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tively late, has a poor prognosis. This staging is applica-ble to clinical and autopsy cases without any histologi-cal data.

Key words: Liver pathology Hepatic fibrosis Hepa-tocellular apoptosis Portal venous insufficiency Idiopathic portal hypertension

Introduction

Idiopathic portal hypertension (IPH) is characterized bya long-standing non-cirrhotic portal hypertension be-cause of the intrahepatic block of small portal veinbranches [32, 37 ] . Pathologically, portal phlebosclero-sis, obliteration of intrahepatic small portal veins, andsubcapsular parenchymal atrophy with unusual approx-imation of portal tracts and hepatic veins to each otherare characteristic of IPH livers (Figs. 15) [25, 36 ] .Hepatocellular atrophy with sinusoidal dilatation andportal and intralobular fibrosis are also found in IPH

livers, to various degrees and in various combinations[47] . Hepatocellular nodular hyperplasia is not uncom-mon, either [4, 25 ] . However, early or primary changesor lesions causally related to intrahepatic portal venousblock have not yet been identified, although several eti-ological factors have been proposed.

In this review, we first describe the clinical featuresand hemodynamic character of IPH. Then, we try tocategorize the primary and secondary pathological

Review

Summary

Idiopathic portal hypertension (IPH) is characterized bya long-standing presinusoidal portal hypertension of un-known etiology in adults. Some unidentified agent(s)affect(s) the intrahepatic small portal veins or portaltracts. Immunological disturbance, thromboembolism,infectious etiology and/or increased fibrogenesis in por-tal tracts are suspected as being candidates for the pri-

mary agent(s). During the long clinical course of IPH,several pathological changes may occur, including sub-capsular parenchymal atrophy, atrophy of the liver, por-tal and parenchymal fibrosis, and portal venous phle-bosclerosis and thrombosis. The last-named of these le-sions is mostly found in patients with a history of splenectomy. Subcapsular parenchymal and hepatic at-rophy may result from a hepatocellular dropout viaapoptosis or necrosis because of intrahepatic hemody-namic disturbances, particularly chronic portal venousblood insufficiency. Pericellular fibrosis and thin fi-brous septa are also frequently found and associatedwith activated perisinusoidal cells positive for smooth

muscle actin. At the same time, vague nodular hyper-plasia of hepatocytes not surrounded by fibrous septa isnot infrequently seen. It may resemble nodular regener-ative hyperplasia, partial nodular transformation, orfocal nodular hyperplasia. However, liver cirrhosis doesnot occur even at the terminal stage. Taking these find-ings into consideration, a new staging of IPH with acombination of hepatic parenchymal atrophy and portalvenous thrombosis was proposed: non-atrophic liverwithout subcapsular parenchymal atrophy (stage I),non-atrophic liver with subcapsular parenchymal atro-phy (stage II), atrophic liver with subcapsular paren-chymal atrophy (stage III), and portal venous occlusivethrombosis (stage IV). IPH livers are likely to progressfrom stage I to stage III. Stage IV, which occurs rela-

Pathology and Pathogenesis of Idiopathic PortalHypertension with an Emphasis on the Liver

Yasuni Nakanuma 1 , K oichi Tsuneyama 1 , M akoto O hbu 2 andK azuyoshi Katayanagi 1

1Department of Pathology (II) , K anazawa University School of M edicine, K anazawa, and2

Department of Pathology, K itasato U niversity School of M edicine, Sagamihara, Japan

Pathol. Res. Pract. 197: 6576 (2001) 0344-0338/01/197/2-65 $15.00/0

PATHOLOGYRESEARCH AND PRACTICE Urba n &Fischer Verlaght tp: //w w w.u rba nfischer.de/journa ls/prp

Address for correspondence: Yasuni Nakanuma, SecondDepartment of Pathology, Kanazawa University School of

Medicine, Kanazawa 920-8640, Japan.Tel.: ++88-076-265-2195, Fax: ++88-076-234-4229.E-mail: [email protected]


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66 Y. Nakanuma et al.

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Fig. 1. Cut surface of autopsy liver of idiopathic portal hyper-etnsion. The liver is atrophic, and portal tracts (large arrows)and hepatic veins (small arrow) are unusually approximated tothe hepatic capsule. Intrahepatic large portal vein ( V ) is dilat-ed.

Fig. 3. Small portal tract in idiopathic portal hypertension.This portal tract (arrow) is densely sclerotic, and hepaticartery and bile ducts are identifiable. However, portal vein isobliterated. 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 vanGieson stain.

Fig. 5. A medium-sized portal tract in idiopathic portal hy-

pertension. Portal tract is densely fibrotic, and a medium-sized portal vein (arrow) shows phlebosclerosis with muscu-lar hyperplasia. HE.

Fig. 2. Histological section of autopsy liver of idiopathic por-

tal hypertension. Portal tracts and hepatic vein tributaries areunusually close to the hepatic capsule, and the subcapsularhepatic parenchyma is atrophic. Arrow, hepatic capsule. HE.


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changes in IPH livers with respect to the progression of pathological changes as a consequence of long-standinghemodynamic alterations. The recent progress in the

etiopathogenetic study of IPH is also reviewed. Finally,a new staging of IPH taking the progressive secondaryhepatic lesions into consideration is proposed for aclearer and easier evaluation of the clinicopathologicalfeatures of this disease. This review is based on 97 liverspecimens from cases fulfilling the criteria for IPH ob-tained from the file of hepatobiliary diseases in our lab-oratory and affiliated hospitals.

Main Clinical Findings and Prognosis

Main clinical findings. IPH affects preferentially mid-dle to old aged women in Japan, while the equivalentdisease in India, non-cirrhotic portal fibrosis of the liver(NCPF), usually affects young men [24, 37 ] . This dis-ease is characterized by overt splenomegaly with portalhypertension, and by relatively mild abnormalities inliver function tests [35 ] . There are no laboratory find-ings characteristic of IPH, and IPH patients have nostigmata of chronic liver disease, such as spider an-giomas or palmar erythema. Levels of one or moreblood elements are decreased, and pancytopenia iscommon. Serologically, IPH is not causally related tochronic infection of HBV or HCV. Radiologically, the

established IPH livers show central hypertrophy and pe-ripheral atrophy [20 ] . Esophageal varices and bleedingare also common.

Prognosis of IPH. The disease is relatively benign if variceal bleeding is controlled or prevented, and does notprogress to cirrhosis. However, some IPH cases withhepatic failure have been reported [5, 6, 14 ] . Ichimura etal. [14] followed 171 patients with IPH and reported that20 patients died (6 from bleeding in the gastro-intestinaltract, 5 from hepatic insufficiency and 9 from other caus-es). Male patients with a disease onset at less than 40years of age had poorer prognoses. The occurrence of oc-clusive portal venous thrombosis indicates poor progno-sis, and in fact, in autopsy cases, occlusive portal venousthromboembolism is not infrequently encountered. Inpatients with collagen vascular disease [15, 45 ] , an asso-ciation with IPH is regarded as being one of the most im-portant complications affecting prognosis.

Hemodynamics of IPH in comparison withliver cirrhosis

Portal vein pressure is significantly elevated in liver cir-rhosis and IPH. In liver cirrhosis, portal venous bloodflow into the liver is almost normal, while intrahepaticvascular resistance at the postsinusoidal level is

markedly increased [31] . In addition, hepatic arterialblood flow into the liver is increased, and there aremany arterio-portal venous (AP) shunts in the liver.By contrast, in IPH there is an increase in the portal ve-nous blood flow into the liver, in the diameter of portalvein trunks, and in presinusoidal vascular resistance,but a decrease in the hepatic arterial flow into the liver;A-P shunt is negligible. Extrahepatic portal-systemicshunts are present in IPH and liver cirrhosis. In cirrho-sis, portography reveals distortion of the intrahepaticvasculatures and hepatofugal flow, and arteriogramsshow a characteristical corkscrew appearance. Al-though the portograms in IPH vary among cases, dilata-tion of the hilar portal veins and intrahepatic largebranches, irregular and often obtuse-angled divisions of the peripheral branches, occasional abrupt interrup-tions, and an avascular area beneath the liver surface arefrequently seen. Non-opacification of some of the largeintrahepatic portal branches and a paucity of medium-

Idiopathic Portal Hypertension 67

A

B

Fig. 6. Intimal edema and fibrosis of portal vein branches: Asmall portal vein (arrows) shows intimal edema and fibrosiswith mild lymphocytic infiltration (a kind of phlebitis). Theoutline of this vein is well delineated by Elastica van Giesonstain (B). V , hepatic arterial branch. A: HE; B: Elastica vanGieson stain. A and B are serial sections of the same portaltract.


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frequently expressed on the microvasculature of portaltracts in IPH; this expression may be a factor initiatingthe immunological assault on portal microvessels in

IPH [45, 50, 51 ] . An increased level of interferon (IFN)in portal venous blood may be responsible for thisHLA-DR expression [58 ] .

As for the adhesion molecules, which are importantin the interaction between lymphocytes and accessoryand target cells, the serum level of soluble VCAM-1 isfound to be increased [58] . The level of soluble ICAM-1 of IPH patients is slightly elevated but not differentfrom that in patients with other diseases. VCAM-1 isexpressed in the sinusoidal lining cells and portal ve-nous endothelial cells in several IPH patients. Increasedexpression of VCAM-1 may reflect an immunopatho-logical phenomenon in the occurrence of IPH.

Progressive fibrosis

Connective tissue growth factor (CTGF) stimulates invitro fibroblast proliferation and the synthesis of extra-cellular matrix [40] . It is known that the serum level of CTGF is increased in patients with PSS and pulmonaryfibrosis. In addition, it appears that production of CTGFis involved in the development or maintenance ratherthan the initiation of fibrosis in PSS. Recently, in-creased serum levels of CTGF were found in IPH pa-tients (Tsuneyama et al, in preparation). There are case

reports of IPH with PSS, suggesting that CTGF is animportant fibrogenetic factor in situ in portal venous fi-brosis of IPH, as speculated in PSS. In the group withchronic hepatitis, an increase in CTGF immunostainingwas associated with a higher score of fibrosis; CTGFwas strongly expressed during liver fibrogenesis, andhepatic stellate cells seemed to be the major cellularsource of CTGF in the liver [40 ] . In IPH, similar pro-cesses are effective, although the exact mechanism of the fibrogenesis in portal fibrosis remains speculative.

Thrombosis and clotting abnormalities

Mural and even occlusive thromboembolism of hilarand intrahepatic large portal veins occur secondary toIPH (Fig. 7 ), an event that may aggravate the liverpathology of IPH. In portal venous thrombosis, defi-ciencies in natural anticoagulants, such as protein C andfactor V Leiden mutation, are strongly associated withthrombosis [7, 39, 54 ] . The deficiencies produce a fa-vorable medium for thrombus generation in the portalvein [7] . In Japan, direct evidence for portal venousthrombosis as a primary factor of IPH is still lacking[35 ] . The calculated incidence of portal vein thrombo-sis was angiographically 0.573% of all cirrhotic pa-tients without splenectomy in the past [37 ] , althoughthe incidence of portal vein thrombosis unrelated tosplenectomy was angiographically 2.86% in IPH.

sized portal branches could be interpreted as a late andsecondary complication of portal venous thromboem-bolism [9] .

Characteristic changes in IPH include frequent hep-atic vein-to-hepatic vein anastomoses, narrower anglesbetween large veins and their tributaries, smooth andwavy middle-sized to large branches (giving a generalweeping willow appearance), homogeneous sinu-soidal filling, and minimal to no filling of the portal ve-nous system on wedged retrograde portography [10 ] . Incirrhosis, by contrast, changes include rare vein-to-veinanastomoses, wide angles between veins and tribu-taries, irregular stenosis of large veins and branches atvarious levels, spotty sinusoidal filling, and frequentretrograde flow in the portal venous system.

IPH is also characterized by marked splenomegaly.Marked splenomegaly with increased blood inflow can-not be simply attributed to congestion, and it remains anenigma.

Etiopathogenesis of IPH

The primary factor(s) involved in the development of presinusoidal portal hypertension may vary with theetiopathogenesis. In this context, IPH could be hetero-geneous. The following points may represent factorsplaying a role in the etiology of IPH.

Immunological factors

A number of immunological abnormalities, such as hy-pergammaglobulinemia and antinuclear antibodies withhigh titer, occur in patients with IPH. LE cell phenome-na were also positive in some patients [15, 23 ] . In addi-tion, IPH associated with systemic lupus erythematosus(SLE), chronic thyroiditis, mixed connective tissue dis-ease, and progressive systemic sclerosis (PSS) has beenreported [26, 28, 29, 50, 51, 42 ] . The presence of anti-cardiolipin antibody, indicated by positivity for lupusanticoagulant, is suggestive of the presence of a com-mon immunological mechanism in the etiology of IPHand SLE. Raynauds phenomenon associated with posi-tive anti-RNP antibody is also associated with IPH.Usually, IPH and other autoimmune or collagen vascu-lar diseases develop simultaneously [45] .

Immunopathologically, in IPH livers, there are lym-phoid cells in portal tracts, particularly at early stages[32] . Surgical specimens show more lymphoid cells. Asdescribed below, edema and fibrosis with lymphocyticinfiltration into the intima of the small portal veins isalso known to occur in IPH livers (Figs. 6A, 6B) [29,51] . These lymphoid cells may be involved in the im-munopathological processes of IPH [58 ] .

HLA-DR antigen, which is involved in immunerecognition and other immunological reactions, is more



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cy, while some hepatic and portal changes may be relat-ed to the primary or initiating factor(s). Histologicalheterogeneity is a fundamental character of IPH. In ad-

vanced cases, enlarged portal tracts are distributed un-evenly and often positioned closely together, so that thenormal lobular or acinar architecture is profoundly dis-torted. 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 IPHlivers

The acinar architecture is distorted as follows: 1) for-mation of isolated aberrant vessels with a random distri-bution; 2) displaced and abnormally large hepatic veinbranches and 3) slender, curved fibrous septa (hairlinesepta). The histological changes include the followinglesions:

Hepatic parenchymal atrophy. Atrophy of IPH liversis recognizable by three parameters. First, the weight of the liver is reduced in about one half of the cases, al-though there is a wide variation. The IPH liver is usual-ly atrophic, especially at a late stage. Next, the atrophyof hepatic parenchyma is recognizable by atrophy of hepatic lobules (Fig. 8) [36 ] , an observation preferen-tially made in perivenular areas and also between hy-

perplastic hepatocellular nodules; hepatocytes are moreor less atrophic or small. Congestion is sometimes seenin these atrophic areas. Third, on gross examination at-rophy tends to occur at the hepatic periphery or in sub-capsular regions (subcapsular hepatic parenchymal at-rophy) (Figs. 1, 2, 7). There is unusual approximationof portal tracts and hepatic vein tributaries close to thehepatic capsule. In these areas, hepatic parenchyma isvariably lost.


Fig. 7. The cut surface of autopsy liver of idiopathic portalhypertension. Intrahepatic portal veins are occluded by orga-

nizing and fresh thromboemboli (large arrows). Portal tractsand hepatic veins (small arrows) are unusually approximate tothe hepatic capsule.

Fig. 8. Histology of idiopathic portal hypertension. Portal

tracts and hepatic vein tributaries are crowded, suggestinghepatic atrophy and small sized hepatic lobules. Elastica vanGieson staining.

Infectious etiology

That the number of IPH patients is decreasing in devel-oped countries might be attributed to improvements inthe environment or public health. To obtain clues as tothe etiopathogenesis of IPH, an attempt was made toproduce a hepatic lesion similar to that in IPH by re-

peated injection of aggregated killed non-pathogenic E.coli directly into the portal vein [18, 49 ] . In the treateddogs, the histology of the liver showed dense fibrosis inthe portal tract and aberrant vasculatures around theportal area. Portal pressure was elevated and middle-to-small-sized portal branches were decreased in number,as revealed by portography. These changes closelymimic those seen in human IPH. It is possible that theappearance of an antigen, such as bacteria from the in-testine to the portal venous system, plays an etiologicrole in IPH.

IPH related to toxic or chemical environmental factors

Presinusoidal portal hypertension resembling IPH isknown to develop in patients treated with chemothera-peutic agents and during arsenic intoxication and vinylchloride polymerization [13, 52 ] . The histological andclinical hemodynamic similarity of these cases to IPHsuggests that IPH sometimes may result from unknowntoxic, possible environmental, chemicals and drugs.

Pathology of IPH Livers

The pathological features of IPH livers are basicallynon-pathognomonic. Most of these changes could bethe result of a long-standing portal venous insufficien-


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accumulated in the perivenular areas and also aroundatrophic hepatocytes in the hepatic parenchyma (Fig.10). Activated perisinusoidal cells are known to active-ly produce extracellular matrix proteins, including col-lagen, laminin and fibronectin [8,11,41,43,44,59 ] . Por-tal venous insufficiency may activate perisinusoidalcells and then contribute to the development and pro-

gression of mild fibrosis in IPH.Sinusoidal dilatation and aberrant blood vessels. Si-nusoidal dilatation is not infrequent in IPH. In somecases, the sinusoidal dilatation is associated with fi-brous septa and is related to aberrant blood vessels inthe hepatic parenchyma. Aberrant blood vessels, whichare defined as dilated blood vessels in the hepaticparenchyma immediately adjacent to the peripheral por-tal tract (Fig. 11), appear under conditions of extrahep-atic portal obstruction and IPH [36] .

Ohbu et al. [30] showed that aberrant vessels are fre-quently found in IPH and extrahepatic portal obstruc-

tion. Aberrant vessels demonstrate the same immunore-activity as do portal veins for collagen type IV, laminin,factor VIII and ulex europaeus agglutinin-I. It has beenconcluded that they arise from the vasa septalis or inletvenules, which would be used as intrahepatic shuntsdraining portal blood flow blocked by stenosed portalveins. Increased portal pressure would be expected toenhance the development of aberrant vessels.

Nodular hepatocellular hyperplasia. Nodular regener-ation is found in one third or more of IPH cases (Fig. 12)[4, 25 ] . Atrophy and nodular hyperplasia of the hepaticparenchyma are regarded as constituting a chronic re-sponse to ischemia in IPH [47] , although it remains un-clear why hepatocellular hyperplasia is predominant in

Pathogenesis of hepatic parenchymal atrophy: Dis-ordered intrahepatic hemodynamics, particularly chron-ic portal venous insufficiency, may be responsible for

the progression of hepatic parenchymal atrophy [1, 36 ] .In experimental animals, ischemia, particularly portalvenous insufficiency, is known to cause hepatocellularatrophy and apoptosis [1, 16, 22, 57 ] . Wanless et al.[47] also reported that atrophy and nodular hyperplasiaconstitute a chronic response to ischemia, and that vas-cular obliteration is an important cause of apoptosis andatrophy, which are found in chronic liver diseases in-cluding IPH.

Hepatocellular apoptosis is a process of ischemichepatic parenchymal atrophy or dropout. Two types of eosinophilic hepatocellular changes are presumed to beapoptotic in origin. This was defined by round aci-dophilic bodies and stellate-shaped acidophilic bodies[47] . Either of these apoptotic changes is usually foundfocally in the hepatic parenchyma in IPH. They aremore or less frequent in areas with sinusoidal dilatation.

Focal necrosis is characterized by the dropout of hep-atocytes and lymphoid cell infiltration. Focal necrosis isoccasionally associated with pigmented macrophagesscattered throughout the hepatic parenchyma of IPH .

Parenchymal collapse is probably due to portal venousocclusion, such as thromboembolism, which is also su-perimposed in IPH livers, particularly at terminal stages.Occasionally, the hepatic segment collapses totally.

Waving of the hepatic surface is characterized bygranularity of the hepatic capsule and loss of hepaticparenchyma. The hepatic surface is nodular, appearingas liver cirrhosis. This is an extreme feature of peripher-al hepatic parenchymal atrophy with fibrous over-growth. In the deeper areas, such fibrosis is minimal,and so is nodularity.

Parenchymal fibrosis. Hepatic parenchymal fibrosis isdivided into three categories: pericellular fibrosis, in-tralobular slender fibrous septa, and slender fibroussepta from the portal tracts. These changes are more orless mild and focal, when compared to other fibroticprogressive liver diseases.

Pericellular fibrosis found around the hepatic cords isfrequently seen in the perivenular areas, and also be-tween hyperplastic hepatocellular nodules (Fig. 9). Inthese areas, hepatocytes are atrophic, and sinusoidswere dilated, linking neighboring central veins. In-tralobular fibrous slender septa were seen in more than50% of IPH cases. Slender fibrous septa from the fibrot-ic portal tracts are seen focally in IPH. These fibroussepta link neighboring portal tracts.

Pathogenesis of parenchymal fibrosis: Microcircula-tory changes, particularly portal venous insufficiency,may be related to pericellular fibrosis. Interestingly,smooth muscle antigen (ASMA)-positive, activatedperisinusoidal cells (myofibroblasts) are increased or


A B

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


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changes are incomplete or immature in their morpholo-gies and/or focal in their distribution in IPH, as com-pared to those without portal hypertension .

Hepatic vein tributaries and terminal hepaticvenules. Some terminal and sublobular hepatic veinsshow phlebitis or some eccentric fibrosis, without clearevidence of luminal compression or occlusion [36 ] .Small hepatic veins also frequently show fibrous thick-ening of their walls.

Portal fibrosis and vascular damage

Changes in the portal tract include fibro-elastosis, phle-bosclerosis, portal venous dilatation and obliteration,and capillary dilatation. Pathological changes of portaltracts differ depending on the size of the portal tracts;these are also quite heterogeneous and dependent on theplace and the patient, probably reflecting the stage orprogression of IPH.

Portal fibrosis and periductal fibrosis. Portal tractsshow dense collagen deposition. They are variably en-larged, although they are usually round and occasional-ly show spike-like fibrous septa growing into the hepat-ic parenchyma. A lot of elastic fibers are also present.Disordered synthesis and degradation of fibrosis andextracellular matrix (ECM) may be responsible for

dense portal fibrosis. Portal tract inflammation charac-terized by infiltration of lymphoid cells is also seen,particularly in wedge biopsy cases.

Periductal fibrosis is also frequently seen at the levelof medium-sized interlobular bile ducts and septal bileducts. This may be due to an insufficiency of peribiliaryvascular plexus, because their changes resemble the ad-verse effects of transcatheter arterial embolization ther-apy or chemoembolization [17] . It is possible that por-tal venous vascular compression by portal fibrosis or ar-terial hypoperfusion leads to the ductal changes in IPH.Loss of bile ducts is a rare complication [27 ] .

Vascular changesGrossly visible intrahepatic portal veins including

hilar portal veins and extrahepatic portal veinsThese are open or even dilated in established IPH liv-

ers, although they constantly show phlebosclerosis andintimal thickening to various degrees and distribution,suggesting the organization of repeated mural and pos-sibly occlusive thromboembolism. The medial muscleis also increased (arterialization). Fresh occlusivethromboembolism, which is often superimposed, is fre-quent in autopsy cases. Thrombotic processes of theportal venous system eventually occur, particularlyafter splenectomy [50] . Portal venous blood stasis maybe responsible for this. Some main branches of the por-tal vein are occasionally occluded by an old thrombus

some cases and absent in others. These nodular changesare similar to nodular regenerative hyperplasia, focalnodular hyperplasia, partial nodular transformation and

macroregenerative nodules of the liver, although this


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Fig. 10. Immunostaining of -smooth muscle antigen ( -SMA) in idiopathic portal hypertension. Perisinusoidal cellsin perivenular areas are positive for -SMA and increased inthe perivenular area. V , central vein; P, portal tract.Fig. 11. Histology of idiopathic portal hypertension. Arrowsdenote aberrant vessels in the hepatic parenchyma adjacent tofibrotic portal tract (P) in which original portal veins are oblit-erated. HE.

Fig. 12. Histology of idiopathic portal hypertension. Vaguenodular hyperplasia of hepatocytes is seen (N) in the hepaticlobule. P, portal tract. Reticulin stain.


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with recanalization, and extrahepatic portal venous ob-struction of adults with features of IPH in the liver canbe included in IPH (Fig. 7) [38 ] .

Small portal vein branchesPortal venous obliteration or luminal narrowing is a

rather constant finding, particularly at autopsy [33] , al-though portal veins are dilated and some have herniatedinto the surrounding hepatic parenchyma, particularlyin needle biopsy specimens. Phlebosclerosis of medi-um-sized intrahepatic portal veins is a frequent and con-stant lesion that is recognizable at wedge biopsy or au-topsy. This lesion is associated with muscular hypertro-phy. Medium-sized portal vein branches occasionallyshow intimal thickening and even recanalization. In ad-dition, edematous and fibrous thickening of the intima

with inflammatory cell infiltration in the intima of por-tal vein branches is occasionally seen (Figs. 6A, 6B).This lesion may be a kind of phlebitis . Although this le-sion is focal, it is rather characteristic of IPH and maybe a primary lesion of IPH according to Ohbu [29 ] . It isexclusively found in IPH livers, which may reflect theimmunological pathogenesis of IPH.

Lymphatics. The number of lymphatics was higher inthe IPH samples than in the control samples, suggestingthat the increased lymph flow may in turn reduce thehigh portal vein pressure in IPH.

Hepatic arterial changes. Our preliminary study dis-closed that hepatic arterial branches are increased nei-ther in number nor in the luminal area in IPH, reflectingthe decreased arterial blood flow in the liver.

Diagnosis of IPH by needle or wedge biopsy

IPH is a clinical syndrome of pre-sinusoidal long-stand-ing portal hypertension. Although the degree and distri-bution of the pathological changes related to IPH aregenerally heterogeneous, thus creating sampling errorsfor biopsy, histopathological study is necessary to rendera diagnosis of IPH. The most important task for patholo-

gists is to exclude liver cirrhosis, particularly macron-odular liver cirrhosis. Biopsy specimens, particularlyneedle biopsy, not infrequently show nonspecificchanges, i.e., non-diagnostic changes. Liver biopsies re-veal portal fibrosis with subintimal thickening or luminalobliteration of terminal portal vein branches, and a strik-ing peri-ductal fibrosis, supporting the diagnosis of IPH[53] . When portal hypertension occurs in associationwith a radiologically patent portal vein and an essentiallynormal liver biopsy specimen, IPH must be considered.

Comparison with equivalent and related diseases

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

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 butalso pathological features, such as portal venous andportal tract abnormalities, and also parenchymal atro-phy perhaps as a result of portal circulatory insufficien-cy [36 ] . The clinical and pathological features of thesediseases may be the same, although their etiopathogen-esis may differ according to location.

In addition, extrahepatic portal venous obstructionwith clinicopathological features of IPH could be in-cluded in the category of IPH. Such cases must be IPHoriginally, because there are several IPH cases in whichportal venous thrombosis and portal venous obstructionoccur secondarily in the course of IPH (stage IV, seebelow).

In addition, there are also patients with spontaneousportal-systemic shunt and hepatic encephalopathy with-out splenomegaly. The liver histology of these patientsresembles IPH but with normal portal pressure [48 ] .Such cases could also constitute a variant of IPH inwhich portal blood flow into the shunt and thereby clin-ically detectable portal hypertension and splenomegalydo not occur.

Related diseases. Incomplete septal cirrhosis: In incom-plete septal cirrhosis, slender septal fibrosis is an exten-

sion of portal fibrosis and perivenular fibrosis, and subdi-vides the parenchyma into inconspicuous nodules. Theselivers also show an abnormal spacing between the portaltracts and veins, and small hypoplastic portal tracts with-in the parenchyma. This could be a late manifestation of IPH [5, 6, 25 ] , although the differentiation from macron-odular cirrhosis is controversial in several cases.

Nodular regenerative hyperplasia (NRH): This dis-ease is characterized by non-cirrhotic regenerative nod-ules in the liver and occurs in portal hypertensive casesas well as in cases without portal hypertension. Thesenodulations generally involve the whole liver. Distin-guishing NRH with portal hypertension from IPH withparenchymal nodular hyperplasia is difficult, and suchcases could be included in IPH.

Partial nodular transformation: This disease is char-acterized by grossly visible nodulations without fibroussepta, mainly involving the hepatic hilar regions. Someof these cases may occur as a compensatory hypertrophyof the liver in non-portal hypertensive cases, such aspartial biliary occlusion, although the cases associatedwith non-cirrhotic portal hypertension may belong toIPH.Similar but different diseases. Myeloproliferative dis-orders: In myeloproliferative disorders such asmyelofibrosis or polycythemia vera, non-cirrhotic por-tal hypertension can develop. In such cases, thrombosisof portal veins and hepatic veins is a common cause of



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sy specimens. The parenchymal nodular changes of theliver 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 recogniz-

able, morphological factors in this new staging, i.e., thepresence or absence of peripheral parenchymal atrophy,the size or weight of the liver, and obstructive portalvein thrombosis of the intrahepatic large portal veinsand/or portal vein trunk. All of these factors are recog-nizable grossly as well as by imaging, radio-isotopescanning, peritoneoscopy, and/or portography.

Evaluation of three parameters. Evaluation of the sizeor weight of liver: It is important to ascertain the weightof the IPH livers. Some livers were swollen, while oth-ers were markedly atrophic. The size of the liver isevaluable by imaging modalities, particularly computedtomography [12, 60 ] .

Evaluation of subcapsular hepatic parenchymal at-rophy: Subcapsular hepatic parenchymal atrophy is rec-ognizable grossly on the cut surface of the autopsy liver.Magnetic resonance imaging (MRI) shows the proximi-ty of medium-sized intrahepatic vessels to each otherand to the liver surface [2, 3, 21 ] . Computed tomogra-phy (CT) during arterial portography shows abnormallyshort distances between some of the medium-sized por-

tal branches and the liver surface [20] . Portographyshows a lack of filling between the surface of the liverand peripheral vessels. Peripheral regional enhance-ment of the liver was seen in the arterial phase. On por-tograms taken via the superior mesenteric artery,markedly decreased portal venous perfusion was seenin the peripheral region of the liver.

Evaluation of portal venous thrombosis: Assessmentof portal vein patency and portal flow is most simplyaccomplished using Doppler ultrasonography, whichalso provides information about the hepatic veins andinferior vena cava. Portography of either kind is usefulfor the demonstration of occlusive portal veins.

Proposal of a new staging system based on gross andimaging features. By a combination of these grossfindings, IPH livers were categorized into four groups(Stage I, II, III, and IV) as shown below. Their schemesand likely progression are shown in Fig. 13. Stage I isearly IPH, while stages II and III are advanced. To date,a staging system has not yet been described in the litera-ture. This staging system can be applied to patients bycombining imaging procedures with peritoneoscopy,and also to autopsy livers. In addition, the histologicalchanges of IPH are known to be heterogeneous, andsampling errors are unavoidable, so the gross findingsor imaging findings are considered more useful in stag-ing. However, stage I cases are rare.

portal hypertension [56 ] . However, in a few cases withportal hypertension, increased portal blood flow frommarked splenomegaly associated with extramedullary

hematopoiesis could play a role in portal hypertension.Nodular regenerative hyperplasia of the liver is also en-countered [55 ] .

Presinusoidal portal hypertension related to medicaltreatments and intoxication: There is an association be-tween a long-standing presinusoidal portal hyperten-sion resembling IPH and the use of chemotherapeuticagents, particularly thioguanine [46] . Mild sclerosis of some small portal triads and perisinusoidal fibrosis arethe only abnormalities seen. Chronic arsenic intoxica-tion, usually for psoriasis, is also known to be associat-ed with such a syndrome [13 ] . A peculiar pattern of pro-gressive portal tract, inconspicuous intralobular andconspicuous capsular fibrosis accompanied by spleno-megaly was also observed in five workers with vinylchloride polymerization [52] . Hypertrophy and hyper-plasia of both hepatocytes and hepatic and splenic mes-enchymal cells were also seen [61 ] .

Furthermore, a similar syndrome occurs followingrenal transplantation. These patients had been treatedwith azathioprine and prednisolone for several years. Inthese patients, the spleen might have played an impor-tant role in the development of this syndrome. Micro-scopic examination of liver biopsies taken at the opera-tion revealed lymphoplasmacytic infiltration with bile

duct hyperplasia but no evidence of periportal fibrosisexcept for very mild perisinusoidal fibrosis.

Proposal of a New Staging of IPH

It is generally thought that the IPH liver itself is alreadyat the end-stage pathologically when diagnosed clini-cally. So, little is known about the pathological stagesof IPH. However, as mentioned in the pathology of IPHlivers, most pathological changes to IPH livers seem tobe a consequence of a long-standing portal venous in-sufficiency in the liver. Therefore, these changes appearto progress and increase in their degree and extent dur-ing a long clinical course. Almost all chronic diseases of hepatocellular, biliary and hepatic venous obstructivediseases are known to be followed by the developmentof liver cirrhosis. Although the chronic effect of intra-hepatic portal venous blocks on the liver may not leadto cirrhotic transformation, a pathological progressionmay evolve that may also be effective in IPH livers.

By a combination of gross features, IPH livers couldbe grouped into several categories which may reflectthe stage of the pathological progression of IPH orprognosis. The histological features of IPH should notbe used as parameters for the pathological staging of IPH, because these are very heterogeneous, and sam-pling errors are likely to occur in needle or wedge biop-



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Stage I: Absence of peripheral parenchymal atrophy.The liver is usually not atrophic nor even swollen, andthe surface is speculated to be smooth. IPH diagnosed atthis stage is rare. Etiologic factor(s) remain to be identi-

fied at this stage.Stage II: Presence of peripheral parenchymal atrophy

in non-atrophic liver. The surface is uneven or waveyand even vaguely nodular. The cut surface shows dis-tinct subcapsular atrophy characterized by the closeproximity of portal tracts or hepatic veins to the hepaticcapsule.

Stage III: Presence of peripheral parenchymal atro-phy in atrophic liver. The surface is uneven or wavy,and even vaguely nodular. The cut surface shows dis-tinct subcapsular atrophy. Occasionally, there is col-lapse involving areas or segments of the liver.

Stage IV: Presence of obstructive thrombosis of in-trahepatic large portal veins or portal vein trunk. This isregarded as being the superimposition of thromboem-

bolism of portal veins, but is more frequent in stage IIand even more frequent at stage III. At autopsy, stage IVis relatively common.

Superimposition of occlusive thrombosis of the intra-hepatic large portal veins and/or portal vein trunk means a poor prognosis, and in fact, such patients fre-quently die of portal venous thrombosis. So, this factorwas adopted as an independent staging factor in thissystem, for stage IV, when such a factor is found to beindependent of other factors. In stage I, II and III livers,the intrahepatic large portal veins and extrahepatic por-tal veins show luminal thickening and even calcifica-tion, suggesting repeated thrombosis. As for stages I, II,and III, the histopathological changes may progress inthis order. Portal venous occlusive thrombosis is likelyto develop at advanced stages of IPH.

Conclusion

The recent progress in the study of IPH with respect toetiopathogenesis and pathology was reviewed. The pro-posal of a new staging system is based on the gross fea-tures of IPH, which reflect the secondary pathologicalfeatures. The etiology could be multiple. It seems possi-ble that IPH is heterogeneous in its initiation and/orprogression depending on the etiology. The liver pathol-ogy characterized by occlusive changes of the intrahep-

atic portal radicles, portal and periportal fibrosis, and ir-regularly distributed parenchymal atrophies suggestssome sort of portal venopathy that causes decreasedportal perfusion of peripheral liver parenchyma. Themost important issues of the pathobiology of IPH to beaddressed and clarified in the near future are:1) What are the etiologies?2) How does portal hypertension develop and whichpathological changes reflect the presinusoidal portal hy-pertension? and3) How do secondary changes of the liver caused by in-trahepatic hemodynamic alterations in IPH progress?

Acknowledgements. This study was supported by theJapanese Study Group of Intrahepatic Hemodynamic Alter-ations (Chairman: Prof. Keizo Sugimachi, Professor of Surgery, Kyushu University, Graduate School of Medicine,Fukuoka, Japan).

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Fig. 13. Scheme of proposed staging of idiopathic portal hy-pertension. Stage I progresses to stage II, and stage II to stage

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