CHAPTER I

INTRODUCTION

Approximately 90% of patients with cirrhosis will have developed esophageal varices within 10 years. Esophageal variceal haemorrhage is a devastating complication of cirrhosis with mortality as high as 2550%.

Red sign and variceal size (medium to large grade) on endoscopy are representative for bleeding risk of esophageal varices. Severity of liver function reserve and presence of ascites are also important risk factors for variceal bleeding.(1,2) The bleeding risk decreases over time from the time that varices are identified; most bleeding episodes occur within the first 2 years after identification of varices. Once bleeding occurs, spontaneous cessation of bleeding occurs in only up to 40% of individuals, and the bleeding is associated with the mortality of 20% or more at 6 weeks.(3,4) Patients who survived an episode of acute variceal hemorrhage have a high risk of rebleeding and death. The median rebleeding rate in untreated individuals is around 60% within 1-2 years of the index bleeding, with a mortality of 33% . Therefore, care should be taken to prevent recurrent bleeding prior to discharge from the hospital for patients who have recovered from an episode of variceal bleeding.(5,6) This paper will mainly discuss the esophageal varices as the complication of hepatic cirrhosis.

CHAPTER II

ANATOMY (7)Theliveris located in the right upperquadrant, from the fifthintercostalspace in themidclavicular linedown to theright

HYPERLINK "http://hopkins-gi.org/HTD/HTD_Term.aspx?CurrentUDV=31&TD_ID=5C4E70E9-8A1F-4F24-8312-457447B332FD"costal margin. Theliverweighs approximately 1800 g in men and 1400 g in women. The surfaces of theliverare smooth andconvexin thesuperior,anterior, and rightlateralregions. Indentations from thecolon, right kidney,duodenum, and stomach are apparent on theposteriorsurface.

The line between thevena cavaandgallbladderdivides theliverinto right and left lobes. Each lobe has an independentvascularandductsupply. Theliveris further divided into eight segments, each containing apedicleofportalvessels, ducts, andhepaticveins.

The portal venous system extends from the intestinal capillaries to the hepatic sinusoid. This venous system carries the blood from the abdominal gastrointestinal tract, thepancreas,gallbladder, andspleenback to the heart (coursing through theliver). The largest vessel in this system is theportalvein, which is formed by the union of the splenic vein and superior mesentric veins. The left gastric and right gastric veins and the posterior superior pancreaticoduodenal veins drain directly into the portal vein. Theportalvein runsposteriorto thepancreas, and itsextrahepaticlength may be anywhere from 59 cm. At theporta hepatis, it divides into the right and leftportalveins within theliver, and the cystic vein typically drains into the righthepaticbranch.

Theportalvein supplies 70% of the blood flow to theliver, but only 40% of theliveroxygen supply. The remainder of the blood comes from thehepaticartery, and blood from both of these vessels mixes in the sinusoids.Theliverreceives a tremendous volume of blood, on the order of 1.5 liters per minute. The dual blood supply allows theliverto remain relatively resistant tohypoxemia. Unlike the systemic vasculature, the hepatic vascular system is less influenced by vasodilatation and vasoconstriction. This is because the sinusoidal pressures remain relatively constant despite changes in blood flow. A classic example ishepaticveinocclusionresulting in high sinusoidal pressure and extracellularextravasationof fluid. To maintain a constant inflow of blood to theliver,hepaticartery blood flow is inversely related toportalvein flow. This appears to be hormonallymediatedrather thanneurallymediated, since it persists in the transplantedliver.

CHAPTER III

A. CIRRHOSIS HEPATIS

1. Definition

Cirrhosis is a complication of manyliver diseasesthat is characterized by abnormal structure and function of the liver. The diseases that lead to cirrhosis do so because they injure and kill liver cells, and the inflammation and repair that is associated with the dying liver cells causes scar tissue to form. The liver cells that do not die multiply in an attempt to replace the cells that have died. This results in clusters of newly-formed liver cells (regenerative nodules) within the scar tissue.2. EpidemiologyChronic liver disease and cirrhosis result in about 35,000 deaths each year in the United States. Cirrhosis is the ninth leading cause of death in the United States and is responsible for 1.2% of all US deaths. Many patients die from the disease in their fifth or sixth decade of life.

Each year, 2000 additional deaths are attributed tofulminant hepatic failure(FHF). FHF may be caused viral hepatitis (eg, hepatitis A and B), drugs (eg, acetaminophen), toxins (eg,Amanita phalloides,the yellow death-cap mushroom), autoimmune hepatitis, Wilson disease, or a variety of less common etiologies. Cryptogenic causes are responsible for one third of fulminant cases. Patients with the syndrome of FHF have a 50-80% mortality rate unless they are salvaged by liver transplantation.

3. EtiologyIn western countries the causes of liver cirrhosis are common due to alcoholism, while in Indonesia, especially due to infection with hepatitis B or C virus. The results in Indonesia said the most common cause of liver cirrhosis are hepatitis B virus (30-40%), hepatitis C virus (30-40%), and unknown causes (10-20%). As for some of the etiology of liver cirrhosis include:

a) Alcoholis a very common cause of cirrhosis, particularly in the Western world. The development of cirrhosis depends upon the amount and regularity of alcohol intake. Chronic, high levels of alcohol consumption injure liver cells. b) Nonalcoholic fatty liver disease (NAFLD)refers to a wide spectrum of liver diseases that, like alcoholic liver disease, ranges from simple steatosis, to nonalcoholic steatohepatitis (NASH), to cirrhosis. All stages ofNAFLDhave in common the accumulation of fat in liver cells. The term nonalcoholic is used because NAFLD occurs in individuals who do not consume excessive amounts of alcohol, yet, in many respects, the microscopic picture of NAFLD is similar to what can be seen in liver disease that is due to excessive alcohol. NAFLD is associated with a condition calledinsulin resistance, which, in turn, is associated with themetabolic syndromeanddiabetesmellitus type 2.Obesityis the most important cause of insulin resistance, metabolic syndrome, and type 2 diabetes. NAFLD is the most common liver disease in the United States and is responsible for 24% of all liver disease. In fact, the number of livers that are transplanted for NAFLD-related cirrhosis is on the rise.Public healthofficials are worried that the currentepidemicofobesitywill dramatically increase the development of NAFLD and cirrhosis in the population.c) Cryptogenic cirrhosis(cirrhosis due to unidentified causes)is a common reason for liver transplantation. It is termed cryptogenic cirrhosis because for many years doctors have been unable to explain why a proportion of patients developed cirrhosis. Doctors now believe that cryptogenic cirrhosis is due to NASH (nonalcoholic steatohepatitis) caused by long standing obesity, type 2 diabetes, andinsulinresistance. The fat in the liver of patients with NASH is believed to disappear with the onset of cirrhosis, and this has made it difficult for doctors to make the connection between NASH and cryptogenic cirrhosis for a long time. One important clue that NASH leads to cryptogenic cirrhosis is the finding of a high occurrence of NASH in the new livers of patients undergoingliver transplantfor cryptogenic cirrhosis. Finally, a study from France suggests that patients with NASH have a similar risk of developing cirrhosis as patients with long standing infection withhepatitis Cvirus. (See discussion that follows.) However, the progression to cirrhosis from NASH is thought to be slow and the diagnosis of cirrhosis typically is made in patients in their sixties.d) Chronic viral hepatitisis a condition wherehepatitis Borhepatitis Cvirus infects the liver for years. Most patients withviral hepatitiswill not develop chronic hepatitis and cirrhosis. For example, the majority of patients infected withhepatitis Arecover completely within weeks, without developing chronic infection. In contrast, some patients infected with hepatitis B virus and most patients infected with hepatitis C virus develop chronic hepatitis, which, in turn, causes progressive liver damage and leads to cirrhosis, and, sometimes, liver cancers.e) Inherited (genetic) disordersresult in the accumulation of toxic substances in the liver which lead to tissue damage and cirrhosis. Examples include the abnormal accumulation of iron (hemochromatosis) or copper (Wilson's disease). Inhemochromatosis, patients inherit a tendency to absorb an excessive amount of iron from food. Over time, iron accumulation in different organs throughout the body causes cirrhosis,arthritis,heart muscledamage leading toheart failure, and testicular dysfunction causing loss of sexual drive. Treatment is aimed at preventing damage to organs by removing iron from the body through bloodletting (removing blood). InWilson disease, there is an inherited abnormality in one of the proteins that controls copper in the body. Over time, copper accumulates in the liver, eyes, and brain. Cirrhosis,tremor,psychiatricdisturbances and otherneurologicaldifficulties occur if the condition is not treated early. Treatment is with oral medication that increases the amount of copper that is eliminated from the body in the urine.f) Primary biliary cirrhosis (PBC)is a liver disease caused by an abnormality of the immune system that is found predominantly in women. The abnormal immunity in PBC causes chronic inflammation and destruction of the small bile ducts within the liver. The bile ducts are passages within the liver through which bile travels to the intestine. Bile is a fluid produced by the liver that contains substances required for digestion and absorption of fat in the intestine, as well as other compounds that are waste products, such as the pigment bilirubin. (Bilirubin is produced by the breakdown ofhemoglobinfrom old red blood cells.). Along with thegallbladder, the bile ducts make up thebiliarytract. InPBC, the destruction of the small bile ducts blocks the normal flow of bile into the intestine. As the inflammation continues to destroy more of the bile ducts, it also spreads to destroy nearby liver cells. As the destruction of the hepatocytes proceeds, scar tissue (fibrosis) forms and spreads throughout the areas of destruction. The combined effects of progressive inflammation, scarring, and the toxic effects of accumulating waste products culminates in cirrhosis.g) Primary sclerosing cholangitis (PSC)is an uncommon disease found frequently in patients withulcerative colitis. In PSC, the large bile ducts outside of the liver become inflamed, narrowed, and obstructed. Obstruction to the flow of bile leads to infections of the bile ducts and jaundice and eventually causes cirrhosis. In some patients, injury to the bile ducts (usually as a result of surgery) also can cause obstruction and cirrhosis of the liver.h) Autoimmune hepatitisis a liver disease caused by an abnormality of the immune system that is found more commonly in women. The abnormal immune activity in autoimmune hepatitis causes progressive inflammation and destruction of liver cells (hepatocytes), leading ultimately to cirrhosis.i) Infants can be born without bile ducts (biliary atresia)and ultimately develop cirrhosis. Other infants are born lacking vital enzymes for controlling sugars that leads to the accumulation of sugars and cirrhosis. On rare occasions, the absence of a specific enzyme can cause cirrhosis and scarring of the lung (alpha 1 antitrypsin deficiency).j) Less common causes of cirrhosis include unusual reactions to some drugs and prolonged exposure to toxins, as well as chronicheart failure(cardiac cirrhosis).In certain parts of the world (particularly Northern Africa), infection of the liver with a parasite (schistosomiasis) is the most common cause of liver disease and cirrhosis.4. PathogenesisLiver responds the cell damage by forming extracellular matrix containing collagen, glycoproteins, and proteoglikans. Stellate cell extracellular matrix play a role in shaping this.

In an acute injury, stellate cells reshaping the extracellular matrix is thus found to swelling of the liver. However, there are several factors that cause parakrine stellate cells into collagen-producing cells. Parakrine factors may be released by hepatocytes, Kupffer cells, and sinusoidal endothelial response to prolonged injury. For example, elevated levels of the cytokine transforming growth facto beta 1 (TGF-beta1) was found in patients with chronic hepatitis C and cirrhosis patients. TGF-beta1 then activates stellate cells to produce collagen type 1 and ultimately shrinking the size of the liver.

Increased deposition of collagen in the perisinusoidal and reduced the size of hepatic endothelial fenestra cause kapilerisasi (such as capillary endothelial pore size) of the sinusoid. Stellate cell in producing the collagen to contract large enough to suppress local presence perisinusoidal stellate cell contractility kapilarisasi and that causes a lot of emphasis on the veins in the liver that disrupts the blood flow to the liver cells and liver cells eventually die. Hepatocyte death in large numbers will cause a lot of damaged liver function that causes many clinical symptoms. Pressure on the veins in the liver can lead to portal hypertension. Portal hypertension is a major cause of the state of the clinical manifestations.5. Sign and symtoms(12)Many people with cirrhosis have no symptoms during the early phases of the disease.Symptoms are caused by either of 2 problems. Gradual failure of the liver to carry out its natural functions and distortion of the liver's usual shape and size because of scarringThe most common symptoms of cirrhosis are tiredness(fatigue) or even exhaustion, weakness, nausea, loss of appetite leading toweight loss, loss of sex drive. Symptoms may not appear until complications of cirrhosis set in. Many people do not know they have cirrhosis until they have acomplication. The symtoms are fever, vomiting, diarhhea, jaundice, yellowing of the skin and eyes from deposition ofbilirubinin these tissues. Bilirubin is a product of the breakdown of old blood cells in the liver. Itchingcan be happen from deposition in the skin of products of the breakdown of bile. Beside that, from fluid retention causes abdominal swelling, edema, and difficulty breathing. Because one of the functions of the liver is secreting hormones, so in cirrhosis hepatic gynecomastia, scrotal swellin, and the abnormal menstrual periods can be found in this disease. Bleeding from gums ornoseand easy brusing are often happend due to impaired production of clotting factors in cirrhosis.CHAPTER III

B. ESOPHAGEAL VARICES

1. DefinitionEsophageal varices are abnormal, enlarged veins in the lower part of the esophagus the tube that connects the throat and stomach. Esophageal varices occur most often in people with serious liver diseases.Esophageal varices develop when normal blood flow to your liver is slowed. The blood then backs up into nearby smaller blood vessels, such as those in your esophagus, causing the vessels to swell. Sometimes, esophageal varices can rupture, causing life-threatening bleeding.

2. EpidemiologiAlthough varices can occur anywhere along the gastrointestinal tract tubular, varices often occur in a few centimeters of the distal end of the esophagus. Approximately 50% of patients with cirrhosis have gastroesophageal varices. Gastric varices occur in 5-33% of cases of portal hypertension. The frequency of esophageal varices ranged between 30-70% in patients with cirrhosis, and 9-36% of patients with high-risk varices. (11)3. Etiology Esophageal varices are most often a complication of cirrhosis irreversible scarring of the liver. Other diseases and conditions also can cause esophageal varices. Causes can include:a) Severe liver scarring (cirrhosis).A number of liver diseases can result in cirrhosis, such as hepatitis infection, alcoholic liver disease and a bile duct disorder called primary biliary cirrhosis.b) Blood clot (thrombosis).A blood clot in the portal vein or in a vein that feeds into the portal vein called the splenic vein can cause esophageal varices.c) A parasitic infection.Schistosomiasis is a parasitic infection found in parts of Africa, South America, the Caribbean, the Middle East and Southeast Asia. The parasite can damage the liver, as well as the lungs, intestine and bladder.d) A syndrome that causes blood to back up in your liver.Budd-Chiari syndrome is a rare condition that causes blood clots that can block the veins that carry blood out of your liver4. Pathogenesis

Cirrhosis, the end stage of chronic liver disease, is the most common cause of portal hypertension. Portal venous pressure (P) is the product of vascular resistance (R) and blood flow (Q) in the portal bed (Ohms law; Fig. 1). In cirrhosis, both intrahepatic vascular resistance and portal flow are increased.

Portal hypertension leads to the formation of portosystemic collaterals. However, due to their higher resistance and increased portal venous inflow, these collaterals are unable to decrease the hypertension. Portal hypertension is best assessed (indirectly) using the wedged hepatic venous pressure (WHVP) measurement. A pressure difference between the portal and systemic circulation (the hepatic venous pressure gradient, HVPG) of 1012 mmHg is necessary (but not sufficient) for varices to form. The normal HVPG is 35 mmHg. Single measurements are useful for determining the prognosis of both compensated and decompensated cirrhosis, while repeat measurements are useful for monitoring the response to pharmacological therapy and the progression of liver disease.(10)Varices rupture if the wall tension becomes too great. The likelihood that a varix will rupture and bleed increases with increasing size/diameter of the varix and with increasing variceal pressure, which is again proportionate to the HVPG. Conversely, varices do not bleed if the HVPG is below 12 mmHg. The risk of rebleeding decreases significantly with reductions in HVPG greater than 20% from baseline. (11)5. Sign and symtoms

Esophageal varices usually don't cause signs and symptoms unless they bleed. Signs and symptoms of bleeding esophageal varices include: Vomiting blood

Black, tarry or bloody stools6. Risk factor

An international normalized ratio (INR) score > 1.5, a portal vein diameter of > 13 mm, and thrombocytopenia have been found to be predictive of the likelihood of varices being present in cirrhotics. If none, one, two, or all three of these conditions are met, then < 10%, 2050%, 4060%, and > 90% of the patients are estimated to have varices, respectively. The presence of one or more of these conditions represents an indication for endoscopy to search for varices and carry out primary prophylaxis against bleeding in cirrhotic patients. (10,11)CHAPTER IV

DISCUSSIONEsophageal varices are the major complication of portal hypertension. It is detected in about 50% of cirrhosis patients, and approximately 515% of cirrhosis patients show newly formed varices or worsening of varices each year [15].

As other parenchyma tissue, the liver normally contains epithelial component (hepatocytes), endothelial layer (of the liver characterized by the presence fenestra), tissue macrophages (Kupffer cells), and perivascular mesenchymal cells called stelata cells. Stelata cells that are normally involved in the storage of fat and vitamin A will be transformed into cells that resemble miofibroblas in case of injury in the liver. This led a change in the extracellular matrix, the production of collagen become increase and forming tissue fibrosis.

Contraction of activated stellate cells is promoted by increased vasoconstrictor endothelin and a reduction in the vasodilator nitric oxide within the liver. Therefore, intrahepatic resistance increases. In contrast to its intrahepatic levels, nitric oxide concentrations are elevated in the peripheral and splanchnic circulation. This results in decreased systemic and splanchnic vascular resistance, thus increasing portal blood flow.(14)

Portal hypertension is associated with both increased portal inflow and increased outflow resistance. The portal hypertension is directly related to portal inflow and/or outflow resistance,as determined by Ohms law portal pressure = portal venous inflow outflow resistance.

Portal venous inflow is affected by hyperdynamic circulation, which is characterized by systemic and splanchnic vasodilatation, low systemic resistance, plasma volume expansion, and high cardiac index. Splanchnic vasodilatation contributes to increasing substantial blood volume which returns to portal venous system. Peripheral vasodilatation activates endogenous neurohumoral systems that cause sodium retention, which leads to expansion of the plasma volume, followed by an increase in the cardiac index.(13)One of the potential for communication between circulation splancnic intraabdominal and systemic venous circulation is through the esophagus. If the portal venous blood flow to the liver is hampered by cirrhosis or other causes, portal hypertension that occur trigger the formation of collateral bypass channels in a meeting place for portal and systemic systems. Therefore, the portal blood flow diverted through the stomach into the coronary venous plexus of subepithelial and submucosal esophageal veins, then into the azygos vein and superior vena cava. Increased pressure in the esophageal plexus causes them to dilate and winding serpentine known as varices. Patients with cirrhosis are experiencing varices at a rate of 5% -15% per year, so that the veins found in approximately two-thirds of all patients with cirrhosis. (13)

Ruptured varices occur when the strain in the wall of varices is too big. Possible wall varices (varix) will have a tear in line with the magnitude / diameter varix variseal and with increased pressure, which again is equivalent to the HVPG. Wall varices will not tear if HVPG pressure less than 12 mmHg.

In ideal circumstances, patients with known varices should receive treatment to reduce their risk of bleeding.The non-selective-blockers(e.g.,propranolol10mg ,timololornadolol20mg) and nitrates (e.g.isosorbide mononitrate(IMN) 20mg BD) have been evaluated for primary prophylaxis. Non-selective-blockers(but not cardioselective-blockerslike atenolol) are preferred because they decrease both cardiac output by 1blockade and splanchnic blood flow by blocking vasodilating 2receptors at splanchnic vasculature. The effectiveness of this treatment has been shown by a number of different studies.(15,16)Endoscopic variceal band ligation may be an alternative for patients who cannot tolerate, or have contraindications to beta-blockers. The best approach for patients with acute variceal bleeding is the combination of vasoactive drugs and endoscopic therapy. Terlipressin is administered as 2mg IV bolus and 1mg every six hours for 2-5 days. Somatostatin is given as an IV 250mcg bolus followed by 250mcg/hour infusion and octreotide is administered as a bolus injection of 50mcg followed by an infusion at a rate of 50mcg/hour. Somatostatin or octreotide therapy should be maintained for 5 days to prevent early re-bleeding. Regarding endoscopic therapy, EVL is preferred but sclerotherapy may be used depending on the endoscopists experience and the particular circumstances found during endoscopy. (17,18)The first-line treatment for prevention of recurrent variceal haemorrhage is betablockers, endoscopic variceal ligation or the combination of beta-blockers and endoscopic variceal ligation. TIPS or surgical shunt appears to be more appropriate for patients who are non-compliant or refractory to pharmacological and endoscopic therapy.(19) ALGORITHM: PRIMARY PROPHYLAXIS OF VARICEAL BLEED

ALGORITHM: MANAGEMENT OF ACUTE VARICEAL BLEEDINGCHAPTER V

CONCLUSIONCirrhosis is a condition that is defined histopathologically and has a variety of clinical manifestations and complications, some of which can be life-threatening, portal hypertension is directly responsible for the two major complications of cirrhosis, variceal hemorrhage. Variceal hemorrhage is an immediate life-threatening problem with a 2030% mortality associated with each episode of bleeding.

In normal condition, the liver has system receives blood from the mesenteric veins, stomach, lymph nodes, and pancreas enter through the hepatic artery and portal vein. Blood sent to the liver via the portal triad consisting of a branch of the portal vein, hepatic artery and bile duct. Then it will continous to the lobul liver sinusoid space. Blood that has filtered into the central vein and then into the hepatic vein larger toward the inferior vena cava. In cirrhosis, the presence of fibrotic tissue in the sinusoids interfere the normal blood flow to the liver lobul, it will cause the portal hypertension that can develop into varices.There are treatments to stop bleeding in such as vaso-active drugs, vasopressin, somatostatin, octreotide, endoscopic sclerotherapy and banding, and endoscopic variceal ligation. -Blockers and endoscopic variceal band ligation are the treatments to prevent bleeding.REFERENCES

1. R. De Franchis and M. Primignani, Natural history of portal hypertension in patients with cirrhosis, Clinics in Liver Disease, vol. 5, no. 3, pp. 645663, 2001. 2. C. Merkel, M. Zoli, S. Siringo et al., Prognostic indicators of risk for first variceal bleeding in cirrhosis: a multicenter study in 711 patients to validate and improve the North Italian Endoscopic Club (NIEC) index, American Journal of Gastroenterology, vol. 95, no. 10, pp. 29152920, 2000. 3. G. DAmico and R. De Franchis, Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators, Hepatology, vol. 38, no. 3, pp. 599612, 2003.4. N. Carbonell, A. Pauwels, L. Serfaty, O. Fourdan, V. G. Levy, and R. Poupon, Improved survival after variceal bleeding in patients with cirrhosis over the past two decades, Hepatology,vol. 40, no. 3, pp. 652659, 2004.5. G. DAmico, L. Pagliaro, J. Bosch, and D. Patch, Pharmacological treatment of portal hypertension: an evidence-based approach, Seminars in Liver Disease, vol. 19, no. 4, pp. 475 505, 1999.6. J. Bosch and J. C. Garca-Pagan, Prevention of variceal rebleeding, The Lancet, vol. 361, no. 9361, pp. 952954, 2003.7. Anatomy of Hepar and Portal Vein. Available at : http://hopkins-gi.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Cat_ID=BB532D8A-43CB-416C-9FD2-A07AC6426961&GDL_Disease_ID=E19DBE4A-EE02-4BDE-9FF9-A8371834DE4A . Accessed on 2 january 20138. Cirrhosis of liver. Available at : http://www.liver.ca/liver_disease/adult_liver_diseases/cirrhosis_of_the_liver.aspx. Accesed on 2 january 2013.9. Cirrhosis. Available at: http://www.liverfoundation.org/abouttheliver/info/cirrhosis/. Accesed on 2 january 2013.10. Dite, P., et al. World Gastroenterology Organization Practice Guideline: Esophageal Varices. 2008.11. Dombro MR, Griffiths 5-Minute Clinical Consult, Philadelphia : Lippincott Williams & Wilkins, 2006.12. Cirrhosis symtoms. Available at : http://www.emedicinehealth.com/cirrhosis/page3_em.htm#cirrhosis_symptoms . Accesed on 2 january 2013.13. A. J. Sanyal, J. Bosch, A. Blei, and V. Arroyo, Portal hypertension and its complications, Gastroenterology, vol. 134, no. 6, pp. 17151728, 2008.14. Gressner AM,Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-_ as major players and therapeutic targets. J Cell Biol Med. 2006;10:7699.15. Lebrec D, Poynard T, Hillon P, Benhamou J-P (1981). "Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study".N Engl J Med305(23): 13711374.16. Talwalkar JA, Kamath PS (2004). "An evidence-based medicine approach to beta-blocker therapy in patients with cirrhosis".Am J Med116(11): 759766. 17. Groszmann RJ, Garcia-Tsao G, Bosch J,et al.(2005). "Beta-Blockers to Prevent Gastroesophageal Varices in Patients with Cirrhosis".N Engl J Med353(21): 22542261.18. Karsan HA, Morton SC, Shekelle PG, et al. Combination endoscopic band ligation and sclerotherapy compared with endoscopic band ligation alone for the secondary prophylaxis of esophageal variceal hemorrhage: a meta-analysis. Dig Dis Sci. 2005;50(2):399-406.19. 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(3):337-45.

Fig 3. The pathogenesis of oesophageal varices

Sodium retention

Maintains portal hypertension

Increase portal blood flow

Collaterals

Increased intrahepatic resistance

Decreased intrahepatic NO

Decreased systemic + splanchnic vascular resistance

Increased splanchnic + peripheral NO

Cirrhosis

Shock, in severe cases

Fig 1. Anatomy of hepar and system portal

Fig 2. Stages of liver damage

Fig 4. Esophageal varices

Suspected acute variceal bleeding (AVB)

Resuscitation, IV access, GXM

Terlipressin / Octreotide / Somatostatin for 2-5 days

Antibiotic Prophylaxis for 7 days in patients with cirrhosis

Endoscopy service

unavailable

Balloon tamponade

if active bleeding

Transfer to

endoscopy centre

Urgent Endoscopy

Oesophageal varices

Gastric varices

EVL preferred;

sclerotherapy if EVL

difficult

Injection with

cyanoacrylate

Persistent active

bleeding

Persistent active bleeding

TIPS or surgical

intervention

Beta-blockers, EVL

or both

Repeat endoscopic

therapy

TIPS or surgical

shunt

YES

NO

If Childs C cirrhosis consider

liver transplant evaluation

EVL if beta-blocker

contraindicated or

intolerant

Beta-blocker therapy

(HYPERLINK "http://en.wikipedia.org/wiki/Propranolol" \o "Propranolol"propranolol10mg ,HYPERLINK "http://en.wikipedia.org/wiki/Timolol" \o "Timolol"timololorHYPERLINK "http://en.wikipedia.org/wiki/Nadolol" \o "Nadolol"nadolol20mg) and nitrates (e.g.HYPERLINK "http://en.wikipedia.org/wiki/Isosorbide_mononitrate" \o "Isosorbide mononitrate"isosorbide mononitrate(IMN) 20mg BD))

Large varices (Grade 3)

or moderate varices

(Grade 2) with

endoscopic red wale

signs or Childs C

cirrhosis

4