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| __NOTOC__ | | __NOTOC__ |
| {{Spontaneous bacterial peritonitis}} | | {{Spontaneous bacterial peritonitis}} |
| {{CMG}}; {{AE}} {{ADI}} {{SCh}} | | {{CMG}}; {{AE}} {{SCh}} {{AY}} |
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| ==Overview== | | ==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 into the blood stream.<ref name="pmid4018735">{{cite journal| author=Runyon BA, Morrissey RL, Hoefs JC, Wyle FA| title=Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis. | journal=Hepatology | year= 1985 | volume= 5 | issue= 4 | pages= 634-7 | pmid=4018735 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4018735 }} </ref><ref name="pmid15138202">{{cite journal| author=Runyon BA| title=Early events in spontaneous bacterial peritonitis. | journal=Gut | year= 2004 | volume= 53 | issue= 6 | pages= 782-4 | pmid=15138202 | doi= | pmc=1774068 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15138202 }} </ref><ref name="pmid15920324">{{cite journal| author=Sheer TA, Runyon BA| title=Spontaneous bacterial peritonitis. | journal=Dig Dis | year= 2005 | volume= 23 | issue= 1 | pages= 39-46 | pmid=15920324 | doi=10.1159/000084724 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15920324 }} </ref> Factors related to cirrhosis and ascites predispose to the development of SBP, they include : 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 cirrhosis and aquired state of immunodeficiency, the following changes in the immune defences can be present : malfunctioning of the [[Reticulo-endothelial system|reticulo-endothelial]] and neutrophilic system, reduced [[cellular]] and [[humoral]] bactericidal function which favor the spread of [[bacteria]] to the [[blood stream]]. Bacteremia in healthy individuals results in rapid coating by [[IgG]] and/or [[Complement]] components and removal of the bacteria by [[neutrophils]] in the circulation. In cirrhosis, decreased serum levels of [[complement]] components (C3, C4), impaired [[chemotaxis]], poor function and [[phagocytic]] activity of [[neutrophils]], decreased function of [[Fc receptor|Fc]]-gamma-receptors in [[macrophages]], hepatic [[Reticuloendothelial system]] (RES) dysfunction, with reduced [[Kupffer cells]], intrahepatic and extra porto systemic shunts prevent circulating bacteria from encountering the kupper cells and impaired neutrophilic function result in decreased immune response and clearance of the bacteria. The consequence of these abnormalities is prolongation of [[bacteremia]] and eventual seeding of other sites, including the ascitic fluid. The presence of bacteria in ascitic fluid does not consititute to peritonitis without signs and symptoms. Ascitic fluid due to cirrhosis can mount a [[humoral]] self-defense with the help of [[complement]] system. Patients with adequate activity of this vital [[bactericidal]] system do not develop ascitic fluid infections. Patients with ascitic fluid C3 less than1g/dl and a protein level less than 1g/dl have an increased predisposition to [[SBP]]. Low complement levels result in inadequate killing of the bacteria lead to the development of infection. Finally, [[Bacteremia]]/ Endotoxemia leads to activation of [[cytokine]] cascade and release effector molecules such as [[NO]] and [[TNF]] casuing [[vasodilation]] and reduced renal perfusion.
| | [[Bacterial overgrowth|Intestinal bacterial overgrowth]] in [[Cirrhosis|cirrhotic]] patients, defective intestinal barrier and defective [[Immune response|host immune response]] are the 3 determinant factors for [[Bacterial|bacterial translocation]] explaining SBP. |
| | | ==Pathogenesis== |
| == Pathophysiology == | | Three factors play a role in the pathogenesis of SBP: |
| {| align=center
| | * '''[[Bacterial overgrowth]] in [[Cirrhosis|cirrhotic patients]]:''' secondary to [[Motility|decreased intestinal motility]] and frequent use of [[Proton pump inhibitor|PPIs]] in this population of patients. |
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| {{familytree/start}}
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| {{familytree | boxstyle=background: #FFF0F5; color: #000000;| | | A01 | | A01=Patients with '''decompensated [[cirrhosis]] leading to '''[[portal Hypertension]]<ref name="pmid1505916">{{cite journal| author=Llach J, Rimola A, Navasa M, Ginès P, Salmerón JM, Ginès A et al.| title=Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration. | journal=Hepatology | year= 1992 | volume= 16 | issue= 3 | pages= 724-7 | pmid=1505916 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1505916 }} </ref><ref name="pmid11211904">{{cite journal| author=Cirera I, Bauer TM, Navasa M, Vila J, Grande L, Taurá P et al.| title=Bacterial translocation of enteric organisms in patients with cirrhosis. | journal=J Hepatol | year= 2001 | volume= 34 | issue= 1 | pages= 32-7 | pmid=11211904 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11211904 }} </ref>'''}}
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| {{familytree | | | |!| |}}
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| {{familytree | boxstyle=background: #FFF0F5; color: #000000;| | | B01 | | B01='''Intestinal hypo-motility''' and '''local pro-[[inflammatory]] phenomenon'''<ref name="pmid9794900">{{cite journal| author=Chang CS, Chen GH, Lien HC, Yeh HZ| title=Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. | journal=Hepatology | year= 1998 | volume= 28 | issue= 5 | pages= 1187-90 | pmid=9794900 | doi=10.1002/hep.510280504 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9794900 }} </ref>}}
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| {{familytree | | | |!| |}}
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| {{familytree | boxstyle=background: #FFF0F5; color: #000000;| | | C01 | | C01='''Bacterial overgrowth:'''<br>
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| Increased intestinal permeability''' and '''decreased local and systemic [[immune system]] in [[cirrhosis]] and its relation to bacterial infections and prognosis. <ref name="pmid9794900">{{cite journal| author=Chang CS, Chen GH, Lien HC, Yeh HZ| title=Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. | journal=Hepatology | year= 1998 | volume= 28 | issue= 5 | pages= 1187-90 | pmid=9794900 | doi=10.1002/hep.510280504 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9794900 }} </ref><ref name="pmid11693333">{{cite journal| author=Bauer TM, Steinbrückner B, Brinkmann FE, Ditzen AK, Schwacha H, Aponte JJ et al.| title=Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. | journal=Am J Gastroenterol | year= 2001 | volume= 96 | issue= 10 | pages= 2962-7 | pmid=11693333 | doi=10.1111/j.1572-0241.2001.04668.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11693333</ref><ref name="pmid6693068">{{cite journal| author=Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J| title=Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. | journal=Hepatology | year= 1984 | volume= 4 | issue= 1 | pages= 53-8 | pmid=6693068 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6693068 }} </ref>}}
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| {{familytree | | | |!| |}}
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| {{Familytree|boxstyle=background: #FFF0F5; color: #000000;width: 400px; text-align: left; font-size: 90%; padding: 0px;| | | D01 | |D01=<div style="padding: 15px;"><BIG>'''Routes of entry of pathogens into the ascitic fluid'''</BIG>
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| :Escape of enteric bacteria to systemic circulation through:<ref name="pmid15723320">{{cite journal| author=Wiest R, Garcia-Tsao G| title=Bacterial translocation (BT) in cirrhosis. | journal=Hepatology | year= 2005 | volume= 41 | issue= 3 | pages= 422-33 | pmid=15723320 | doi=10.1002/hep.20632 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15723320 }} </ref>
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| :❑ Bacterial translocation<ref name="pmid11211904">{{cite journal| author=Cirera I, Bauer TM, Navasa M, Vila J, Grande L, Taurá P et al.| title=Bacterial translocation of enteric organisms in patients with cirrhosis. | journal=J Hepatol | year= 2001 | volume= 34 | issue= 1 | pages= 32-7 | pmid=11211904 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11211904 }} </ref>
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| ::• Luminal bacteria within colonize mesenteric [[lymph nodes]].<ref name="pmid7890896">{{cite journal| author=Runyon BA, Squier S, Borzio M| title=Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis. | journal=J Hepatol | year= 1994 | volume= 21 | issue= 5 | pages= 792-6 | pmid=7890896 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7890896 }} </ref>
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| ::• Organisms from the mesenteric [[lymph nodes]] → Systemic circulation through thoracic duct lymph → percolates through the liver and weep across Glisson's capsule → Ascitic fluid.
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| ::• Transient [[bacteremia]] → Prolonged bacteremia ( due to ↓ Reticulo endothelial system activity ) → Ascites Colonization ( due to ↓ ascitic fluid bactericidal activity ) → Spontaneous bacterial [[peritonitis]] )
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| :❑ Portal Vein
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| ::• Porto-systemic shunt
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| ::• ↓RES function in the liver
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| :❑ Lymphatic rupture
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| ::• Contaminated lymph carried by lymphatics
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| ::• Ruptured Lymphatics due to high flow and high pressure associated with [[portal hypertension]] ( '''BACTERASCITES''' )<ref name="pmid8677940">{{cite journal| author=Ho H, Zuckerman MJ, Ho TK, Guerra LG, Verghese A, Casner PR| title=Prevalence of associated infections in community-acquired spontaneous bacterial peritonitis. | journal=Am J Gastroenterol | year= 1996 | volume= 91 | issue= 4 | pages= 735-42 | pmid=8677940 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8677940 }} </ref>
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| :❑ Other source of organisms
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| ::• IV catheters, skin, urinary, and respiratory tract</div>}}
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| {{familytree | | | |!| |}}
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| {{Familytree|boxstyle=background: #FFF0F5; color: #000000;width: 400px; text-align: left; font-size: 90%; padding: 0px;| | | E01 | |E01=<div style="padding: 15px;"><BIG>'''Endotoxemia''' and '''[[Cytokine]] response'''</BIG>
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| :❑ Endotoxemia → release of pro-inflammatory [[cytokines]] produced by [[macrophages]] and other host cells in response to bacteria in the serum and peritoneal exudate
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| ::• [[Tumor necrosis factor-α]] (TNF-α)
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| ::• [[Interleukin]] (IL)-1,6
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| ::• [[Interferon-γ]] (IFN-γ)
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| ::• [[Soluble adhesion molecules]]
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| :❑ Systemic and Abdominal manifestations of [[peritonitis]] mediated by '''[[cytokines]]'''<ref name="pmid11713936">{{cite journal| author=Such J, Hillebrand DJ, Guarner C, Berk L, Zapater P, Westengard J et al.| title=Tumor necrosis factor-alpha, interleukin-6, and nitric oxide in sterile ascitic fluid and serum from patients with cirrhosis who subsequently develop ascitic fluid infection. | journal=Dig Dis Sci | year= 2001 | volume= 46 | issue= 11 | pages= 2360-6 | pmid=11713936 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11713936 }} </ref><ref name="pmid15138202">{{cite journal| author=Runyon BA| title=Early events in spontaneous bacterial peritonitis. | journal=Gut | year= 2004 | volume= 53 | issue= 6 | pages= 782-4 | pmid=15138202 | doi= | pmc=1774068 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15138202 }} </ref>
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| ::• 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.<ref name="pmid3894229">{{cite journal| author=Dunn DL, Barke RA, Knight NB, Humphrey EW, Simmons RL| title=Role of resident macrophages, peripheral neutrophils, and translymphatic absorption in bacterial clearance from the peritoneal cavity. | journal=Infect Immun | year= 1985 | volume= 49 | issue= 2 | pages= 257-64 | pmid=3894229 | doi= | pmc=262007 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3894229 }} </ref><ref name="pmid11713936">{{cite journal| author=Such J, Hillebrand DJ, Guarner C, Berk L, Zapater P, Westengard J et al.| title=Tumor necrosis factor-alpha, interleukin-6, and nitric oxide in sterile ascitic fluid and serum from patients with cirrhosis who subsequently develop ascitic fluid infection. | journal=Dig Dis Sci | year= 2001 | volume= 46 | issue= 11 | pages= 2360-6 | pmid=11713936 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11713936 }} </ref><ref name="NavasaFollo1998">{{cite journal|last1=Navasa|first1=Miguel|last2=Follo|first2=Antonio|last3=Filella|first3=Xavier|last4=Jiménez|first4=Wladimiro|last5=Francitorra|first5=Anna|last6=Planas|first6=Ramón|last7=Rimola|first7=Antoni|last8=Arroyo|first8=Vicente|last9=Rodés|first9=Joan|title=Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: Relationship with the development of renal impairment and mortality|journal=Hepatology|volume=27|issue=5|year=1998|pages=1227–1232|issn=02709139|doi=10.1002/hep.510270507}}</ref>
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| ::• 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.<ref name="pmid3894229">{{cite journal| author=Dunn DL, Barke RA, Knight NB, Humphrey EW, Simmons RL| title=Role of resident macrophages, peripheral neutrophils, and translymphatic absorption in bacterial clearance from the peritoneal cavity. | journal=Infect Immun | year= 1985 | volume= 49 | issue= 2 | pages= 257-64 | pmid=3894229 | doi= | pmc=262007 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3894229 }} </ref></div>}}
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| {{familytree | | | |!| |}}
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| {{Familytree|boxstyle=background: #FFF0F5; color: #000000;width: 400px; text-align: left; font-size: 90%; padding: 0px;| | | F01 | |F01=<div style="padding: 15px;"><BIG>'''Host response'''</BIG>
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| :❑ Local response
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| Outpouring of fluid into the peritoneal cavity at sites of irritation with:
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| ::• High protein content (>3 g/dL)
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| ::• Many cells, primarily [[polymorphonuclear leukocytes]], that [[phagocytose]] and kill organisms
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| ::• Formation of Fibrinous [[exudate]] on the inflamed peritoneal surfaces → Adhesion formation between adjacent bowel, [[mesentery]], and [[omentum]]
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| ::• Localization of the inflammatory process is aided further by inhibition of motility in the involved intestinal loops
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| ::• 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
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| ::• If peritoneal defenses aided by the appropriate supportive measures control the [[inflammatory]] process, the disease may resolve spontaneously ('''Sterile ascites''')<ref name="pmid4018735">{{cite journal| author=Runyon BA, Morrissey RL, Hoefs JC, Wyle FA| title=Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis. | journal=Hepatology | year= 1985 | volume= 5 | issue= 4 | pages= 634-7 | pmid=4018735 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4018735 }} </ref><ref name="pmid4018735">{{cite journal| author=Runyon BA, Morrissey RL, Hoefs JC, Wyle FA| title=Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis. | journal=Hepatology | year= 1985 | volume= 5 | issue= 4 | pages= 634-7 | pmid=4018735 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4018735 }} </ref><ref name="pmid8677940">{{cite journal| author=Ho H, Zuckerman MJ, Ho TK, Guerra LG, Verghese A, Casner PR| title=Prevalence of associated infections in community-acquired spontaneous bacterial peritonitis. | journal=Am J Gastroenterol | year= 1996 | volume= 91 | issue= 4 | pages= 735-42 | pmid=8677940 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8677940 }} </ref> → Consumption of humoral bactericidal factors due to frequent colonization → Increased susceptibility to '''SBP'''<ref name="pmid3257456">{{cite journal| author=Titó L, Rimola A, Ginès P, Llach J, Arroyo V, Rodés J| title=Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. | journal=Hepatology | year= 1988 | volume= 8 | issue= 1 | pages= 27-31 | pmid=3257456 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3257456 }} </ref>
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| ::• 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.<ref name="pmid3371881">{{cite journal| author=Runyon BA| title=Patients with deficient ascitic fluid opsonic activity are predisposed to spontaneous bacterial peritonitis. | journal=Hepatology | year= 1988 | volume= 8 | issue= 3 | pages= 632-5 | pmid=3371881 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3371881 }} </ref><ref name="pmid6500513">{{cite journal | author = Runyon BA, Hoefs JC | title = Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis | journal = Hepatology | volume = 4 | issue = 6 | pages = 1209–11 | year = 1984 | pmid = 6500513 | doi = 10.1002/hep.1840040619| url = | issn = }}</ref>
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| ::• Second possible outcome is a confined '''[[abscess]]'''
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| ::• 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.
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| :❑ Systemic response
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| [[Gastrointestinal]]
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| ::• [[Paralysis]] of the bowel due to local [[inflammation]]
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| ::• Progressive accumulation of fluid and electrolytes in the lumen of the adynamic bowel → distention of the bowel → inhibition of the capillary inflow and secretions
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| ::• GI bleeding because of excessive [[inflammation]] and tissue damage → ↑ [[vasodilatation]] and ↓organ perfusion
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| [[Cardiovascular]]
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| ::• Shift of fluid into the peritoneal cavity and bowel lumen → ↓ Effective circulating blood volume → ↑ [[Hematocrit]] and
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| ::• ↑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).
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| ::• 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.
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| ::• Failure to sustain increased [[cardiac output]] results in progressive [[lactic acidosis]], [[oliguria]], [[hypotension]], and ultimately death if the [[infection]] cannot be controlled.
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| [[Respiratory]]
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| ::• [[Intra-peritoneal]] [[inflammation]] → high and fixed [[diaphragm]] → pain on respiration → basilar [[atelectasis]] with intrapulmonary shunting of blood
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| ::• Decompensation of [[respiratory]] function due to delay in the intervention → [[hypoxemia]] + [[hypo-capnia]] ([[respiratory alkalosis]]) followed by [[hypercapnia]] ([[respiratory acidosis]])
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| ::• [[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]].
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| [[Renal]]
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| ::• SBP → Splanchnic arterial [[vasodilation]] and systemic [[vascular resistance]] → ↓ Effective [[arterial]] blood volume → stimulation of systemic [[vasoconstrictors]] ([[RAAS]], [[Sympathetic Nervous System]], [[Arginine vasopressin]]) → renal [[vasoconstriction]]
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| ::• Advanced [[cirrhosis]] → ↓ production of local [[vasodilators]] and ↑ production of local [[vasoconstrictors]]<ref name="pmid11713936">{{cite journal| author=Such J, Hillebrand DJ, Guarner C, Berk L, Zapater P, Westengard J et al.| title=Tumor necrosis factor-alpha, interleukin-6, and nitric oxide in sterile ascitic fluid and serum from patients with cirrhosis who subsequently develop ascitic fluid infection. | journal=Dig Dis Sci | year= 2001 | volume= 46 | issue= 11 | pages= 2360-6 | pmid=11713936 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11713936 }} </ref> → Hepatorenal syndrome and death.<ref name="pmid15138202">{{cite journal| author=Runyon BA| title=Early events in spontaneous bacterial peritonitis. | journal=Gut | year= 2004 | volume= 53 | issue= 6 | pages= 782-4 | pmid=15138202 | doi= | pmc=1774068 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15138202 }} </ref>
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| ::• ↓ Organ perfusion → [[Ischemic]] and Toxic [[Acute Tubular Necrosis]] → [[Acute Renal Failure]] → Death in (30-40%) of patients.
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| [[Metabolic]]
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| ::• [[Infection]] → ↓body stores of [[Glycogen]] → catabolism of protein (muscle) and →extreme wasting and rapid weight loss of severely infected patients
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| ::• Infection → ↓Body heat production → exhaustion and death
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| [[Central nervous system]]
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| ::• [[Hepatic Encephalopathy]] may occur due to [[inflammation]], [[Oxidative stress]] and Intestinal [[ammonia]] production on crossing the [[blood-brain barrier]] → [[altered mentation]].
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| [[Hematological]]
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| ::• [[Sepsis]] → [[DIC]]</div>}}
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| {{family tree/end}}
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| |}
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| <br>
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| <br>
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| ==Diagramatic representation of pathological bacterial translocation and the associated host response==
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| === Bacterial Translocation ===
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| It is defined as the translocation of either bacteria or bacterial products such as [[lipopolysaccharides]] (LPS), bacterial DNA, peptidoglycans, muramyl-dipeptides from gut into mesenteric [[lymph nodes]].<ref name="pmid154474">Berg RD, Garlington AW (1979) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=154474 Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model.] ''Infect Immun'' 23 (2):403-11. PMID: [https://pubmed.gov/154474 154474]</ref>
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| '''Physiological:''' It is the normal bacterial translocation in healthy individuals due to lack of pro-inflammatory responses against commensal bacteria. Physiological translocation is crucial for the development of host immunity response.
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| '''Pathological:''' It is developed due to abnormal increase in physiological translocation in both rate and degree by breaking the normal immunological barriers.
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| '''Barriers that limit pathological transmission:'''
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| # '''Interstinal lumen and it's secretory components such as inner and outer mucus layer, antimicrobial peptides''': This is the primary barrier that limit direct contact between the intestinal bacteria and the epithelial cell surface
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| # '''Epithelial barrier with the gut-associated lymphatic tissue ([[Gut-associated lymphoid tissue|GALT]]) and [[autonomic nervous system]]''': This is a mechanical barrier with local immunological response elements (e.g., [[TNF]] and other pro-inflammatory [[cytokines]]) that rapidly detects and kill the pathogen that manage to penetrate.<ref name="pmid26301048">{{cite journal| author=Tsiaoussis GI, Assimakopoulos SF, Tsamandas AC, Triantos CK, Thomopoulos KC| title=Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications. | journal=World J Hepatol | year= 2015 | volume= 7 | issue= 17 | pages= 2058-68 | pmid=26301048 | doi=10.4254/wjh.v7.i17.2058 | pmc=4539399 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26301048 }} </ref>
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| # '''Systemic immune system:''' This includes hematogenous ([[Portal venous system|portal venous]]) and lymphatic (ductus thoracicus) route of delivery that acts as a third immune barrier to prevent or minimize the pathogen to disseminate systemically from local immune system such as lymph nodes.
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| | |
| === '''Mechanism of pathological bacterial translocation''' ===
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| Breaking these immune barriers can progress physiological bacterial translocation into pathological bacterial translocation.
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| {| border="1"
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| |-
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| ! rowspan="5" |Bacterial Translocation
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| ! colspan="3" |[[File:Pathophysiology of bacterial tranlocation.jpg|800px]]
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| <SMALL><SMALL><SMALL>Adapted from '''Journal of hepatology:Pathological bacterial translocation in liver cirrhosis'''.<ref name=AASLD2013>{{cite web
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| | title = Pathological bacterial translocation in liver cirrhosis
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| | url = http://www.journal-of-hepatology.eu/article/S0168-8278(13)00602-8/abstract
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| }}</ref></SMALL></SMALL></SMALL>
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| |-
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| ! rowspan="2" |'''I. Immune response by'''
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| '''gut associated lymphoid tissue'''
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| !'''A'''. '''Innate immunity'''
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| |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.<ref name="pmid11477402">Akira S, Takeda K, Kaisho T (2001) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11477402 Toll-like receptors: critical proteins linking innate and acquired immunity.] ''Nat Immunol'' 2 (8):675-80. [http://dx.doi.org/10.1038/90609 DOI:10.1038/90609] PMID: [https://pubmed.gov/11477402 11477402]</ref>
| |
| '''Mechanism of breaking of innate immunity'''
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| # [[Dendritic cells]] below the epithelial layer allows pathogen via dendritic processes with out affecting tight junction function.
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| # Disruption of epithelial barrier by antigenic properties of the pathogen with the underlying epithelial layer and compromises its epithelial integrity.
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| # Access provided by M- cells overlying payers patches with in the villous epithelium through antigen presenting cells.<ref name="pmid19907495">Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M et al. (2009) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19907495 Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response.] ''Nature'' 462 (7270):226-30. [http://dx.doi.org/10.1038/nature08529 DOI:10.1038/nature08529] PMID: [https://pubmed.gov/19907495 19907495]</ref>
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| |-
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| !B. Adaptive immunity
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| |align=center|Bacterial translocation through epithelial cells
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| ⬇
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|
| |
|
| Release of chemokines form epithelial cells.<ref name="pmid11167998">{{cite journal| author=Girón-González JA, Rodríguez-Ramos C, Elvira J, Galán F, Del Alamo CF, Díaz F et al.| title=Serial analysis of serum and ascitic fluid levels of soluble adhesion molecules and chemokines in patients with spontaneous bacterial peritonitis. | journal=Clin Exp Immunol | year= 2001 | volume= 123 | issue= 1 | pages= 56-61 | pmid=11167998 | doi= | pmc=1905962 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11167998 }} </ref>
| | * '''Defective intestinal barrier:''' secretory and physical barriers (which normally prevent bacteria from moving from the [[Lumen|intestinal lumen]]) are defective in [[Cirrhosis|cirrhotic patients]] <ref name="pmid16680233">{{cite journal |vauthors=Căruntu FA, Benea L |title=Spontaneous bacterial peritonitis: pathogenesis, diagnosis, treatment |journal=J Gastrointestin Liver Dis |volume=15 |issue=1 |pages=51–6 |year=2006 |pmid=16680233 |doi= |url=}}</ref> |
|
| |
|
| ⬇
| | * '''[[Immunity suppression|Decreased immunity]]:''' both local and systemic immunity are decreased in [[Cirrhosis|cirrhotic patients]]. |
| | ===A. Bacterial overgrowth:=== |
| | * [[Motility|Intestinal motility]] decreases with [[cirrhosis]]. Increased [[Sympathetic control|sympathetic drive]] and [[Oxidant|oxidant stress]] are believed to be the reasons for the reduced mobility. |
| | * Also, [[Cirrhosis|cirrhotic patients]] administer [[Proton pump inhibitor|PPIs]] more frequently than other patient populations. |
| | * The diminished [[Motility|intestinal motility]] makes the intestinal contents more stagnant and allows the [[Bacteria|bacterial contents]] to overgrow and thus predisposes to SBP.<ref name="pmid9794900">{{cite journal |vauthors=Chang CS, Chen GH, Lien HC, Yeh HZ |title=Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis |journal=Hepatology |volume=28 |issue=5 |pages=1187–90 |year=1998 |pmid=9794900 |doi=10.1002/hep.510280504 |url=}}</ref> |
|
| |
|
| Recruitment of dendritic cells towards mucosa
| | ===B. Increased bowel permeability:=== |
|
| |
|
| ⬇
| | Normally, the [[intestinal mucosa]] is impermeable to [[bacteria]] because of two lines of defense<ref name="pmid9794900">{{cite journal |vauthors=Chang CS, Chen GH, Lien HC, Yeh HZ |title=Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis |journal=Hepatology |volume=28 |issue=5 |pages=1187–90 |year=1998 |pmid=9794900 |doi=10.1002/hep.510280504 |url=}}</ref>;the secretory component and physical component. Both are affected by the development of cirrhosis. |
| | * The '''secretory defense''' mechanism is composed of [[Mucin|mucins]], [[immunoglobulins]] and [[bile salts]]. Bile salts are protective through preventing adherence and internalization of bacteria. [[Bile acid|Bile acids]] are decreased in cirrhosis partly due to reduced secretion from [[Cirrhosis|diseased liver]] and partly from [[Conjugation|increased conjugation]] by the flourishing [[intestinal flora]]. This gives bacteria easier access through the [[Mucosal|mucosa]] especially that [[E.coli]] (which is the most common strain isolated from SBP patients) has high ability to adhere to the [[intestinal mucosa]] and evade the host [[Immune system|immune defenses]]. |
| | * The physical component is the [[intestinal epithelium]] itself. [[Intestinal mucosa]] is more permeable as a result of increased [[Oxidant|oxidant stress]],[[Cytokines|NO proinflammatory cytokines]] & increased intercellular spaces as a result of [[vasodilation]], [[edema]] from [[portal hypertension]]. |
|
| |
|
| Dendritic cells induces adaptive immunity through mucosal B and T lymphocytes<ref name="pmid22611024">Muñoz L, José Borrero M, Ubeda M, Lario M, Díaz D, Francés R et al. (2012) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=22611024 Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis.] ''Hepatology'' 56 (5):1861-9. [http://dx.doi.org/10.1002/hep.25854 DOI:10.1002/hep.25854] PMID: [https://pubmed.gov/22611024 22611024]</ref>
| | ===C. Decreased local and systemic immune responses:=== |
| | * [[Kupffer cells]] (local [[macrophages]] of the liver) normally contribute in eradicating infection with [[neutrophils]]. But as a result of the extrahepatic portosystemic shunts, bacteria in the circulation do not come in contact with these cells. |
| | * As a result of defective liver synthetic functions, [[complement]] levels decrease (both in [[serum]] and [[Ascites|ascitic fluid]]). |
| | * The [[neutrophils]] seem to have declined [[Granulocyte|granulocyte functions]] as adherence, [[chemotaxis]], and bacterial killing. |
|
| |
|
| ⬇
| | Bacteria that translocate are carried through [[lymphatics]]. It can reach the [[Ascitic|ascitic fluid]] either through the circulation then through the liver. It can have access to the [[peritoneal cavity]]. Another way is through rupture of the [[lymphatic vessel]] carrying the contaminated lymph under pressure from [[portal hypertension]] and the increased [[lymph]] content. |
| | |
| '''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 [[IgA]] 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.<ref name="pmid22306056">Kirkland D, Benson A, Mirpuri J, Pifer R, Hou B, DeFranco AL et al. (2012) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=22306056 B cell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteria during colonic damage.] ''Immunity'' 36 (2):228-38. [http://dx.doi.org/10.1016/j.immuni.2011.11.019 DOI:10.1016/j.immuni.2011.11.019] PMID: [https://pubmed.gov/22306056 22306056]</ref><ref name="pmid21932384">Doi H, Iyer TK, Carpenter E, Li H, Chang KM, Vonderheide RH et al. (2012) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21932384 Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population.] ''Hepatology'' 55 (3):709-19. [http://dx.doi.org/10.1002/hep.24689 DOI:10.1002/hep.24689] PMID: [https://pubmed.gov/21932384 21932384]</ref><ref name="pmid7911786">Gautreaux MD, Deitch EA, Berg RD (1994) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7911786 T lymphocytes in host defense against bacterial translocation from the gastrointestinal tract.] ''Infect Immun'' 62 (7):2874-84. PMID: [https://pubmed.gov/7911786 7911786]</ref><ref name="pmid6966611">Owens WE, Berg RD (1980) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6966611 Bacterial translocation from the gastrointestinal tract of athymic (nu/nu) mice.] ''Infect Immun'' 27 (2):461-7. PMID: [https://pubmed.gov/6966611 6966611]</ref>
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| |-
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| ! colspan="2" |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:'''<ref name="pmid6693068">{{cite journal| author=Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J| title=Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. | journal=Hepatology | year= 1984 | volume= 4 | issue= 1 | pages= 53-8 | pmid=6693068 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6693068 }} </ref><ref name="pmid11950821">{{cite journal| author=Trevisani F, Castelli E, Foschi FG, Parazza M, Loggi E, Bertelli M et al.| title=Impaired tuftsin activity in cirrhosis: relationship with splenic function and clinical outcome. | journal=Gut | year= 2002 | volume= 50 | issue= 5 | pages= 707-12 | pmid=11950821 | doi= | pmc=1773217 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11950821 }} </ref>
| |
| * Deficient innate and adaptive immunity
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| * Impaired chemotactic, opsonic, phagocytic activity of macropharges
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| * Impaired RES activity
| |
| |-
| |
| ! colspan="2" |III. Systemic immune response
| |
| |Translocation beyond MLN through hematogenous or lymphatic path is specific and depends on the microbial-specific systemic immune response.<ref name="pmid10864873">{{cite journal| author=Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM| title=A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. | journal=Science | year= 2000 | volume= 288 | issue= 5474 | pages= 2222-6 | pmid=10864873 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10864873 }}</ref> 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.<ref name="pmid3371881">{{cite journal| author=Runyon BA| title=Patients with deficient ascitic fluid opsonic activity are predisposed to spontaneous bacterial peritonitis. | journal=Hepatology | year= 1988 | volume= 8 | issue= 3 | pages= 632-5 | pmid=3371881 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3371881 }} </ref><ref name="pmid15920324">{{cite journal| author=Sheer TA, Runyon BA| title=Spontaneous bacterial peritonitis. | journal=Dig Dis | year= 2005 | volume= 23 | issue= 1 | pages= 39-46 | pmid=15920324 | doi=10.1159/000084724 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15920324 }} </ref>
| |
| | |
| * With respect to compromised [[immune system|host defenses]], patients with severe acute or chronic liver disease are often deficient in [[Complement system|complement]] and may also have malfunctioning of the [[neutrophil]]ic and [[reticuloendothelial systems]].<ref name="pmid19561863">Alaniz C, Regal RE (2009) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19561863 Spontaneous bacterial peritonitis: a review of treatment options.] ''P T'' 34 (4):204-10. PMID: [https://pubmed.gov/19561863 19561863]</ref>
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| | |
| * 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.<ref name="pmid19561863" /><ref name="pmid3770358">Runyon BA (1986) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=3770358 Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.] ''Gastroenterology'' 91 (6):1343-6. PMID: [https://pubmed.gov/3770358 3770358]</ref><ref name="pmid4018735" />
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| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |
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| {{WH}}
| | [[Category:Emergency mdicine]] |
| {{WS}}
| | [[Category:Disease]] |
| | | [[Category:Up-To-Date]] |
| [[Category:Gastroenterology]] | |
| [[Category:Emergency medicine]] | |
| [[Category:Infectious disease]] | | [[Category:Infectious disease]] |