Extrahepatic portal vein obstruction (EHPVO) is an important cause of portal
hypertension (PH) among children. It is characterized mainly by portal vein thrombosis
(PVT), and is detected in 40% of children with upper gastrointestinal bleeding
(UGIB) caused by esophageal varices. It may be asymptomatic. However, the mortality
and morbidity rates are high, due to UGIB. Approximately 79% of children diagnosed
with PVT will have at least one episode of UGIB in their lifetime.
The present article aims to build up the profile of children with PVT, to investigate
the predisposing factors, complications, and therapeutic approach, by reviewing
the medical literature
Anatomy and embryology
liver originates from the anterior primitive intestine, and its primordial form
- pars hepatis - develops as a duodenal diverticulum in the fourth gestational
week. Its full development occurs in the third month. Fetal hepatic blood flow
comes from the hepatic artery and from the portal and umbilical veins, which form
the portal sinus. At birth, this flow corresponds to nearly 5% of an infant's
total body weight, whereas, in an adult, it does not exceed 2.5%. The liver is
responsible for hematopoiesis during the fetal period. In the seventh gestational
week, hematopoietic cells outnumber functional hepatocytes. After the second month
of life, the liver no longer produces red blood cells.
liver can be divided into two large lobes (right and left), in additional to the
caudate and quadrate lobes, which are small. On top of that, there is a functional
subdivision, based on blood supply, which divides the liver into eight segments.
Hepatic architecture is extremely complex. The basic functions of the liver are
carried out by hepatocytes.
The liver has a dual blood supply via the hepatic artery and portal vein. The
portal vein carries venous blood from the digestive tract into hepatic sinusoids,
which is drained by the hepatic veins into the inferior vena cava. The portal
vein is formed by the confluence of the superior mesenteric and splenic veins,
ascending behind the common bile duct and the hepatic artery. At the porta
hepatis, it is subdivided into right and left branches (besides providing
the quadrate lobe with an additional branch). These branches ramify to form small
vessels that drain into the sinusoids. The portal vein usually receives the left
gastric, pancreaticoduodenal, and cystic veins. Therefore, it drains blood from
several organs, such as the intestine, spleen, pancreas, and gallbladder.
valves in the portal system are insignificant or nonexistent; the direction of
blood flow is determined by the pressure gradient. Therefore, portal vein obstruction
may increase the blood flow in the connections between portal vein tributaries
and systemic veins, as well as inversion of blood flow at the following venous
- inferior mesenteric vein and inferior vena cava and their tributaries
(superior, middle and inferior rectal veins; common and internal iliac veins);
- gastric veins and superior vena cava and their tributaries (azygos system, vertebral
plexus, esophagogastric veins);
- retroperitoneal veins and vena cava and
azygos venous systems;
- paraumbilical and subcutaneous veins.
Portal vein is responsible for around two thirds of the
blood flow into the liver. It supplies blood that is rich in oxygen, nutrients,
growth factors, hormones, among other elements. Although the liver receives a
large amount of blood (approximately 25% of the cardiac output per minute), the
portal vein only withstands low pressures. PH occurs when portal vein pressure
exceeds 10 mmHg.
Doppler ultrasonography shows a continuous blood flow, with a normal range from
15 to 30 cm/s.
An increase in portal pressure results from the oscillation of intravascular pressure
(hyperdynamic state) and from the elevated resistance to this flow. Thus, oscillation
of pressure within blood vessels is directly proportional to the flow within the
portal system and to the resistance to this flow (Ohm's law). In turn, resistance
to blood flow is inversely proportional to the fourth power of the radius of the
vessel (Poiseuille's law).
Based on these physical laws, one may conclude that small variations in portal
vessels cause large increases in pressure.
PH can be extrahepatic (prehepatic
obstruction), intrahepatic or post-sinusoidal (Table 1). Another classification
takes into account the etiology of PH: cirrhotic and noncirrhotic.
The consequences of PH are related to the interactions produced by the development
of portal systemic collaterals, which cause UGIB.
Causes of portal hypertension in children
obstruction - portal vein thrombosis
Portal vein obstruction can occur
at any site of the portal system. Obstruction is often associated with portal
vein thrombosis, extrinsic tumor compression (hepatocellular carcinoma) and compression
by an extrahepatic malignant tumor (especially pancreatic adenocarcinoma). In
adult patients, PVT is usually secondary to some systemic diseases (e.g.: cancers),
which account for nearly 40% of PH cases.
In children, portal vein obstruction results from thrombosis and often develops
into PH of varying grades.
Thrombosis can affect only the portal vein and
its tributaries or the superior mesenteric or splenic vein. The size of the thrombus
determines different clinical manifestations. Orllof et al. determined the site
of blood flow obstruction in 200 children and young adults. The authors observed
that 67% of patients showed only portal vein obstruction, whereas 28% showed portal
and splenic vein involvement, and 5% had portal vein and superior mesenteric thrombosis.
Pathophysiology and etiology of portal vein thrombosis
Cessation of blood flow in the portal system causes small clinical
problems due to compensatory mechanisms: immediate reflex vasodilatation of the
hepatic artery and formation of collateral vessels that envelop and bypass the
thrombotic site. As a general rule, initial thrombus formation is asymptomatic,
and the only sign may be the formation of new vessels, which, in Doppler ultrasonography,
is known as "portal cavernoma" or "cavernomatous transformation,"
due to the volume of blood at the site.
These plexuses with hepatopetal flow are not sufficient to release the system's
pressure, resulting in hepatofugal flows. These natural (spontaneous) shunts may
become pronounced, have exuberant clinical expression and may require surgical
The pathophysiology of thrombus formation in the portal system
is still unclear. Admittedly, there may be a combination between prethrombotic
factors and local factors. Local factors are found in 25% of individuals aged
over 30 years.
The causes of PVT can be split into four different groups: direct injury to the
portal vein and consequent thrombus formation and obstruction, as occurs in omphalitis
or in umbilical catheterization; congenital malformation of the vascular system
with involvement of the portal system associated with other cardiovascular disorders;
indirect factors that predispose to thrombus formation in the portal system; idiopathic
PVT, i.e., the etiology cannot be identified.
Table 2 lists the main causes of PVT.
Causes of portal vein obstruction
Sarin & Agarwal
compared seven studies that assessed the etiology of portal vein obstruction in
infants and children (Table 3). In most cases, the cause could not be identified
and, when it could be, the majority of cases showed direct injury to the umbilical
vascular system (omphalitis and umbilical venous catheterization), or intra-abdominal
or umbilical sepsis. However, there seems to be a relationship between the various
causes, suggesting the coexistence of a prethrombotic state.
Etiology of extrahepatic portal vein obstruction in children
to umbilical catheterization, the predisposing factors are: later insertion, catheter
dwell time over three days, catheter misplacement (either subdiaphragmatic or
peripheral), trauma on catheter insertion, and type of solutions infused.
adults, the main cause of thrombosis is thrombophilia secondary to malignant neoplasms.
Janssen et al.
assessed 172 patients, aged between 14 and 91 years, in a cohort study. They found
that 84% had at least one risk factor for EHPVO, such as malignant hepatobiliary
diseases, inflammatory abdominal diseases, intra-abdominal surgeries, hypercoagulable
states, and myeloproliferative syndrome.
A different category includes cirrhosis-related
PVT. In this case, PVT seems to be associated with the low venous blood flow secondary
to the increase in intrahepatic resistance, presence of portal lymphangitis, and
fibrosis. About 10% of children with biliary atresia also have PVT.
The prevalence of PVT in adults with cirrhosis ranges between 0.6 and 17%.
initially present with UGIB or splenomegaly on routine clinical examination in
The initial presence of hematemesis is usually
dramatic in a previously healthy child, with past history of morbidity, often
without remarkable intercurrent events. Melena may also be observed, but it is
less common than hematemesis. The child can be lethargic, with signs of orthostatic
hypotension. The clinical examination revealing splenomegaly in a child with UGIB
indicates esophageal varices as the most probable site for the bleeding.
frequently, the diagnosis can be based on the investigation of a child with abdominal
pain or with complications related to hypersplenism. The signs and symptoms of
PVT vary considerably (Table 4).
Clinical manifestations of portal vein thrombosis
The physical examination
may reveal splenomegaly; hepatomegaly is not common in children with PVT without
underlying liver disease, as well as stigmata of chronic liver disease. Skin pallor
may be observed.
The episodes of UGIB usually recur while varices are not
completely obliterated or if secondary prophylaxis is not initiated. These episodes
are often precipitated by upper airway infections or use of acetylsalicylic acid
(ASA). Mortality rate secondary to UGIB in patients with isolated PVT is not so
high as that of cirrhotic patients, who have more complications, such as impaired
liver function, refractory ascites, and encephalopathy.
abnormalities associated with PVT have been described, such as malformations of
the heart, of large vessels, of the biliary tract, and of the renal system.
ascites may develop after episodes of UGIB. However, patients with long-established
PH secondary to PVT may have ascites without any predisposing factors. This same
group of patients may have low albumin levels, increased prothrombin time, and
elevated aminotransferase levels. This hepatic dysfunction can be attributed to
the prolonged decrease in portal circulation and/or to the development of portal
biliopathy, which shows that the disease may have a progressive course.
syndrome is rare in PVT without cirrhosis, as well as encephalopathy, but it might
Gupta et al. assessed 54 adults diagnosed with cirrhosis and 50 with EHPVO; only
two patients with prehepatic obstruction developed hepatopulmonary syndrome without
any detectable predisposing factors.
results show normal aminotransferase and albumin levels and normal coagulation
profile, except for patients with associated cirrhosis. These results may also
be abnormal in patients with long-established PVT, even in the absence of cirrhosis.
Albumin levels may be low and associated with ascites shortly after the episodes
of UGIB. Thrombocytopenia and leukopenia are common findings.
In general, children diagnosed with long-established
PVT are more prone to showing growth deficit. The factor that predisposes to this
manifestation is still unknown. It has been assumed that chronic anemia (secondary
to losses caused by bleeding and/or hypersplenism), intestinal venous congestion
with secondary malabsorption and abdominal distension may interfere with growth
rate. Another hypothesis is that the low supply of blood to the liver due to the
formation of systemic collaterals in PVT patients may cause hepatotrophic hormone
deprivation, thus interfering with the child's global growth.
assessed 33 children with PVT; 55% of them were below the 5th percentile for weight-for-age
and height-for-age. Based on the high serum levels of growth hormone and of somatostatins
(IGF-I), they concluded that there was some resistance to the action of the growth
hormone. On the other hand, Bellomo-Brandão et al. studied 24 children
with EHPVO and did not observe growth retardation in any of them. They suggested
that pediatric care associated with endoscopic sclerotherapy favored growth, since
they reduced the consequences of PH.
The natural history of PVT encompasses the formation
of numerous collaterals at the porta hepatis and around bile ducts, which
may cause compression on bile ducts. With the progression of the disease, there
may be stenosis and formation of calculi in the common bile duct and in its branches,
as well as in intrahepatic bile ducts, causing secondary biliary cirrhosis. Portal
biliopathy appears in adulthood. Jaundice and pain are rare, except in the presence
of cholangitis. Its course is silent and progressive and is detected because of
its most common complication: biliary cirrhosis.
Escalation of alkaline phosphatase to levels that are two times to five times
greater than the highest benchmark value helps with the diagnosis of this biliary
complication of portal vein thrombosis. Endoscopic retrograde cholangiopancreatography
(ERCP) can identify portal biliopathy in 80 to 100% of affected patients, by detecting
abnormalities in intrahepatic and/or extrahepatic bile ducts (localized dilatations
or strictures) and in the gallbladder (wall disorders, kinking and lithiasis).
Therefore, according to the extension of the injury found on ERCP, it is possible
to classify portal biliopathy into three types, of which type I is the mildest,
as shown in Table 5.
Table 5 -
Classification of endoscopic retrograde cholangiopancreatographic findings secondary
to portal biliopathy
C deficiency, an endogenous tissue factor pathway inhibitor, is common among children
and adolescents with PVT, but it does not seem to have a genetic etiology or to
be the main cause of thrombosis. According to a study undertaken by Universidade
Federal do Rio Grande do Sul, in Brazil, protein C deficiency is secondary to
consumption resulting from portosystemic shunts of PH and to the possible reduction
in the liver synthesis of anticoagulant factors as a result of decreased blood
flow into the liver in PVT.
Splenomegaly is the second major clinical
manifestation of PVT. Moderate hypersplenism can be detected by leukopenia and
thrombocytopenia in approximately 40 to 80% of the patients. Although there is
a decrease in platelet count, platelets are functionally normal.
may have normal humoral immunity. However, some will show abnormal cell-mediated
immunity due to the sequestration of T lymphocytes by the spleen. Nevertheless,
manifestations related to immunological disorders are rare among children.
and esophagogastric varices
The main clinical manifestation of
PVT at diagnosis is variceal bleeding. Nearly 90 to 95% of PVT patients have esophageal
varices, and 35 to 40% have gastric varices. The frequency of hypertensive gastropathy,
which is lower in PVT patients than in cirrhotic ones, seems to be related to
the severity of liver disease.
Mortality from gastrointestinal bleeding secondary to variceal rupture amounts
to approximately 2 to 5% in PVT patients.
varices are found in 80 to 90% of patients with portal vein obstruction. They
usually are of grade III (larger than 6 mm and protruding into the intestinal
lumen). They rarely bleed, but when they do, they cause severe complications.
All children with hemorrhoids should be investigated as to the probability of
Colopathy secondary to PH affects approximately 54% of patients.
PVT patients have variceal bleeding in their first years of life. The risk for
gastrointestinal bleeding does not seem to decrease with age. Adolescents with
PVT who did not receive adequate treatment are at a high risk for bleeding in
can be observed in extrahepatic portal vein obstruction even without being related
to gastrointestinal bleeding or other triggering factors. It develops in patients
with long-established disease.
PVT should be suspected in
all children with splenomegaly, without hepatomegaly and hematemesis, with normal
liver function test results. Liver biopsy is normal in children without associated
Doppler ultrasonography is the most widely used diagnostic exam in pediatric patients,
with a high sensitivity (s = 94-100%) and specificity (sp = 90-96%), even though
it is an operator-dependent diagnostic method.
Chronicity of PVT is defined by Doppler ultrasonography by means of visualization
of the formation of new vessels around the thrombus (cavernoma). Some diagnostic
exams should not be routinely used in pediatric patients due to their risk: splenoportography
and arterial portography, nuclear magnetic resonance (angiography), computed tomography
All patients must be submitted to upper gastrointestinal endoscopy
to check for the presence of esophagogastric varices, which will allow for a better
planned therapeutic approach.
Laboratory exams show normal liver function
in most patients, except in those who have a prolonged decrease in portal circulation,
or portal biliopathy. Assessment of associated cirrhosis depends on abnormal histological
findings in biopsied liver samples. In adults, associated diseases, such as myeloproliferative
disease, malignant tumors, coagulation disorders, among others,
should be ruled out. There is a high predictive diagnostic value of PVT in cases
of UGIB without jaundice.
It is important
to establish the differential diagnosis with other causes of splenomegaly and
pancytopenia, such as oncohematologic diseases, and infectious parasitic diseases.
distinction between the various causes of PH is of paramount importance, especially
between cirrhosis and PVT, so that the appropriate therapeutic approach can be
implemented. Quite often, PVT patients are younger, have normal liver function,
show better tolerance of variceal bleeding, do not lapse into hepatic coma, and
their hemoglobin levels are lower than those of cirrhotic patients.
Treatment of acute thrombosis
In newborns submitted to umbilical vein catheterization or children
with some trauma or intra-abdominal injury that predisposes to portal vein thrombosis,
the first step is to determine the level of involvement of the blood vessel, so
that the best therapeutic approach can be chosen.
If the child does not
show any symptoms of intestinal ischemia, the following procedures should be performed:
assess the removal of umbilical venous access in newborns;
- start thrombolytic
therapy with urokinase (in case of small and localized thrombus) or heparin (in
case of systemic injury). Thrombolytic therapy prevents intestinal ischemia in
the short run, and extrahepatic PH in the long run.
This therapy should last for at least 6 months.
Otherwise, if the patient
is symptomatic, with intestinal ischemia, immediate surgical treatment should
be implemented by transjugular catheterization or laparotomy with thrombectomy.
bleeding and esophagogastric varices
The approach to UGIB includes
the following: 1) primary prophylaxis (patient at a high risk for UGIB, but who
has never had bleeding episodes); 2) management of acute bleeding and; 3) secondary
prophylaxis (to eliminate varices in patients with history of UGIB).
use of drug therapy or endoscopy in children with esophageal varices before the
first bleeding episode is controversial and there is no consensus about it in
the medical literature.
In adults with cirrhosis and large varices, beta blockers reduce the risk of bleeding
and seem to reduce the mortality associated with UGIB.
This type of treatment is already established for this age group. Esophageal variceal
band ligation (EVBL) has proved efficient as primary prophylaxis in adults, whereas
the use of sclerotherapy has been discontinued due to the high incidence of complications.
The current trend consists of the use of primary prophylaxis in pediatric patients,
even though there is a paucity of studies involving children.
to the risks of any extensive bleeding, patients with upper gastrointestinal bleeding
should be immediately sent to a referral hospital for a more adequate approach.
First, the patient receives cardiorespiratory resuscitation and then bleeding
varices are treated.
Children with this condition are admitted to the emergency
room and necessitate blood derivative transfusion (if hemoglobin < 9 mg/dl),
continuous octreotide infusion (dose of 1 to 2 µg/kg/h) and endoscopic treatment
by way of elastic ligature or sclerotherapy. If bleeding persists after these
measures, an option is to use the Sengstaken-Blackmore tube or a second emergency
endoscopic treatment before the decision to operate on the patient.
the recurrence of UGIB secondary to variceal bleeding is crucial in the follow-up
of patients with PH. The treatment involves drug therapy with, for instance, propranolol
(1-6 mg/kg/day, given orally, twice or three times a day), endoscopy (sclerotherapy
or elastic ligature) and portosystemic shunts.
blockers are the only pharmacological agents with proven efficacy in reducing
the risk of recurrent bleeding in adults. Studies involving children are scarce.
The dose should be gradually increased until 25% of the baseline heart rate at
rest is reached. In children, the initial dose usually corresponds to 1 mg/kg/day.
Adverse effects and the necessity of a long-term and continuous therapy may be
a limiting factor.
The management of children with bleeding complications
caused by PH has changed considerably with the improvement of endoscopic techniques
in the last 2 decades. Endoscopic sclerotherapy has therefore been the initial
treatment of choice for children with variceal bleeding. Recently, EVBL has been
more frequently used, replacing sclerotherapy, since it has a lower incidence
There are only non-controlled descriptive studies with
children, comparing the efficacy of endoscopic treatments for varices (ligature
and sclerotherapy). Celinska-Cedro et al. assessed 37 children with PH (15 with
PVT) and concluded that elastic ligature is a safe and efficient as primary prophylaxis,
regardless of the cause of PH.
et al.36 assessed recurrent bleeding rates in a randomized trial with 49 children
with extrahepatic portal vein obstruction. They concluded that recurrent bleeding
rates were higher in the group submitted to endoscopic sclerotherapy than in the
elastic ligature group (25 and 4%, respectively, with p = 0.049). After variceal
eradication, 17.4% of the children submitted to elastic ligature showed recurrence
of esophageal variceal bleeding, and 10% of those submitted to sclerotherapy had
recurrent bleeding (p = 0.67). EVBL seems to eradicate esophageal varices in a
shorter time frame, with fewer sessions, with less rebleeding and with fewer complications.
is recommended that an annual endoscopic follow-up be performed during the first
4 years after variceal eradication, due to the risk of rebleeding.
Patients should be advised not to take ASA.
has been a consensus agreement on the conservative treatment of patients with
extrahepatic PH, thus avoiding surgical interventions. However, the following
aspects should be taken into consideration: risk of death (albeit low), high risk
for post-transfusion hepatitis, children's and parents' anxiety towards possible
new episodes of UGIB, and cost of hospitalizations. Sclerotherapy and EVBL, although
efficient in the prophylaxis against UGIB, do not eliminate PH and also have complications.
Moreover, multiple procedures are often necessary for variceal obliteration, with
risk of recurrent bleeding until the varices can be totally eradicated. Conversely,
portosystemic shunts directly decompress the portal venous system, reducing the
risk of rebleeding and of other complications, such as hypersplenism and growth
retardation. In some international referral services, portosystemic shunts are
widely recommended, offering good results, fewer complications and shorter hospital
stay. Distal splenorenal shunt procedure and Rex shunting have been preferred.
aim of shunting procedures is to transfer blood from portal to systemic circulation.
As a result of a decrease in portal pressure, there may be a reduction in blood
supply to the liver and development of hepatic encephalopathy, at a lesser frequency
than in cirrhotic patients.
The following surgical procedures should be considered:
shunts: distal splenorenal shunt, mesocaval shunt with jugular vein interposition,
proximal splenorenal shunt with splenectomy, inferior mesorenal shunt, portocaval
shunt and Rex shunt;
- TIPS: transjugular intrahepatic portosystemic shunt;
- gastrosplenic decompression.
The major indications
for surgery are: 1) persistent bleeding following endoscopic treatment; 2) prominent
splenomegaly, with symptomatic hypersplenism; 3) growth retardation; 4) symptomatic
portal biliopathy. The distal splenorenal shunt is still the treatment of choice
in cases in which endoscopic treatment does not yield good results.
An alternative is the use of Rex shunting, a type of portosystemic shunt with
a left mesenteric portal bypass that restores blood flow to the liver, supplying
it with hepatotrophic substances and other nutrients.
et al. carried out a retrospective 35-year study of 162 patients with PVT (74%
aged between 1 and 16 years) submitted to portosystemic shunting (distal splenorenal
shunt, proximal splenorenal shunt with splenectomy or mesocaval shunt). The cause
of thrombosis was not identified in 110 of these patients (68%). Approximately
96% showed hematemesis, 94% revealed melena and 100% had anemia. All of them had
at least two episodes of UGIB (and at least one of the bleedings required blood
transfusion) and were referred to the authors due to prolonged treatment, without
satisfactory therapeutic response. The survival rate after a 10-year postoperative
follow-up amounted to 96%; 98% of the patients reported that their quality of
life was remarkably improved. Only 2% had complications, such as shunt thrombosis
and recurrent bleeding. No case of encephalopathy secondary to portosystemic shunting
with scheduled splenectomy must be immunized with pneumococcal vaccine before
Some surgical complications, which result from the invasive procedure, include:
Central venous catheter infection, sepsis, atelectasis, among others, in the immediate
2) Recurrent variceal bleeding due to stenosis at
the anastomosis or venous thrombosis, hepatic encephalopathy, intestinal obstruction,
in the late postoperative period.
Despite the lower risk of encephalopathy
inherent to the shunting procedure, PVT patients are at a greater risk for stenosis
or thrombosis at the surgical anastomosis.
on where gallstones are located or on the site of stenosis, the clinical manifestation
will determine the surgical approach that should be used. If cholangitis or cholelithiasis
is present, cholecystectomy, biliary stenting or endoscopic sphincterotomy is
recommended. If the patient is asymptomatic, portosystemic shunting should be
scheduled in order to prevent future complications that may arise from the progression
There is a paucity of studies on the growth and development
of children with EHPVO secondary to PVT. Surgically treated children (portosystemic
shunting) often show improved growth. Some authors recommend surgical decompression
in selected children in order to recover their growth.
PVT is one of the most important
causes of gastrointestinal bleeding among children. The bleeding episodes are
characterized by high morbidity: frequent hospital admissions, increase in school
absenteeism, emotional stress for the children and their families, in addition
to high hospital expenses. Therefore, it is necessary to approach these patients
appropriately so that the quality of life of children with portal vein thrombosis
and of their families can be improved.