Esophageal varices in liver cirrhosis - bleeding prevention

Zoran Joksimović (1), Dušan Bastać (2)
(1) Internistic ordination "Joksimović", Bor, (2) Internistic ordination "Dr Bastać", Zaječar

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.

INTRODUCTION

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 [1]. 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 [2]. About 20% patients with cirrhosis have high varices which presents a real threat for bleeding [3]. 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 [4]. 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 [5]. 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 [6]. 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 [1].

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 [9]. 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 posthepatic hypertensions.
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 WHVP
• 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 [11]. 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 [12]. 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 ascites
• 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 difficult.

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 [14]. 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 [15]. 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 frequency.
Beta blockers decrease for about 50% the risk for the appearance of the first bleeding [16]. 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 [17].
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 [18]. 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 [19]. 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 [12]. 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 [20].

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 [21]. 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 [22]. 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 [23]. 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 [24]. 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 [25]. 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 [26]. 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 [27]. 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 [28]. 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 [29].
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 [30]. It is necessary to have a regular control of the flow through the stent by the use of ultrasound measuring with pulse Colour Doppler [31]. 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 [32].
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 [33]. 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 [34].
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 [35].
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 [36]. 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 [37].
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 [38]. 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 [39]. 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 [40]. Spironolakton metabolit - canrenon shows similar effects [41].
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 [44].
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 [45].

CONCLUSION

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.

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