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Clin Liver Dis 10 (2006) 627–651

Noncirrhotic Portal Hypertension
Shiv Kumar Sarin, MD, DM*,
Ashish Kumar, MD, DM
Department of Gastroenterology, G B Pant Hospital, Room 201, Academic Block,
New Delhi 110 002, India

Portal hypertension is characterized by an increase in portal pressure
(O10 mm Hg), and could be a result of cirrhosis of the liver or noncirrhotic
diseases. Noncirrhotic portal hypertension (NCPH), as it generally is
termed, is a heterogeneous group of diseases that is due to intrahepatic or
extrahepatic etiologies. In general, the lesions in NCPH are vascular in nature and can be classified based on the site of resistance to blood flow as
‘‘prehepatic,’’ ‘‘hepatic,’’ and ‘‘posthepatic.’’ The ‘‘hepatic’’ causes of
NCPH can be subdivided into ‘‘presinusoidal,’’ ‘‘sinusoidal,’’ and ‘‘postsinusoidal’’ (Box 1).
Portal pressure is difficult to measure because direct puncture of the deepseated portal vein is impractical. By wedging a catheter into the hepatic vein,
the hepatic sinusoidal pressure can be measured. The difference between the
wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure gives the hepatic venous pressure gradient (HVPG), which reflects portal pressure in cirrhotic patients (see the article by Groszmann and
colleagues elsewhere in this issue). In NCPH, HVPG usually is near normal
or is elevated only mildly, and is significantly lower than the portal vein
pressure [1–3]. In most of the diseases that are grouped under the category
of NCPH (see Box 1), portal hypertension is a late manifestation of the disease. Noncirrhotic portal fibrosis (NCPF) and extrahepatic portal vein obstruction (EHPVO) are two diseases that are common in developing
countries and most often present only with features of portal hypertension
and not of parenchymal dysfunction (Fig. 1). These will be described here
in detail.

* Corresponding author.
E-mail address: (S.K. Sarin).
1089-3261/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.



Box 1. Classification and causes of noncirrhotic portal
Extrahepatic portal vein obstruction (portal vein thrombosis)
Splenic vein thrombosis
Splanchnic arteriovenous fistula
Splenomegaly (eg, lymphoma, Goucher’s disease)
Noncirrhotic portal fibrosis
Idiopathic portal hypertension
Hepatoportal sclerosis
Primary or secondary biliary cirrhosis (precirrhotic stage)
Sclerosing cholangitis
Congenital hepatic fibrosis
Peliosis hepatitis
Hepatic arterioportal fistula
Early myeloproliferative diseases and myelofibrosis
Vinyl chloride, arsenic, or azathioprine hepatotoxicity
Partial nodular transformation
Alcoholic hepatitis
Hypervitaminosis A
Incomplete septal fibrosis
Nodular regenerative hyperplasia
Methotrexate hepatoxicity
Secondary syphilis
Veno-occlusive disease
Hepatic vein thrombosis (Budd-Chiari syndrome)
Inferior vena caval web
Constrictive pericarditis
Tricuspid regurgitation
Severe right-sided heart failure
Restrictive cardiomyopathy



Fig. 1. Two common causes of noncirrhotic portal hypertension: NCPF and EHPVO. Abbreviations: EHPVO, extrahepatic portal vein obstruction; NCPF, non-cirrhotic portal fibrosis;
PHT, portal hypertension.

Noncirrhotic portal fibrosis
Since the initial description of anemia with splenomegaly by Banti in
1889 [4] and of massive splenomegaly without gross liver pathology by Ravenna in 1940 [5], the understanding of this disease has improved significantly. It has become clear that this entity is distinct from cirrhosis. In
the late 1950s, terms such as ‘‘tropical splenomegaly syndrome’’ or ‘‘Bengal
splenomegaly’’ were coined. In the early 1960s, Indian clinicians described
a group of adult patients who had noncirrhotic disease with portal hypertension that presented with recurrent episodes of bleeding without ascites or encephalopathy [6,7]. Mikkelsen and colleagues [8] from the United States
subsequently identified concentric thickening or sclerosis of the portal vein
and its radicals in patients who had portal hypertension without cirrhosis;
they called this condition ‘‘hepatoportal sclerosis.’’ Boyer and colleagues
[9] described a similar group of patients under the term ‘‘idiopathic portal
hypertension’’ (IPH), and emphasized that such patients have a more favorable prognosis than do cirrhotics. They also suggested that portal pylephlebitis might be a causative factor [10]. The term NCPF was used first by Basu
and colleagues [11] in 1967 and subsequently was endorsed by the Indian
Council of Medical Research. This condition was reported simultaneously
from Japan, where a condition close to NCPF is termed ‘‘IPH’’ [12,13].
NCPF or IPH has been reported from all parts of the world [14–22], more
so from developing countries [7,15,23–25]. It is believed to account for
nearly one fifth of all cases of variceal bleeding. The condition is seen commonly in people who are socio-economically disadvantaged. Improved hygiene and standards of living could explain the rarity of the disease in the



West and its declining incidence in Japan. Although in 1985, the reported
incidence of IPH in Japan was 0.75/100,000 population, in 1992 11 new patients were reported [26]. It will be interesting to see if this trend is seen in
other developing countries, such as India, with improvement in hygienic
Although the terms NCPF and IPH often have been used interchangeably, there are subtle differences between the two diseases. NCPF is more
common in men [23,24]. This is in contrast to IPH in Japan, Europe, and
the United States, where the disease is more common in women. The
mean age of patients who have NCPF varies from 25 to 35 years, which
is much younger than for patients who have IPH. There also are distinct differences in the prevalence of autoantibodies and histopathology of the two
It is likely that the liver behaves in a similar manner to various insults,
which results in NCPF. No definite etiopathologic agent or group of diseases has been identified clearly as the cause for development of portal hypertension in NCPF. Several hypotheses have been proposed.
Infective hypothesis
NCPF has been seen commonly in patients from low socioeconomic
backgrounds. Abdominal infection at birth or in early childhood has been
alleged to play an important role [24]. Umbilical sepsis, bacterial infections,
and diarrheal episodes in infancy and in early childhood are likely to lead to
portal pyemia and pylephlebitis, which result in thrombosis, sclerosis, and
obstruction of small- and medium-sized portal vein radicals [8,23]. Although
the investigators in India consider thrombosis to be the initial event, the Japanese clinicians believe thrombosis to be a result of portal sclerosis [13,27].
In experimental studies, IPH, like changes in the liver and the development of portal hypertension, have been reported after injecting dead nonpathogenic colon bacilli into the portal vein of rabbits and dogs [28,29].
In another model of indwelling cannulation of the gastrosplenic vein, repeated injections of Escherichia coli resulted in the development of splenomegaly and an increase in portal pressure at 3 months [30].
Exposure to trace metals and chemicals
Prolonged ingestion of arsenic in the drinking water has been incriminated in the causation of NCPF [31,32]. In patients with chronic arsenic ingestion, the liver histology reveals periportal fibrosis and incomplete septal
cirrhosis, with or without development of neovascularization within the expanded portal zones that is suggestive of NCPF or IPH. In patients from
Iran, a history of pica was obtained in nearly half of the patients [14]. A histologic picture that resembles NCPF has been observed following chronic



exposure to vinyl chloride monomers, copper sulfate (vineyard sprayers),
protracted treatment with methotrexate, hypervitaminosis A, and in recipients of renal allografts who received treatment with 6-mercaptopurine, azathioprine, and corticosteroids.
In mice that were fed arsenic for a prolonged period, the authors [33] observed a 4 to 14 fold increase in hepatic hydroxyproline and hepatic collagen
compared with control mice; however, the features of NCPF or portal hypertension did not develop in any animal. These observations suggest that
although arsenic ingestion could induce hepatic fibrogenesis, it cannot be incriminated directly in the causation of NCPF.
Immunologic and immunogenetic hypothesis
There is some evidence to suggest a deranged immune response and reduced cell-mediated immunity in patients who have NCPF [34]; however,
it is not clear whether these changes are the cause or the result of portal hypertension in NCPF. The IPH in Japan is associated frequently with autoimmune disorders, such as systemic lupus erythematosus, progressive
systemic sclerosis, thyroiditis, and mixed connective tissue disease [35,36].
Three fourths of these patients test positive for anti-ds DNA antibody
and one fourth test positive for antinuclear antibody [36]. Such a high prevalence of associated autoimmune conditions has not been reported on the
Indian subcontinent; however, familial aggregation and a high frequency
of HLA-DR3 have been found in patients who have NCPF [37].
Repeated injections of splenic extract, Freund’s adjuvant, and egg albumin produce splenomegaly and histologic lesions similar to IPH in rabbits
[38]. In a recent study, injection of splenic extract in presensitized rabbits resulted in the development of an NCPF-like picture, with splenomegaly and
an increase in portal pressure with negligible parenchymal injury [30].
Unifying hypothesis
Although the role of infection and inflammation of the portal system is
convincing, the etiopathogenesis of NCPF remains conjectural. Based on
the available information, the authors had proposed a hypothesis for the development of NCPF and EHPVO. Both of these venous inflow tract diseases
could develop in an individual who is genetically predisposed to thrombotic
disorders, when infection or a prothrombotic event may precipitate thrombosis in the portal vein or its radicals. If it is a major thrombotic event that
occurs at birth or at an early age in life, the main portal vein is likely to get
occluded, which results in the development of EHPVO (Fig. 2). In the event
of repeated microthrombotic events, the small or medium branches of the
portal vein are affected and NCPF develops and manifests in a young adult
who has portal hypertension. It also is likely that recanalization of the major
portal vein branches occurs in patients who have NCPF. Infection and
endotoxemia are considered to be the major initiating events for the



Infection/Inflammation/Other causes
(Manifested in

Chronic / Mild
(Manifested in

Occlusive thrombus
in main portal vein

Chronic antigenemia

Occlusion of
main portal vein / cavernoma

Presinusoidal fibrosis
Stimulation of
reticuloendothelial system


Presinusoidal resistance


Fig. 2. Etiopathogenesis of NCPF and EHPVO. Abbreviations: EHPVO, extrahepatic portal
vein obstruction; NCPF, non-cirrhotic portal fibrosis; PHT, portal hypertension.

For some time, NCPF was considered as a diagnosis of exclusion. Subsequently, salient histologic features that are characteristic of this condition
were described to make it a distinct clinicopathologic entity.
Gross pathology
Often, the liver is normal, but it can be nodular in 10% to 15% of cases.
Some patients may have extensive subhepatic and portal fibrosis, and nodular transformation of the liver has been described from IPH [39]. Progression from IPH to incomplete septal cirrhosis may occur in advanced stages
[40]. Generally, the portal vein is dilated with thickened and sclerosed walls.
Autopsy series commonly show thrombosis in the medium and small (diameter!300 mm) portal vein branches [35,41].
The wedge hepatic biopsy specimens that were obtained from patients
who are undergoing shunt surgery have shown fibrosis of the portal areas
along with marked, but patchy and segmental, subendothelial thickening
of the large and medium-sized branches of the portal vein. Nayak and Ramalingaswamy [42] called these changes ‘‘obliterative portovenopathy’’ of the
liver. The intimal thickening of intrahepatic portal venous channels, which is
associated with obliteration of small portal venules and emergence of new
aberrant portal channels, is quite characteristic of NCPF [43]. Evidence of
previous phlebothrombosis is suggested by the presence of old mural



thrombi that are incorporated in the wall, mural thickening of the extrahepatic portal vein, and coexistence of lesions that are characteristic of NCPF
and EHPVO in the same patient. Pathology of IPH differs from that of
NCPF because of the associated autoimmune conditions [15,36]. It is suggested that parenchymal lesions are secondary to portal malperfusion.
Many of these morphologic changes are observed in normal livers, but their
intensity is low and they are located mainly in subcapsular areas.
A widening of the space of Disse with haphazardly arranged collagen
bands in the perisinusoidal space that leads to capillarization of sinusoids
may be seen. These changes suggest that the disease process in NCPF is diffuse.
The portal vein pressures are elevated markedly in patients who have
NCPF. Two pathoanatomic sites of obstruction have been identified. A
pressure gradient exists between the spleen and the liver (intrasplenic pressure  intrahepatic pressure [IHP]) and another exists between the IHP
and the WHVP (IHP  WHVP) [44] Generally, the WHVP is normal or
only slightly elevated in NCPF. Variceal pressure also has been studied in
these patients and is comparable to that in cirrhotic portal hypertension
[44,45]. Intravariceal pressure closely reflects portal pressure in patients
who have NCPF and is the investigation of choice for measurement of portal pressure. Splenic and portal vein blood flow are known to be increased
markedly in Japanese patients who have IPH, which is suggestive of a hyperdynamic circulatory state.
Clinical features
Patients who have NCPF generally are young and come from low socioeconomic backgrounds. Most studies report a slight male preponderance
[23,25]. The patients commonly present with one or more well-tolerated episodes of gastrointestinal hemorrhage, a long-standing mass in the left upper
quadrant (splenomegaly), and consequences of hypersplenism. Development of ascites, jaundice, and hepatic encephalopathy is uncommon and
may be seen only after an episode of gastrointestinal hemorrhage. Of all
of the causes of portal hypertension, a massive and disproportionately large
spleen is seen most commonly in NCPF. Left upper quadrant pain that is
due to perisplenitis and splenic infarction is not uncommon [46]. The clinical
presentation of NCPF is distinct from IPH in several regards. Like cirrhosis,
NCPF also may have odd presentations, such as glomerulonephritis [47,48]
or hypoxemia [49].
Over a 22-year period (1983–2004), the authors saw 307 patients who had
NCPF, whereas EHPVO was diagnosed in 499 patients. The demographic
profile of these patients is shown in Table 1 [50,51].



Table 1
Profile of patients who have noncirrhotic portal fibrosis and extrahepatic portal vein

NCPF (n ¼ 307)

EHPVO (n ¼ 499)

Mean age (y)
Sex (males/females)
Hematemesis/melena (%)
Mass in LUQ (%)
Ascites (transient) (%)
Jaundice (%)
Esophageal varices (%)
Portal gastropathy (%)
Portal biliopathy (%)



Abbreviation: LUQ, left upper quadrant.
Data from Refs. [1,50,51].

Laboratory features
Patients who have NCPF generally have preserved hepatic function. The
tests of liver function are normal. Monoethylglycinexylidide extraction also
has been reported to be normal in NCPF [52]. Anemia is common, and it
can be microcytic, hypochromic (due to gastrointestinal blood loss) or normocytic, normochromic (due to hypersplenism). Leukopenia (!4000 cells/
mm3) and thrombocytopenia (!50,000 cells/mm3) are not uncommon. Although asymptomatic hypersplenism is common, symptomatic hypersplenism is rare in NCPF. Coagulation and platelet function anomalies also
have been observed in patients who have NCPH [53]. Mild compensated disseminated intravascular coagulation secondary to endotoxemia or portosystemic collaterals has been reported in a fair proportion of these patients
[53,54]. Biliary lipid composition is normal in patients who have NCPF [55].
The frequency of hepatitis B and C in nontransfused patients who have
NCPF is not higher than that seen in the general population.
Autonomic dysfunction has been well documented in cirrhosis. It also has
been reported in NCPF [56], which suggests some contribution of portal hypertension because liver functions are near normal in NCPF.
Ultrasonography is the investigation of choice. It shows a dilated and patent splenoportal axis with significantly thickened walls of the portal vein and
its main branches. This is quite consistent with the initial description of
‘‘hepatoportal sclerosis’’ that was given to this disease. Doppler studies are
helpful in identifying an occasional patient who has a thrombus in the intrahepatic branch of the portal vein. Spontaneous splenorenal shunts are seen in
about 10% to 15% of patients who have NCPF, this is more frequently than
seen in cirrhotics [57,58]. CT portography and CT hepatic angiography also
have been recommended to distinguish between NCPF and cirrhosis.



Portal biliopathy, defined as anomalies of the biliary system and gall
bladder in patients who have portal hypertension, is seen commonly in patients who have EHPVO. It also is not uncommon in patients who have
NCPF [59].
Esophagogastric varices are seen in 85% to 95% of patients who have
NCPF. Furthermore, patients who have NCPH have large varices more often (90%) compared with cirrhotic patients (70%) [60]. Anorectal varices
also are more common (90% versus 56%) and are bigger in size [61]. Variceal pressure, either measured directly or with a pressure gauge, is reported
to be comparable in patients who have NCPH or cirrhosis [44,45]; however,
for any given variceal pressure, cirrhotic patients are more likely to bleed.
Gastric varices are more common in NCPF than in cirrhosis [62]. Portal hypertensive gastropathy is uncommon and is a rare cause of upper gastrointestinal (UGI) bleed at the first presentation in patients who have NCPF.
Gastropathy does develop after variceal obliteration, but it often is transitory and nonprogressive in patients who have NCPF [62].
Differential diagnosis
The diagnosis of NCPF is easy. Child’s A cirrhosis may be confused with
NCPF; however, the tests of liver function, viral serology, and histology
(lobular disarray, pseudolobule formation) can distinguish between the
two. Moreover, a disproportionately large spleen with a dilated and thickened portal vein favors the diagnosis of NCPF. NCPF can be differentiated
from acute-onset EHPVO easily. It may not be easy to differentiate NCPF
from chronic EHPVO, because both groups of patients present with UGI
bleed and splenomegaly.
Tropical splenomegaly syndrome is another condition in the tropics that
presents with massive splenomegaly; however, portal hypertension is uncommon in these patients and the WHVP is within normal limits [63]. Moreover, elevated serum IgM levels and high malarial antibody titers are
common in tropical splenomegaly syndrome.
Management of variceal bleeding and hypersplenism are the key issues in
patients who have NCPF. For acutely bleeding varices, variceal band ligation and endoscopic sclerotherapy are equally efficacious (approximately
95% success in control of acute bleed) [64]. Both techniques also are quite
effective in achieving variceal obliteration with a low variceal recurrence
rate of about 20% [62,64]. Prevention of rebleeding with the use of nonselective b-blockers has been reported [65]. The authors [66] found b-blocker
and endoscopic variceal ligation to be equally efficacious for primary



prophylaxis in noncirrhotic patients [66]. Gastric varices, which are more
common in NCPF, can be managed with cyanoacrylate glue injection and
rarely require surgical intervention [67,68]. Interventional radiologic procedures have been reported to be effective in patients who have IPH. These include splenic embolization, percutaneous transhepatic obliteration, and
a transjugular intrahepatic portosystemic shunt (TIPS) procedure [69].
The authors also performed a TIPS procedure in three patients who had
NCPF with gastric varices; the shunts were patent at 12 months. The role
of surgery is limited in variceal bleed because it is required in less than
5% of cases of NCPF that fail to respond to endoscopic therapy [70]. Selective shunts, like distal splenorenal shunts, are preferred because they have
a lower incidence of postshunt encephalopathy; however, if massive splenomegaly is present, the proximal shunt with splenectomy is a good choice.
Surgery also is indicated for patients who have symptomatic hypersplenism,
for patients who hail from distant areas, or for those who desire one-time
Exsanguinating hemorrhage is the most common cause of death in patients who have NCPF or IPH. Prophylactic devascularization has been advocated by certain Japanese workers for patients who have IPH. The
surgical mortality after emergency shunts is about 10%. Shunt occlusion,
overt chronic porto-systemic encephalopathy, and rebleeding after elective
shunt surgery are seen in about 10% of patients [71,72]. Recently, the development of membranoproliferative glomerulonephritis and other renal
anomalies have been reported following shunt surgery in patients who
have NCPF [47]. The morbidity and mortality after shunt surgery and the
limited expertise that is available to carry out these procedures have restricted the use of surgery in the management of patients who have NCPF.
The prognosis of patients who have NCPF is good. The mortality from
an acute bleed in NCPF is significantly lower than that observed in cirrhotic
patients [71]. After successful eradication of esophagogastric varices, the authors have observed nearly 100% 2- and 5-year survival in these patients.
The long-term outcome of shunt surgery also is favorable and 88% 5-year
survival has been reported [72]. Shunt occlusion, postshunt encephalopathy,
and renal dysfunction may cause some morbidity.

Extrahepatic portal vein obstruction
The second common cause of NCPH is EHPVO. EHPVO is a vascular
disorder of the liver and is defined as obstruction of the extrahepatic portal
vein with or without involvement of the intrahepatic portal veins or splenic
or superior mesenteric veins (Fig. 3). Isolated occlusion of the splenic vein or
superior mesenteric vein does not constitute EHPVO [73].



Fig. 3. Extrahepatic portal vein obstruction. Abbreviation: CBD, common bile duct. (Adapted
from Lebrec D, Benhamou JP. Noncirrhotic intrahepatic portal hypertension. Semin Liver Dis

Earlier, the term ‘‘portal vein thrombosis’’ (PVT) often was exchanged
loosely with EHPVO; however, the former term has some limitations. First,
it does not exclude the intrahepatic PVT that is due to cirrhosis of the liver
or invasion by hepatocellular carcinoma. Second, the term does not include
formation of portal cavernoma and development of portal hypertension that
are inherent to long-standing disease. Therefore, the term EHPVO is preferred because it connotes a distinct disease entity, and not primarily an association of a primary liver disease. PVT, a known complication of liver
cirrhosis and hepatocellular carcinoma, generally is not included in the disease entity EHPVO.
EHPVO is a common cause of portal hypertension in developing countries but is less prevalent in the West where it is the second most common
cause of portal hypertension, even in the West. In the west, EHPVO accounts for 5% to 10% of all cases of portal hypertension, but in developing
countries, this proportion is higher and may reach 15% to 20%. In children,
EHPVO accounts for 80% to 90% of cases of portal hypertension [1]. In
children, EHPVO usually is an isolated condition and only is recognized
when the child develops symptoms. In adults, the diagnosis is made earlier



because the patients are under observation for another disease. Most commonly, blockage occurs at the site of portal vein formation (90%); total
blockage of the splenoportal axis is seen in only 10%.
The etiology of EHPVO has not been well studied and varies considerably with age and the geographic region (Box 2).

Box 2. Causes of extrahepatic portal vein obstruction
Portosplenic vein inflammation or injury
Umbilical sepsis
Umbilical catheterization
Neonatal peritonitis
Abdominal trauma
Iatrogenic operative trauma to the portal vein
Indirect causes
Neonatal systemic sepsis from nonintra-abdominal sources
Multiple exchange transfusions
Hypercoagulable states
Myeloproliferative disorders (eg, polycythemia rubra vera,
essential thrombocytosis, myelofibrosis)
Antiphospholipid syndrome
Anticardiolipin antibody
Protein C, S, antithrombin III deficiency
Factor V Leiden deficiency
G20210A prothrombin gene mutation
Methylene tetrahydrofolate reductase gene mutation (C677T)
Paroxysmal nocturnal hemoglobinuria
Drugs (eg, oral contraceptives)
Pregnancy/post partum
Congenital abnormalities
Portal vein stenosis
Portal vein atresia or agenesis.
Secondary involvement of portal vein
Liver diseases: cirrhosis, hepatocellular carcinoma
Pancreatic diseases: chronic pancreatitis, trauma, tumors



Infection. Generally, it is believed that EHPVO in children has a primary
component of infection and portal phlebitis with thrombosis as a secondary
event. Omphalitis and neonatal umbilical sepsis that may be overt or go unrecognized commonly have been alleged to cause inflammation in the umbilical stump before normal obliteration of these veins. This inflammation can
proceed proximally to involve the portal venous system. Umbilical vein cannulation for exchange transfusion also could be responsible for the development of EHPVO [74]. Repeated abdominal infections, sepsis, abdominal
surgery in childhood, and trauma also can lead to EHPVO. Other factors,
such as dehydration, also have been suggested [75].
Congenital anomaly. Obstruction can occur anywhere along the line of left
and right vitelline veins from which the portal vein develops. Congenital defects of other systems, such as the cardiovascular system, have been reported
Prothrombotic state. Unlike in adults, studies of thrombophilic disorders in
children are scanty. In the small number of patients that has been studied,
the frequency of prothrombotic disorders was found to be variable [77].
Idiopathic. Despite all efforts, the cause of the blocked portal vein remains
obscure in 50% to 90% of children.
Prothrombotic disorders. There is increasing evidence that prothrombotic
disorders are seen more commonly in patients who have EHPVO. In one
study from the West, latent myeloproliferative disorders were reported in
patients who had EHPVO of unknown etiology. Of 54 patients with ‘‘idiopathic’’ EHPVO, 2 (8%) developed an overt myeloproliferative disorder after
a median follow up of 96 months [78]. The investigators suggested that the
progression of the underlying hematologic disease with ‘‘ongoing thrombosis’’ might influence the course of bleeding in these patients, particularly in
the long-term, and, therefore, must be looked for in every patient. Other
workers have not corroborated these findings. In a recent study, the risk
for EHPVO was found increased in the presence of thrombophilia resulting
from the prothrombin G20210A mutation and from the deficiencies of the
naturally occurring anticoagulant proteins but not from factor V Leiden [79].
Infection. The role of infection in EHPVO in adults is limited to intra-abdominal sepsis. Abdominal surgery, a thrombotic stimulus (eg, pregnancy,
oral contraceptives) and the presence of underlying prothrombotic disorder
may be causative.
In an adult who has EHPVO, one needs to exclude the possibility of
underlying cirrhosis and hepatocellular carcinoma. PVT is an important



complication of cirrhosis, with incidences of between 0.6% and 16% in patients who have well-compensated disease [80–83]. An increased frequency is
seen in those who have decompensated disease, and in up to 35% of cirrhotic patients who have hepatocellular carcinoma [82], in whom the thrombosis also may be due to extension of the tumor. In patients who have an
identified cause, general thrombophilic factors account for 60% of cases,
and local factors account for 40% [78]. In a large proportion of patients,
the cause of adult EHPVO remains obscure, however. ‘‘Sinistral’’ or left
sided-portal hypertension, with localized thrombosis of the splenic vein, occurs in 7% of patients who have chronic pancreatitis [84]. PVT follows splenectomy in 6% to 8% of cases [85], but other interventions, including local
ablative therapy for hepatocellular carcinoma [86] and fine-needle aspiration
of a pancreatic mass [87], also have been linked with its development. These
conditions need to be excluded for the diagnosis of EHPVO.
The liver is smooth to finely granular with preserved architecture. Mild or
sometimes moderate hepatic fibrosis is seen in up to 40% of adult patients,
partly as a result of parenchymal extinction. Such periportal fibrosis could
arise from nonspecific or specific inflammation or from chemical irritation
as a result of hepatocellular breakdown products. Vascular lesions have
been demonstrated in approximately 48% of cases in the form of multiple
portal vein channels in small portal tracts in addition to mild portal fibrosis
in a majority. Phlebothrombosis of intrahepatic portal vein branches is less
common than in NCPF, and it was suggested that phlebothrombosis is
a common pathogenic denominator in NCPF and EHPVO.
Although the pathology of the liver is not characteristic in EHPVO, the
pathology of the portal vein is typical and is termed cavernous malformation of the portal vein. It is made up of a cluster of variable-sized vessels
that is arranged haphazardly within a connective tissue support and the
original portal vein cannot be identified. Usually, it is located at the hilum
of the liver and can extend for a variable length inside and outside the liver.
Although hamartomatous and neoplastic theories have been proposed, most
investigators believe that these features are the end result of thrombosis of
the portal vein.
Pathophysiology of extrahepatic portal vain obstruction
The prehepatic block of EHPVO with normal hepatic sinusoidal pressure
and a high pressure in the obstructed splanchnic bed results in the formation
of multiple hepatopetal thin winding collaterals. These collaterals are seen
on angiography as ‘‘cavernous transformation’’ and were shown by ultrasound Doppler studies to provide a significant component of the total hepatic blood flow in these patients. These collaterals join the intrahepatic



portal vein branches at various levels. This is a kind of neovascularization to
compensate for the portal vein block.
Functional status of liver
Impairment of the hepatic storage capacity and transport maximum for
bromsulphathaline has been documented. The portal vein obstruction, reduced portal blood flow, and more dependence of the liver on hepatic arterial
blood in EHPVO may contribute to a decreased functional status of the liver.
Clinical presentation and course
EHPVO can present as early as 6 weeks after birth or may not become
manifest until adulthood. The presentations also may vary with the onset
of clinical disease (recent or chronic) and the age of presentation (childhood
or adulthood).
Hematemesis is the most common presentation for patients who have
portal venous obstruction. Most often, it is sudden and massive and rarely
is associated with hepatocellular dysfunction. Patients often experience
more than one episode before presentation. There are no good predictors
of rebleeding because the splenic size and portal pressure do not correlate
with the incidence or severity of hematemesis. Except for occasional reports,
there are no definitive data to suggest that the frequency of variceal bleeding
decreases after puberty [88].
Generally, patients who have EHPVO bleed from esophagogastric varices; however, ectopic varices (eg, duodenum, anorectal region, biliary tree
and gallbladder) also are common in these patients. Patients who have ectopic varices can present with bleeding from the rectum, obscure gastrointestinal bleed, or biliary obstruction [61,89].
Anemia and splenomegaly are the other common presentations in children who have EHPVO [90]. Although a reduction in one or more hematopoietic cell lines is common, symptomatic hypersplenism is found in less
than 5% of the patients. Occasionally, the massive splenomegaly itself or
the severe left upper quadrant pain that is due to splenic infarction or perisplenitis brings the patient to the physician [90].
Ascites is not a common presenting feature in children who have
EHPVO. It may manifest transiently in about 10% to 20% of children following hemorrhage or surgery [91]. It is, however, observed more frequently
in adult patients who have long-standing portal hypertension. The appearance of ascites generally correlates with the deterioration of liver function
and decrease in serum albumin levels that are seen with increasing age in patients who have EHPVO [91].
Jaundice also may be a presenting feature of portal vein occlusion and
may result from bile duct compression that is due to large dilated venous
collaterals running near the common bile duct. This type of jaundice is obstructive in nature and is due to portal biliopathy. The role of other factors,



such as parenchymal dysfunction, deprivation of portal blood to the liver,
and hypoxemia, has not been studied adequately.
Portal biliopathy refers to abnormalities of the extrahepatic and intrahepatic bile ducts with or without anomalies of the gall bladder wall in patients
who have portal hypertension (Fig. 4). The changes include indentations of
paracholedochal collaterals on the bile duct, localized strictures, angulation
of ducts, displacement of ducts and stones in the common bile duct and focal narrowing, dilatations, irregular walls, and clustering of intrahepatic
branches in the hepatic ducts. Gall bladder varices are common [89] and
carry a significant amount of blood around the gall bladder. These do not
affect gall bladder contractility. The frequency of gallstones was reported
to be higher in patients who have EHPVO [92,93].
Although biliopathy is seen in 80% to 100% of cases, only a few patients
are symptomatic [94]. Symptomatic patients usually are adults, which indicates that portal biliopathy is a progressive disease. Complications, such as
cholangitis, secondary biliary cirrhosis, gall stones, hemobilia, hypoalbuminemia, and coagulation disturbances, have been reported.
Generally, growth retardation is seen when EHPVO develops before puberty. Growth patterns in patients who have EHPVO indicate that nearly
one third is short in stature and has significantly diminished growth velocity.
This could be a result of deprivation of the portal blood that has hepatotrophic factors in it [95,96]. Growth spurts have been observed after shunt surgery in patients who have EHPVO [97].
The hepatic vein pressure gradient (WHVP  free hepatic venous pressure) is within normal limits and intrasplenic pressure is significantly

Fig. 4. Portal biliopathy: endoscopic retrograde cholangio-pancreatography showing irregularities of the common bile duct and intrahepatic biliary radicals.



elevated, which indicate the presinusoidal nature of the block. Intravariceal
pressure is the ideal method for measuring the portal pressure in patients
who have NCPH. Total hepatic blood flow is normal or decreased; however,
hepatic arterial flow is increased after portal venous obstruction. Systemic
vascular resistance is significantly lower and cardiac output is significantly
higher in patients who have EHPVO, which indicates a hyperdynamic circulatory state similar to that found in patients who have cirrhosis [98,99].
Autonomic dysfunction
Impaired cardiovascular autonomic reflexes occur in subjects who have
portal hypertension that is due to EHPVO. The role of autonomic nervous
dysfunction in the pathogenesis of characteristic hemodynamic disturbances
of portal hypertension is controversial. It was suggested that disturbances in
autonomic cardiovascular reflexes may contribute to the hemodynamic abnormalities in cirrhosis, but only to a small extent in patients who have
EHPVO [100].
Coagulation abnormalities
Coagulation abnormalities have been reported in patients who have
EHPVO. Although one study found normal coagulation studies, others reported abnormal prothrombin time, partial thromboplastin time, and platelet function [101]. It was suggested that abnormal coagulation in patients
who have EHPVO results from mild compensated disseminated intravascular coagulation secondary to portosystemic shunting [53].
Immune status
The humoral immunity is normal in patients who have EHPVO as compared with patients who have cirrhosis, in whom it is grossly abnormal. The
cell-mediated immunity shows qualitatively similar defects in patients who
have EHPVO or chronic liver disease. The defects in cell-mediated immunity
result, in part, from sequestration of T cells by the spleen, and, in part, from
the presence of factors in the serum that influence the kinetics of lymphocyte
response [102].
The presence of esophageal varices in a child with normal or near normal
liver function tests should raise the possibility of EHPVO. In an adult, compensated cirrhosis may produce a similar picture. Recent EHPVO may be
symptomatic or even asymptomatic. Therefore, the diagnosis may be difficult and a high index of suspicion is needed. Imaging remains the mainstay
for the diagnosis of EHPVO.
Ultrasound is precise for the detection of portal cavernoma and is the investigation of choice. Cavernous transformation produces a distinctive



tangle of tortuous vessels in the porta hepatis. An ultrasound Doppler is,
however, essential to detect a recently formed thrombus that is virtually anechoic and splenoportal collaterals and shunts (Fig. 5). Contrast enhanced
CT, CT arterial portography, and MR angiography also have a high degree
of sensitivity and specificity (Fig. 6). Liver biopsy is not indicated in all patients who have EHPVO; however, it is helpful whenever there is suspicion
of any parenchymal liver involvement.
Once the diagnosis of EHPVO is established, it also is important that investigations to unearth the pathogenesis of EHPVO be undertaken. Tests
for confirming the overt or the occult myeloproliferative disorder need to
be done; however, sensitive tests, such as endogenous erythroid colony assessment and identification of dysmorphic megakaryocytes, are not readily
available. Tests for risk factors for venous thromboembolism, such as factor
V Leiden mutation (odds ratio w12) and G20210A prothrombin gene mutation (odds ratio w2), and levels of protein C and S and antithrombin III
also can be helpful. These studies are likely to be more rewarding in adult
Western adult patients.
UGI endoscopy is helpful to confirm the presence of varices. Endoscopic
retrograde cholangio-pancreatography (ERCP) is not recommended in the
routine work-up of children who have EHPVO. A therapeutic ERCP procedure should be planned only if there are features of cholangitis or obstructive jaundice.
The management of EHPVO needs to be tailored according to the age of
the patient, the site of obstruction, and the clinical manifestations. Variceal
hemorrhage is the major complication that requires therapy. Patients who
have portal hypertension who have not bled from varices can be observed

Fig. 5. (A) Ultrasound Doppler showing portal cavernoma in a patient who has EHPVO. (B)
Doppler of the same patient showing flow of blood through the portal cavernoma. Abbreviation: PVC, portal venous cavernoma.



Fig. 6. MR angiography showing portal cavernoma. PC, portal cavernoma; SV: splenic vein.

because bleeding may not occur for many years. In general, hypersplenism is
not an indication for surgical intervention, but in an occasional patient, profound thrombocytopenia with bleeding, repeated infections, or physical discomfort that is caused by massive splenomegaly may be sufficiently severe to
merit splenectomy.
Treatment of variceal bleeding
Patients who have EHPVO essentially have normal livers and tolerate
variceal bleeding. In patients who have left-sided portal hypertension, splenectomy alone is curative.
There are limited data on the use of pharmacologic agents for the control
of acute bleeding or preventing rebleeding in patients who have EHPVO.
Based on the evidence available in cirrhotic patients, one could use these
agents in patients who have EHPVO [73].
Endoscopic sclerotherapy and band ligation were effective in the control
of acute variceal bleeding in several studies [103]. Endoscopic band ligation
is superior to sclerotherapy in preventing rebleeding. Injection of cyanoacrylate is effective in the management of gastric variceal bleeding. Propranolol was effective in a small number of patients who had EHPVO for
prevention of rebleed.
Shunt surgery is reserved for patients who fail endoscopic therapy or
have significant growth retardation before puberty, symptomatic portal biliopathy, and symptomatic hypersplenism. It also can be offered to patients
who demand a ‘‘one-time’’ treatment. Total and selective shunts have been
used [104].
Rex shunts (mesenterico-left portal bypass) in children who have EHPVO
are effective and are considered to be more physiologic because they restore
normal portal flow to the liver [105].



Management of portal biliopathy
Symptomatic portal biliopathy is predominantly due to compression of
the bile ducts and is an indication for intervention. An algorithmic approach
to such patients is helpful (Fig. 7). Although choledocholithiasis can be
managed by endoscopic sphincterotomy, the biliary obstruction persists
and the risk for recurrent stone disease, cholangitis secondary biliary cirrhosis, continues. It is the next most common cause of death after variceal
bleeding in patients who have EHPVO.
Anticoagulant therapy
Acute PVT can be treated by anticoagulant therapy, rapid thrombolysis,
or by removal of the thrombus through the transjugular route. In documented prothrombotic disorders, it is recommended as a life long-therapy
for preventing the progression of thrombosis. The role of anticoagulant
therapy in chronic EHPVO is not clear and only can be considered if there
is a history of recurrent thrombotic episodes and after shunt surgery. It is
not clear whether anticoagulant therapy can increase the risk for gastrointestinal bleeding or the severity of bleeding.
Symptoms +

Portal Hypertension


6-8 wk

Dilated CBD/ IHBR on USG
Cholangitis +

Emergency ERCP

Portal Biliopathy
Stone (+)

Stone (-)

Stone extraction

Dominant Stricture

Mild Changes

Balloon Dilatation ± Stenting
Shunt Surgery
Persistence of Symptoms
Biliary Diversion

Fig. 7. An algorithmic approach to the management of portal biliopathy. Abbreviations: ALP,
alkaline phosphates; CBD, common bile duct; ERCP, endoscopic retrograde cholangio-pancreatography; IHBR, intra-hepatic biliary radicals; USG, ultrasonography.



In summary, patients who have NCPH pose special challenges to clinicians. It is worthwhile to know the spectrum of presentation, rational diagnostic tests, and appropriate management of these patients.

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