ANNALS OF GASTROENTEROLOGY 2001, 14(3):205-211 Current view Bacterial infection in the pathogenesis of variceal bleeding. Is there any role for antibiotic prophylaxis in the cirrhotic patient? J. Goulis SUMMARY The incidence of bacterial infections in cirrhotic pa- tients is high, particularly in patients admitted to hospi- Bacterial infections are frequent in cirrhotic patients par- tal. According to several studies 30% - 50% of cirrhotic ticularly in those admitted to hospital. Several risk factors patients are diagnosed with bacterial infections at ad- have been implicated to explain the propensity of cirrhotic mission and between 15% and 35% developed this type patients to develop bacterial infections, such as iatrogenic of complication during hospitalization.1,2 These data are factors that may disrupt the natural defense barriers, the in sharp contrast with the hospital-acquired infection rate occurrence of bacterial translocation from the intestinal in a general hospital patient population, which ranges lumen to extraintestinal sites, the depression of hepatic between 5% and 7%. The most frequent types of infec- reticuloendothelial system function and the decreased op- tion in cirrhotic patients are urinary tract infections (12%- sonic activity of serum and ascitic fluid seen in cirrhosis. 29%), spontaneous bacterial peritonitis (10%-30%), res- Particularly in cirrhotic patients with gastrointestinal he- piratory tract infections (6%-15%), and bacteremia (5%- morrhage, bacterial infections have an incidence of 35% to 10%).2 66% and are closely related to the recurrence of hemorrhage Two important clinical characteristics of bacterial and survival. Although gastrointestinal hemorrhage can infections in cirrhotic patients need to be underlined: predispose cirrhotic patients to bacteremia there is recent data that support the hypothesis that bacterial infection 1) The atypical clinical presentation of bacterial infec- may initiate gastrointestinal hemorrhage, particularly tions in these patients, in whom the first sign of in- variceal bleeding in cirrhosis. The strong association be- fection may be an abrupt deterioration of liver func- tween bacterial infections and gastrointestinal hemorrhage tion or the development of unexplained renal dys- in cirrhosis has led to the use of antibiotic prophylaxis in function. the setting of acute variceal bleeding. A recent meta-analy- 2) The absence of fever, even in cirrhotic patients with sis demonstrated that antibiotic prophylaxis in cirrhotic severe infections.3 patients with gastrointestinal bleeding decreases the rate of bacterial infections and increases short-term survival. Spontaneous bacterial peritonitis (SBP) is the most char- PATHOPHYSIOLOGY OF BACTERIAL acteristic infectious complication of cirrhotic patients and INFECTIONS IN CIRRHOSIS it is diagnosed according to certain diagnostic criteria. Risk factors Third-generation cephalosporins are the first-choice anti- biotic treatment in SBP, although selected patients with Iatrogenic factors uncomplicated SBP may be treated with oral quinolones. Cirrhotic patients are frequently subjected to several Selective intestinal decontamination with norfloxacin is safe invasive diagnostic and therapeutic procedures that may and effective in the primary and secondary prophylaxis of alter the natural defense barriers and therefore increase SBP. the risk of bacterial infections. In addition to procedures well known to predispose to infection, such as intrave- Fourth Department of Medicine, Aristotle University of Thessalo- nous or urethral catheters, endoscopic sclerotherapy for niki, Hippokration General Hospital, Thessaloniki, Greece bleeding oesophageal varices, the placement of transjug- 206 J. GOULIS ular intrahepatic porosystemic shunts (TIPS) or perito- tients.11,12 neovenous shunts (LeVeen shunts) may be associated The pathogenesis of the depression of phagocytic with an increased incidence of bacteremia.2 Endoscopic activity of the reticuloendothelial system in cirrhosis has sclerotherapy and TIPS placement can cause transient not been clarified. Most studies suggest that this impair- bacteremia, but usually not clinically significant bacteri- ment could be attributed to the presence of anatomic or al infections. However in several series the incidence of functional intrahepatic portosystemic shunts, which cause bacterial infections after the insertion of a LeVeen shunt the escape of the blood from the phagocytic action of for the treatment of ascites was approximately 20%.4,5 the reticuloendothelial Kupffer cells.13 Several other Changes in the intestinal flora and the intestinal mechanisms have also been proposed, including the re- barrier duction of the phagocytic activity of monocytes (which Bacterial infections in cirrhotic patients are caused, are considered as the Kupffer cells precursors) and an predominantly, by enteric organisms. Whereas aerobic impaired function of macrophage Fc gamma receptors, gram-negative bacilli are present in low numbers in the which are important in the host defense, since they par- 14 small bowel of normal subjects, these microorganisms ticipate in the clearance of IgG-coated microorganisms. have been reported significantly increased in the jejunal flora of many cirrhotic patients.6 Experimental studies Decreased opsonic activity of serum and ascitic have shown that, in cirrhotic rats with ascites, there is an fluid increased passage of bacteria normally colonizing the Serum opsonic activity is markedly reduced in cirrhot- gastrointestinal tract from the intestinal lumen to extrain- ic patients, mainly due to the decreased levels of com- testinal sites, including mesenteric lymph nodes and the plement and fibronectin. These substances are necessary systemic circulation. This process has been called bacte- for the opsonization and phagocytosis of microorganisms. rial translocation.7-9 The change in the intestinal flora Moreover, the deficiency of serum complement and fi- caused by the abnormal small-bowel colonization in cir- bronectin levels can be aggravated in the setting of mas- rhosis may increase the chance of aerobic gram-nega- sive variceal hemorrhage, frequently seen in cirrhotic tive bacteria invading the systemic circulation and cause patients, when loss of opsonins in the shed blood is re- infections of enteric origin in cirrhotic patients. placed by saline.15 The causes of bacterial translocation are a disruption Opsonic activity of ascitic fluid in cirrhosis is directly of the intestinal permeability barrier, bacterial over- correlated with the concentration of defensive substanc- growth and/or a decrease in host immune defenses. A es, such as immunoglobulins, complement, and fibronec- recent study has shown that the marked oedema and in- tin, and with the concentration of total protein in ascites.16 flammation of the submucosa of cirrhotic rats with as- Recent studies have demonstrated an inverse and statis- cites may predispose these animals to a rupture in the tically significant correlation between ascitic fluid opsonic intestinal permeability barrier, and thus favor bacterial activity, as represented by total protein concentration of translocation.9 Changed permeability of the intestinal ascitic fluid, and the risk of spontaneous bacterial peri- mucosa has been seen in hemorrhagic shock due to tonitis in cirrhotic patients with ascites. According to variceal bleeding which is a frequent event in cirrhotic these studies, cirrhotic patients with ascites and protein patients.10 concentration in ascitic fluid below 1 gr/dL develop sta- tistically significantly more often spontaneous bacterial Depression of activity of the reticuloendothelial peritonitis during hospitalization or one-year follow-up, system than patients with ascitic protein concentration over 1 The reticuloendothelial system of the liver, comprised gr/dL.17 Moreover, protein concentration in ascitic fluid, mainly of Kupffer cells and endothelial sinusoidal cells, together with serum bilirubin concentration, have been constitutes approximately 90% of the whole reticuloen- identified as the only prognostic factors for the first epi- dothelial system throughout the body. Several studies sode of spontaneous bacterial peritonitis.18 The very low have shown that many cirrhotic patients have marked concentrations of total protein in ascitic fluid depend not depression of hepatic reticuloendothelial system func- only on the severity of liver failure but also on the vol- tion. In addition it has been shown that the risk of ac- ume of water diluting these ascitic fluid solutes. This last quiring bacteremia and spontaneous bacterial peritoni- notion is supported by the finding that diuretic-induced tis in cirrhosis is directly related to the degree of dys- reduction of water in ascitic fluid increases the total pro- function of the reticuloendothelial system in these pa- tein concentration and the antibacterial capacity of as- Bacterial infection in the pathogenesis of variceal bleeding. Is there any role for antibiotic prophylaxis in the cirrhotic patient? 207 cites, and by the common observation in clinical prac- variceal bleeding are subjected to several invasive thera- tice that spontaneous bacterial peritonitis occurs predom- peutic procedures such as placement of intravenous and inantly in cirrhotics with large-volume ascites.2 urethral catheters, endoscopic sclerotherapy and the placement of TIPS, which could break the natural de- Neutrophil leucocyte dysfunction fence barriers. The occurrence of hematemesis,