SCOPE OF WORK
The scope of work is to present, in addition to the pathophysiology
of portal hypertension and bleeding from varices, the preventive actions
for prevention of the first bleeding, as well as actions for treatment
of the acute bleeding in order to prevent repeated hemorragia.
Portal vein system transfers 1500 ml of blood into the liver from the
spleen, stomach, small and large intestines. The obstruction of the flow
in this vein of various ethiology results into the increase of vein
portal pressure. As an answer to the increased vein pressure, a
collateral vein circulation is developed towards the system veins with
an aim to bypass the obstructed blood flow. Those portosystem
collaterals connect the portal vein system with the upper and lower
hollow vein. High portal pressure is the main cause of development of
portosystem collaterals, but there are other factors that could also be
included, as for example active angiogenesis. The most important
portosystem anstomose are gastroesophageal collaterals. By blood
drainage towards vein azigos, those collaterals form the esophageal
varices responsible for the most frequent complications of portal
hypertension – massive bleeding from the upper parts of digestive tract
. The most common reason (in about 90% of all cases) of portal
hypertension is liver cirrhosis. Liver cirrhosis is a worldwide problem.
It could be found in all social layers, races, age groups and both
sexes, although male mortality caused by this disease is two times
higher than female mortality. The most common causes of liver cirrhosis
are alcoholism and virus hepatitis. Data on disease prevalence and
incidence are unknown because the disease is often asymptomatic and
sometimes is even discovered in autopsy. Based on autopsy findings,
prevalence of cirrhosis is 4-10%, and incidence 240 patients per million
of inhabitants annually . About 20% patients with cirrhosis have high
varices which presents a real threat for bleeding . The first
bleeding ends with mortality in about 30% cases. Out of this, 8% die
during the first two days due to unrestrainable bleeding, and the others
die during six weeks from initial bleeding. In this period, the repeated
bleed-ing appears in 40% of patients . The risk of repeated bleeding
is the highest in the first five days, and then it decreases gradually
so that within six weeks it becomes equal with the risk for the first
bleeding . The degree of cirrhosis and size of varices influence the
risk of repeated bleeding. The risk increases in alcoholic cirrhosis if
the patient does not abstain . One third of patients with compensated
and two thirds with decompensated liver cirrhosis have varices during
disease diagnostics. In the first two years of disease 8% of patients
and after 6 years 30% of patients with liver cirrhosis develop de novo
esophageal varices. The risk for bleeding appearance in the first year
upon identification of varices is 30%. Bleedings from esophageal varices
are 10% of all bleedings from the upper parts of gastrointestinal tract
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION
AND BLEEDING FROM ESOPHAGEAL VARICES
According to the laws of chemodynamics, the pres-sure in vein flow
increases proportionally to blood flow and resistance in blood vessels.
The flow through this system in some physiological states (i.e. after
eating) increases for 20%, but simultaneously, due to compliance of
blood vessels in healthy liver, the resistance also decreases, such as
the pressure value is in normal limits. In patients with portal
hypertension, due to the increased resistance in blood vessels in the
front of the liver, in the liver and beside it, the pressure in the
portal vein increases. The latest studies point out a role of
endotheline –1(ET-1) and nitrogen monoxide (NO) in pathogenesis of
portal hypertension and esophageal varices. ET-1 is a powerful
vasoconstrictor that is synthesized by the sinusoidal liver cells. It
results into increased resistance in cirrhosis and development of liver
fibrosis. NO is vasodilateal substance that is also synthesized by the
sinusoidal cells. In liver cirrhosis, NO synthesis is decreased, and the
enzyme level, that determines its synthesis (endothelial nitric oxide
synthasea - NOS) is decreased [1,7].
The pressure in the portal vein is measured by the use of venous
catheterisation. Normally, this pres-sure is 5-10 mmHg. By the Free
Hepatic Venous Pressure (FHVP) and Wedged Hepatic Venous Pressure (WHVP),
the Hepatic Pressure Venous Gradient (WHVP – FHVP = HPVG) is determined,
that is equal to the pressure in portal vein . In healthy people,
HPVG < 5mmHg. When HPVG>12 mmHg, the portal hypertension becomes
clinically important, due to the appearance of varices bleeding at this
value of HPVG. Therefore, in preventive actions for treatment of
esophageal varices, there is a tendency to decrease the pressure in the
portal vein below the limit pressure, and it means that HPVG is
maintained below 12 mmHg [8,9,10].
According to the localisation of pathophysiological disorders that
results into increased resistance, there are prehepatic, hepatic and
Hepatic hypertension is divided into:
- Presinusoidal (for exp.thrombosis of portal vein,
schistosomiasis, primary biliary cirrhosis) – those disorders are
characterised by the in-crease of portal venous pressure, but normal
- sinusoidal (for exp.cirrhosis) – characterised by the increased
HVPG and WHVP
- postsinusoidal (for exp.Budd-Chiari syndrome, venousocclusion
diseases where the central liver venulae are affected) -
characterised by the increased WHVP [1,8].
DIAGNOSIS OF PORTAL HYPERTENSION AND VARICES
Due to high mortality (30-40%) and bad prognosis and results in
patients after the first bleeding from varices, timely diagnosis of
portal hypertension is very important. Portal hypertension and varices
have to be in our minds for every patient with liver cirrhosis. These
patients very often complain of general weakness, poor appetite and
yellowish colour of skin and white of the eyes in their anamnesis.
In clinical status, subicterus or expressed icterus is found as well as
haematoma, spider naevus on skin of thoracic cage and back, palmar
erythema of palms, increased firm unequal – knotty liver. In case of
decompensated liver cirrhosis, the following is stated: endemata of
shanks, ascites and recognizable look of "frog stomach" with atrophy of
extremity musculature. The increased spleen and dilated veins on abdomen
wall (often characteristic look of "caput medusae") are typical signs of
portal hyper-tension . In laboratory findings of patients with liver
cirrhosis, the liver enzymes are very often increased, decreased
albumins, increased globulins, extended prothrombin time. In patients
with in-creased spleen, the signs of hypersplenism (with decreased
number of erythrocyte, leucocyte and thrombocyte). Colour Doppler
ultrasound examination, as a non-invasive method, is the first of
diagnostic procedures that is indicated, and shows typi-cal changes of
portal hypertension. Diagnostic method of choice is upper digestive
endoscopy (UDE) that shows both changes in esophagus and in cardia and
fundus of the stomach in inverse endoscopy . The known risk factors
of bleeding from esophageal varices are:
- Size of varices – larger varices bleed more often, but patient
can bleed also from small varices
- Presence of endoscopic cherry red spots
- Degree of child classification especially in the presence of
- Active drinking of alcohol
- Other local changes in esophagus, reflux of esophagitis in the
first place, although esophagitis has no initiative role for
bleeding but extends bleeding and makes stoppage of bleeding
Since UDE is an invasive method, and large varices, that present the
risk for bleeding, are found in only about 20% of patients with liver
cirrhosis, some authors propose selection of patients for obliged UDE.
It is proposed that the patients for obliged endoscopy are those with
the following clinical, i.e. diagnostic, characteristics:
- Thrombocytepenia < 100 x109
- Prothrombin activity < 70%
- Increased spleen
- Ultrasound measured diameter of portal vein > 13 mm.
Those criteria are typical for patients with large varices [3, 13].
TREATMENTS FOR PREVENTION OF THE FIRST BLEEDING FROM VARICES
First bleeding from esophageal varices could be therefore prevented
by the use of medicine and/or endoscopy. By the use of medicine, the
first bleeding is prevented by pressure decrease in the portal vein. We
try to dose the medicines such as HPVG below 12 mm Hg or to decrease
HPVG for 20% regarding the starting values before treatment.
Non-selective beta blockers of adrenergic receptors in monotherapy or in
combination with long-effect nitrates decrease satisfactorily HPVG in
about 60% of patients. In the rest 40% of patients, they are
insufficiently effective . Propranolol and nadolol are most
frequently used beta blockers. They result in a decreased heart index by
blockading beta 1 receptor in the heart.
In splanchnic arteries, they result in reflexive activation of alpha
receptors, and vasodilatation is prevented by simultaneous beta 2
blockade. As a final effect, the vasoconstriction in splanchnic arteries
appears to be what decreases the flow in the portal vein, and in this
way decreases the pressure in it . It is necessary to determine the
dosage of beta blockers for every patient individually, and gradually
increase the dosage. The dosage of medicine is increased until
realization of heart frequency is 55-60 strokes in a minute. Precise
effect of beta blockers is determined by measuring of HPVG before
treatment and three months after starting of the therapy.
As HPVG is an invasive method and practically accessible only in great
centres, the routine dosage is determined according to the heart
Beta blockers decrease for about 50% the risk for the appearance of the
first bleeding . If in control the HPVG is not decreased below 12 mm
Hg or it is not decreased for 20%, it is necessary to add long-effect
nitrates. Long-effect nitrates (Isosorbid-5-mononitrate and
Isosorbid-dinitrate) decrease pressure in liver veins and portosystem
collaterals. They result in generalised vasodilatation and reflex
contraction of splanchnic arteries which decreases the inflow and
pressure in the portal vein .
Nitrates are also donors of vasodilators NO which are synthesised in
liver cirrhosis less than in healthy liver. Due to vasodilatation, the
unwanted effects could be developed regarding to the system hypertension
that could also result into renal insufficiency. If it is known that
metabolic equilibrium of patients with liver cirrhosis is very labile,
then it is understandable how important it is to have a good evaluation
of indications and nitrate dosage in patients with liver cirrhosis.
Therefore nitrates are not suitable as monotherapy, but in combination
with beta blockers . Combination of nitrates and beta blockers is
more effective in prevention of the first bleeding than monotherapy with
beta blockers. During seven-year monitoring, bleeding incidence in
patients with monotherapy with beta blockers was 29%. When beta blockers
are combined with nitrates, the incidence is decreased to 12%.
There were no important differences in unwanted effects and mortality
between the groups . A very good alternative in medicament
prevention of the first bleeding from esophageal varices was programmed
endoscopic treatment of varices where thrombosis and decreased varices
are realized. Liging of varices has become a prevalent method over
sclerosing with alcohol and other solutions. In sclerosing - the
sclerosing media: alcohol solutions (polydocanol, ethanolamine) or
tissue adhesive N-butyl-2-cyanoakrylat (Histoacryl) are injected into
varices cavity and a polymerisation embolus is formed which stops
bleeding. The results of embolysation with Histoacryl are better than
with alcoholic solutions especially in patients with large varices and
developed cirrhosis, and they are competed in lower mortality and rare
bleeding recidives. In liging of varices, the complications are rarely
and less serious as to the complications in sclerosing . Metha-analyses
of clinical studies have shown that for prevention of the first
bleeding, the programmed ligation of varices is more effective than
therapy with beta blockers. Mortality is equal regardless of the method.
Programmed liging is proposed to the patients with large varices who do
not bear treatment with beta blockers .
TREATMENTS FOR PREVENTION OF REPEATED BLEEDING FROM VARICES
Mortality due to bleeding from varices is the highest after bleeding.
It decreases within the elapsed time. Bleeding is most often repeated
after two weeks from the first bleeding and up to sixth weeks there is
65% of repeated bleedings. In patients with liver cirrhosis, a
possibility of repeated bleedings is equal to statistical probability of
the first bleeding . Due to high mortality in repeated bleeding, it
is necessary to take measures in order to decrease the risk of possible
repeated bleeding. Also in this group of patients, beta blockers
decrease significantly the possibility of repeated bleeding and improve
survival in the long run. The results are better with less complications
of basic disease . Chemodynamic monitoring by measurement of HVPG
monotherapy with beta blockers decreases HPVG at satisfied level in 338%
patients. Long-effect nitrates could be also added to beta blockers. The
combination of beta blockers and nitrates de-creases HPVG at satisfied
level in 59% of patients . There are many unwanted effects in
combined treatment. The survival of patients does not differ from that
in the first three years. After the third year, the survival is higher
in a group of patients with combined therapy . For prevention of
repeated bleeding from esophageal varices, programmed endoscopic
sclerosing, that is liging of varices, is also applied. Sclerosing is
carried out several times in time within 7 to 14 days. This pro-cedure
is usually repeated 4-6 times until all varices are sclerosed. Esophagus
stenosis due to ulcer healing after sclerosing could be a complication
of sclerosing . As varices upon sclerosing are repeated in 50-70%
cases, esophagoscopy and sclerosing have to be repeated every 6-12
months. Programmed liging of varices is also repeated (usually 3-4
times) with a range of several weeks until all varices are removed.
Complications in liging are rare in comparison to sclerosing. Those are
usually surface ulcer and rarely esophagus shrinking . A lack of
programmed liging of varices results into early recidives of varices,
because ligature cannot surround the paraesophageal veins, where new
varices are developed. In spite of this, liging has an advantage over
sclerosing, and it is proposed as endoscopic method of choice for
prevention of repeated bleeding of esophageal varices . During
sclerosing, the sclerosing solution causes thrombosis of paraesophageal
veins; therefore some authors propose combined endoscopic treatment of
liging and sclerosing with small quantities of sclerosing solution. In
such combination of techniques, hard complications are less than in
sclerosing itself . There are no differences in the frequency of
bleeding recidives. Appearance of esophagus stenosis is more frequent
than in a group treated only by liging .
One of possibilities for prevention the repeated bleeding from
esophageal varices is programmed position of transjugular
intrahepathitic portosystem shunt (TIPS) which results in decreased
pressure in portal veins.
The absolute contraindications for TIPS are deterioration of right
heart, hard liver insufficiency and hard portosystem encephalopathies.
In about 20% of patients, after two years, stenosis and/or occlusion or
stent breaking down appear with resultant repeated bleeding from varices.
The majority of those cases are solved by intervene radiology
operations: recannalisation of the existing or positioning of new stent.
The new models of stent, covered with plastic materials, are more stable
and rarely break down . It is necessary to have a regular control of
the flow through the stent by the use of ultrasound measuring with pulse
Colour Doppler . For the aim of prevention of repeated bleeding,
TIPS is proposed to the patients with liver cirrhosis, who are
candidates for liver transplantation because other methods are not
successful for them .
Surgical operation "shunt" is proposed as a good solution to the
patients with good preserved liver functions. Those operations are often
followed by postoperative complications and high mortality. Better
results with fewer complications are realized by formation of selective
"shunts" that partly pre-serve the flow through the portal vein . In
patients with thrombosis of the portal vein or lineal veins and
therefore not candidates for TIPS or surgical operation "shunt", with
good preserved liver functions, prevention of repeated bleeding from
varices is possible to try by devascularisation of esophagogastritic
crossing per "Siguira" method .
High mortality in bleeding from esophageal varices is a cause of
intensive investigations for new therapeutic possibilities in the field
of bleeding prevention.
The attempts to combine liging and coagulation of varices by the use of
argon plasma have pointed out that this method could be successful
because it shows better results than with only liging use .
Bosetan, antagonist of endotelitic receptors, have showed decrease of
pressure in portal vein for 20% in investigations on perphusion model of
liver with cirrhosis. Those investigations open the new prospects in
prevention the bleeding from esophageal varices . Great care is
pointed out to vasodilatator nitrogen oxide NO. An experiment is
interesting with changed adenovirus, created by genetic engi-neering to
form large quantity of NO-synthesis. After initiation of virus, an
important and short-term pressure decrease of portal vein has appeared
Many investigations are directed to discovery of new substances with
effect on pressure in portal vein. In patient with liver cirrhosis, the
system of rennin-angiotenzin-aldosteron was activated due to a fact that
many investigations are directed to analyzing the angotenzin convertase
and angiotenzin II inhibitor, pressure in portal vein, and their
possible use in prevention of bleeding from varices. The use of those
substances is limited by their unwanted effects, first of all
hypotension and worse renal function. It was found out tha angiotenzin
II causess contraction and proliferation of activated starlike liver
cells and increases synthesis of fibtin, makig more rapid fibrosis and
liver cirrhosis . Blockator of angiotenzitic receptors losartan
inhibits contraction and decreases proliferation of activated startlike
liver cells. By this way, besides de-crease of portal vein pressure, it
also decreases fibrin synthesis and breaks process of fibrosis and liver
cirrhosis . It was also found out that the inhibitor angiotenzin of
converting enzyme kapto-pril, used in rats, have significantly slow down
development of liver fibrosis, caused by binding the hepatic ducts .
Spironolakton metabolit - canrenon shows similar effects .
Investigations with medicines from the group of agonist and antagonist
of adrenergetic receptors are also carried out, but the limits are
similar as well as limits of medicine with action on system rennin
angiotenzin aldosteron. Blocator alfa-1 of adrenergetic receptors
prazosin is combination with pro-pranolol have efficeitnly decreased
PVPG, even more effective than combination of proplanolol and
long-effect nitrates, but with much more side ef-fects [42,43].
Carvedilol is one of the latest beta blockers with a feature of alfa
blocade with very efficient decrease of pressure in portal vein, but its
use is often followed by unwanted distinctive sys-tem hypertension. Some
clinical studies are under development that has to point out objectively
its place in prevention the bleeding from esophageal varices. It has not
yet been recommended to use small dosages that could be increased
depending on the values of the blood pressure system .
Although clinical studies have not confirmed a hypothesis that bacterial
infection is an initial moment in bleeding from esophageal varices, some
authors think that preventive role of antibiotics in combination with
other vasoactive medicines is intended in liver cirrhosis .
With bleeding appearance from esophageal varices in patients with
liver cirrhosis, prognosis for the disease results has been much worse.
Prevention of the first bleeding from esophageal varices in patients
with liver cirrhosis is therefore very important. The results of
clinical studies have shown that for this aim the use of beta blockers
propranolol and nadolol is the most suitable. If there are no unwanted
effects, the patient can use those medicines for life. Upon treatment of
acute hemorragia, prevention of repeated bleeding from esophageal
varices is continued. For this aim, if beta blockers are insufficient,
they are combined with long-term nitrates.
Criterion for nitrate introduction is measuring of HPVG that has to be
below 12 mm Hg or 20% lower than the starting value. If this method is
inaccessible, we take into consideration clinical parameters. Programmed
endoscopic treatment by sclerosing and liging of varices can be also
added by therapy with vasoactive medicaments. Compara-tive analyses have
shown that complications of endoscopic therapy are frequent in
sclerosing; therefore modern clinical studies proclaim liging of varices
as a method of choice in prevention of bleeding from esophageal varices.
Positioning of TIPS for prevention of repeated bleeding from varices is
proposed to the patients with liver cirrho-sis with good preserved liver
functions, and due to the ethiology of portal hypertension they are not
candidates for liver transplantation. Surgical operation "shunt" is
proposed to the patients with good preserved liver function, and due to
the ethiology of portal hypertension they are not candidates for TIPS.
New possibilities for prevention and treatment of esophageal varices are
being intensively investigated. Good results of some experimental
studies are waiting for clinical confirmation.
- Samy A Azer Esophageal Varices
- Kuntz E, Kuntz HD. Hepatology - principles and practice. Berlin,
Heidelberg, New York: Springer-Verlag; 2002.
- Chalasani N, Imperiale TF, Ismail A, Sood G, Carey M, Wilcox CM,
et al. Predictors of large esophageal varices in patients with
cirrhosis. Am J Gastroenterol 1999; 94(11): 3285-91.
- Gorjup B Zdravljenje in preprečevanje kvavitve varic požiralnika
- D'Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein
pressure gradient reduction and prevention of variceal bleeding in
cirrhosis: a systematic review.Gastroenterology. 2006
- De Franchis R, Primignani M. Why do varices bleed?
Gastroenterology Clin N Am 1992; 21: 85-101.
- Groszmann RJ, Glickman M, Blei AT, Storer E, Conn HO. Wedged and
free hepatic venous pressure measured with a balloon catheter. :
Gastroenterology. 1979 Feb;76(2):253-8.
- Glišić Lj ,Perišić V,Davčev P,Hadžić N,Satler
J.Gastroenterologija “Naučna Knjiga “ Beograd 1990. str 348-350
- Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE,
Glickman M. Portal pressure, presence of gastroesophageal varices
and variceal bleeding. Hepatology 1985; 5: 419-24.
- Sherman IA, Dlugosz JA, Barker F, Sadeghi FM, Pang KS. Dynamics
of arterial and portal venous flow interactions in perfused rat
liver: an intravital microscopic study. Am J Physiol 1996;
- Popović O Gastroenterologija u sto lekcija “Savinac” Beograd
1995. str 227-229
- Teodorović J,Jereb B GASTROENTEROLOGIJA I deo Excelsior ,Beograd
- Schepis F, Camme C, Niceforo D, Magnano A, Pallio S, Cinquegrani
M, et al. Which patients should undergo endoscopic screening for
esophageal varices detection? Hepatology 2001; 33: 333-8.
- Merkel C, Bolognesi M, Sacerdoti D, Bombonato G, Bellini B,
Bighin R, et al. The hemodynamic response to medical treatment of
portal hypertension as a predictor of clinical effectiveness in the
primary prophylaxis of variceal bleeding in cirrhosis. Hepatology
2000; 32: 930-4.
- Hillon P, Lebrec D, Munoz C, Jungers M, Goldfarb G, Benhamou JP.
Comparison of the effects of a cardioselective and a nonselective
beta-blocker on portal hypertension in patients with cirrhosis.
Hepatology 1982; 2: 528-31.
- Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N
Engl J Med 2001; 345: 669-81.
- Escorsell A, Feu F, Bordas JM, Garcia-Pagan JC, Luca A, Bosch J,
et al. Effects of isosorbide-5-mononitrate on variceal pressure and
systemic and splanchnic haemodynamic in patients with cirrhosis. J
Hepatol 1996; 24: 423-9.
- Angelico M, Lionetti R. Long-acting nitrates in portal
hypertension: to be or not to be? Dig Liver Dis 2001; 33: 205-11.
- Merkel C, Marin R, Sacerdoti D, Donada C, Cavallarin G, Torboli
P, et al. Long term results of a clinical trial of nadolol with or
without isosorbide mononitrate for primary prophylaxis of variceal
bleeding in cirrhosis. Hepatology 2000; 31: 324-9.
- Imperiale TF, Chalasani N. A meta-analysis of endoscopic
variceal ligation for primary prophylaxis of esophageal variceal
bleeding. Hepatology 2001; 33: 802-7.
- Smith JL, Graham DY. Variceal hemorrhage: a critical evaluation
of survival analysis. Gastroenterology 1982; 82: 968-73.
- Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Beta-adrenergic
antagonists in the prevention of gastrointestinal rebleeding in
patients with cirrhosis: a meta-analysis. Hepatology 1997; 25:
- Bureau C, Peron JM, Alric L, Morales J, Sanchez J, Barange K, et
al. "A La Carte" treatment of portal hypertension: Adapting medical
therapy to hemodynamic response for the prevention of bleeding.
Hepatology 2002; 36: 1361-6.
- Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP.
Isosorbide mononitrate and propranolol compared with propranolol
alone for the prevention of variceal rebleeding. Hepatology 2000;
- Santambrogio R, Opocher E, Costa M, Bruno S, Ceretti AP, Spina
GP. Natural history of a randomized trial comparing distal spleno-renal
shunt with endoscopic sclerotherapy in the prevention of variceal
rebleeding: a lesson from the past.
World J Gastroenterol. 2006 Oct 21;12(39):6331-8
- Waked I, Korula J. Analysis of long-term endoscopic surveillance
during follow-up after variceal sclerotherapy from a 13-year
experience. Am J Med 1997; 102: 192-9.
- Young MF, Sanowski RA, Rasche R. Comparison and characterization
of ulcerations induced by endoscopic ligation of esophageal varices
versus endoscopic sclerotherapy. Gastrointest Endosc 1993; 39:
- Dagher L, Burroughs A. Variceal bleeding and portal hypertensive
gastropathy. Eur J Gastroenterol Hepatol 2001; 13: 81-8.
- Singh P, Pooran N, Indaram A, Bank S. Combined ligation and
sclerotherapy versus ligation alone for secondary prophylaxis of
esophageal variceal bleeding: a meta-analysis. Am J Gastroenterol
2002; 97: 623-9.
- Ong JP, Sands M, Younossi ZM. Transjugular intrahepatic
portosystemic shunts (TIPS): a decade later. J Clin Gastroenterol
2000; 30: 14-28.
- Ferguson JM, Jalan R, Redhead DN, Hayes PC, Allan PL. The role
of duplex and colour Doppler ultrasound in the follow-up evaluation
of transjugular intrahepatic portosystemic stent shunt (TIPSS). Br J
Radiol 1995; 68: 587-9.
- Rosch J, Keller FS. Transjugular intrahepatic portosystemic
shunt: present status, comparison with endoscopic therapy and shunt
surgery, and future prospectives.World J Surg 2001; 25: 337-45.
- Orozco H, Mercado MA. The evolution of portal hypertension
surgery: lessons from 1000 operations and 50 years' experience. Arch
Surg 2000; 135: 1389-93.
- Selzner M, Tuttle-Newhall JE, Dahm F, Suhocki P, Clavien PA.
Current indication of a modified Sugiura procedure in the management
of variceal bleeding. J Am Coll Surg 2001; 193: 166-73.
- Cipolletta L, Bianco MA, Rotondano G, Marmo R, Meucci C, Piscopo
R. Argon plasma coagulation prevents variceal recurrence after band
ligation of esophageal varices: preliminary results of a prospective
randomized trial.Gastrointest Endosc 2002; 56: 467-71.
- Sogni P, Moreau R, Gomola A, Gadano A, Cailmail S, Calmus Y, et
al. Beneficial hemodynamic effects of bosentan, a mixed ET(A) and
ET(B) receptor antagonist, in portal hypertensive rats. Hepatology
1998; 28: 655-9.
- Fevery J, Roskams T, Van de Casteele M, Omasta A, Janssens S,
Desmet V, et al. NO synthase in the liver: prospects of in vivo gene
transfer. Digestion 1998; 59 Suppl 2: 58-9.
- Garcia-Tsao G: Angiotensin II receptor antagonists in the
pharmacological therapy of portal hypertension: a caution.
Gastroenterology 1999 Sep; 117(3): 740-2
- Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, et al. Angiotensin II induces contraction and
proliferation of human hepatic stellate cells. Gastroenterology
2000; 118: 1149-56.
- Jonsson JR, Clouston AD, Ando Y, Kellemen LI, Horn MJ, Adamson
MD, et al. Angiotensin-converting enzyme inhibition attenuates the
progression of rat hepatic fibrosis. Gastroenterology 2001; 121:
- Caligiuri A, De Franco RM, Romanelli RG, Gentilini A, Meucci M,
Failli P, et al. Antifibrogenic effects of canrenone, an
antialdosteronic drug, on human hepatic stellate cells.
Gastroenterology 2003; 124: 504-20.
- Albillos A, Garcia-Pagan JC, Iborra J, Bandi JC, Cacho G, Perez-Paramo
M, et al. Propranolol plus prazosin compared with propranolol plus
isosorbide-5-mononitrate in the treatment of portal hypertension.
Gastroenterology 1998; 115: 116-23.
- Wang HM, Lo GH, Chen WC, Tsai WL, Chan HH, Cheng LC, Hsu PI, Lai
KH. Comparison of endoscopic variceal ligation and nadolol plus
isosorbide-5-mononitrate in the prevention of first variceal
bleeding in cirrhotic patients.
J Chin Med Assoc. 2006 Oct;69(10):453-60.
- Tripathi D, Therapondos G, Lui HF, Stanley AJ, Hayes PC.
Haemodynamic effects of acute and chronic administration of low-dose
carvedilol, a vasodilating beta-blocker, in patients with cirrhosis
and portal hypertension. Aliment Pharmacol Ther 2002; 16: 373-80.
- Goulis J, Patch D, Borroughs AK. Bacterial infection in the
pathogenesis of variceal bleeding. Lancet 1999; 353: 139-42.