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Histopathology 2003, 42, 251–264

Clinicopathological features of nine cases of non-cirrhotic
portal hypertension: current definitions and criteria
are inadequate
C Ibarrola & F Colina
Pathology Department, University Hospital ‘Doce de Octubre’, Madrid, Spain
Date of submission 4 July 2002
Accepted for publication 22 October 2002

Ibarrola C & Colina F
(2003) Histopathology 42, 251–264

Clinicopathological features of nine cases of non-cirrhotic portal hypertension: current
definitions and criteria are inadequate
Aims: The clinicopathological features of nine patients
with non-cirrhotic portal hypertension were studied
and an attempt was made to apply the descriptive
criteria of experts to the morphological alterations of
the livers in order to classify them adequately.
Methods and results: Clinical and biochemical data and
the alterations in livers resected at transplantation
(n ¼ 7) or at autopsy (n ¼ 2) were gathered in five
males and four females (ages 15–78 years) without
aetiological factors for chronic hepatic disease who had
oesophageal varices and splenomegaly in the absence
of typical cirrhosis. Noting the luminal obstruction of
the three hepatic vascular trees, hyperplastic nodule
size and distribution, and the density of fibrosis, an
attempt was made to assign each case to one of
the following diagnostic categories: idiopathic portal
hypertension, diffuse nodular regenerative hyperplasia,
partial nodular transformation and incomplete septal
cirrhosis. When a case could not be categorized into
one of these groups, it was listed as non-cirrhotic
irregular architectural transformation. Only three
cases could be assigned to one pure diagnostic category

(two diffuse nodular regenerative hyperplasias and one
incomplete septal cirrhosis). Three other cases could
not be classified due to the heterogeneity of their
lesions. In the remaining three cases, the hepatic
morphology was a mixture of hilar partial nodular
transformation combined with another abnormal
architectural pattern in the peripheral parenchyma:
diffuse nodular regenerative hyperplasia in two cases
and idiopathic portal hypertension in the other. In seven
cases, old thromboses in the hilar portal tree were
observed. Stenoses were observed in some of the arterial
branches in five cases and in some hepatic venous
branches in four. However, no obstructions could be
discovered in small or large portal veins in the two
classical diffuse nodular regenerative hyperplasia cases.
Conclusions: The hepatic morphology in this group of
non-cirrhotic portal hypertension patients was an
abnormal remodelling of the liver associated with the
frequent development of irregular hyperplastic nodules
and frequent obstructions of the pre- and intrahepatic
vascular lumens. It was very difficult to apply the
nomenclature proposed by international experts.

Keywords: regenerative nodular hyperplasia, partial nodular transformation, incomplete septal cirrhosis, idiopathic
portal hypertension, focal nodular hyperplasia

Introduction
Non-cirrhotic portal hypertension is a little known
aetiopathogenic condition characterized by the
presence of splenomegaly, oesophageal varices and

alteration of hepatic function in the absence of cirrhosis. Its greatest prevalence has been observed in India
where it represents 20–25% of the cases that bleed due
to oesophageal varices.1 Aetiopathogenically, it has
been described in association with blood coagulation

Address for correspondence: Dr Francisco Colina, Departamento de Anatomı´a Patolo´gica, Hospital Universitario ‘Doce de Octubre’, Ctra. de
Andalucı´a Km 5400, Madrid 28041, Spain. e-mail: pcolina@inves.es
2003 Blackwell Publishing Limited.

252

C Ibarrola & F Colina

alterations,2,3 with exposure to toxic substances or to
drugs,4–6 with immunological alterations7,8 and with
systemic or intra-abdominal infections.9,10 Most of
the cases present with thrombosis or sclerosis in the
intrahepatic portal venous system9–11 with variable
involvement of the prehepatic portal system.12,13
Deficient and irregular afferent irrigation of the liver
has been proposed as the pathogenic mechanism of the
increase in resistance to blood flow and consequently of
the portal hypertension.14,15 The liver morphology of
patients with this syndrome has shown greatly varying
alterations that frequently include architectural
distortion associated with irregular hyperplastic nodules.16–18 This variability and the fact that many cases
have been studied in different countries by different
groups of authors have given rise to different designations for very similar clinicopathological pictures.
Among the designations used most are idiopathic
portal hypertension in Japan,19 non-cirrhotic portal
fibrosis in India,17,20 and hepatoportal sclerosis in the
USA21 and France.22 Several experts15,16,22–25 have
proposed terminologies that are theoretically applicable
to the morphological alterations found in these
patients’ livers.
We investigated the clinicopathological features of
nine patients with non-cirrhotic portal hypertension,
histopathologically studying the complete liver, to
assess the possibility of classifying them, applying the
morphological criteria described by experts, and to try
to relate the hepatic architectural alteration to the
alterations in the vascular tree.

Materials and methods
Among the non-cirrhotic portal hypertension cases
that were not associated with the Budd–Chiari syndrome, nine cases were chosen from the files of the
Hospital ‘12 de Octubre’ Pathology Department for
retrospective study. Two of these cases came from
autopsies and seven from resections for hepatic transplantation, and were sufficiently documented (clinical
history, hepatic function tests, imaging) and with
adequate histopathological material (description and
gross photographs, tissue samples from the parenchyma and from the hepatic hilum embedded in
paraffin).
The criteria used to include them in this series were:
(i) portal hypertension documented at least by the
existence of oesophageal varices and splenomegaly;
(ii) absence of conventional hepatic cirrhosis defined as
diffuse nodules totally surrounded by fibrous septa;26
(iii) absence of aetiological factors for chronic liver
disease (absence of anti-HCV, of HBsAg, of non-

organ-specific autoantibodies and of a history of
alcoholism).
Considering the features of architectural distortion,
hyperplastic nodules and fibrosis of the parenchyma,
an attempt was made to classify each liver into one of
the following diagnostic categories, following the definitional criteria used by Nakanuma et al.16 and the
terminology for hepatic nodular lesions recommended
by an International Working Party.23
Idiopathic portal hypertension
The liver shows portal tracts with fibrous enlargement
and occasional slender fibrous septa, although without formation of fibrosis bridges, except in the
subcapsular regions, where a subdivision of parenchyma is occasionally seen. The characteristics of
the other categories are not prominent or extensive in
this group.
Diffuse nodular regenerative hyperplasia
Monoacinar regenerative hepatocytic nodules, diffusely
distributed and not surrounded by fibrous septa, that
occupy the entire organ. Generally, they are the size of
a hepatic lobule or less and affect the periportal areas.
The hepatocytes that make up the nodules are hyperplastic and are located in two to three cell thick
trabeculae, and in the internodular zones the hepatocytes are atrophic.
Partial nodular transformation
Multiple nodules of hyperplastic hepatocytes forming
confluent masses of several centimetres in diameter
located in the perihilar region of the liver around the
large portal tracts.
Incomplete septal cirrhosis
Inconspicuous large diffusely distributed nodules that
occupy the entire piece, defined by frequently incomplete slender fibrous septa. The septa originate from
portal or perivenular fibrosis. In addition, these livers
show hypoplastic portal tracts in areas of hepatocytic
hyperplasia and the distances between the portal tracts
themselves and between the portal tracts and central
veins are abnormal. The hypoplastic portal tracts
generally contain the portal vein branch, hepatic
artery branch and bile duct having abnormal diameters
and in unusual proportions and distribution.
The finding of two well-circumscribed lesions with
multinodular hyperplastic hepatic parenchyma and
ductules in an irregular distribution with a star-shaped
fibrous scar that contained large vessels in one of these
livers led to the use of the term focal nodular
hyperplasia for them.23
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

Non-cirrhotic portal hypertension

The following method was used to assess the different
hepatic vascular trees and microscopic lesions of the
liver.
e x t e r n a l s u r f a c e an d s e c t i o n s u rf a c e s
of the l i v er s
The livers were examined in an initial section in the
horizontal plane from the main hepatic veins to the
round ligament and in successive 10 mm thick sections
parallel to the initial section. After the first section, a
prism that included the complete hilum with four
sections perpendicular to the initial horizontal section
was obtained. This prism was then sectioned into
sagittal sections from left to right, which made it
possible to examine the large hilar vessels. Several of
these sections, in which the portal and arterial vascular
trunks, their immediate branches and the bifurcation of
the bile tract were represented, were embedded in
paraffin for the microscopic study. Samples of the main
hepatic veins and of the parenchyma from both lobes,
of the nodular zones and of the major zones of fibrosis
were taken. They were stained after processing in
paraffin with H&E, Wilder, Masson trichrome, periodic
acid–Schiff after digestion with diastase, Perls’ and
Shikata’s orcein. The mean number of 100 mm2 and
4 lm thick sections studied per case was 24 (range
1400–4600 mm2). At least two to five histological
sections of the large vessels (portal vein, hepatic artery,
hepatic veins), 14 sections of the middle sized veins
(mean of one to two veins per 10 mm2 of hepatic
tissue) and 238 sections of small sized veins (mean of
17 veins per 10 mm2 of hepatic tissue) in each liver
were evaluated.
assessment of nodules, fibrosis and vascular
le si ons
Regenerative nodules are defined as that region of the
parenchyma enlarged by hepatocytic hyperplasia, and
can be monoacinar nodules (one single intranodular portal space) or multiacinar nodules (more
than one intranodular portal space).23 The following
characteristics were assessed: size and uniformity (regular, irregular) of the regenerative nodules;
their distribution was considered as ‘partial’ when
the nodulation occupied a more or less extensive
defined region of the parenchyma (hilar, lobar),
or as ‘patchy’ when the location was random and
discontinuous, or ‘diffuse’ when it occupied all the
parenchyma.
The fibrosis density was assessed semiquantitatively
according to the density of the fibrous septa using a
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

253

scale from 0 to 3, in which 0 was equivalent to absence
of septa, 1 to occasional septa, 2 to moderate density
and 3 to numerous septa. In addition, the existence of
sinusoidal collagenization was recorded.
Luminal obstructions of the portal venous tree, of the
arterial tree and of the hepatic venous tree were
assessed, as follows: (i) the location in the large veins or
those whose luminal diameter was >3 mm (including
the hilar portal venous trunk and its first two branches
as well as the two main hepatic veins and their
immediate afferent branches), in medium-sized veins or
those whose luminal diameter was between 0.2 and
3 mm and in small veins or whose diameter was
<0.2 mm (including the terminal and preterminal
veins). The decrease in luminal diameters of the large,
median and small arteries was also assessed and
classified by size according to whether they accompanied the portal vein of corresponding size; (ii) the
proportion of the luminal diameter affected by vascular
obstructions in the large vessels and the morphological
type of the obstructive lesions (previous old or recent
thrombosis, intimal fibrosis, myointimal hyperplasia
and medial hyperplasia); (iii) the existence of cavernomatosis was investigated in the hilum.

Results
clinical charact erist ics ( tab le

1)

Five males and four females whose ages ranged from 15
to 78 years were studied. One of the cases was an
incidental autopsy finding. The initial symptoms or signs
that led to the study of the disease were upper digestive
haemorrhage (n ¼ 3), alterations in hepatic function
tests (n ¼ 3), and ascites (n ¼ 2). Three other patients
suffered upper digestive haemorrhage and one of these
recurrent ascites. In addition, one developed intense
jaundice and oedema, a second one pleural effusion, and
a third an encephalopathy episode. Nine patients showed
marked splenomegaly and oesophageal varices, and
hepatomegaly was observed in three of them. The
clinical follow-up ranged from 1 month to 10 years
(mean 6.2 years). The splenomegaly and hepatomegaly
were maintained during the clinical course.
Two diagnoses of blood hypercoagulability (polycythaemia vera and erythrocytosis), two cases of right
cardiac failure, one of systemic lupus erythematosus,
one of Crohn’s disease, one of hepatotoxicity (adulterated toxic oil syndrome), two of diabetes mellitus type 2
and one of hepatic hydatid cyst were associated with
the portal hypertension syndrome (Table 1) in these
patients. Other associated diagnoses were: prostatic
adenocarcinoma, a background of leptomeningitis and

Yes

Yes

ALT of liver function No
test ⁄ upper digestive
haemorrhage
No

Yes

Ascites ⁄ upper
digestive
haemorrhage

Ascites ⁄ pleural
effusion

15M

36F

46F

4

5

6

Yes

ALT of liver function Yes
test ⁄ upper digestive
haemorrhage

26M

9

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

The age shown corresponds to the patient at the onset of the clinical picture.
*Autopsy cases.

Yes

No

ALT of
liver function test

49F

8*

Yes

Upper digestive
haemorrhage ⁄
encephalopathy,
ascites

57M

7

No

Yes

No

Upper digestive
haemorrhage ⁄
right iliac fossa
pain, asthenia,
anorexia

30F

3

Yes

Yes

No

Upper digestive
haemorrhage ⁄
jaundice, oedema

Yes

No

Yes

Yes

Yes

No

No

Yes

No

No

Yes

No

No

No

No

No

Other diagnoses

Steroids

Toxic oil
syndrome

Levodopacarbidopa

Diuretics

Steroids

No

No

No

6 years

5 years

10 years

10 years

1 month

No

Evolution
time

Crohn’s disease
with resection
of terminal ileum

Severe pulmonary
hypertension
Right cardiac failure
Adrenal gland
adenoma

3 years

12 years

>1 year
Type 2 diabetes
mellitus, Erythrocytosis
Restless leg
syndrome

Type 2 diabetes
mellitus, Partial
hepatic resection
due to hydatid
cysts (one in hepatic
hilum at present)

Systemic lupus
erythematosus

History of retinal
vasculitis and
leptomeningitis

Cholecystectomy
due to cholelithiasis
Spastic colon

No

Melphalan,
Polycythaemia vera
anti-androgens Right cardiac failure
Prostate carcinoma

36M

No

2

No

Yes

Yes

Autopsy finding

78M

1*

Yes

Oesophageal
Hepatomegaly Splenomegaly varices
Ascites Encephalopathy Drugs

Age
(years), Initial sign ⁄
Case gender others

Table 1. Clinical data

254
C Ibarrola & F Colina

2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

Non-cirrhotic portal hypertension

255

Table 2. Biochemical data
Case

Aph

GGT

AST

ALT

Bilirubin

Prothrombin
time

Number of
observations

Period of
observation (years)

1

265

35

33

24

0.8

55

1

2

99

160

30

18

4.5

63

1

3

140.2 ⁄ 62.3
(65–217)

37.1 ⁄ 13.1
(23–62)

45.2 ⁄ 11.2
(30–69)

52.4 ⁄ 20.3
(40–99)

1.1 ⁄ 0.4
(0.9–1)

70.2 ⁄ 12
(60–85)

8

10

4

195.4 ⁄ 63.1
(146–301)

52.6 ⁄ 8.7
(40–66)

41.3 ⁄ 6.6
(30–50)

25.4 ⁄ 13.5
(11–39)

5.2 ⁄ 1.8
(4.1–7.7)

52 ⁄ 9.9
(45–59)

7

4

5

370.5 ⁄ 116.7
(288–453)

38.7 ⁄ 14.6
(23–52)

36.7 ⁄ 16.5
(20–53)

24 ⁄ 3.5
(20–26)

1.5 ⁄ 0.7
(1–2)

55

3

4

6

743 ⁄ 276.9
(539–1150)

50.7 ⁄ 13.3
(38–67)

67 ⁄ 11.6
(52–78)

70.5 ⁄ 12.9
(59–72)

1.4 ⁄ 0.2
(1.2–1.7)

65.5 ⁄ 6.3
(61–70)

4

2

7

131.7 ⁄ 108.1
(59–256)

194.3 ⁄ 241.5
(20–470)

21.7 ⁄ 10.4
(10–30)

34.7 ⁄ 27
(11–64)

3.4 ⁄ 1.1
(2.4–4.7)

72 ⁄ 25.5
(54–90)

3

1

8

328

57

41

42

2.4

50

1

1

9

594.5 ⁄ 48.8
(560–626)

78 ⁄ 5.6
(78–83)

48 ⁄ 31.1
(26–70)

76 ⁄ 48.1
(42–110)

0.8 ⁄ 0.2
(0.7–0.9)

57.5 ⁄ 3.5
(55–60)

2

4

Mean ⁄ standard deviation (range).
Aph, Alkaline phosphatase; ALT, alanine aminotransferase, AST, aspartate aminotransferase; GGT, gamma-glutamyl
transpeptidase.
Normal values: Aph < 115 IU ⁄ l, ALT < 40 IU ⁄ L, AST < 40 IU ⁄ L, bilirubin total < 1. 0 mg ⁄ dl, GGT < 45 IU ⁄ L, prothrombin
time 100%.

retinal vasculitis, adrenal gland adenoma, cholecystectomy due to cholelithiasis and spastic colon.
liver function tests
The hepatic function tests were altered in all the cases
(Table 2), although in a variable way. Prothrombin
activity was significantly decreased in nine cases. The
most frequent and severely increased serum levels were
alkaline phosphatase (n ¼ 8), which reached values of
twice the normal level in seven cases, and bilirubin
(n ¼ 6), that exceeded 3 mg ⁄ dl on three occasions.
Elevations of GGT values (n ¼ 7), AST (n ¼ 5) and ALT
(n ¼ 4) were frequent, although generally mild.
mo r p h ol o g i c a l c h a ra c t e r i s t i c s
Morphology of the hepatic parenchyma (Table 3)
Hyperplastic nodules in the hepatic parenchyma of
variable extent and characteristics were observed in
every case. Three cases (two diffuse nodular regenerative hyperplasia and one incomplete septal cirrhosis)
could be adequately classified into one of the categories
proposed (Figure 1a,b). Three others showed mixed
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

characteristics: partial nodular transformation in the
perihilar parenchyma that was associated in the
peripheral parenchyma with a pattern of diffuse nodular regenerative hyperplasia (Figure 2a) in two of
them (cases 2 and 6) and with a pattern of idiopathic
portal hypertension in the third (case 3). Classification
by accepted terminology was impossible in the remaining three cases due to the heterogeneity and irregular
distribution of the parenchymal alterations. One of
these cases (case 4) showed an intense reduction in the
size of its right lobe and an increase in the size of the left
one (Figure 2b). The large left lobe showed a pattern of
diffuse nodular regenerative hyperplasia and the small
right lobe showed nodulation with irregular size and
distribution alternating with extensive areas with
broad fibrous septa and parenchymal collapse. Another
liver (case 9) showed a reduction of its right and left
lateral sectors together with hyperplasia of its most
central sectors and also showed mono- and multiacinar hyperplastic nodules distributed in a disseminated and random way among areas without nodulation
(Figure 3a). The fibrous septa were concentrated in the
sectors that were reduced in size. A final case that could
not be classified (case 7) also showed irregular patchy

Mixed

Monoacinar

Mixed

Monoacinar

Multiacinar

Monoacinar
Mixed

No

Monoacinar

Monoacinar

Non-perihilar
nodulation

Mixed

Monoacinar

Mixed

Multiacinar

Multiacinar

Monoacinar
Mixed

Multiacinar

Multiacinar

Monoacinar

Perihilar
nodulation

Patchy
Irregular

Diffuse
Regular

Patchy
Irregular

Diffuse
Irregular

Diffuse
Regular

Diffuse
Regular
Diffuse
Irregular

Partial
Regular

Diffuse
Irregular

Diffuse
Regular

Distribution of
the nodulation

Non-cirrhotic irregular architectural
transformation

Partial nodular transformation +
diffuse nodular regenerative hyperplasia

Grade 2 ⁄ no

Grade 2 ⁄ no

Incomplete septal cirrhosis

Grade 3 ⁄ no

Diffuse nodular regenerative hyperplasia

Non-cirrhotic irregular architectural
transformation (diffuse nodular regenerative
hyperplasia in left hepatic lobe
and extinctions in right hepatic lobe)

Grade 2 ⁄ mild
Grade 3 ⁄ extensive

Grade 0 ⁄ extensive

Partial nodular transformation +
idiopathic portal hypertension

Grade 2 ⁄ no

Non-cirrhotic irregular architectural
transformation

Partial nodular transformation +
diffuse nodular regenerative hyperplasia

Grade 0 ⁄ no

Grade 0 ⁄ no

Diffuse nodular regenerative hyperplasia

Diagnostic category

Grade 1 ⁄ mild

Fibrosis:
septal ⁄ sinusoidal

*Intense reduction in size of right lobe and enlargement of left lobe.
†In addition, this case showed two focal nodular hyperplasias.
‡Intense reduction of size of posterior sector (segment VI and VII of right hepatic lobe) and of lateral sector (segments II and III of left hepatic lobe) and increase of
anterior (right hepatic lobe) and medial (left hepatic lobe) sector, as well as of caudate lobe (segment I).

Left hepatic lobe +
right hepatic lobe

Left hepatic lobe +
right hepatic lobe

6

9‡

Left hepatic lobe +
right hepatic lobe

5

Left hepatic lobe +
right hepatic lobe

Left hepatic lobe
Right hepatic lobe

4*

8

Left hepatic lobe +
right hepatic lobe

3

Left hepatic lobe +
right hepatic lobe

Left hepatic lobe +
right hepatic lobe

2

7†

Left hepatic lobe +
right hepatic lobe

Situation of the
nodules

1

Case

Table 3. Distribution and characteristics of the nodulation and fibrosis

256
C Ibarrola & F Colina

2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

Non-cirrhotic portal hypertension

nodulation on a background of absence of nodulation
and of fibrosis; also two of its nodulations were similar
to focal nodular hyperplasias (Figure 3b), since they
showed a typical star-shaped central scar. Noncirrhotic ‘irregular architectural transformation’ of
the parenchyma was chosen as a possible nomenclature for these last three cases. Necroinflammation was
not observed in any case (Figure 4).
Vascular lesions (Table 4)
Vascular alterations were detected histologically in
eight of the nine cases. The only case (case 8) in
which no lesion could be discovered in any of the
vascular trees was a diffuse nodular regenerative
hyperplasia; however, severe but irregular sinusoidal
collagenization was present. The most frequent
lesions were obstructions of the portal venous tree
(n ¼ 7). The obstructions in the large portal veins
(n ¼ 7) were due to previous old thrombosis with the
classical lamellar disposition of collagen in the vascular lumen, and they were observed in the hilar trunk
and ⁄ or in a main portal branch (Figure 5a). Cavernomas existed in three cases, bypassing the total
obstruction of the hilar portal trunk or a main
branch. In these seven cases, the small portal veins
presented alterations that included their absence in
some portal tracts, in their replacement by numerous
vascular channels (angiomatosis) or in parietal intimal fibrosis reducing their lumina. Furthermore, in
six of these cases, the median portal veins showed
intimal fibrosis or proliferation of the smooth muscle
fibres in their medial layer (medial hyperplasia) or in
their intimal layer (myointimal hyperplasia) (Figure 5b,c). Recent thrombosis was not observed in
these median or small portal branches.
The hepatic arterial system showed partial obstruction in five cases. In three cases, the hilar arterial
trunk was involved and showed 20–30% reduction
in luminal diameter (Figure 6a). The medium-sized
arterial branches were partially occluded in three
livers and the small ones were also partially occluded
in three livers. The decrease in their luminal diameters was due to intimal fibrosis and ⁄ or to medial
hyperplasia and ⁄ or to myointimal hyperplasia (Figure 6b).
The hepatic venous system showed partial obstructions in three cases, with involvement of the large
branches in one, of the medium-sized branches in three
and of the small in two cases. The lesion observed in all
of them was intimal fibrosis, which was not totally
obstructive of its lumen in any case (Figure 7). The
efferent hepatic venous system lesions were combined
in three cases with the portal system obstructions and
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

257

also with involvement of the arterial tree in one of
them.
Association between vascular lesions and morphological
patterns of the parenchyma
A repeated search failed to demonstrate obstructions in
the portal tree in the two livers with pure diffuse
nodular regenerative hyperplasia. One of them showed
stenosis throughout the arterial tree and intimal
fibrosis in some medium and small hepatic veins. The
other showed only severe sinusoidal fibrosis. A diffuse
nodular regenerative hyperplasia pattern was observed
in the left hyperplastic lobe of case 4 that also presented
right lobar atrophy. In this left lobe there were portal
venous obstructions, but these were exclusively in the
small branches, without any obstruction of the main
left branch of the portal vein or of the hilar portal vein
trunk.
In the three partial nodular transformations, the
obstructions were found in the portal and arterial tree,
with no participation of the hepatic venous tree. Their
portal system showed segmental obstructions in the
hilar trunk and in the medium-sized and small branches. A 20–25% reduction of the luminal diameter of
the large arterial branches was observed in the two
livers with a partial nodular transformation pattern
associated with diffuse nodular regenerative hyperplasia; however, only the small arterial branches showed
obstructions in the liver with a mixed partial nodular
transformation and idiopathic portal hypertension
pattern.
Two of the irregular architectural transformations—those with gross reduction in the size of one
lobe (case 4) or of the peripheral sectors (case 9)—and
the incomplete septal cirrhosis showed a hepatic
venous tree with stenosis, obstructions or irregular
dilatations. The lesion of the hepatic veins was combined with obstructive lesions of the portal venous tree
in these three cases (Figure 5a,b). In case 4, in the
hilum, only the right main portal branch, which is the
one that should irrigate the lobe reduced in size, was
obstructed. In both this case and case 9, the obstructions of the hepatic veins were observed only in the
reduced sized zones associated with the greatest fibrosis
of the parenchyma. In case 9, in addition to stenosis
and obstructions of the hepatic veins of all sizes,
irregular dilatations of some large hepatic veins were
observed. In the incomplete septal cirrhosis case, all the
portal system was stenosed irregularly and the median
hepatic veins were difficult to identify, as they were
included in the fibrous septa. The final case of the three
with irregular architectural transformation (case 7)
was the only one among the nine cases in which the

258

C Ibarrola & F Colina

Figure 1. a, Diffuse nodular regenerative hyperplasia (case 1):
regular parenchymal micronodules without fibrous septa diffusely
distributed throughout the liver. b, Incomplete septal cirrhosis
(case 5): regular parenchymal macronodules delineated by incomplete slender fibrous septa and diffusely distributed throughout the
liver.

portal venous system was exclusively involved and
showed segmental obstructions in its pathway.

Discussion
The sporadic character of non-cirrhotic portal hypertension explains the limited series reported in western
countries.9,22,27–29 The greatest experience comes from
Japan19 and India.20 We are ignorant as to whether
the histopathology of the liver varies between these
endemic regions and Europe. The dispersed information
published and the variety and irregularity of the
hepatic lesions associated with this syndrome have
made it difficult to have a homogeneous morphological
nomenclature in spite of efforts by experts.15,16,22–25
The definition of non-cirrhotic portal hypertension
syndrome is based on a clinical picture of chronic
portal hypertension that is not associated with

Figure 2. a, Partial nodular transformation and diffuse nodular
regenerative hyperplasia (case 2): confluent parenchymal nodules
around the large perihilar portal tracts and diffuse parenchymal
micronodulation in the peripheral region. b, Non-cirrhotic irregular
architectural transformation (case 4): enlarged left lobe with a diffuse
nodular regenerative hyperplasia pattern and shrinkage of the right
lobe with multiple large areas of extinction.

conventional hepatic cirrhosis and in which there are
no aetiological factors of chronic liver disease.19,30
Several clinical and pathological pictures are included
within this syndrome. Among these, there are some
that are very similar morphologically: these being
called idiopathic portal hypertension,9,18,30 non-cirrhotic portal fibrosis17 and hepatoportal sclerosis.21 In
them, the liver architecture is described as mildly
distorted due to the existence of irregular distances
between the portal venous and hepatic venous structures11,19 and they frequently also present nodular
regenerative foci.8,9,17,20 In other types of non-cirrhotic
portal hypertension called diffuse nodular regenerative
hyperplasia, partial nodular transformation and
incomplete septal cirrhosis,31 more frequently described in Western countries, the liver presents
greater architectural distortion and the regenerative
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

Non-cirrhotic portal hypertension

Figure 3. a, Non-cirrhotic irregular architectural transformation:
cut surface of liver showing variably sized parenchymal nodules
randomly distributed. b, Non-cirrhotic irregular architectural transformation (case 7): circumscribed lesion of hyperplastic parenchyma
with a central stellate fibrous scar similar to classical focal nodular
hyperplasia.

Figure 4. Thin portal fibrous septa irregularly distributed in the liver.
Note the absence of necroinflammation.
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

259

nodulation is more prominent. They share the presence
of thrombotic type obliterative vascular lesions, mostly
in the portal venous vessels, and the absence of
relevant necroinflammatory signs. It has been suggested that all these conditions could represent the same
lesional spectrum, the different stages of the same
disease,16 or the final stage common to different
diseases with varying aetiologies.32
The findings of this series illustrate the variety of
possible morphological patterns in livers with noncirrhotic portal hypertension and show that there is:
1. Global remodelling of the hepatic architecture as
a common characteristic of all of them. Extensive areas
of nodular hyperplasia alternating with atrophic areas
were observed in every case. The nodulation was
frequently heterogeneous as in other published series.16,17,29 The fibrosis was also irregular and frequently presented as parenchymal loss,33 that was very
evident in the lobe and in the reduced sized sectors of
two of the cases, or as numerous incomplete slender
septa, in a diffuse distribution in the case of incomplete
septal cirrhosis.31
2. An obstructive portal vasculopathy was demonstrated in seven of the nine cases. The obstructions in
these seven cases were in the form of hilar trunk
and ⁄ or main portal branch thrombosis, transformed
either into eccentric intimal sclerosis, in recanalized
thrombosis, or in cavernomas. Furthermore, these
seven cases also showed some medium and small
portal venous branches that were partially or totally
obliterated by fibrosis (eccentric or concentric) or
replaced by numerous vascular canals, that possibly
represent recanalization of previous thromboses.
3. An absence or scarcity of relevant necroinflammation.
Pre-intrahepatic afferent obstructive vasculopathy
may be the primary lesion responsible for these features
and some authors use the term ‘portal obliterative
venopathy’ for them.3 In this and in other series, portal
vasculopathy frequently also combines with hepatic
venous and arterial vessel lesions.15 All these vascular
lesions17 support the hypothesis that irregular blood
perfusion is the pathogenic factor in hepatic parenchymal remodelling9,11,18 that determines the development of hyperplastic nodulation in the best irrigated
areas and atrophy in those worst irrigated.14,15 It has
also been proposed that certain types of vascular lesion
patterns are associated with a certain type of parenchymal lesion.3 The perihilar nodulation in partial
nodular transformation has been related to a partial
obstruction of the large portal veins, as was observed in
three of these cases. Diffuse monoacinar nodulation in
the diffuse nodular regenerative hyperplasia has been

No

No

Right lobe
90% (right branch
of main portal vein)
(recanalized
thrombosis)

100%
(thrombosis,
cavernoma)

90%
(recanalized
thrombosis)

6 Partial nodular
transformation +
diffuse nodular
regenerative
hyperplasia

7 Irregular
architectural
transformation

5 Incomplete septal 100%
cirrhosis
(thrombosis,
cavernoma)

Yes (absence) No

No

Left lobe
(hilum + left
branch of main
portal vein)

4 Irregular
architectural
transformation
(diffuse nodular
regenerative
hyperplasia
in left lobe
and extinctions
in right lobe)

Small

Yes (intimal Yes
fibrosis)
(absence)

No

No

No

No

No

Yes (intimal Yes
fibrosis)
(absence)

No

Yes (absence) No

No

Yes (intimal Yes (absence
fibrosis)
or intimal
fibrosis)

No

No

No

25% (intimal
fibrosis, medial
hyperplasia)

No

Small

No

No

Yes (medial
hyperplasia)

No

No

Yes (intimal No
fibrosis)

Yes (medial Yes (medial
hyperplasia) hyperplasia)

No

No

No

No

Yes (medial Yes (medial
hyperplasia) hyperplasia)

Medium

20% (myointimal No
hyperplasia)

30% (intimal
fibrosis)

Yes (intimal No
fibrosis)

Yes (intimal
fibrosis)

No

No

No

Yes

No

No

No

No

Yes (absence
Yes
(medial and or intimal
myointimal fibrosis)
hyperplasia)

70%
(thrombosis)

No

Yes

No

3 Partial nodular
transformation +
idiopathic portal
hypertension

Yes (intimal
fibrosis)

Yes
(intimal
fibrosis)

30%
(thrombosis)

No

2 Partial nodular
transformation +
diffuse nodular
regenerative

No

No

Small

No

Medium

Large
(% luminal
obstruction)

Large
(% luminal
obstruction) Medium

Large (% luminal
obstruction)

1 Diffuse nodular
regenerative
hyperplasia

Case

Hepatic arteries

Hepatic veins

Portal veins

Table 4. Location and type of obstructive vascular lesions

260
C Ibarrola & F Colina

2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

*Main trunk permeable with intimal fibrosis that reduces 20% of the lumen. Right branch divided into three with total luminal obstruction by recanalized thrombosis
(cavernoma).
†Dilatations and obstructions only in the atrophic subcapsular zones.

No
No
No
Yes† (intimal
fibrosis)
Yes† (intimal
fibrosis)
20%†
(intimal
fibrosis)
Yes (absence
or angiomatoid
lesions)
20%*
9 Irregular
architectural
transformation

Yes (intimal
fibrosis)

No
No
No
No
8 Diffuse nodular
regenerative
hyperplasia

No

No

No

No

No

Non-cirrhotic portal hypertension

2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

261

Figure 5. Portal veins. a, Intrahepatic right branch of main portal
vein showing an organized and partially occluding thrombus. Beside
it, parenchymal nodules impart a striking resemblance to cirrhosis
(case 4). b, Portal vein with eccentric myointimal hyperplasia
(humps). c, Abnormal portal tracts with the veins as small as the
arteries.

related to disseminated obstructions of the microvasculature (sinusoids or small portal veins)14,15 and the
two diffuse nodular regenerative hyperplasias of this
series were the only conditions without lesions in the
large or medium portal vessels. One of them showed

262

C Ibarrola & F Colina

Figure 6. Hepatic arteries. a, Large hilar branch with eccentric
fibrous intimal thickening. b, Small branch with concentric medial
hyperplasia.

Figure 7. Hepatic veins. Medium hepatic vein showing partial
occlusion by fibrosis.

extensive sinusoidal fibrosis as the only lesion of the
hepatic circulation, and we did not observe microvascular obstructions in the other. However, it is possible

that microthrombi existed in the microvasculature but
disappeared due to fibrinolysis, as has been described in
cases of diffuse nodular regenerative hyperplasia associated with coagulopathies.2,3 The parenchymal pattern of diffuse nodular regenerative hyperplasia also
existed in the hyperplastic lobe of one case in which the
vascular obstructions were found in the small portal
venous branches of this lobe. On the other hand, the
greatest density of fibrosis, the incomplete septal
cirrhosis pattern, the disappearance of one lobe and
the extinction of hepatic sectors were all lesions that
coincided with the combined obstruction of the afferent
and efferent vascular system as the Wanless double-hit
theory proposes.33 Finally, it should be mentioned that
in one case, two lesions similar to focal nodular
hyperplasia were seen,34,35 these lesions being characterized by a focal hepatic vascular alteration with
surrounding nodulation, and their coincidence in one
of these cases, improbably explained by chance,
suggests that vasculopathy is a common pathogenic
factor in its association with non-cirrhotic portal
hypertension.36,37
The nomenclature proposed by experts15,16,22–25
made it possible to classify accurately only diffuse
nodular regenerative hyperplasia and incomplete septal
cirrhosis as clearly defined entities. In three other cases,
only the use of combined terms made it possible to
provide an adequate description of the hepatic morphology. The literature frequently refers to similar
combinations of morphological patterns of partial
nodular transformation in the hilum with peripheral
diffuse nodular regenerative hyperplasia or peripheral
idiopathic portal hypertension.16,38 Sometimes, such
mixtures have been simply referred to as partial
nodular transformation,9,39 but the International
Working Party proposes abandoning the term partial
nodular transformation and including these combined
cases of partial nodular transformation and diffuse
nodular regenerative hyperplasia in the concept of
diffuse nodular regenerative hyperplasia.23 Three cases
could not be classified, even by resorting to mixing
categories, and the best of the possible descriptive terms
was that of non-cirrhotic ‘irregular architectural
transformation’, since they showed very grossly
deformed livers with nodules that were very irregularly
distributed and whose size was very irregular, located
in a non-regenerative but distorted tissue background.
Two of them could be called ‘lobar or segmental
hyperplasia’, a term used by Wanless39 and by the
International Working Party23 in their classifications of
regenerative pictures. However, this term only describes the gross aspect without specifying the hepatic
histological picture, and Wanless states that up to 50%
2003 Blackwell Publishing Ltd, Histopathology, 42, 251–264.

Non-cirrhotic portal hypertension

of the livers with non-cirrhotic portal hypertension and
13% of the livers with classical cirrhosis show this
lobar or segmental hyperplasia, so that it does not seem
to be an adequate term for such unclassifiable cases.39
The location of the primary vascular lesion could be
a useful method to classify these liver diseases as the
International Working Party proposes.23 The problem
is that many of these cases show lesions in all the portal
vessels, frequently associated with a lesion of the other
hepatic vascular systems. It is probable that many of
the reported cases were evolutionally advanced, showing vascular obstructions and architectural alterations
superimposed on the initial vascular and parenchymal
lesions.
Regarding the aetiopathogenesis, the clinical pictures associated with the non-cirrhotic portal hypertension in six cases of this series could contribute to
irregular blood perfusion of the hepatic parenchyma
through greater viscosity of the blood (erythrocytosis,
polycythaemia vera), or chronic venous stasis (right
cardiac failure, pulmonary hypertension), or local
compression of the vessels (hilar hepatic hydatid cyst),
or a lesion of the hepatic vessel wall similar to those
described in association with toxicity in the toxic oil
syndrome,4,6 or through vasculitis and ⁄ or chronic
inflammatory disease (systemic lupus erythematosus,
Crohn’s disease). However, no associated disease that
could suggest a pathogenetic clue was found in three
cases.
The lack of knowledge of many of these aspects
should encourage more morphological studies of
hepatectomy specimens in non-cirrhotic portal hypertension syndrome in western countries so as to be
able to define clinicopathological entities more precisely.

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