Variceal bleeding in cirrhosis

D Amico, G., Pietrosi, G., Tarantino, I., Pagliaro, L. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis a Cochrane meta-analysis. Gastroenterology 2003 124 1277-1291... 

Henderson, J.M., Kutner, M.H., Millikan., W.J. jr., Gaiambos, J.T., Riepe, St.P., Brooks, W.S., Bryan, F.C., Warren, W.D. Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis. A prospective, randomized trial. Ann. Intern. Med. 1990 112 262-269... 

Merkel, C., Marin, R., Enzo, E., Donada, C., Cavallarin, G., Torboli, P, Amodio, P., Sebastianelli, G., Sacerdoti, D., Felder, M., Mazzaro, C., Beltrame, R, Gatta, A. Randomised trial of nadolol or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Lancet 1996 348 1677-1681... 

Borgonovo, G., Costantini, M., Grange, D., Vons, C., Smadja, C., Franco, D. Comparison of a modified Sugiura procedure with portal systemic shunt for prevention of recurrent variceal bleeding in cirrhosis. Surge 1996 119 214-221... 

Teran JC, Imperiale TF, Mullen KD, et al. Primary prophylaxis of variceal bleeding in cirrhosis A cost-effectiveness analysis. Gastroenterology 1997 112 473-482. 

R, Gassull, M.A., Teres, X, Arroyo, V., Rodes, X Impact of shunt surgery for variceal bleeding in the natural history of ascites in cirrhosis a retrospective study. Hepatology 1994 20 584-591... 

Saab, S., DeRosa, V., Nieto, J., Durazo, F., Han, S., Roth, B. Costs and clinical outcomes of primary prophylaxis of variceal bleeding in patients with hepatic cirrhosis A decision analytic model. Amer. J. Gastroenterol. 2003 98 763-770... 

Aspirin can increase the risk of variceal bleeding in patients with cirrhosis. In fact, according to a case-control study (147), patients with cirrhosis and esophageal or cardiac varices who take NSAIDs are three times more likely to have a first episode of variceal bleeding compared with similar patients who are not taking NSAIDs. 

P Blockers may be of some value in the treatment of patients undergoing withdrawal from alcohol or those with akathisia. Propranolol and nadolol are efficacious in the primary prevention of variceal bleeding in patients with portal hypertension caused by hepatic cirrhosis. 

Cirrhosis is the progressive replacement of normal hepatic cells by fibrous scar tissue. This scarring is accompanied by the loss of viable hepatocytes, which are the functional cells of the liver. Progressive cirrhosis is irreversible and leads to portal hypertension that is in turn responsible for many of the complications of advanced liver disease. These consequences include (but are not limited to) spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and variceal bleeding.1... 

In some cases, cirrhosis is diagnosed incidentally before the patient develops symptoms or acute complications. Other patients may have decompensated cirrhosis at initial presentation they may present with variceal bleeding, ascites, SBP, or HE. Patients may also have some of the laboratory abnormalities and/or signs and symptoms listed above that are associated with cirrhosis.28... 

Hemorrhage from varices occurs in 25% to 40% of patients with cirrhosis, and each episode of bleeding carries a 25% to 30% risk of death. 

Acute fresh bleeding from the upper gastrointestinal tract is a mandatory cause of hospital referral. About half of all cases are due to peptic ulceration, and variceal bleeding accounts for a varying, but generally minor component of the remainder depending on the frequency of alcoholic cirrhosis or of hepatitis B-induced cirrhosis in the population. 

Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension Is caused by Increased blood flow within the portal venous system and increased resistance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstriction of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding. 

Beta-receptor antagonists have been found to diminish portal vein pressure in patients with cirrhosis. There is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis. Nadolol in combination with isosorbide mononitrate appears to be more efficacious than sclerotherapy in preventing re-bleeding in patients who have previously bled from esophageal varices. 

Transjugular intrahepatic portosystemic shunt (TIPS) is a side-to-side non-selective portosystemic shunt that is frequently performed in cirrhosis to manage the complications of portal hypertension, such as variceal bleeding. The observation that the bioavailability of oral midazolam was significantly higher in cirrhotic patients with TIPS than in cirrhotic controls and healthy volunteers [57] may be due to reduced intestinal CYP3A activity or reduced contact with CYP3A in the entero-cyte due to increased splanchnic blood flow [57, 92]. 

Portal pressure is a function of resistance in the portal venous system and ih.e flow of blood through it. In cirrhosis, portal venous resistance is increased, and inflow of blood is increased by splanchnic vasodilatation and elevation of cardiac output. Variceal bleeding is increasingly likely as the pressure gradient between the portal and systemic venous systems rises beyond 12 mmHg. 

Liver transplantation not only removes the continued risk of variceal bleeding, but also eliminates the underlying liver disease causing portal hypertension. However, due to the scarcity of liver donors, limited financial resources and the life-long immunosuppression required, this major surgical intervention can only rarely be considered - perhaps in cases where a previous shunt operation or the creation of a TIPS was not possible. The survival rate for transplantation is higher than when recurrent bleeding is treated by repeated sclerotherapy (73% versus 17% after 4 years). The indication for transplantation (e. g. cirrhosis Child B or C) should be set as early as possible, (s. p. 872)... 

Ory, G., Spahr, L., Megevand, J.M., Becker, C., Hadengue, A. The long-term efficacy of the intrahepatic portosystemic shunt (TIPS) for the treatment of bleeding anorectal varices in cirrhosis. A case report and review of the literature. Digestion 2001 64 261-264... 

Complications such as variceal bleeding, hepatic encephalopathy, ascites and infections as well as reduced renal function also influence the mortality rate of liver cirrhosis (in Germany some 25,000/year). The main causes of death are hepatic coma or liver failure (25-40%), bleeding (20-30%), infections (about 10%) and HCC (about 5%). Spontaneous bacterial peritonitis is fatal in 50-70%, and with liver dysfunction even in 90% of cases. Occurrence of the hepatorenal syndrome is almost invariably fatal. 

Hepatic steatosis with Mallory inclusion bodies has been reported with nifedipine (28). In patients with liver cirrhosis, nifedipine increases portal pressure due to splanchnic vasodilatation (29) whether this increases the risk of variceal bleeding is unknown. 

Variceal bleeding is a frequent and serious event in cirrhosis, and carries an increased risk of death (SEDA-22, 218). Therapy to prevent bleeding is therefore essential in these patients. Propranolol alone has been compared with propranolol plus isosorbide-5-mononitrate in a randomized, double-blind study in 95 patients (21). The combined treatment reduced the incidence of variceal bleeding compared with propranolol alone, but without any improvement in survival Isosorbide-5-mononitrate added to propranolol appeared to be less well tolerated than propranolol alone, since seven patients had to be withdrawn from treatment because of adverse effects (four with feehngs of faintness, two with headache, one with angina-like chest pain), compared with one with atrioventricular block taking propranolol alone. 

Isosorbide-5-mononitrate has been tested with and without propranolol in a placebo-controlled study in 30 patients with liver cirrhosis and esophageal varices (22). The aim of the study was to assess the severity of previously reported adverse effects (that is renal dysfunction and hepatic encephalopathy) when vasoactive drugs are used to prevent variceal bleeding. Neither isosorbide-5-mononitrate nor propranolol alone or together had any adverse effect on subclinical hepatic encephalopathy or renal function in patients with well-compensated cirrhosis. Severe headache in those taking isosorbide caused three patients to withdraw. 

In 125 patients with cirrhosis who were admitted to hospital with a first episode of bleeding related to esophageal or cardiac varices, compared with 75 patients with cirrhosis, but no previous or current history of variceal bleeding, who were admitted to the same hospitals, a questionnaire showed that more patients with a first episode of bleeding had used aspirin, either alone or in combination with other NSAIDs compared with controls (OR = 4.9). This increased risk of bleeding was seen only in patients with grade 2 or grade 3 varices. 

Liver biopsies performed in patients with chronic HBV infection are classified as chronic persistent hepatitis, chronic active hepatitis, and cirrhosis. Histologic results do not correlate with symptoms and often patients are asymptomatic until the development of cirrhosis. " Cirrhosis is manifested by interlacing strands of fibrous tissue with nodules of regenerating cells resulting in a characteristic small and knobby-appearing liver. This form of injury is irreversible and can be exacerbated by heavy alcohol consumption and concomitant infection with HCV or HIV. Hepatic decompensation as a result of cirrhosis includes ascites, jaundice, variceal bleeding, and hepatic encephalopathy. The 5-year risk of decompensation after the development of cirrhosis is estimated to be 20%. ... 

Octreotide for IV injection is used in the treatment of acute bleeding from esophageal varices. Variceal bleeding occurs in about half the patients with cirrhosis of the liver and is responsible for about one-third of deaths in these patients. Octreotide is a potent vasoconstrictor that reduces portal and collateral blood flow by constricting visceral vessels, which leads to reduced portal blood pressure and decreases the bleeding. 

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