Histopathology of portal hypertension: a practical guideline [611762]

REVIEW
Histopathology of portal hypertension: a practical guideline
T Roskams, A Baptista,1L Bianchi,2A Burt,3F Callea,4H Denk,5J De Groote,6V Desmet,
S Hubscher,7K Ishak,8R MacSween,9B Portmann,10H Poulson,11P Scheuer,12L Terracciano2
& H Thaler13
Department of Pathology, K.U. Leuven, Leuven, Belgium,1Hospital de Santa Maria, Lisboa, Portugal,2University of Basel,
Basel, Switzerland,3University of Newcastle, Newcastle, UK,4Spedali Civili of Brescia, Brescia, Italy,5University of Graz,
Graz, Austria,6Department of Hepatology, K.U. Leuven, Leuven, Belgium,7Department of Pathology, University of
Birmingham, Birmingham, UK,8Armed Forces Institute of Pathology, Washington, DC, USA,9Department of Pathology,
Western Infirmary, University of Glasgow, Glasgow and10Institute of Liver Studies, Kings College Hospital, London, UK,
11Frederics Berg, Denmark,12Department of Pathology, Royal Free Hospital, London, UK, and13Wien, Austria
Roskams T, Baptista A, Bianchi L, Burt A, Callea F, Denk H, De Groote J, Desmet V, Hubscher S, Ishak K, MacSween
R, Portmann B, Poulson H, Scheuer P, Terracciano L & Thaler H
(2003) Histopathology 42, 2–13
Histopathology of portal hypertension: a practical guideline
Keywords: portal hypertension, non-cirrhotic portal hypertension, nodular regenerative hyperplasia, incomplete
septal cirrhosis, hepatoportal sclerosis, idiopathic portal hypertension, partial nodular transformation
Introduction
Portal hypertension may be clinically silent for a
variable time period, and is often discovered due to
late complications like haemorrhage from oesophagealvarices. However, clinically silent portal hypertensioncan be associated with non-specific liver function testdisturbances (raise in alkaline phosphatases, gammaglutamyl transpeptidase), resulting in the taking of aliver biopsy. It is therefore important for the pathologistto recognize alterations in the microvasculature of the
liver, which are present at this stage. In our experience
with referred biopsies, intrahepatic (vascular) changesin portal hypertension are often overlooked. This articleis aimed to provide a practical guideline for pathologistswith interest in liver pathology.
Recognition of portal vessel abnormalities requires a
systematic analysis of the biopsy, considering architec-tural disturbances, as well as portal and lobularalterations. A good connective tissue stain is essential
to evaluate the degree of fibrosis (Sirius Red, trichrome,reticulin). A reticulin stain is particularly useful for the
identification of discrete nodular lesions, for instance in
nodular regenerative hyperplasia or to ascertain thediagnosis of cirrhosis in fragmented biopsy specimens.An elastica Van Gieson stain is useful to evaluatevascular lesions.
Classification of portal hypertension
Portal hypertension is mainly the result of obstructionto the hepatic blood flow and can be classifiedaccording to the organ or vessel that contains theobstructing lesion: thrombosis of splenic and portalveins, fibrosis or cirrhosis of the liver, diseases ofhepatic veins and the inferior vena cava, and heartdisease.
1Another classification, based on hepatic
venous pressure measurements by hepatic vein cath-
eterization, distinguishes between presinusoidal, sinu-
soidal, and post-sinusoidal portal hypertension.2,3
Finally, distinction is made between cirrhotic andnon-cirrhotic portal hypertension. Cirrhosis is theAddress for correspondence: Tania Roskams MD, PhD, Department of
Pathology, University Hospitals Leuven, Minderbroederstraat 12,
B-3000 Leuven, Belgium. e-mail: tania.roskams@uz.kuleuven.ac.be
/C2112003 Blackwell Publishing Limited.Histopathology 2003, 42, 2–13

hepatic lesion most commonly associated with portal
hypertension. Non-cirrhotic portal hypertension devel-ops in the wake of an injury that is specificallydirected to vessels or portal structures, so that septa
are absent or minimal. Wanless subdivides intrahepatic
non-cirrhotic portal hypertension into ‘microvasculardiseases’ (confined to intrahepatic portal veins of<0.2 mm in diameter) and ‘macrovascular diseases’(lesions of intrahepatic portal veins of >0.2 mm indiameter and the portal vein.
4The different nomencla-
tures are summarized in Figure 1. Table 1 gives anoverview of the different causes of intrahepatic portal
hypertension, excluding cirrhosis. Idiopathic portal
hypertension is defined as non-cirrhotic portal hyper-tension in the absence of a known cause of liverdisease, with a patent extrahepatic portal vein andaccompanied by splenomegaly.
5–7Diseases similar to
idiopathic portal hypertension are known in the Indiansubcontinent as non-cirrhotic portal fibrosis
8and
elsewhere as hepatoportal sclerosis.9
There are several problems in interpreting vascular
lesions in portal hypertension. One is that obstructionto blood flow often occurs at several levels simulta-neously, e.g. extrahepatic portal vein thrombosis isaccompanied by obliteration of intrahepatic portalveins of all sizes, and often alterations of sinusoids as
well.
10A second problem is that acute vascular lesions
often remain clinically silent so that only non-specificsequelae are seen: an organized thrombus has a non-
specific appearance and it becomes impossible to
distinguish primary from secondary lesions.
In order to make this article of more practical use,
histopathological lesions suggesting portal hyperten-sion will be described in the order we usually examine aliver biopsy: first architectural and portal tract changeswill be described, followed by discussion of parenchy-mal changes, and finally special features pointing
towards certain aetiological diagnoses will be discussed.
Architectural changes
cirrhosis
Cirrhosis is the most common cause of portal hyper-
tension. Cirrhosis is ‘a diffuse process characterized by
fibrosis and a conversion of normal architecture into
structurally abnormal nodules’.11The presence of
fibrosis differentiates cirrhosis from nodular regenerat-ive hyperplasia. The diffuse character of cirrhosisdifferentiates it from focal nodular hyperplasia. In a
Figure 1. Classification of
portal hypertension. Schematic
representation of the various
classifications of portal hyper-tension (according to the site ofthe obstructing lesions with
respect to sinusoids, presence of
cirrhosis, intrahepatic bloodvessels, or the liver organ),emphasizing their partially
overlapping nature. (Modified
after VJ Desmet. Portal hyper-tension: pathological anatomy.
In Holstege A, Hahn EG,
Scholmerig J eds. Portal hyper-
tension. Dordrecht: Kluwer
Academic Publishers, 1995;
107–120.)Histopathology of portal hypertension 3
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

Table 1. Causes of intrahepatic non-cirrhotic portal hypertension
Presinusoidal
Developmental abnormalities
Adult polycystic disease
Hereditary haemorrhagic telangiectasiaArteriovenous fistulas
Congenital hepatic fibrosis
Phlebosclerosis of portal vein
Idiopathic portal hypertension
Alcoholic liver disease
Nodular regenerative hyperplasia
Biliary diseases (primary biliary cirrhosis, autoimmune cholangiopathy, primary sclerosing cholangitis)
Toxic (arsenic, vinyl chloride)
Thrombosis of portal vein branches
Hypercoagulable states (oral contraceptives, pregnancy, polycythemia rubra vera, protein C deficiency)
Vascular injury (trauma, pylephlebitis, pancreatitis)Stasis (compression by tumours)
Granulomatous lesions (sarcoidosis, schistosomiasis, mineral oil granuloma)
Neoplastic occlusion of the portal vein
Lymphoma
Epithelioid haemangioendothelioma
Epithelial malignancies
Chronic lymphocytic leukaemia
Thrombosis of the splenic vein
Chronic pancreatitis
SinusoidalFibrosis of space of Disse
Drug-induced (methotrexate, azathioprine, amiodarone, perhexilene maleate)
Alcoholic liver damage
Toxic (arsenic, vinyl chloride, copper)Metabolic (diabetes, mucopolysaccharidosis, cholesterol ester storage disease, Gaucher’s disease, Zellweger syndrome)Inflammatory (viral hepatitis, healed congenital syphilis, chronic Q fever, healed cytomegalovirus hepatitis)
Miscellaneous: Crohn’s disease, thrombocytopenic purpura
Amyloid or light chain deposition in Disse’s spaceDefenestration of sinusoidal lining
Early non-cirrhotic alcoholic liver disease
Destruction or collapse of sinusoids
Acute necroinflammatory diseases
Infiltrative diseases
Mastocytosis
Agnogenic myeloid metaplasia
Gaucher’s disease
Primary vascular malignancies
Epithelioid haemangioendothelioma
Angiosarcoma4 T Roskams et al.
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

needle biopsy, the diagnosis of cirrhosis can be difficult
due to sampling error. Fibrosis can be extensive withinthe liver without cirrhosis being present (e.g. non-cirrhotic portal hypertension in precirrhotic alcoholichepatitis,
12congenital hepatic fibrosis, and schisto-
somiasis). Modern imaging techniques are availableindicating the diffuse nature of the process. Nonethe-less, many of the complications of cirrhosis may occur
at the stage of non-cirrhotic severe fibrosis of the liver.
Most forms of cirrhosis have presinusoidal, sinusoidaland post-sinusoidal components to their accompanyingportal hypertension.
13Compression of hepatic veins by
regenerating cirrhotic nodules14and distortion of the
vasculature by fibrosis15–18are the main causes of
increased vascular resistance. Additional componentsare narrowing of sinusoids by hypertrophic hepato-
cytes, deposition of fibrous tissue, basement membrane
components, and mesenchymal cells in the space ofDisse and a phenotypic change of sinusoidal lining cells(defenestration of endothelial cells) with reduced por-osity.
12,19The latter phenomenon is referred to as‘capillarization of sinusoids’20and venularization of
sinusoids.21The vascular changes in cirrhosis are
irreversible because of the development of intrahepaticportohepatic venous anastomoses.
22,23It is noteworthy
that, in a considerable number of cirrhotic livers,macrovascular and microvascular injury of portal veinbranches can be observed together with occlusivelesions of the hepatic veins,
24,25again emphasizing
that the increased vascular resistance in portal hyper-
tension occurs simultaneously at multiple anatomicalsites.
So-called incomplete septal cirrhosis, a term intro-
duced by Popper,
26is a lesion frequently seen in
association with portal hypertension.27,28The term
cirrhosis is not strictly accurate in this context, as thecharacteristic finding is the presence of periportal
fibrous septa ending ‘blindly’ in the liver parenchyma,
without fibrous bridging (Figures 2 and 3). Incompleteseptal cirrhosis is an entity which lies somewherebetween vascular diseases without fibrosis (idiopathicportal hypertension, nodular regenerative hyperplasia,Table 1. (Continued )
Hypertrophy of Kupffer’s cells
Parasites (visceral leishmaniasis, toxoplasmosis)
Metabolic (Gaucher’s disease)
Compression of sinusoids by markedly hypertrophied hepatocytes
Microvesicular steatosis (alcohol, acute fatty liver of pregnancy)
Post-sinusoidal
Hepatic vein thrombosis
Myeloproliferative disorders
Veno-occlusive disease
Acute radiation injury
Toxic injury (aflatoxin, alkaloids of Senecio or Crotalaria)
Drug-induced injury (azathioprine, dacarbazine, thioguanine)
Phlebosclerosis of hepatic vein
Alcoholic liver disease
Chronic radiation injuryHypervitaminosis A
E-ferol injury
Primary vascular malignancies
Epithelioid haemangioendothelioma
Angiosarcoma
Granulomatous phlebitis
Sarcoidosis
Mycobacterium avium intracellulare
Lipogranulomas
Mineral oil granulomasHistopathology of portal hypertension 5
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

partial nodular transformation) on the one hand and
true cirrhosis on the other.29,30Incomplete septal
cirrhosis is also characterized by poorly defined nodu-larity of the parenchyma, compression with crowdingof reticulin fibres between adjacent hyperplastic zones,abnormal spacing of portal tracts and central veins,dilatation of sinusoids
27,31and increased numbers of
paraportal thin-walled vascular channels (Figures 2
and 3). The latter are also referred to as shunt vessels,
aberrant vessels,32megasinusoids,7periportal angio-
matosis,27or herniation33(Figures 2 and 3).
Portal tract changes
A normal portal tract (Figure 4) consists of fibroustissue containing a bile duct of approximately the samesize as the accompanying branch of the hepatic artery.
The portal vein branch has a diameter which is severaltimes larger than that of the artery. In addition,lymphatic vessels can be recognized. These do not have
smooth muscle fibres in their wall, whereas all portal
vein branches do (demonstrable with an immuno-histochemical reaction for a-smooth muscle actin).
34
In portal hypertension, the number of portal vein
branches is reduced, while there is an increase in thenumber of lymphatic vessels.
35The portal vein bran-
ches show a thickened smooth muscle wall35,36which
is probably a response to the increased pressure
(Figure 5). Experimental anastomosis of the hepatic
artery and the portal vein in dogs leads to thickening of
Figure 2. Liver biopsy showing incomplete septal cirrhosis with
vague nodularity of the parenchyma and formation of incomplete,blind ending septa. Portal tracts show abnormal vessels, such as
dilated portal veins (v), protruding into the parenchyma. An excess of
draining veins is also seen ( *). (Sirius Red stain.)
Figure 3. Higher magnification of liver biopsy showing incomplete
septal cirrhosis. A fine, incomplete septum (short arrow) and
paraportal shunt vessels (long arrows) at the edge of the portal tract
are present. (Sirius Red stain.)
Figure 5. Liver biopsy of patient with thrombosis of the portal vein.
Portal tract showing hepatic artery branch and interlobular bile ductof approximately the same size. The branch of the portal vein (v)shows narrowing of the lumen and hyperplasia of the smooth muscle
wall (arterialization of the portal vein). The bile duct shows slight
periductal fibrosis. (H&E stain.)
Figure 4. Normal portal tract showing a branch of the hepatic artery
and the interlobular bile duct of approximately the same diameter
and a branch of the portal vein of more than three times the diameter
of the artery. (H&E stain.)6 T Roskams et al.
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

the media of portal vein branches, with development of
portal hypertension.37This suggests that the portal
veins react to increased flow and pressure by increasingtheir vascular resistance.
38,39
thrombosis of extrahepatic portal vein
Thrombosis of the extrahepatic portal vein affects bothchildren and adults and is the leading cause ofextrahepatic portal hypertension in patients withouthepatic disease in Western countries.
40It accounts for
60% of cases of portal hypertension in children and isassociated with a variety of conditions.
41The most
common cause in children is neonatal umbilical sepsis,while in adults, cirrhosis and neoplastic disease are
important causes.
40Other causes are vascular injury
(e.g. trauma, pylephlebitis, pancreatitis), stasis (e.g. incongenital vascular abnormalities, or due to compres-sion by tumours), and hypercoagulable states (e.g. poly-cythemia rubra vera, oral contraceptives, pregnancy,protein C deficiency).
40,42Thrombosis of the splenic
vein, caused by, for example, chronic pancreatitis, canalso cause portal hypertension.
Thrombi in such large veins usually recanalize, while
extended thrombosis in small veins usually results inpermanent fibrous obliteration of their lumena. There-fore, after thrombosis of extrahepatic large veins, oftenonly residual lesions in smaller intrahepatic veins arerecognized and a diagnosis of idiopathic portal hyper-tension is made.
42
macrovascular portal vein disease
In macrovascular portal vein disease, eccentric intimalthickening of the larger portal veins suggests organizedthrombosis. Smooth muscle hyperplasia of the media isa frequent finding.
36,43Infrequently, veins come to
resemble arteries (arterialization)36(Figure 5). The
accompanying bile ducts may show periductal fibro-
sis.44,45If larger intrahepatic portal vein branches are
primarily affected, changes in small portal tracts areusually patchy in distribution: portal tracts with absentor obliterated veins tend to occur together in a focaldistribution, sometimes alternating with areas contain-ing normal portal tracts. Thin-walled portal veins witha still patent lumen are often dilated because the raisedportal pressure is transmitted to them. This feature is
absent in patients with extrahepatic portal vein
obstruction.
42Peripheral small portal tracts, in which
the portal vein branch is absent or obliterated, stillcontain normal bile ducts and arteries and the inter-stitial collagen bundles retain their normal coarseappearance. Obliterated small portal vein branchesmay be present as a bundle of smooth muscle fibres or
a clump of interwoven elastic tissue and are bestrecognized on a connective tissue or elastic stain.Aberrant vessels, located close to the portal area, mayoccur (so-called ‘paraportal shunt vessels’). Thesevessels may be mistaken for hepatic veins, but theycorrespond to collateral pathways supplying blood to
the hepatic parenchyma.
46
microvascular portal vein disease
Obliteration of small portal veins in microvascular
portal vein disease is the basic lesion in nodularregenerative hyperplasia. Such obliterative lesionsmay occur in any inflammatory hepatic disease
(viral hepatitis, tuberculosis, sarcoidosis) in a great
variety of systemic conditions with microvasculardisease, due to toxins, in biliary diseases, haematolog-ical disorders, etc. (Table 2). A comprehensive reviewof diseases associated with non-cirrhotic portal hyper-tension was provided by Ishak.
47In small portal tracts,
bile duct and artery are located in close proximity tothe portal vein branches. Therefore, portal vein oblit-
eration may be secondary to arterial or ductal inflam-
mation.
4Some small portal tracts may be totally
replaced by fibrous cords.4,48In larger portal tracts
(with veins 100–200 lm diameter) the original struc-
tures can still be recognized. Intimal fibrous thickeningsuggestive of recanalized thrombus may be seen in theportal veins. In patients with a history of arteritis,asymmetric thinning or scarring of arteries may be
observed. The portal tract changes in microvascular
disease are more uniformly distributed than in macro-vascular disease, so that vascular lesions are less likelyto be missed in a needle biopsy. Large intrahepaticportal veins and the extrahepatic portal vein arenormal.
Parenchymal changes
Histopathological changes in the parenchyma may beseen which are helpful in establishing or refining thediagnosis of portal hypertension. Long-term obstruc-tion of the extrahepatic portal vein may result ingeneralized atrophy of the liver parenchyma. Whenthere is major obstruction of the extrahepatic portalvein, nodularity is rarely seen.
The parenchyma in macrovascular portal vein dis-
ease is characterized by larger contiguous regions ofboth atrophy and of non-atrophic parenchyma; thelatter may form macronodules. These nodules (often upto 100 mm or more in diameter) are situated deep in theliver and are centred on the first and second order portalHistopathology of portal hypertension 7
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

Table 2. Diseases associated with nodular regenerative hyperplasia
Inflammatory hepatic disease
Viral hepatitis
Tuberculosis
Sarcoidosis
Biliary diseases
Primary biliary cirrhosis
Autoimmune cholangiopathy
Primary sclerosing cholangitis
Toxic liver damage
Arsenic
CopperVinyl chlorideToxic oil syndromeImmunosuppressive drugsCorticosteroidsContraceptive drugs
Androgenic-anabolic steroids
Systemic conditions
Rheumatoid arthritis with rheumatoid arteritis
Felty’s syndrome (rheumatoid arthritis, leukopenia, splenomegaly)Systemic lupus erythematosusPolyarteritis nodosaHashimoto’s thyroiditisHyperthyroidismIdiopathic thrombocytopenic purpuraMonoclonal gammopathiesDiabetesAmyloidosisLight chain deposit disease
Scleroderma
Others
Hereditary haemorrhagic telangiectasia
Down’s syndromePersistent ductus venosusGlomerulonephritis
Following renal dialysis or renal transplantation for end-stage renal disease
Following bone marrow transplantationCongestive heart failureSubacute bacterial endocarditisCardiac valvulopathies
Primary pulmonary hypertension
Malignancies
Lymphoma
Hodgkin’s diseaseHistiocytosis X
Other malignant tumours
Myeloproliferative disorders
Polycythaemia vera
Chronic myeloid leukaemiaMyeloid metaplasiaPrimary thrombocythaemia8 T Roskams et al.
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

vein branches. This is called ‘partial nodular transfor-
mation’45,49or ‘macronodular transformation’,43
a condition which can be recognized only on grossexamination.
In microvascular portal vein disease, the paren-
chyma shows micronodular transformation, nodularregenerative hyperplasia,
43,50where the nodules cor-
respond to individual liver lobules, with hyperplasia in
periportal zones and atrophy in centrolobular zones.When a small needle biopsy contains only a few portaltracts, this nodular transformation (best seen on areticulin stain) may provide the only clue to thepresence of small portal vein obstruction (Figures 6and 7).
Focal dilatation of sinusoids (Figure 8) and perisinu-
soidal fibrosis may be present.
41Fibrosis and deposition
of basement membrane components in Disse’s space,eventually accompanied by hyperplasia of hepaticstellate cells and their transdifferentiation towardsmyofibroblasts, may be part of a drug-induced(methotrexate, azathioprine, amiodarone, perhexilenemaleate), alcohol-induced, toxin-induced (arsenic,vinyl chloride), metabolic (diabetes, mucopolysacchar-
idosis, cholesterol ester storage disease) or inflamma-
tory (viral hepatitis) liver disease, causing portalhypertension.
47Abnormal deposits in the space of
Disse also occur in amyloidosis or light chain depositdisease.
51,52Defenestration of endothelial cells, leading
to reduction in porosity of the sinusoidal wall, canbe observed ultrastructurally in early non-cirrhoticalcoholic liver disease.
53
There have been case reports of portal hypertension
in patients with infiltrative diseases such as masto-cytosis,
54agnogenic myeloid metaplasia55and
Gaucher’s disease,56suggesting that obstruction con-
fined to the sinusoids may produce portal hypertension.However, undocumented portal vascular lesions couldbe responsible, as lesions of large and small portal veinswere found at autopsy in these patients.
57Moreover,
experience with amyloidosis indicates that even in
massive perisinusoidal amyloid deposition, portalhypertension is rarely seen.
51By analogy, perisinusoi-
dal fibrosis alone is probably not sufficient to produceportal hypertension.
Congestion of centrolobular sinusoids usually indi-
cates venous outflow block, such as hepatic veinthrombosis, veno-occlusive or congestive heart disease.
The causative venous lesion may not, however, be
found in needle biopsies. In acute outflow block,atrophy and necrosis of liver cell plates is seen. Itshould be noted, however, that sinusoidal dilatationnot necessarily reflects an outflow block, but may becaused by obstruction of portal vein radicals. In chronichepatic vein obstruction, fibrosis develops within a few
weeks, followed by nodular regeneration of the paren-chyma within a few months. Central–central fibroussepta are formed, surrounding parenchymal nodules inwhich the portal tracts are centrally located. Thissparing of the portal tracts in the fibrotic processeventually results in a ‘cirrhosis’ with ‘reversed lobu-
lation’. In hepatic vein thrombosis, secondary throm-
bosis of small portal veins is common. Moreover,fibrous obliteration of small hepatic veins may beidentical to the lesions of veno-occlusive disease. In trueveno-occlusive disease there is a non-thrombotic oblit-eration of small intrahepatic veins by loose connectivetissue as a result of radiation-, toxic-, or drug-inducedliver injury.
58–60The clinical syndrome of veno-
occlusive disease occurs in up to one-half of the
patients undergoing bone marrow transplantation.58
Inalcoholic liver disease, perivenular fibrosis can resultin hepatic vein obliteration, compromising hepaticvenous outflow.
61
Special features of diagnostic value
The presence of epithelioid granulomas suggestssarcoidosis or tuberculosis; granulomatous phlebitiscan be present in these conditions.
62Granulomas
can also be present in primary biliary cirrhosis(PBC) or autoimmune-cholangitis. In PBC ⁄auto-
immune cholangitis, bile duct lesions and signs ofchronic cholestasis (periportal cholate stasis withaccumulation of copper and copper-binding protein
in hepatocytes, foamy macrophages) can be seen.
Granulomas containing eggs are found in schisto-somiasis. The eggs of Schistosoma japonicum are more
numerous and slightly smaller than those ofS. mansoni and their morphology is different. Schisto-
somiasis initially starts as microvascular portaldisease with embolization of eggs, producing stasisand inflammation of smaller portal vein radicles.
Secondary thrombosis of larger portal vein branches
may give rise to macrovascular disease.
48The
granulomatous reaction around eggs leads to fibrousobliteration of portal vein branches, portal fibrosis,and septal fibrosis.
63
Mallory bodies, neutrophil satellitosis, in combina-
tion with steatosis, perivenular fibrosis of the centro-lobular veins and perisinusoidal fibrosis all point
towards alcohol-induced liver disease or non-alcoholic
steatohepatitis.
Hypoplasia of intrahepatic portal vein radicles and
abnormalities in the branching pattern of the portalvein (‘pollard willow’ pattern) is usually associatedwith congenital lesions of the intrahepatic bile ducts,Histopathology of portal hypertension 9
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

know as ‘ductal plate malformation’.64,65This lesion is
seen in congenital hepatic fibrosis, Caroli’s syndromeand some forms of extrahepatic bile duct atresia
64
(Figure 9).
Patients with hereditary haemorrhagic telangiecta-
sia (Osler–Rendu–Weber) can develop portal hyperten-sion due to the formation of arteriovenous fistulas (withincreased blood flow) and nodular transformation ofthe parenchyma.
66Several patterns of lesions can be
seen: large abnormal arterial and venous structures inenlarged portal tracts, dilated sinusoids with perisinu-
soidal fibrosis, and thick-walled vascular structures
crossing the parenchyma.
67Conclusions
Portal hypertension is the result of obstruction of thehepatic blood flow. Cirrhosis is the most commoncause of portal hypertension, which mostly haspresinusoidal, sinusoidal and post-sinusoidal compo-nents. So-called incomplete septal cirrhosis lies some-where in between vascular diseases without fibrosis
(e.g. nodular regenerative hyperplasia) and true
cirrhosis. Portal tract changes seen in portal hyper-tension are: reduction of the number of portal veinbranches and thickening of the smooth muscle wall ofportal veins, together with formation of paraportal
Figure 9. Liver biopsy of patient with Caroli syndrome (Caroli disease
with congenital hepatic fibrosis). The portal tract lacks a portal vein
branch. Bile duct structures are arranged in a ductal plate
configuration (small arrows), forming two concentric ringswith bile concrements. At the edge of the portal tract, shuntvessels (long arrows) can be seen. (Sirius red stain.)
Figure 7. Liver biopsy showing nodular regenerative hyperplasia.
Compression of liver cell plates is seen in between hyperplasticnodules with crowding of reticulin fibres, but no real fibrous septum
formation. (Reticulin stain.)
Figure 6. Liver biopsy of patient in the early stage of primary
sclerosing cholangitis, showing nodular regenerative hyperplasia.
The parenchyma shows vague nodularity with compression of livercell plates (small arrows) in between hyperplastic nodules. The portaltract (left side of figure) contains a bile duct with involution of the
epithelium and a thickened basement membrane (long arrow). (Sirius
Red stain.)
Figure 8. Liver biopsy of patient with viral hepatitis C in a stage of
minimal fibrosis but with signs of portal hypertension. In the portaltract, a dense inflammatory infiltrate is present. The portal vein
branch is not recognizable. The periportal parenchyma shows
sinusoidal dilatation. (H&E stain.)10 T Roskams et al.
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

shunt vessels. In macrovascular portal vein disease
eccentric intimal thickening of the larger portal veinssuggests thrombosis. Changes in small portal tractsare usually patchy in distribution. In extrahepaticvein obstruction this patchy distribution of lesions isabsent. In microvascular portal vein disease, the basiclesion is nodular regenerative hyperplasia. Parenchy-
mal changes are helpful in refining the diagnosis of
portal hypertension: long-term obstruction of theportal vein may result in general atrophy of the liverparenchyma. In macrovascular disease regions ofatrophy alternate with regions of compensatoryhyperplasia, resulting in ‘partial nodular transforma-tion’. In microvascular portal vein disease, the liverparenchyma shows nodular regenerative hyperplasia,
where the nodules correspond to individual liver
lobules.
Perisinusoidal fibrosis, abnormal deposits in Disse’s
space (like in amyloidosis or light chain depositdisease), or infiltrative diseases which cause obstruc-tion of sinusoids (e.g. mastocytosis, Gaucher’s disease)can also contribute to enhanced vascular resistanceand to portal hypertension.
Finally, congestion of centrolobular sinusoids
suggests a venous outflow block like hepatic veinthrombosis, veno-occlusive disease or congestive heartfailure.
In conclusion, vascular lesions causing portal
hypertension often give rise to only minimal liverfunction test disturbances. Changes in the microvas-culature of the liver almost certainly exist before
portal hypertension is clinically manifest. It is there-
fore important for pathologists to recognize thesehistological lesions.
References
1. Boyer T. Portal hypertension and bleeding esophageal varices. In
Zakim D, Boyer T eds. Hepatology, a textbook of liver disease , 2nd
edn. Philadelphia: Saunders, 1990; 572–615.
2. Lebrec D. Hepatic vein catheterization. In Okuda K, Benhamou
J-P eds. Portal hypertension: clinical and physiological aspects .
Tokyo: Springer-Verlag, 1991; 117–125.
3. Benhamou J-P, Valla D. Intrahepatic portal hypertension. In
Bircher J, Benhamou J-P, McIntyre N, Rizzetto M, Rodes J eds.
Oxford textbook of clinical hepatology . Oxford: Oxford University
Press, 1999; 661–669.
4. Wanless I. Vascular disorders. In McSween R, Anthony P,
Scheuer P, Burt A, Portmann B eds. Pathology of the liver . New
York: Churchill Livingstone, 1994; 535–562.
5. Okuda K, Kono K, Ohnishi K, Kimura K, Omata M, Koen H et al.
Clinical study of eighty-six cases of idiopathic portal hypertension
and comparison with cirrhosis with splenomegaly. Gastroenter-
ology 1984; 86; 600–610.6. Sarin S. Non-cirrhotic portal hypertension. In Bosch J, Grosz-
mann R eds. Portal hypertension: pathophysiology and treatment .
Oxford: Blackwell, 1994; 27–53.
7. Ludwig J, Hashimoto E, Obata H, Baldus W. Idiopathic portal
hypertension. a histopathological study of 26 Japanese cases.
Histopathology 1993; 22; 227–234.
8. Nayak N. Pathology of non-cirrhotic portal fibrosis of India. In
Okuda K, Omata M eds. Idiopathic portal hypertension . Tokyo:
University of Tokyo Press, 1983; 37–47.
9. Mikkelsen WP, Edmondson HA, Peters RL, Redeker AG, Reynolds
TR. Extra- and intrahepatic portal hypertension without cirrhosis
(hepatoportal sclerosis). Ann. Surg. 1965; 162; 602–620.
10. Wanless I, Peterson P, Das A, Boitnott J, Moore G, Bernier V.
Hepatic vascular disease and portal hypertension in polycyth-emia vera and agnogenic myeloid metaplasia. A clinicopatho-
logical study of 145 patients examined at autopsy. Hepatology
1990; 12; 1166–1174.
11. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer P, Sobin
LH. The morphology of cirrhosis. J. Clin. Pathol. 1978; 31;
395–414.
12. Mak KM, Lieber CS. Alterations in endothelial fenestrations in
liver sinusoids of baboons fed alcohol: a scanning electron
microscopic study. Hepatology 1984; 4;386–391.
13. Zimmerman H, Lewis J, Kassianides C. Cirrhosis. In Okuda K,
Benhamou J-P eds. Portal hypertension: clinical and physiological
aspects . Tokyo: Springer-Verlag, 1991; 251–270.
14. Kelty R, Baggenstoss A, Butt H. The relation of the regenerated
liver nodule to the vascular bed in cirrhosis. Gastroenterology
1950; 15; 285–295.
15. McIndoe A. Vascular lesions of portal cirrhosis. Arch. Pathol. Lab.
Med. 1928; 5;23–40.
16. Picchiotti R, Mingazzini P, Scucchi L. Correlation between
sinusoidal pressure and liver morphology in cirrhosis. J. Hepatol.
1994; 20; 364–369.
17. Popper H, Elias H, Petty DE. Vascular patterns of the cirrhotic
liver. Am. J. Clin. Pathol. 1952; 22; 717–729.
18. Krogsgaard K, Christensen E, Gluud C, Henriksen J, Christoffer-
sen P. Variables predicting elevated portal pressure in alcoholic
liver disease. Results of a multivariate analysis. Scand. J.
Gastroenterol. 1987; 22; 82–86.
19. Le Bail B, Bioulac-Sage P, Senuita R, Quinton A, Saric J,
Balabaud C. Fine structure of hepatic sinusoids and sinusoidal
cells in disease. J. Electron. Microsc. Tech . 1990; 14; 257–282.
20. Schaffner F, Popper H. Capillarization of hepatic sinusoids in
man. Gastroenterology 1963; 44; 239–242.
21. Bhunchet E, Fujieda K. Capillarization and venularization of
hepatic sinusoids on porcine serum-induced rat liver fibrosis: amechanism to maintain liver blood flow. Hepatology 1993; 18;
1450–1458.
22. Desmet VJ. Fibrosis of the liver: a pathologist’s view . Dordrecht:
Kluwer Academic Publishers, 1994.
23. Gaudio E, Pannarale L, Onori P, Riggio O. A scanning electron
microscopic study of liver microcirculation disarrangement in
experimental rat cirrhosis. Hepatology 1993; 17; 477–485.
24. Nakanuma Y, Ohta G, Doishita K. Quantitation and serial section
observations of focal venocclusive lesions of hepatic veins in liver
cirrhosis. Virchows Arch. (A) 1985; 405; 429–438.
25. Wanless I. Secondary portal and hepatic vein thrombosis in
cirrhosis: a quantative study. Hepatology 1994; 19; 1391.
26. Popper H. What are the major types of hepatic cirrhosis? Philadel-
phia: W.B. Saunders, 1966.Histopathology of portal hypertension 11
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

27. Sciot R., Staessen D, Van Damme B, Van Steenbergen W, Fevery
J, De Groote J et al. Incomplete septal cirrhosis: histopathological
aspects. Histopathology 1988; 13; 593–603.
28. Nevens F, Staessen D, Sciot R, Van Damme B, Desmet V, Fevery J.
Clinical aspects of incomplete septal cirrhosis in comparison
with macronodular cirrhosis. Gastroenterology 1994; 106;
459–463.
29. Sciot R, Van Damme B, Desmet V. Does incomplete septal
cirrhosis link non-cirrhotic nodulations with cirrhosis? Histo-
pathology 1989; 15; 318–320.
30. Desmet VJ, Sciot R, Van Eyken P. Differential diagnosis and
prognosis of cirrhosis: role of liver biopsy. Acta Gastroenterol. Belg.
1990; 53; 198–208.
31. Barnett J, Appelmans H, Moseley R. A familial form of incomplete
septal cirrhosis. Gastroenterology 1992; 102; 674–678.
32. Ohbu M, Okudaira M, Watanabe K et al. Histopathological study
of intrahepatic aberrant vessels in cases of non-cirrhotic portalhypertension. Hepatology 1994; 20; 302–308.
33. Bioulac-Sage P, Le Bail B, Bernard P, Balabaud C. Hepatoportal
sclerosis. Seminars Liver Dis. 1995; 15; 329–339.
34. Masuda T, Oikawa H, Sato S, Satodate S, Suzuki S, Sato S.
Distinguishing small lymph vessels in the portal tracts of
human liver from portal veins by immunohistochemistry for
alpha smooth muscle actin. Int. Hepatol. Commun. 1996; 4;
277–282.
35. Oikawa H, Masuda T, Sato S-I, Yashima A, Suzuki K, Sato S et al.
Changes in lymph vessels and portal veins in the portal tract of
patients with idiopathic portal hypertension: a morphometricstudy. Hepatology 1998; 27; 1607–1610.
36. Nakanuma Y, Hoso M, Sasaki M, Terada T, Katayanagi K,
Nonomura A et al. Histopathology of the liver in non-cirrhotic
portal hypertension of unknown etiology. Histopathology 1996;
28; 195–204.
37. Siderys H, Judd D, Herendeen T. The experimental production of
elevated portal pressure by increasing portal vein flow. Surg.
Gynecol. Obstet. 1965; 120; 514–516.
38. Malmqvist U. Effects of long-term portal hypertension on
structure, active force and content of contractile and structural
proteins in smooth muscle of the rat portal vein. Acta Physiol.
Scand. 1994; 150; 171–179.
39. Nio M, Takahashi T, Ohi R. Changes of intrahepatic portal veins
in biliary atresia: formation and development of medial smooth
muscles correlated with portal hypertension. In Ohi R ed. Biliary
atresia. Tokyo: Professional Postgraduate Services, 1987;
243–250.
40. Cohen J, Edelman R., Chopra S. Portal vein thrombosis: a review.
Am. J. Med. 1992; 92; 173–182.
41. Bernard O, Alvarez F, Brunelle F, Hadchouel P, Allagille D. Portal
hypertension in children. Clin. Gastroenterol. 1985; 14; 33–55.
42. Wanless I. Pathology of non-cirrhotic portal hypertension.
In Okuda K, Benhamou J-P eds. Portal hypertension: clinical
and physiological aspects . Tokyo: Springer-Verlag, 1991; 393–
399.
43. Wanless IR. Micronodular transformation (nodular regenerative
hyperplasia) of the liver. a report of 64 cases among 2.500autopsies and a new classification of benign hepatocellular
nodules. Hepatology 1990; 11; 787–797.
44. Kobayashi S, Nakanuma Y, Matsui O. Histopathology of portal
tracts in livers after transcatheter arterial chemo-embolization
therapy for hepatocellular carcinoma. J. Gastroenterol. Hepatol.
1993; 9;45–54.45. Sherlock S, Feldman CA, Moran B, Scheuer PJ. Partial nodular
transformation of the liver with portal hypertension. Am. J. Med.
1966; 40; 195–203.
46. Fukuda K, Kage M, Arakawa M, Nakashima T. Portal vein
or hepatic vein? A curious aberrant vasculature in the
liver with idiopathic portal hypertension. Acta Pathol. Jpn. 1985;
35; 885–897.
47. Ishak K. Nodular regenerative hyperplasia, blood disorders and
other uncommon diseases associated with intrahepatic portalhypertension. In Okuda K, Benhamou J-P eds. Portal hyperten-
sion: clinical and physiological aspects . Tokyo: Springer-Verlag,
1991; 325–342.
48. Wanless IR. The pathophysiology of non-cirrhotic portal hyperten-
sion: a pathologist’s perspective . Lancaster: MTP Press, 1987.
49. International Working Party. Terminology of nodular hepato-
cellular lesions. Hepatology 1995; 22; 983–993.
50. Stromeyer FW, Ishak KG. Nodular transformation (nodular
‘regenerative’ hyperplasia) of the liver. A clinicopathologic study
of 30 cases. Hum. Pathol. 1981; 12; 60–71.
51. Melkebeke P, Vandepitte J, Hannon R, Fevery J. Huge hepato-
megaly, jaundice, and portal hypertension due to amyloidosis ofthe liver. Digestion 1980; 20; 351–357.
52. Bedossa P, Fabre M, Paraf F, Martin E, Lamaigre G. Light chain
deposition disease with liver dysfunction. Hum. Pathol. 1988; 19;
1008–1014.
53. Horn T, Christofferson P. Sinusoidal endothelial cells: a SEM
investigation of the fenestration in normal and diseased human
liver. In Bioulac-Sage P, Balabaud C eds. Sinusoids in human liver:
health and disease. Rijswijk: Kupffer Cell Foundation, 1988;
189–206.
54. Grundfest S, Cooperman A, Ferguson R. Portal hypertension
associated with systemic mastocytosis and splenomegaly. Gastro-
enterology 1980; 78; 370–373.
55. Roux D, Merlio J, Quinton A, Lamouliatte H, Balabaud C,
Bioulac-Sage P. Agnogenic myeloid metaplasia, portal hyperten-sion and sinusoidal abnormalities. Gastroenterology 1987; 92;
1067–1072.
56. James S, Stromeyer F, Cheng C, Barranger J. Liver abnormalities
in patients with Gaucher’s disease. Gastroenterology 1981; 80;
126–133.
57. Wanless IR, Godwin TA, Allen F, Feder A. Nodular regenerative
hyperplasia of the liver in hematologic disorders: a possible
response to obliterative portal venopathy. Medicine 1980; 59;
367–379.
58. Bearman S. The syndrome of hepatic veno-occlusive disease after
marrow transplantation. Blood 1995; 85; 3005–3020.
59. Shulman H, Fisher L, Schoch H et al. Venoocclusive disease of the
liver after marrow transplantation: histological correlates of
clinical signs and symptoms. Hepatology 1994; 19; 1171–
1180.
60. Shulman H, Gown A, Nugent D. Hepatic veno-occlusive disease
after bone marrow transplantation. Immunohistochemical iden-
tification of the material within occluded central venules. Am. J.
Pathol. 1987; 127; 549–558.
61. Ishak KG, Zimmerman HJ, Ray MB. Alcoholic liver disease:
pathologic, pathogenetic and clinical aspects. Alcohol Clin. Exp.
Res. 1991; 15; 45–66.
62. Denk H, Scheuer PJ, Baptista A, Bianchi L, Callea F, De Groote J
et al. Guidelines for the diagnosis and interpretation of hepatic
granulomas. Histopathology 1994; 25; 209–218.12 T Roskams et al.
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.

63. Kage M, Nakashima T. The pathology of Schistosomiasis.
In Okuda K, Benhamou J-P eds. Portal hypertension: clinical
and physiological aspects . Tokyo: Springer-Verlag, 1991;
289–299.
64. Desmet VJ. Congenital diseases of intrahepatic bile ducts:
variations on the theme ‘ductal plate malformation’. Hepatology
1992; 16; 1069–1083.65. Desmet VJ. What is congenital hepatic fibrosis? Histopathology
1992; 20; 465–477.
66. Wanless I, Gryfe A. Nodular transformation of the liver in
hereditary hemorrhagic telangiectasia. Arch. Pathol. Lab. Med.
1986; 110; 331–335.
67. Daly J, Schiller A. The liver in hemorrhagic telangiectasia (Osler–
Rendu disease). Am. J. Med. 1976; 60; 723–726.Histopathology of portal hypertension 13
/C2112003 Blackwell Publishing Ltd, Histopathology ,42, 2–13.