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]

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.

Pathophysiology

Pathogenesis of spontaneous bacterial peritonitis

Patients with Decompensated Cirrhosis leading to Portal Hypertension                   Hypo-motility and local pro-inflammatory phenomenon                   'Bacterial overgrowth'Increased intestinal permeability and Decreased local and systemic immune system                   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 ( BACTERASCITES ) • 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 ❑ 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 momentum • 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 • Intraperitoneal 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 + hypocapnia (respiratory alkalosis) followed by hypercapnia (respiratory acidosis) • Pulmonary edema results because of increased pulmonary capillary leakage as a consequence of hypoalbuminemia 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 csystemic vascular resistance → ↓ Effective arterial blood volume → stimulation o systemic vasoconstrictors (RAAS, Sympathetic Nervous System, Arginine vasopressin) → renal vasoconstriction • Advanced cirrhosis → ↓ production o local vasodilators and ↑ production o 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

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. Following steps may explain the underlying process in a comprehensive way:

• Spontaneous bacterial peritonitis is thought to result from a combination of factors related to cirrhosis and ascites such as:

Natural barriers

Routes of infection

• Hematogenous
• Lymphogenous
• Transmural migration through an intact bowel wall from the intestinal lumen
• Bacterial translocation: Enteric bacteria from the bowel lumen → Mesenteric lymph nodes → Systemic circulation (via the thoracic duct)
• Enteric bacteria → Portal vein → liver / portosystemic shunts ( in portal hypertension) → Systemic circulation.
• Conn and Fessel postulated that organisms removed from the systemic circulation by the liver contaminate hepatic lymph and pass through the permeable lymphatic walls into the ascitic fluid
• Enteric bacteria may also gain access to the peritoneal cavity by traversing directly the intact intestinal wall.

Hypo-motility

• Distal propulsion of luminal contents by intestinal peristalsis is a critical factor in the inhibition of bacterial colonization and replication in the proximal gastro-intestinal tract, which leads to bacterial overgrowth.

Intestinal bacterial overgrowth

• Probably due to disturbances in the intestinal peristalsis, gastric acid and mucosal immunity in cirrhotic patients.
• Studies have shown that the incidenceof bacterial overgrowth in the small intestine was significantly higher in liver cirrhotic patients with history of SBP than in those without SBP (70% vs. 20%).
• Once bacteria reach a critical concentration in the gut lumen, they “spill over”, and escape the gut, “translocating” to mesenteric lymph nodes.Then they enter lymph, blood, and eventually ascitic fluid.

Cytokine response

• • Prolonged bacteremia secondary to compromised host defenses
  • Intrahepatic shunting of colonized blood and
  • Defective bactericidal activity within the ascitic fluid. 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.