Pathogenesis of spontaneous bacterial peritonitis

INTRODUCTION — Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection without an evident intra-abdominal surgically treatable source [1]. The presence of infection is documented by a positive ascitic fluid bacterial culture and an elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN) count (≥250 cells/mm³).

The absolute PMN count is calculated by multiplying the total white blood cell count (or total "nucleated cell" count) by the percentage of PMNs in the differential. The cell count and differential are performed manually without formal quality control. The accuracy of these tests is totally dependent upon the skill and interest of the medical technologist. (See "Spontaneous bacterial peritonitis in adults: Diagnosis".)

This topic will review our understanding of the pathogenesis of SBP. The clinical manifestations, diagnosis, and treatment of SBP are discussed separately. (See "Spontaneous bacterial peritonitis in adults: Clinical manifestations" and "Spontaneous bacterial peritonitis in adults: Diagnosis" and "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis".)

PATHOGENESIS — When the phrase spontaneous bacterial peritonitis was coined in 1964, the descriptor "spontaneous" was used because the pathogenesis of the infection was not apparent [1]. Over the past decades, this void of information has been at least partially filled [2]  (figure 1).

Microbiology and bacterial entry into ascitic fluid — One of the early steps in the development of SBP is a disturbance in gut flora with overgrowth and extraintestinal dissemination of a specific organism, most commonly Escherichia coli (table 1) [3,4]. Cirrhosis predisposes to the development of bacterial overgrowth, possibly because of altered small intestinal motility [5], and the presence of hypochlorhydria due to use of proton pump inhibitors [6]. In addition, patients with cirrhosis may have increased intestinal permeability [7].

However, the role of bacterial overgrowth in the pathogenesis of SBP remains unsettled. In one study, small bowel motility and bacterial overgrowth were compared in 20 patients with cirrhosis and a history of SBP and 20 patients with cirrhosis without a history of SBP [8]. The prevalence of bacterial overgrowth was higher in the patients with a history of SBP (70 versus 20 percent); these patients also exhibited more severe small intestinal motility disturbances. In contrast, in another study, the presence of bacterial overgrowth was not associated with the development of SBP [9]. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis".)

Whether or not they are present in increased numbers, bacteria within the gut lumen can traverse the intestinal wall, and colonize mesenteric lymph nodes. This phenomenon is called translocation and has been documented to occur in animal models of cirrhosis and SBP [3,4]. Bacterascites can occur if the lymphatics carrying the contaminated lymph rupture because of the high flow and high pressure associated with portal hypertension [10]. Alternatively, the organism can move from the mesenteric lymphatics to the systemic circulation and then percolate through the liver and weep across Glisson's capsule to enter the ascitic fluid.

Several studies have demonstrated that bacterial translocation is also increased in patients with advanced cirrhosis [11,12]. In an illustrative study, mesenteric lymph nodes were obtained from 101 patients with cirrhosis and from 35 non-cirrhotic controls [12]. Enteric organisms were grown from culture in only 8.6 percent of controls compared to 3.4, 8.1, and 30.8 percent of patients with Child class A, B, and C cirrhosis, respectively. Selective intestinal decontamination reduced the rate of positive cultures to that of non-cirrhotic patients.

Other studies have shown molecular evidence of bacterial translocation and suggested that it occurs prior to the development of clinical SBP [13,14]. Patients with cirrhosis and ascites can have bacterial DNA in their serum and ascitic fluid even when viable organisms cannot be cultured [15]. Low levels of translocation of intact bacteria or pieces of bacteria may lead to activation of tumor necrosis factor (TNF), which may explain the higher levels of TNF that have been observed in patients who ultimately develop SBP compared with controls [16]. The presence of bacterial DNA in serum and ascitic fluid is a risk factor for death in patients with cirrhosis [17]. Proton pump inhibitors increased bacterial translocation in an animal model of SBP and also increase the risk of SBP in humans [18,19]. Proton pump inhibitors have also been shown in humans to decrease phagocyte oxidative burst; this could further handicap defenses against resident bacteria [20].

A novel mechanism that appears to enhance translocation is reduction in thickness of colonic mucus followed by bacteria-to-epithelial cell contact [21]. Bacteria isolated from patients with SBP have been shown to disrupt cell junctions [21]. Blocking this disruption could provide a nonantibiotic method of preventing SBP.  

Bacteria that eventually cause SBP can also originate in sites other than the gut via bacteremic seeding. These include urinary tract infections [22], pneumococcal sepsis [10], cellulitis, pharyngitis, and dental infections. These infections are labeled "spontaneous" because they are not amenable to surgical therapy. Surgically treatable infections, eg, perforated duodenal ulcer, that lead to ascitic fluid infection are called secondary bacterial peritonitis. (See "Spontaneous bacterial peritonitis in adults: Diagnosis".) The pathogenesis of this form of peritonitis is quite different than that of SBP; millions of bacteria flood into the peritoneum through the rent in the gut wall.

Host defenses — Once the organism enters ascitic fluid, a battle ensues between the virulence of the bacteria and the host's resistance to infection. Microbes that cause SBP are usually serum-resistant, ie, they cannot be killed by serum alone but also require functional phagocytes [23]. Foreign matter is first "opsonized" with complement and/or globulin so that it is more identifiable by and digestible to phagocytes [23].

The resident macrophages represent the first line of defense of the peritoneal cavity [24,25]. If these phagocytes fail to eradicate the colonizing microbes, complement is activated and cytokines are released. PMNs enter the peritoneum to seek and destroy the invading organisms. If, however, complement levels are inadequate or the PMNs are dysfunctional, then colonization may not be contained and a potentially fatal infection may ensue.

Cirrhosis is actually one of the most common forms of acquired immune deficiency, creating an environment that facilitates the persistence of peritoneal infection [26].

●Serum complement deficiency is quite common in patients with liver disease that is advanced enough to produce ascites [27]. Furthermore, ascitic fluid is frequently a fivefold or even 10-fold dilution of serum in patients with cirrhosis; thus, ascitic fluid complement concentrations may drop to levels similar to those of the serum of patients with congenital complement deficiency [27,28].

●The function of both motile (eg, PMNs) and stationary phagocytes (eg, Kupffer cells) is reduced in patients with advanced liver disease [29-31].

RISK FACTORS FOR SBP — The vast majority of patients with SBP have advanced cirrhosis [1]. Other risk factors for SBP include [27,32-35]:

●Ascitic fluid total protein concentration less than 1 g/dL (<10 g/L).

●Prior episode of SBP.

●Serum total bilirubin concentration above 2.5 mg/dL.

●Variceal hemorrhage.

●Possibly malnutrition [11].

●Use of proton pump inhibitors [18,36-38].

●Use of nonselective beta blockers [38].

In a database study including over 350,000 patients with cirrhosis, use of proton pump inhibitors was associated with higher risk of SBP compared with no proton pump inhibitor use (odds ratio [OR] 2.31, 95% CI 2.21-2.42) [38]. Similarly, use of nonselective beta blockers was associated with higher risk of SBP (OR 1.26, 95% CI 1.21-1.31). These findings support evaluating the indications for and risk of using such medications in patients with cirrhosis, and these issues are discussed separately. (See "Overview of medication adjustments for adult patients with cirrhosis" and "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

The combination of certain clinical and laboratory features is also associated with an increased risk of SBP [39,40]:

●An ascitic fluid total protein <1.5 g/dL (<15 g/L) with

●Child-Pugh score ≥9 points with serum bilirubin ≥3 mg/dL or with

●Plasma creatinine ≥1.2 mg/dL, blood urea nitrogen ≥25 mg/dL or plasma sodium ≤130 mEq/L

Patients who meet the above combination criteria should be considered candidates for antibiotic prophylaxis. (See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis".)

Malignancy-related ascites and cardiac ascites can become infected, but this is rare enough to be the subject of case reports [41,42]. When peritoneal carcinomatosis is associated with SBP, the organism is unusual and quite virulent, eg, Salmonella [43]. Nephrotic ascites can also become spontaneously infected [44].

Genetic variation in TNFA (TNFA c.-238A allele) has been associated with a decreased risk of serious bacterial infections in patients awaiting liver transplantation (hazard ratio 0.42, 95% CI 0.20-0.90) [45].

SUMMARY AND RECOMMENDATIONS

●Background – Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection without an evident intra-abdominal surgically treatable source. (See 'Introduction' above.)

When the phrase spontaneous bacterial peritonitis was coined in 1964, the descriptor "spontaneous" was used because the pathogenesis of the infection was not apparent. Over the past decades, this void of information has been at least partially filled (figure 1). (See 'Pathogenesis' above.)

●Microbiology – One of the early steps in the development of SBP is a disturbance in gut flora with overgrowth and extraintestinal dissemination of a specific organism, most commonly Escherichia coli (table 1). Cirrhosis predisposes to the development of bacterial overgrowth, possibly because of altered small intestinal motility, and the presence of hypochlorhydria due to use of proton pump inhibitors. In addition, patients with cirrhosis may have increased intestinal permeability. (See 'Microbiology and bacterial entry into ascitic fluid' above.)

●Host defenses – Cirrhosis represents a form of acquired immune deficiency, creating an environment that facilitates the persistence of peritoneal infection. Mechanisms resulting in altered host defenses in patients with cirrhosis include complement deficiency and reduced phagocytosis. (See 'Host defenses' above.)

●Risk factors – The vast majority of patients with SBP have advanced cirrhosis, but additional risk factors have been identified (see 'Risk factors for SBP' above):

•Ascitic fluid total protein concentration less than 1 g/dL (<10 g/L)

•Prior episode of SBP

•Serum total bilirubin concentration above 2.5 mg/dL

•Variceal hemorrhage

•Possibly malnutrition

•Use of proton pump inhibitors

•Use of nonselective beta blockers

●Management – Treatment and prophylaxis of SBP are discussed separately. (See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis".)