal trunk of a patient with IPH in transverse section, showing partial loss of the internal elastic lamina (arrow) and thickening of the intima and media. Muscle fibers in the media are replaced by a dense proliferation of elastic fibers. Elastica van Gieson, x 40.
PHLEBOSCLEROSIS
Thrombosis in the portal trunk The frequency and features of the thrombi detected are shown in Table 3. Thrombosis was frequently found in eight of the IPH subgroup (66.7%), four patients (20.0%) of the LC subgroup, and nine patients (23.1%) of the LC+ HCC subgroup (six of whom had tumor thrombi). The thrombi varied from fresh to well-organized. Fresh red thrombi that were probably formed during the terminal stages were found in four subjects with IPH. Three of them had mural thrombi, and the remaining one had a thrombus which almost completely obstructed the portal trunk. Mural thrombi that were either partially or well-organized were also found in four other
OF EXTRAHEPATIC PORTAL VEIN
2 I3
subjects with IPH, but there was neither obstruction nor significant narrowing of the portal trunk in these cases.
Histomorphometry of the portal trunk The results are summarized in Fig. 6. 1) Area of the intima, media, and adventitia. The mean area of the intima in the IPH subgroup was significantly greater than those in the other subgroups and in the control group. The mean area of the media in the IPH subgroup was also significantly greater than in the LC HCC sub-
+
Table 2 Main pathological findings of the IPH subgroup Case Pathologic findings Liver wt (g) Spleen wt (g) Intruheputir portal vein Phlebosclerosis: Small Medium-sized Large Obliteration of small portal veins Portal trunk Intima: Thickening Lamination Elastosis Collagenosis Disappearance of elastica lamina
Media: Thickening Elastosis Collagenosis Disappearance of muscle fibers Adventitia: Thickening Elastosis Collagenosis Disappearance of muscle fibers ( ) = splenectomized,
1
2
3
4
5
6
7
8
730 320
870 550
660 360
930 1000
450 560
520 600
1070 720
1340
tt
+ +
ttt tt tt
tt tt tt
ttt tt tt
tt
+
tt
+
tt ttt ttt
tt
ttt
tt
+
tt
ttt
ttt* tt tt ttt
+ +
tt
+
-
ttt* ttt* ttt* tt + ttt + tt ttt ttt ttt ttt + tt ttt tt
+
+ + +
tt
tt
tt ttt tt
+ tt tt
t t + + tt tt tt ttt tt ttt
+ +
ttt tt
+
-
tt
+
tt
-
tt
tt tt ttt
-
tt tt
-
+
+
+
tt tt
+ - =absent,
+
tt
tt tt
-
tt tt
12
I050 850 (390) 700
'950 740
900 290
ttt ttt tt
ttt tt tt
ttt ttt ttt
tt tt
tt +
tt
+
tt
tt
tt
1200
+
+
tt* ttt* + tt ttt ttt tt ttt
tt
-
ttt
-
tt
tt
+
tt ttt tt
tt ttt tt
tt
+ +
tt ttt tt
tt ttt ttt
-
tt
-
ttt
tt
tt ttt ttt
-
-
tt
+
tt
tt ttt tt
+
+
+
tt
+
tt ttt
+
tt tt
tt + + t + + + =slight, tt =moderate, ttt =marked, * =irregular tt
10
ttt* tt* ttt* tt + tt tt tt ttt ttt ttt tt + ttt + tt
+
-
II
9
+
thickening.
214
KAGEETAL
Table 3 Frequency and types of thrombi in the portal trunk Group
Frequency
Fresh"
Partially organizedh
IPH LC LC + HCC Control
8/12 (66.7) 4/20 (20.0)
4 (33.3) 4 (20.0)
9*/39 ( I 5.6) 0/12 (0.0)
I (2.6) 0
2 (16.7) 0 2 (5.2) 0
Well organized' 2 (16.7) 0 0 0
( ) = YO,a = fresh red thrombus without organization, b = partially organized thrombus, c = well-organized thrombus, * = 6 patients had tumor thrombus
group and the control group. No significant differences were observed in the mean area of the adventitia among the groups.
2 ) Thickness of the intima, media, and adventitia. The mean thickness of the intima and media in the IPH subgroup was significantly greater than that in the other subgroups and the control group. No significant differences were found in the mean thickness of the adventitia among the subgroups.
3 ) Outer circumference of the intima, media, and adventitia. No statistically significant differences in the mean outer circumferences of the intima, media, and adventitia were present between the subgroups and the control group, or among the subgroups.
Discussion All of the IPH subgroups had severe portal hypertension and were clinically diagnosed as having IPH, Banti's syndrome, or liver cirrhosis with esophageal varices. In these patients, the liver showed phlebosclerosis of the intrahepatic portal vein associated with scarring and obliteration of its peripheral branches and portal fibrosis. These have been designated as the characteristic changes of IPH. In addition to this intrahepatic portal sclerosis, our study revealed the presence of severe sclerosis of the extrahepatic portal vein in IPH. Phlebosclerosis of the portal trunk in the portal hypertension group was histologically characterized by intimal thickening with changes of the internal elastica lamina, as well as by fibrosis and
Collagen fiber
Elastic fiber Intima
IPH
Media Advent i t ia
t
I
T
I
lntima
LC
Media Advent i t i a lntima
LC -I H C C Media Adventiria
Control
lntima Media Advent i t ia
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
(M)
(M)
moderate
0slight
or absence
Fig. 5 . The degree of proliferation of elastic and collagen fibers in the intima, media, and adventitia of the portal trunk in each group.
PHLEBOSCLEROSIS OF EXTRAHEPATIC PORTAL VEIN
atrophy of the muscle coats in the media and adventitia. Eccentric thickening of the portal vein wall, which Mikkelsen et al. ( 5 ) have described as a characteristic finding in hepatoportal sclerosis, was observed in both patients with IPH and patients with cirrhosis. There were no qualitative differences in the histological findings of portal sclerosis between the IPH subgroup and the other subgroups of the portal hypertension group, but sclerosis of the portal vein with frequent thrombosis was more prominent in the IPH subgroup than the other subgroups. The “end-stage of the portal vein” in Banti’s syndrome, a term which was previously used to describe a severely damaged portal vein (1 I), was almost always found in the IPH subgroup. This “end-stage change” is characterized by destruction of the portal vein due to marked fibrous thickening of the intima and media being composed mainly of elastic fibers. The marked sclerotic changes observed in the extrahepatic portal vein have also been described in some patients by Mikkelsen et al. ( 5 ) from the United States, Boyer et al. (3) and Nayak & Ramalingaswami (4)from India, and Nakanuma
215
et al. (12) from Japan. In those patients as well as ours, marked intimal thickening was striking enough to be regarded as a characteristic feature of IPH. As to the pathogenesis of the intimal thickening, Nayak has speculated that it might be the result of incorporation of mural thrombi into the intima, which over a considerable period of time then become completely organized. Complete intimal incorporation of mural thrombi that finally leads to fibrous thickening of the portal vein wall has been shown in both human and experimental animals (1 3). The frequently noted laminated appearance of the thickened intima in our patients might reflect the organization of numerous mural thrombi superimposed on the underlying lesions of the portal vein. Fresh thrombus formation would thus be a terminal event in the portal trunk. It may be reasonable to predict that such an obliterative thrombotic process in the intrahepatic portal vein system could extend to the extrahepatic portal vein, or that such lesions could occur simultaneously in the entire intrahepatic and extrahepatic portal venous system. The cause of such severe portal phlebosclerosis
A
1
INTIMA
MEDIA
ADVENTlTIA
T
Fig. 6 . Results of histomorphometry. The mean value and standard deviation of the area (A), thickness (B),
INTMA
MEDIA
ADVENTITIA
and outer circumference (C) of the intima, media and adventitia are shown for each group. * p
