Spontaneous bacterial peritonitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2] Shivani Chaparala M.B.B.S [3]

Overview

SBP is a result of culmination of the inability of the gut to contain bacteria and failure of the immune system to eradicate the organisms once they have escaped..Spontaneous bacterial peritonitis is thought to result from a combination of factors related to cirrhosis and ascites such as: Altered microbial flora, Hypo-motility of the intestine, Intestinal bacterial overgrowth, Increased Intestinal mucosal permeability, Bacterial translocation to Lymph nodes. Presence of ascites appears to be an important risk factor for the development of bacterial translocation. In healthy individuals, bacteria that colonize lymph nodes are killed by local immune defenses. However, in the setting of cirrhosis, an acquired state of Immunodeficiency there is: Malfunctioning of the reticulo-endothelial and neutrophilic system, Reduced Cellular and Humoral bactericidal function which favor the spread of bacteria to the blood stream. Alterations in the systemic immune response: Bacteremia in a healthy host results in rapid coating by IgG and/or Complement components and then engulfing and killing by circulating neutrophils. But in cirrhosis, as stated above several abnormalities have been described including : Decreased serum levels of complement components (C3, C4), Impaired chemotaxis, Poor function and phagocytic activity of neutrophils, Decreased function of Fc-gamma-receptors in macrophages. Reticuloendothelial system phagocytic activity: The stationary macrophages, such as the Kupffer cells of the liver, assist the circulating neutrophils in the extraction and killing of particulate matter (e.g., bacteria) from the systemic circulation. In Cirrhosis, there is Hepatic Reticuloendothelial system (RES) dysfunction, Kupffer cells are decreased in number with impaired function along with the malfunctioning of the neutrophilic system. Patients with the most severe dysfunction of RES have the highest risk of bacteremia and concomitant shortened survival, due to sepsis. The presence of intrahepatic and extra hepatic porto-systemic shunts as a consequence of portal hypertension, prevent circulating bacteria from encountering Kupffer cells. The final consequence of these abnormalities is the prolongation of bacteremia and eventual seeding of other sites, including AF. AF defense mechanisms: Decreased local AF opsonic activity: The arrival of bacteria to the AF does not guarantee that infection will develop. Cirrhotic AF is capable of humoral self-defense, mainly on the basis of effectiveness of the complement system, Patients with adequate activity of this vital bactericidal system usually do not develop AF bacterial infections, Patients with AF C3 < 1g/dl and a protein level < 1g/dl have an increased predisposition to SBP, the complement levels may be deficient because of increased consumption of these components or because of impaired synthesis, if the complement levels are adequate to effectively kill the bacteria, infection will not develop, if complement levels are consumed and depleted, killing may be ineffective, frequent colonization of AF by bacteria decreases its antimicrobial ability and can eventually lead to the development of infection Bacteremia/ Endotoxemia leads to activation of cytokine cascade and some of these effector molecules and cytokines that help kill the bacteria have undesired side effects. NO and TNF are important mediators of the further vasodilation and renal failure that too often accompany SBP. Iatrogenic and treatment related factors like PPI, and increased use of invasive procedures and catheters in patients with Cirrhosis and ascites. Other compelling factors like malnutrition and alcohol drinking also predispose to SBP.

Pathophysiology

Patients with decompensated cirrhosis leading to portal Hypertension                   Intestinal hypo-motility and local pro-inflammatory phenomenon                   Bacterial overgrowth: Increased intestinal permeability and decreased local and systemic immune system in cirrhosis and its relation to bacterial infections and prognosis.                   Routes of entry of pathogens into the ascitic fluid Escape of enteric bacteria to systemic circulation through: ❑ Bacterial translocation • Luminal bacteria within colonize mesenteric lymph nodes. • Organisms from the mesenteric lymph nodes → Systemic circulation through thoracic duct lymph → percolates through the liver and weep across Glisson's capsule → Ascitic fluid. • Transient bacteremia → Prolonged bacteremia ( due to ↓ Reticulo endothelial system activity ) → Ascites Colonization ( due to ↓ ascitic fluid bactericidal activity ) → Spontaneous bacterial peritonitis ) ❑ Portal Vein • Porto-systemic shunt • ↓RES function in the liver ❑ Lymphatic rupture • Contaminated lymph carried by lymphatics • Ruptured Lymphatics due to high flow and high pressure associated with portal hypertension ( BACTERASCITES ) ❑ Other source of organisms • IV catheters, skin, urinary, and respiratory tract                   Endotoxemia and Cytokine response ❑ Endotoxemia → release of pro-inflammatory cytokines produced by macrophages and other host cells in response to bacteria in the serum and peritoneal exudate • Tumor necrosis factor-α (TNF-α) • Interleukin (IL)-1,6 • Interferon-γ (IFN-γ) • Soluble adhesion molecules ❑ Systemic and Abdominal manifestations of peritonitis mediated by cytokines • The effector molecules (Nitric oxide) and cytokines,Tumour necrosis factor (TNF) that help kill the bacteria have undesired side effects as they cause vasodilation and renal failure that accompany SBP. • Studies have shown that the presence of whole bacteria or DNA, in serum and ascitic fluid leads to stimulation of immune defences, effector molecules, and cytokines which in turn impact on hemodynamics, renal function and survival.                   Host response ❑ Local response Outpouring of fluid into the peritoneal cavity at sites of irritation with: • High protein content (>3 g/dL) • Many cells, primarily polymorphonuclear leukocytes, that phagocytose and kill organisms • Formation of Fibrinous exudate on the inflamed peritoneal surfaces → Adhesion formation between adjacent bowel, mesentery, and omentum • Localization of the inflammatory process is aided further by inhibition of motility in the involved intestinal loops • The extent and rate of intraperitoneal spread of contamination depend on the volume and nature of the exudate and on the effectiveness of the localizing processes • If peritoneal defenses aided by the appropriate supportive measures control the inflammatory process, the disease may resolve spontaneously (Sterile ascites) → Consumption of humoral bactericidal factors due to frequent colonization → Increased susceptibility to SBP • If the ascitic fluid bactericidal activity is poor-moderate → Culture negative neutrocytic ascites (CNNA) or SBP → delay / inappropriate treatment → death due to sepsis and multi organ failure. • Second possible outcome is a confined abscess • A third possible outcome results when the peritoneal and systemic defense mechanisms are unable to localize the inflammation, which progresses to spreading diffuse peritonitis due to increased virulence of bacteria, greater extent and duration of contamination, and impaired host defenses. ❑ Systemic response Gastrointestinal • Paralysis of the bowel due to local inflammation • Progressive accumulation of fluid and electrolytes in the lumen of the adynamic bowel → distention of the bowel → inhibition of the capillary inflow and secretions • GI bleeding because of excessive inflammation and tissue damage → ↑ vasodilatation and ↓organ perfusion Cardiovascular • Shift of fluid into the peritoneal cavity and bowel lumen → ↓ Effective circulating blood volume → ↑ Hematocrit and • ↑Fluid and electrolyte loss by coexistent fever, vomiting, diarrhea → decreased venous return to the right side of the heart → decrease in cardiac output → hypotension → activation of the sympathetic nervous system and manifestations such as sweating, tachycardia, and cutaneous vasoconstriction (i.e., cold, moist skin and mottled, cyanotic extremities). • If the blood volume replaced is sufficient enough as so to increase the cardiac output 2-3 times normal ( to satisfy the increased metabolic needs of the body in the presence of infection) a halt in the progression of the disease is seen. • Failure to sustain increased cardiac output results in progressive lactic acidosis, oliguria, hypotension, and ultimately death if the infection cannot be controlled. Respiratory • Intra-peritoneal inflammation → high and fixed diaphragm → pain on respiration → basilar atelectasis with intrapulmonary shunting of blood • Decompensation of respiratory function due to delay in the intervention → hypoxemia + hypo-capnia (respiratory alkalosis) followed by hypercapnia (respiratory acidosis) • Pulmonary edema results because of increased pulmonary capillary leakage as a consequence of hypo-albuminemia or direct effects of bacterial toxins (adult respiratory distress syndrome) → progressive hypoxemia with decreasing pulmonary compliance which needs a ventilator assistance with increasingly higher concentrations of inspired oxygen and positive end-expiratory pressure. Renal • SBP → Splanchnic arterial vasodilation and systemic vascular resistance → ↓ Effective arterial blood volume → stimulation of systemic vasoconstrictors (RAAS, Sympathetic Nervous System, Arginine vasopressin) → renal vasoconstriction • Advanced cirrhosis → ↓ production of local vasodilators and ↑ production of local vasoconstrictors → Hepatorenal syndrome and death. • ↓ Organ perfusion → Ischemic and Toxic Acute Tubular Necrosis → Acute Renal Failure → Death in (30-40%) of patients. Metabolic • Infection → ↓body stores of Glycogen → catabolism of protein (muscle) and →extreme wasting and rapid weight loss of severely infected patients • Infection → ↓Body heat production → exhaustion and death Central nervous system • Hepatic Encephalopathy may occur due to inflammation, Oxidative stress and Intestinal ammonia production on crossing the blood-brain barrier → altered mentation. Hematological • Sepsis → DIC

Diagramatic representation of pathological bacterial translocation and the associated host response

Mechanism of pathological bacterial translocation

Breaking these immune barriers can progress physiological BT into pathological BT.

Bacterial Translocation	Adapted from Journal of hepatology:Pathological bacterial translocation in liver cirrhosis.
	I. Immune response by gut associated lymphoid tissue	A. Innate immunity	Innate immunity is the first line of defense mechanism against invading pathogen that detects common bacterial motifs such as microbial-associated molecular patterns (MAMPs) through germline-coded pattern-recognition receptors (PRR) on intestinal cells. Mechanism of breaking of innate immunity Dendritic cells below the epithelial layer allows pathogen via dendritic processes with out affecting tight junction function. Disruption of epithelial barrier by antigenic properties of the pathogen with the underlying epithelial layer and compromises its epithelial integrity. Access provided by M- cells overlying payers patches with in the villous epithelium through antigen presenting cells.
		B. Adaptive immunity	Bacterial translocation through epithelial cells ⬇ Release of chemokines form epithelial cells ⬇ Recruitment of dendritic cells towards mucosa ⬇ Dendritic cells induces adaptive immunity through mucosal B and T lymphocytes ⬇ a. Bacterial antigen present to Matured T- lymphocytes, followed by activation B-lymphocytes through T- helper cells b. Antigen presenting cells present microbial antigen to matured B- lymphocytes, eventually B-cell releases Ig-A mucosal immunoglobulins against pathogen and it's product Mechanism of breaking adaptive immunity: Due to the underlying immunocompromised states such as cirrhosis, there is a depletion of both T and B cells and hypogamaglobilinemia, results in weak development of adaptive immunity with insufficient bacterial killing that leads to lethal dissemination of commensal bacteria.
	II. Mesenteric lymph nodes (MLN)		In a healthy gut, dendritic cells transport pathological bacteria to mesenteric lymph nodes which induces local immune response and are killed without inducing systemic immunity. In immunocompromised state, lack of local immune response by MLN is reduced, eventually permits the translocation of intestinal bacteria systemically, which eventually may lead to sepsis and death. Mechanism involving in spreading bacteria beyond MLN: Deficient innate and adaptive immunity Impaired chemotactic, opsonic, phagocytic activity of macropharges Impaired RES activity
	III. Systemic immune response		Translocation beyond MLN through hematogenous or lymphatic path is specific and depends on the microbial-specific systemic immune response. Lymphatic and portalvenous route in parallel are disrupt in liver cirrhosis which results in dissemination of bacterial pathogen.

Contrary to earlier theories, transmucosal migration of bacteria from the gut to the ascitic fluid is no longer considered to play a major role in the etiology of SBP.

With respect to compromised host defenses, patients with severe acute or chronic liver disease are often deficient in complement and may also have malfunctioning of the neutrophilic and reticuloendothelial systems.

As for the significance of ascitic fluid proteins, it was demonstrated that cirrhotic patients with ascitic protein concentrations below 1 g/dL were 10 times more likely to develop SBP than individuals with higher concentrations. It is thought that the antibacterial, or opsonic, activity of ascitic fluid is closely correlated with the protein concentration. Additional studies have confirmed the validity of the ascitic fluid protein concentration as the best predictor of the first episode of SBP.