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