PATHOLOGY

RESEARCH AND PRACTICE

Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp

Review

Pathology and Pathogenesis of Idiopathic Portal Hypertension with an Emphasis on the Liver
Yasuni Nakanuma1, Koichi Tsuneyama1, Makoto Ohbu2 and Kazuyoshi Katayanagi1
1

Department of Pathology (II), Kanazawa University School of Medicine, Kanazawa, and 2 Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan

Summary
Idiopathic portal hypertension (IPH) is characterized by a long-standing presinusoidal portal hypertension of unknown etiology in adults. Some unidentified agent(s) affect(s) the intrahepatic small portal veins or portal tracts. Immunological disturbance, thromboembolism, infectious etiology and/or increased fibrogenesis in portal tracts are suspected as being candidates for the primary agent(s). During the long clinical course of IPH, several pathological changes may occur, including subcapsular parenchymal atrophy, atrophy of the liver, portal and parenchymal fibrosis, and portal venous phlebosclerosis and thrombosis. The last-named of these lesions is mostly found in patients with a history of splenectomy. Subcapsular parenchymal and hepatic atrophy may result from a hepatocellular dropout via apoptosis or necrosis because of intrahepatic hemodynamic disturbances, particularly chronic portal venous blood insufficiency. Pericellular fibrosis and thin fibrous septa are also frequently found and associated with activated perisinusoidal cells positive for smooth muscle actin. At the same time, vague nodular hyperplasia of hepatocytes not surrounded by fibrous septa is not infrequently seen. It may resemble nodular regenerative hyperplasia, partial nodular transformation, or focal nodular hyperplasia. However, liver cirrhosis does not occur even at the terminal stage. Taking these findings into consideration, a new staging of IPH with a combination of hepatic parenchymal atrophy and portal venous thrombosis was proposed: non-atrophic liver without subcapsular parenchymal atrophy (stage I), non-atrophic liver with subcapsular parenchymal atrophy (stage II), atrophic liver with subcapsular parenchymal atrophy (stage III), and portal venous occlusive thrombosis (stage IV). IPH livers are likely to progress from stage I to stage III. Stage IV, which occurs relaPathol. Res. Pract. 197: 6576 (2001)

tively late, has a poor prognosis. This staging is applicable to clinical and autopsy cases without any histological data. Key words: Liver pathology Hepatic fibrosis Hepatocellular apoptosis Portal venous insufficiency Idiopathic portal hypertension

Introduction
Idiopathic portal hypertension (IPH) is characterized by a long-standing non-cirrhotic portal hypertension because of the intrahepatic block of small portal vein branches [32, 37]. Pathologically, portal phlebosclerosis, obliteration of intrahepatic small portal veins, and subcapsular parenchymal atrophy with unusual approximation of portal tracts and hepatic veins to each other are characteristic of IPH livers (Figs. 15) [25, 36]. Hepatocellular atrophy with sinusoidal dilatation and portal and intralobular fibrosis are also found in IPH livers, to various degrees and in various combinations [47]. Hepatocellular nodular hyperplasia is not uncommon, either [4, 25]. However, early or primary changes or lesions causally related to intrahepatic portal venous block have not yet been identified, although several etiological factors have been proposed. In this review, we first describe the clinical features and hemodynamic character of IPH. Then, we try to categorize the primary and secondary pathological
Address for correspondence: Yasuni Nakanuma, Second Department of Pathology, Kanazawa University School of Medicine, Kanazawa 920-8640, Japan. Tel.: ++88-076-265-2195, Fax: ++88-076-234-4229. E-mail: pbcpsc@kenroku.kanazawa-u.ac.jp
0344-0338/01/197/2-65 $15.00/0

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Fig. 1. Cut surface of autopsy liver of idiopathic portal hyperetnsion. The liver is atrophic, and portal tracts (large arrows) and hepatic veins (small arrow) are unusually approximated to the hepatic capsule. Intrahepatic large portal vein (V) is dilated.

Fig. 3. Small portal tract in idiopathic portal hypertension. This portal tract (arrow) is densely sclerotic, and hepatic artery and bile ducts are identifiable. However, portal vein is obliterated. HE. Fig. 4. Small portal tract in idiopathic portal hypertension. These portal tracts (arrows) are densely sclerotic because of marked elastosis. Portal vein is obliterated. Elastica van Gieson stain. Fig. 2. Histological section of autopsy liver of idiopathic portal hypertension. Portal tracts and hepatic vein tributaries are unusually close to the hepatic capsule, and the subcapsular hepatic parenchyma is atrophic. Arrow, hepatic capsule. HE. Fig. 5. A medium-sized portal tract in idiopathic portal hypertension. Portal tract is densely fibrotic, and a mediumsized portal vein (arrow) shows phlebosclerosis with muscular hyperplasia. HE.

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changes in IPH livers with respect to the progression of pathological changes as a consequence of long-standing hemodynamic alterations. The recent progress in the etiopathogenetic study of IPH is also reviewed. Finally, a new staging of IPH taking the progressive secondary hepatic lesions into consideration is proposed for a clearer and easier evaluation of the clinicopathological features of this disease. This review is based on 97 liver specimens from cases fulfilling the criteria for IPH obtained from the file of hepatobiliary diseases in our laboratory and affiliated hospitals.
A

Main Clinical Findings and Prognosis

Main clinical findings. IPH affects preferentially middle to old aged women in Japan, while the equivalent disease in India, non-cirrhotic portal fibrosis of the liver (NCPF), usually affects young men [24, 37]. This disease is characterized by overt splenomegaly with portal hypertension, and by relatively mild abnormalities in liver function tests [35]. There are no laboratory findings characteristic of IPH, and IPH patients have no stigmata of chronic liver disease, such as spider angiomas or palmar erythema. Levels of one or more blood elements are decreased, and pancytopenia is common. Serologically, IPH is not causally related to chronic infection of HBV or HCV. Radiologically, the established IPH livers show central hypertrophy and peripheral atrophy [20]. Esophageal varices and bleeding are also common. Prognosis of IPH. The disease is relatively benign if variceal bleeding is controlled or prevented, and does not progress to cirrhosis. However, some IPH cases with hepatic failure have been reported [5, 6, 14]. Ichimura et al. [14] followed 171 patients with IPH and reported that 20 patients died (6 from bleeding in the gastro-intestinal tract, 5 from hepatic insufficiency and 9 from other causes). Male patients with a disease onset at less than 40 years of age had poorer prognoses. The occurrence of occlusive portal venous thrombosis indicates poor prognosis, and in fact, in autopsy cases, occlusive portal venous thromboembolism is not infrequently encountered. In patients with collagen vascular disease [15, 45], an association with IPH is regarded as being one of the most important complications affecting prognosis.

Fig. 6. Intimal edema and fibrosis of portal vein branches: A small portal vein (arrows) shows intimal edema and fibrosis with mild lymphocytic infiltration (a kind of phlebitis). The outline of this vein is well delineated by Elastica van Gieson stain (B). V, hepatic arterial branch. A: HE; B: Elastica van Gieson stain. A and B are serial sections of the same portal tract.

Hemodynamics of IPH in comparison with liver cirrhosis

Portal vein pressure is significantly elevated in liver cirrhosis and IPH. In liver cirrhosis, portal venous blood flow into the liver is almost normal, while intrahepatic vascular resistance at the postsinusoidal level is

markedly increased [31]. In addition, hepatic arterial blood flow into the liver is increased, and there are many arterio-portal venous (AP) shunts in the liver. By contrast, in IPH there is an increase in the portal venous blood flow into the liver, in the diameter of portal vein trunks, and in presinusoidal vascular resistance, but a decrease in the hepatic arterial flow into the liver; A-P shunt is negligible. Extrahepatic portal-systemic shunts are present in IPH and liver cirrhosis. In cirrhosis, portography reveals distortion of the intrahepatic vasculatures and hepatofugal flow, and arteriograms show a characteristical corkscrew appearance. Although the portograms in IPH vary among cases, dilatation of the hilar portal veins and intrahepatic large branches, irregular and often obtuse-angled divisions of the peripheral branches, occasional abrupt interruptions, and an avascular area beneath the liver surface are frequently seen. Non-opacification of some of the large intrahepatic portal branches and a paucity of medium-

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sized portal branches could be interpreted as a late and secondary complication of portal venous thromboembolism [9]. Characteristic changes in IPH include frequent hepatic vein-to-hepatic vein anastomoses, narrower angles between large veins and their tributaries, smooth and wavy middle-sized to large branches (giving a general weeping willow appearance), homogeneous sinusoidal filling, and minimal to no filling of the portal venous system on wedged retrograde portography [10]. In cirrhosis, by contrast, changes include rare vein-to-vein anastomoses, wide angles between veins and tributaries, irregular stenosis of large veins and branches at various levels, spotty sinusoidal filling, and frequent retrograde flow in the portal venous system. IPH is also characterized by marked splenomegaly. Marked splenomegaly with increased blood inflow cannot be simply attributed to congestion, and it remains an enigma.

frequently expressed on the microvasculature of portal tracts in IPH; this expression may be a factor initiating the immunological assault on portal microvessels in IPH [45, 50, 51]. An increased level of interferon (IFN) in portal venous blood may be responsible for this HLA-DR expression [58]. As for the adhesion molecules, which are important in the interaction between lymphocytes and accessory and target cells, the serum level of soluble VCAM-1 is found to be increased [58]. The level of soluble ICAM1 of IPH patients is slightly elevated but not different from that in patients with other diseases. VCAM-1 is expressed in the sinusoidal lining cells and portal venous endothelial cells in several IPH patients. Increased expression of VCAM-1 may reflect an immunopathological phenomenon in the occurrence of IPH.
Progressive fibrosis

Etiopathogenesis of IPH
The primary factor(s) involved in the development of presinusoidal portal hypertension may vary with the etiopathogenesis. In this context, IPH could be heterogeneous. The following points may represent factors playing a role in the etiology of IPH.
Immunological factors

A number of immunological abnormalities, such as hypergammaglobulinemia and antinuclear antibodies with high titer, occur in patients with IPH. LE cell phenomena were also positive in some patients [15, 23]. In addition, IPH associated with systemic lupus erythematosus (SLE), chronic thyroiditis, mixed connective tissue disease, and progressive systemic sclerosis (PSS) has been reported [26, 28, 29, 50, 51, 42]. The presence of anticardiolipin antibody, indicated by positivity for lupus anticoagulant, is suggestive of the presence of a common immunological mechanism in the etiology of IPH and SLE. Raynauds phenomenon associated with positive anti-RNP antibody is also associated with IPH. Usually, IPH and other autoimmune or collagen vascular diseases develop simultaneously [45]. Immunopathologically, in IPH livers, there are lymphoid cells in portal tracts, particularly at early stages [32]. Surgical specimens show more lymphoid cells. As described below, edema and fibrosis with lymphocytic infiltration into the intima of the small portal veins is also known to occur in IPH livers (Figs. 6A, 6B) [29, 51]. These lymphoid cells may be involved in the immunopathological processes of IPH [58]. HLA-DR antigen, which is involved in immune recognition and other immunological reactions, is more

Connective tissue growth factor (CTGF) stimulates in vitro fibroblast proliferation and the synthesis of extracellular matrix [40]. It is known that the serum level of CTGF is increased in patients with PSS and pulmonary fibrosis. In addition, it appears that production of CTGF is involved in the development or maintenance rather than the initiation of fibrosis in PSS. Recently, increased serum levels of CTGF were found in IPH patients (Tsuneyama et al, in preparation). There are case reports of IPH with PSS, suggesting that CTGF is an important fibrogenetic factor in situ in portal venous fibrosis of IPH, as speculated in PSS. In the group with chronic hepatitis, an increase in CTGF immunostaining was associated with a higher score of fibrosis; CTGF was strongly expressed during liver fibrogenesis, and hepatic stellate cells seemed to be the major cellular source of CTGF in the liver [40]. In IPH, similar processes are effective, although the exact mechanism of the fibrogenesis in portal fibrosis remains speculative.
Thrombosis and clotting abnormalities

Mural and even occlusive thromboembolism of hilar and intrahepatic large portal veins occur secondary to IPH (Fig. 7), an event that may aggravate the liver pathology of IPH. In portal venous thrombosis, deficiencies in natural anticoagulants, such as protein C and factor V Leiden mutation, are strongly associated with thrombosis [7, 39, 54]. The deficiencies produce a favorable medium for thrombus generation in the portal vein [7]. In Japan, direct evidence for portal venous thrombosis as a primary factor of IPH is still lacking [35]. The calculated incidence of portal vein thrombosis was angiographically 0.573% of all cirrhotic patients without splenectomy in the past [37], although the incidence of portal vein thrombosis unrelated to splenectomy was angiographically 2.86% in IPH.

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cy, while some hepatic and portal changes may be related to the primary or initiating factor(s). Histological heterogeneity is a fundamental character of IPH. In advanced cases, enlarged portal tracts are distributed unevenly and often positioned closely together, so that the normal lobular or acinar architecture is profoundly distorted. Subcapsular parenchymal atrophy is evident [19, 37]. In other cases, the liver histology is almost normal, except for portal venous dilatation or obliteration.
Hepatic parenchyma and hepatic vein tributaries of IPH livers

Fig. 7. The cut surface of autopsy liver of idiopathic portal hypertension. Intrahepatic portal veins are occluded by organizing and fresh thromboemboli (large arrows). Portal tracts and hepatic veins (small arrows) are unusually approximate to the hepatic capsule.

The acinar architecture is distorted as follows: 1) formation of isolated aberrant vessels with a random distribution; 2) displaced and abnormally large hepatic vein branches and 3) slender, curved fibrous septa (hairline septa). The histological changes include the following lesions: Hepatic parenchymal atrophy. Atrophy of IPH livers is recognizable by three parameters. First, the weight of the liver is reduced in about one half of the cases, although there is a wide variation. The IPH liver is usually atrophic, especially at a late stage. Next, the atrophy of hepatic parenchyma is recognizable by atrophy of hepatic lobules (Fig. 8) [36], an observation preferentially made in perivenular areas and also between hyperplastic hepatocellular nodules; hepatocytes are more or less atrophic or small. Congestion is sometimes seen in these atrophic areas. Third, on gross examination atrophy tends to occur at the hepatic periphery or in subcapsular regions (subcapsular hepatic parenchymal atrophy) (Figs. 1, 2, 7). There is unusual approximation of portal tracts and hepatic vein tributaries close to the hepatic capsule. In these areas, hepatic parenchyma is variably lost.

Infectious etiology

That the number of IPH patients is decreasing in developed countries might be attributed to improvements in the environment or public health. To obtain clues as to the etiopathogenesis of IPH, an attempt was made to produce a hepatic lesion similar to that in IPH by repeated injection of aggregated killed non-pathogenic E. coli directly into the portal vein [18, 49]. In the treated dogs, the histology of the liver showed dense fibrosis in the portal tract and aberrant vasculatures around the portal area. Portal pressure was elevated and middle-tosmall-sized portal branches were decreased in number, as revealed by portography. These changes closely mimic those seen in human IPH. It is possible that the appearance of an antigen, such as bacteria from the intestine to the portal venous system, plays an etiologic role in IPH.
IPH related to toxic or chemical environmental factors

Presinusoidal portal hypertension resembling IPH is known to develop in patients treated with chemotherapeutic agents and during arsenic intoxication and vinyl chloride polymerization [13, 52]. The histological and clinical hemodynamic similarity of these cases to IPH suggests that IPH sometimes may result from unknown toxic, possible environmental, chemicals and drugs.

Pathology of IPH Livers

The pathological features of IPH livers are basically non-pathognomonic. Most of these changes could be the result of a long-standing portal venous insufficienFig. 8. Histology of idiopathic portal hypertension. Portal tracts and hepatic vein tributaries are crowded, suggesting hepatic atrophy and small sized hepatic lobules. Elastica van Gieson staining.

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Pathogenesis of hepatic parenchymal atrophy: Disordered intrahepatic hemodynamics, particularly chronic portal venous insufficiency, may be responsible for the progression of hepatic parenchymal atrophy [1, 36]. In experimental animals, ischemia, particularly portal venous insufficiency, is known to cause hepatocellular atrophy and apoptosis [1, 16, 22, 57]. Wanless et al. [47] also reported that atrophy and nodular hyperplasia constitute a chronic response to ischemia, and that vascular obliteration is an important cause of apoptosis and atrophy, which are found in chronic liver diseases including IPH. Hepatocellular apoptosis is a process of ischemic hepatic parenchymal atrophy or dropout. Two types of eosinophilic hepatocellular changes are presumed to be apoptotic in origin. This was defined by round acidophilic bodies and stellate-shaped acidophilic bodies [47]. Either of these apoptotic changes is usually found focally in the hepatic parenchyma in IPH. They are more or less frequent in areas with sinusoidal dilatation. Focal necrosis is characterized by the dropout of hepatocytes and lymphoid cell infiltration. Focal necrosis is occasionally associated with pigmented macrophages scattered throughout the hepatic parenchyma of IPH. Parenchymal collapse is probably due to portal venous occlusion, such as thromboembolism, which is also superimposed in IPH livers, particularly at terminal stages. Occasionally, the hepatic segment collapses totally. Waving of the hepatic surface is characterized by granularity of the hepatic capsule and loss of hepatic parenchyma. The hepatic surface is nodular, appearing as liver cirrhosis. This is an extreme feature of peripheral hepatic parenchymal atrophy with fibrous overgrowth. In the deeper areas, such fibrosis is minimal, and so is nodularity. Parenchymal fibrosis. Hepatic parenchymal fibrosis is divided into three categories: pericellular fibrosis, intralobular slender fibrous septa, and slender fibrous septa from the portal tracts. These changes are more or less mild and focal, when compared to other fibrotic progressive liver diseases. Pericellular fibrosis found around the hepatic cords is frequently seen in the perivenular areas, and also between hyperplastic hepatocellular nodules (Fig. 9). In these areas, hepatocytes are atrophic, and sinusoids were dilated, linking neighboring central veins. Intralobular fibrous slender septa were seen in more than 50% of IPH cases. Slender fibrous septa from the fibrotic portal tracts are seen focally in IPH. These fibrous septa link neighboring portal tracts. Pathogenesis of parenchymal fibrosis: Microcirculatory changes, particularly portal venous insufficiency, may be related to pericellular fibrosis. Interestingly, smooth muscle antigen (ASMA)-positive, activated perisinusoidal cells (myofibroblasts) are increased or

Fig. 9. Histology of idiopathic portal hypertension. A: In perivenular areas, hepatocytes are atrophic with condensation of perisinusoidal fibers (V). P, portal tract. Reticulin stain. B: In perivenular areas there is deposition of collagen fibers (arrow) around atrophic hepatocellular cords. HE.

accumulated in the perivenular areas and also around atrophic hepatocytes in the hepatic parenchyma (Fig. 10). Activated perisinusoidal cells are known to actively produce extracellular matrix proteins, including collagen, laminin and fibronectin [8,11,41,43,44,59]. Portal venous insufficiency may activate perisinusoidal cells and then contribute to the development and progression of mild fibrosis in IPH. Sinusoidal dilatation and aberrant blood vessels. Sinusoidal dilatation is not infrequent in IPH. In some cases, the sinusoidal dilatation is associated with fibrous septa and is related to aberrant blood vessels in the hepatic parenchyma. Aberrant blood vessels, which are defined as dilated blood vessels in the hepatic parenchyma immediately adjacent to the peripheral portal tract (Fig. 11), appear under conditions of extrahepatic portal obstruction and IPH [36]. Ohbu et al. [30] showed that aberrant vessels are frequently found in IPH and extrahepatic portal obstruction. Aberrant vessels demonstrate the same immunoreactivity as do portal veins for collagen type IV, laminin, factor VIII and ulex europaeus agglutinin-I. It has been concluded that they arise from the vasa septalis or inlet venules, which would be used as intrahepatic shunts draining portal blood flow blocked by stenosed portal veins. Increased portal pressure would be expected to enhance the development of aberrant vessels. Nodular hepatocellular hyperplasia. Nodular regeneration is found in one third or more of IPH cases (Fig. 12) [4, 25]. Atrophy and nodular hyperplasia of the hepatic parenchyma are regarded as constituting a chronic response to ischemia in IPH [47], although it remains unclear why hepatocellular hyperplasia is predominant in

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some cases and absent in others. These nodular changes are similar to nodular regenerative hyperplasia, focal nodular hyperplasia, partial nodular transformation and macroregenerative nodules of the liver, although this

changes are incomplete or immature in their morphologies and/or focal in their distribution in IPH, as compared to those without portal hypertension . Hepatic vein tributaries and terminal hepatic venules. Some terminal and sublobular hepatic veins show phlebitis or some eccentric fibrosis, without clear evidence of luminal compression or occlusion [36]. Small hepatic veins also frequently show fibrous thickening of their walls.
Portal fibrosis and vascular damage

10

Changes in the portal tract include fibro-elastosis, phlebosclerosis, portal venous dilatation and obliteration, and capillary dilatation. Pathological changes of portal tracts differ depending on the size of the portal tracts; these are also quite heterogeneous and dependent on the place and the patient, probably reflecting the stage or progression of IPH. Portal fibrosis and periductal fibrosis. Portal tracts show dense collagen deposition. They are variably enlarged, although they are usually round and occasionally show spike-like fibrous septa growing into the hepatic parenchyma. A lot of elastic fibers are also present. Disordered synthesis and degradation of fibrosis and extracellular matrix (ECM) may be responsible for dense portal fibrosis. Portal tract inflammation characterized by infiltration of lymphoid cells is also seen, particularly in wedge biopsy cases. Periductal fibrosis is also frequently seen at the level of medium-sized interlobular bile ducts and septal bile ducts. This may be due to an insufficiency of peribiliary vascular plexus, because their changes resemble the adverse effects of transcatheter arterial embolization therapy or chemoembolization [17]. It is possible that portal venous vascular compression by portal fibrosis or arterial hypoperfusion leads to the ductal changes in IPH. Loss of bile ducts is a rare complication [27]. Vascular changes Grossly visible intrahepatic portal veins including hilar portal veins and extrahepatic portal veins These are open or even dilated in established IPH livers, although they constantly show phlebosclerosis and intimal thickening to various degrees and distribution, suggesting the organization of repeated mural and possibly occlusive thromboembolism. The medial muscle is also increased (arterialization). Fresh occlusive thromboembolism, which is often superimposed, is frequent in autopsy cases. Thrombotic processes of the portal venous system eventually occur, particularly after splenectomy [50]. Portal venous blood stasis may be responsible for this. Some main branches of the portal vein are occasionally occluded by an old thrombus

11

12

Fig. 10. Immunostaining of -smooth muscle antigen (SMA) in idiopathic portal hypertension. Perisinusoidal cells in perivenular areas are positive for -SMA and increased in the perivenular area. V, central vein; P, portal tract. Fig. 11. Histology of idiopathic portal hypertension. Arrows denote aberrant vessels in the hepatic parenchyma adjacent to fibrotic portal tract (P) in which original portal veins are obliterated. HE. Fig. 12. Histology of idiopathic portal hypertension. Vague nodular hyperplasia of hepatocytes is seen (N) in the hepatic lobule. P, portal tract. Reticulin stain.

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with recanalization, and extrahepatic portal venous obstruction of adults with features of IPH in the liver can be included in IPH (Fig. 7) [38]. Small portal vein branches Portal venous obliteration or luminal narrowing is a rather constant finding, particularly at autopsy [33], although portal veins are dilated and some have herniated into the surrounding hepatic parenchyma, particularly in needle biopsy specimens. Phlebosclerosis of medium-sized intrahepatic portal veins is a frequent and constant lesion that is recognizable at wedge biopsy or autopsy. This lesion is associated with muscular hypertrophy. Medium-sized portal vein branches occasionally show intimal thickening and even recanalization. In addition, edematous and fibrous thickening of the intima with inflammatory cell infiltration in the intima of portal vein branches is occasionally seen (Figs. 6A, 6B). This lesion may be a kind of phlebitis. Although this lesion is focal, it is rather characteristic of IPH and may be a primary lesion of IPH according to Ohbu [29]. It is exclusively found in IPH livers, which may reflect the immunological pathogenesis of IPH. Lymphatics. The number of lymphatics was higher in the IPH samples than in the control samples, suggesting that the increased lymph flow may in turn reduce the high portal vein pressure in IPH. Hepatic arterial changes. Our preliminary study disclosed that hepatic arterial branches are increased neither in number nor in the luminal area in IPH, reflecting the decreased arterial blood flow in the liver.
Diagnosis of IPH by needle or wedge biopsy

under different names, such as hepatoportal sclerosis, NCPF, non-cirrhotic intrahepatic portal hypertension, and benign intrahepatic portal hypertension [1, 22]. They share not only clinical and laboratory features but also pathological features, such as portal venous and portal tract abnormalities, and also parenchymal atrophy perhaps as a result of portal circulatory insufficiency [36]. The clinical and pathological features of these diseases may be the same, although their etiopathogenesis may differ according to location. In addition, extrahepatic portal venous obstruction with clinicopathological features of IPH could be included in the category of IPH. Such cases must be IPH originally, because there are several IPH cases in which portal venous thrombosis and portal venous obstruction occur secondarily in the course of IPH (stage IV, see below). In addition, there are also patients with spontaneous portal-systemic shunt and hepatic encephalopathy without splenomegaly. The liver histology of these patients resembles IPH but with normal portal pressure [48]. Such cases could also constitute a variant of IPH in which portal blood flow into the shunt and thereby clinically detectable portal hypertension and splenomegaly do not occur. Related diseases. Incomplete septal cirrhosis: In incomplete septal cirrhosis, slender septal fibrosis is an extension of portal fibrosis and perivenular fibrosis, and subdivides the parenchyma into inconspicuous nodules. These livers also show an abnormal spacing between the portal tracts and veins, and small hypoplastic portal tracts within the parenchyma. This could be a late manifestation of IPH[5, 6, 25], although the differentiation from macronodular cirrhosis is controversial in several cases. Nodular regenerative hyperplasia (NRH): This disease is characterized by non-cirrhotic regenerative nodules in the liver and occurs in portal hypertensive cases as well as in cases without portal hypertension. These nodulations generally involve the whole liver. Distinguishing NRH with portal hypertension from IPH with parenchymal nodular hyperplasia is difficult, and such cases could be included in IPH. Partial nodular transformation: This disease is characterized by grossly visible nodulations without fibrous septa, mainly involving the hepatic hilar regions. Some of these cases may occur as a compensatory hypertrophy of the liver in non-portal hypertensive cases, such as partial biliary occlusion, although the cases associated with non-cirrhotic portal hypertension may belong to IPH. Similar but different diseases. Myeloproliferative disorders: In myeloproliferative disorders such as myelofibrosis or polycythemia vera, non-cirrhotic portal hypertension can develop. In such cases, thrombosis of portal veins and hepatic veins is a common cause of

IPH is a clinical syndrome of pre-sinusoidal long-standing portal hypertension. Although the degree and distribution of the pathological changes related to IPH are generally heterogeneous, thus creating sampling errors for biopsy, histopathological study is necessary to render a diagnosis of IPH. The most important task for pathologists is to exclude liver cirrhosis, particularly macronodular liver cirrhosis. Biopsy specimens, particularly needle biopsy, not infrequently show nonspecific changes, i.e., non-diagnostic changes. Liver biopsies reveal portal fibrosis with subintimal thickening or luminal obliteration of terminal portal vein branches, and a striking peri-ductal fibrosis, supporting the diagnosis of IPH [53]. When portal hypertension occurs in association with a radiologically patent portal vein and an essentially normal liver biopsy specimen, IPH must be considered.
Comparison with equivalent and related diseases

Equivalent or similar diseases. Diseases similar to IPH occur worldwide. These, however, are known

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portal hypertension [56]. However, in a few cases with portal hypertension, increased portal blood flow from marked splenomegaly associated with extramedullary hematopoiesis could play a role in portal hypertension. Nodular regenerative hyperplasia of the liver is also encountered [55]. Presinusoidal portal hypertension related to medical treatments and intoxication: There is an association between a long-standing presinusoidal portal hypertension resembling IPH and the use of chemotherapeutic agents, particularly thioguanine [46]. Mild sclerosis of some small portal triads and perisinusoidal fibrosis are the only abnormalities seen. Chronic arsenic intoxication, usually for psoriasis, is also known to be associated with such a syndrome [13]. A peculiar pattern of progressive portal tract, inconspicuous intralobular and conspicuous capsular fibrosis accompanied by splenomegaly was also observed in five workers with vinyl chloride polymerization [52]. Hypertrophy and hyperplasia of both hepatocytes and hepatic and splenic mesenchymal cells were also seen [61]. Furthermore, a similar syndrome occurs following renal transplantation. These patients had been treated with azathioprine and prednisolone for several years. In these patients, the spleen might have played an important role in the development of this syndrome. Microscopic examination of liver biopsies taken at the operation revealed lymphoplasmacytic infiltration with bile duct hyperplasia but no evidence of periportal fibrosis except for very mild perisinusoidal fibrosis.

sy specimens. The parenchymal nodular changes of the liver are not recommended to be used for the staging of IPH livers either, because they are not always present, and the correlation between them and the progression of IPH remains unclarified. Therefore, we adopted three main, grossly recognizable, morphological factors in this new staging, i.e., the presence or absence of peripheral parenchymal atrophy, the size or weight of the liver, and obstructive portal vein thrombosis of the intrahepatic large portal veins and/or portal vein trunk. All of these factors are recognizable grossly as well as by imaging, radio-isotope scanning, peritoneoscopy, and/or portography. Evaluation of three parameters. Evaluation of the size or weight of liver: It is important to ascertain the weight of the IPH livers. Some livers were swollen, while others were markedly atrophic. The size of the liver is evaluable by imaging modalities, particularly computed tomography [12, 60]. Evaluation of subcapsular hepatic parenchymal atrophy: Subcapsular hepatic parenchymal atrophy is recognizable grossly on the cut surface of the autopsy liver. Magnetic resonance imaging (MRI) shows the proximity of medium-sized intrahepatic vessels to each other and to the liver surface [2, 3, 21]. Computed tomography (CT) during arterial portography shows abnormally short distances between some of the medium-sized portal branches and the liver surface [20]. Portography shows a lack of filling between the surface of the liver and peripheral vessels. Peripheral regional enhancement of the liver was seen in the arterial phase. On portograms taken via the superior mesenteric artery, markedly decreased portal venous perfusion was seen in the peripheral region of the liver. Evaluation of portal venous thrombosis: Assessment of portal vein patency and portal flow is most simply accomplished using Doppler ultrasonography, which also provides information about the hepatic veins and inferior vena cava. Portography of either kind is useful for the demonstration of occlusive portal veins. Proposal of a new staging system based on gross and imaging features. By a combination of these gross findings, IPH livers were categorized into four groups (Stage I, II, III, and IV) as shown below. Their schemes and likely progression are shown in Fig. 13. Stage I is early IPH, while stages II and III are advanced. To date, a staging system has not yet been described in the literature. This staging system can be applied to patients by combining imaging procedures with peritoneoscopy, and also to autopsy livers. In addition, the histological changes of IPH are known to be heterogeneous, and sampling errors are unavoidable, so the gross findings or imaging findings are considered more useful in staging. However, stage I cases are rare.

Proposal of a New Staging of IPH

It is generally thought that the IPH liver itself is already at the end-stage pathologically when diagnosed clinically. So, little is known about the pathological stages of IPH. However, as mentioned in the pathology of IPH livers, most pathological changes to IPH livers seem to be a consequence of a long-standing portal venous insufficiency in the liver. Therefore, these changes appear to progress and increase in their degree and extent during a long clinical course. Almost all chronic diseases of hepatocellular, biliary and hepatic venous obstructive diseases are known to be followed by the development of liver cirrhosis. Although the chronic effect of intrahepatic portal venous blocks on the liver may not lead to cirrhotic transformation, a pathological progression may evolve that may also be effective in IPH livers. By a combination of gross features, IPH livers could be grouped into several categories which may reflect the stage of the pathological progression of IPH or prognosis. The histological features of IPH should not be used as parameters for the pathological staging of IPH, because these are very heterogeneous, and sampling errors are likely to occur in needle or wedge biop-

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bolism of portal veins, but is more frequent in stage II and even more frequent at stage III. At autopsy, stage IV is relatively common. Superimposition of occlusive thrombosis of the intrahepatic large portal veins and/or portal vein trunk means a poor prognosis, and in fact, such patients frequently die of portal venous thrombosis. So, this factor was adopted as an independent staging factor in this system, for stage IV, when such a factor is found to be independent of other factors. In stage I, II and III livers, the intrahepatic large portal veins and extrahepatic portal veins show luminal thickening and even calcification, suggesting repeated thrombosis. As for stages I, II, and III, the histopathological changes may progress in this order. Portal venous occlusive thrombosis is likely to develop at advanced stages of IPH.

Conclusion
The recent progress in the study of IPH with respect to etiopathogenesis and pathology was reviewed. The proposal of a new staging system is based on the gross features of IPH, which reflect the secondary pathological features. The etiology could be multiple. It seems possible that IPH is heterogeneous in its initiation and/or progression depending on the etiology. The liver pathology characterized by occlusive changes of the intrahepatic portal radicles, portal and periportal fibrosis, and irregularly distributed parenchymal atrophies suggests some sort of portal venopathy that causes decreased portal perfusion of peripheral liver parenchyma. The most important issues of the pathobiology of IPH to be addressed and clarified in the near future are: 1) What are the etiologies? 2) How does portal hypertension develop and which pathological changes reflect the presinusoidal portal hypertension? and 3) How do secondary changes of the liver caused by intrahepatic hemodynamic alterations in IPH progress?
Acknowledgements. This study was supported by the Japanese Study Group of Intrahepatic Hemodynamic Alterations (Chairman: Prof. Keizo Sugimachi, Professor of Surgery, Kyushu University, Graduate School of Medicine, Fukuoka, Japan).

Fig. 13. Scheme of proposed staging of idiopathic portal hypertension. Stage I progresses to stage II, and stage II to stage III. In addition, each stage progresses to stage IV, characterized by occlusive portal venous thrombosis. Dotted areas beneath the hepatic capsule represent the subcapsular parenchymal atrophy and even collapse. The size of the liver is decreased at stage III. Phlebosclerosis of the hilar portal vein and of the intrahepatic large portal veins increases from stage I to stage II and from stage II to stage III both in degree and extent.

Stage I: Absence of peripheral parenchymal atrophy. The liver is usually not atrophic nor even swollen, and the surface is speculated to be smooth. IPH diagnosed at this stage is rare. Etiologic factor(s) remain to be identified at this stage. Stage II: Presence of peripheral parenchymal atrophy in non-atrophic liver. The surface is uneven or wavey and even vaguely nodular. The cut surface shows distinct subcapsular atrophy characterized by the close proximity of portal tracts or hepatic veins to the hepatic capsule. Stage III: Presence of peripheral parenchymal atrophy in atrophic liver. The surface is uneven or wavy, and even vaguely nodular. The cut surface shows distinct subcapsular atrophy. Occasionally, there is collapse involving areas or segments of the liver. Stage IV: Presence of obstructive thrombosis of intrahepatic large portal veins or portal vein trunk. This is regarded as being the superimposition of thromboem-

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