Role of Gut Injury in Severe Acute Pancreatitis
Point to be Focus on
• Pancreas• Acute Pancreatitis• Pathogenesis of disease• Clinical Outcome• Inflammatory Process• Gut normal Physiology• Gut Barrier defect• Gut pancreatic access• Gut model• Bacterial translocation• Method of detection • Summary
Overview of Pancreas
The pancreatic gland contains three major types of cells
• The duct cells make up about 10% of the pancreas and secrete
solutions rich in bicarbonate
• The acinar cells comprise over 80% of the pancreas and they
synthesize and secrete pancreatic enzymes
• The islet cells make up about 10% of the pancreas and form the endocrine portion of the pancreas and they secrete the hormones, insulin, glucagon, somatostatin, and pancreatic polypeptide
Spatial Arrangement of Pancreas
Sphincter of oddi
Pancreatitis
• Pancreatitis is an inflammatory process in which pancreatic enzymes auto digest the gland
• The gland can sometimes heal without any impairment of function or any morphologic changes. This process is known as acute pancreatitis i.e.
• It is an irreversible inflammatory disease, contributing to the functional and morphologic loss of the gland, the pathological change referred to as chronic pancreatitis i.e.
Acute Pancreatitis
• Acute inflammatory process involving the pancreas
• Usually painful and self-limited• Inflammatory disorder
Acute pancreatitis
Severe Acute pancreatitisMild Acute pancreatitis
Leads sepsis induce MODSRecover within 1 week
Autodigestion of pancreatic tissue
Release ofenzymes intothe circulation
Activationof whiteblood cells
Localcomplications
Localvascularinsufficiency
Premature enzyme activation
Distantorgan failure
Acute Pancreatitis: PathogenesisAlcohol toxicity Microcirculation
disturbance
• STAGE 1: Local inflammation of pancreas– Edema– Inflammation
• STAGE 2: Inflammatory response– Retroperitoneal edema– Ileus
• STAGE 3: Multiple organ dysfunction– Hypotension/shock– Metabolic disturbances– Sepsis/organ failure
SEVERITYSEVERITYMildMild
SevereSevere
Acute Pancreatitis: Pathogenesis
Acute Pancreatitis: Pathogenesis
• Initiation factor in Earlier period
• Abnormally activation of pancreatic enzyme
• Alcohol toxicity
• Pancreatic Microcirculation Disorder
• Aggravating factors in later period
• Infection: pancreatic abscess
• Intestinal bacteria translocation
• Cytokine and systemic inflammation reaction syndrome
• Free radicals
Severe (Necrotizing)Organ failureMild
No Organ failure80-85%
15-20%
Mortality 1%
Infected necrosis
Sterilenecrosis
Mortality 5% Mortality 25-70%
Acute Pancreatitis : Clinical Outcome
Bacterial Translocation
Severe SIRSSevere suppression of Immune response
Infection /Late MOF
Within 1 week SIRS >1 week Infection-Sepsis
Pro-inflammatory cytokines
Anti-inflammatory cytokines
Biphasic course of AP
Early MOF
Inflammatory Processes
BacteremiaFungemiaViremiaOthers
TraumaBurn
PancreatitisOthers
Adapted from Bone DC et al, 1992
SIRS: Systemic Inflammatory Response Syndrome
• A response of the immune system to inflammation
(pancreatitis, ischemia, burns, multiple trauma, shock, and
organ injury)
Opal SM et al. Crit Care Med. 2000;28:S81-2.
Infection: Part of a Bigger Picture
Infection is a process in which bacteria, viruses,
fungi or other organisms enter the body, attach to
cells, and multiply.
Opal SM et al. Crit Care Med. 2000;28:S81-2.
Definition of Sepsis
Sepsis can now be more accurately defined as a
systemic inflammatory response syndrome (SIRS) resulting from infection.
Infection + SIRS = Sepsis
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Sepsis: A Complex Disease
Opal SM et al. Crit Care Med. 2000;28:S81-2.
SIRS
Others
SepsisInfection
Trauma
Burn
Pancreatitis
Multiple Organ Dysfunction Syndrome
Multiple System Organ Failure is when more than one
organ of the body stops working normally. After the onset
of sepsis where intervention is needed to sustain life.
Core Curriculum for Critical Care Nursing, 2006
Diagnosis of SIRS
• SIRS: A clinical response arising from a nonspecific insult manifested by 2 of the following:– Temperature
38°C or 36°C
– HR 90 beats/min
– Respirations 20/min
– WBC count 12,000/mL or 4,000/mL or >10% immature neutrophils
May be caused by bacterial translocation
Diagnosis of Sepsis
• Bacterial infections are the most common cause of sepsis, but sepsis can also be caused by fungal, parasitic, or viral infections
• The infection can originate from anywhere in the body.
Infection leads Inflammation may result in organ damage.
Role of Gut
• Sepsis• Accounts for > 80% of deaths
• Causative microorganism• Mostly gram negative bacteria (gut origin)
• Mechanism • Translocation of the bacteria across the gut wall via
barrier defect, imbalance of intestinal flora and imbalance of immune system
Pancreatic inflammation
Necrosis
Infected Necrosis
Splanchnic Vasoconstriction
Ischemia
Intestinal Ischemia
reperfusion
Intestinal barrier failure
SIRS/MODS
Bacterial Translocation
Endotoxemia
CytokineOxidative stress
Activated neutrophils
Pancreas Intestine
Interaction Between Pancreas and Intestine
Edema Hypovolemia
Acute Pancreatitis
GI Tract: Normal Pathophysiology
• GI tract protect body from exposure of foreign Ag,
– Barrier, to prevent the passage of harmful intra-luminal entities
» Stomach have acidic pH» Small bowel have alkali Ph» Mucus production throughout GI
– Small Intestine act as a selective filter( allow the translocation of essential nutrients and electrolytes)
Component of Gut• The extrinsic barrier consisting i.e. mucus, bicarbonate, hormones,
cytokines prostaglandins
• The intrinsic barrier is composed of the epithelial cells lining i.e. Junctions and channels• Paracellular pathway (junction)• Transcellular pathway (channel)
Paracellular pathway regulated by 4 specific junction
• Tight Junction • Adherens junction• Desmosomes• Gap junction
TJs Regulate Intestinal Permeability
Normal TJ regulate normal IP
DiseaseNo disease
Disrupted TJ leads to increase IP
• Permeability is a process where molecules are allowed to pass through the epithelial lining by non mediated diffusion
• Barrier properties of the intestinal epithelium are regulated by TJs. It is generally believed that disease related, increase in IP is caused by defects in TJ structure
Function of Gut Depends Upon
• Normal intestinal flora (Ecological Barrier)
• Mucosal Epithelia (Mechanical barrier)
• Secreting IgA and immune cell ( Immune barrier)
Sepsis leads SIRS &MODS
Endotoxemia
Translocation of gram-ve bacteria via Para-cellular or trans-cellular
Excess of Inflammatory mediators oxidative stressNeutrophils transmigration circulate to multiple organ infection
Ischemia-Reperfusion
Mucosal GUT injury
Defected mucosal barrier
Acute pancreatitis
Gut Pancreatic Access
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What is Ischemia Reperfusion Injury
• Interruption of blood supply to gut known as Ischemic injury ( during surgery, AP & trauma etc) which damage tissue
• Restoration of blood flow to ischemic tissue leads to reperfusion injury which exceeds the mucosal damage
Gut
GutMOTOR
GutSTARTER
Neutrophils priming Direct barrier defect
MODSMODS
↑Mortality and morbidity
GUT Hypothesis
Intestinal Ischemia reperfusionPrimary state
GUT as STARTER
MODS
Neutrophils get primed due to mesenteric circulation
Primed neutrophils (inactive) circulate to body until second hit
Endotoxin
Oxygen free radical
Intestinal Ischemia reperfusion
Priming of neutrophils initiated via PLA2
Release proteases Imbalance of
immune responseInflammatory
mediators
GUT as MOTOR
Intestinal barrier defect
Activates immune cells
Ischemia reperfusion injury
Luminal content invadesPortal & Lymphatic system
Bacterial translocation
MODS
Payers patchesMacrophages of
lamia propria, gut Mesenteric lymph
nodeskuppfer cells of
liver
Inflammatory mediators
Malnutrition
Bacterial overgrowth
Immunodeficiency state
Villous atrophy
Ischemia Reperfusion
Intestinal barrier defect
How Intestinal Barrier Get Defected
Bacterial Translocation Depends on 3 Factors
– Small bowel bacterial overgrowth (SIBO)
– Immunodeficiency state
– Physical damage to intestinal mucosa
• When any of this mechanism separately or in combined manner leads to sepsis.
Route of Bacterial Translocation
Entry of bacteria from the gut lumen into the body through two routes•Vascular route (portal vein)
•Lymphatic route (Principal pathway of translocation)
Lymph vessel
Bacteria From the Gut Lumen into Distant Organ
Gut Translocation Mediated by Three Hit Model
• Gut insult by Ischemia
• Restoration of blood flow with migration of neutrophils to intestine
• Loss of integrity of gut barrier function
How to Detect Gut Injury
• Ischemia• SIBO by H2 breath test• Oxidative stress by ELISA• Mucosal acidosis (Tonometer)
• Detection of intestinal villous atrophy• Histological• Ultrastructurally by Electron microscopy
How to Detect Gut Injury
• Intestinal Barrier defect• Functional
– Intestinal permeability test by dual sugar test using HPLC
• Ultrastructurally– TJ and other junction of paracellular junction proteins
• localization of barrier’s protein– expression of barrier’s protein by immuno-histochemistry
• Cellular level– m RNA of these protein by RT PCR
How to Detect Gut Injury
• Sepsis• Culture (Aerobic & anaerobic culture)• 16sRNA PCR
• Endotoxaemia• Endotoxin level
Bacterial Translocation
Endotoxaemia
Gut Pancreatic Access Leads to MODS
Edema, Hypovolemia altered microcirculation
Acute Pancreatitis
SIRS/MODS
CytokineOxidative stress
Activated neutrophils
Pancreatic Necrosis
Intestinal barrier failure
Splanchnic vasoconstriction
Intestinal Ischemia
Intestinal Ischemia reperfusion injury
Gastroenterology, Volume 139;3:2010,813-820
14 studies comprising 1478 patients with acute pancreatitis were meta-analyzed
The relative risk of mortality doubles when OF and IPN are both present and indicates extremely
severe disease.
Patients with OF and no IPN Patients with IPN and no OF
Absolute influence of OF and IPN on mortality is comparable and thus the presence of either
indicates severe disease
AP- Assessment of Severity
Summary
• Association of Gut origin sepsis and MODS in high risk patient group
• Gut ischemia is an dominating factor in MODS
• Several trials suggested• Enteral feeding and selective decontamination
improve clinical outcome
Thank You
Ischemia reperfusion injury
Release of OFR due to excess of lipid per-oxidation of cell membrane via xanthine opathway
OFR initiate migration of activated neutrophils into reperfused tissue
How Gut injury occur
Accumulation of activated neutrophils leads intestinal injury via 3 ways
Releasing OFR↑ Ischemia effect ↑Inflammatory response
Effect of Sepsis
• During septic complication with any of major trauma, IBD, Pancreatitis and surgery, body comes in hyper-metabolite state
• This state leads to consumption of stored protein , energy, imbalance of immune system and deterioration of organ i.e. Liver GI, kidney, heart and lung.
• Gut liver axis have major role in these response
Role of GI in Pathophysiology of Sepsis
• Gut help in maintaining hyper metabolism state during Sepsis, SIRS & MODS
• Change in GIT structure &function• Abnormal colonization of bacteria• Bacterial translocation• Absorption of toxins
• They trigger activation of pro-inflammatory cytokines and release other mediators in metabolic response to sepsis
Evidence of gut injury in SAP
• Intestinal atrophy with nutrition depletion
• Intestinal ischemia (mucosal acidosis) can predict death with overall accuracy 82%
• Increased intestinal permeability correlated with severity of AP
• Bacterial translocation suggest septic complications
• Endotoxaemia correlates severity of disease suggest complication and mortality rate