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Normal Pancreas

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Stimulation of Nitric oxide (iNOS) and Cyclooxygenase (COX 2) ... ( Effect rather than cause) (Zuidema, 1959; Shaper 1960) Cassava Toxicity (Cyanogen toxicity) ... – PowerPoint PPT presentation

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Title: Normal Pancreas


1
Dutta Gupta Pathology and pathogenesis
Pathogenesis
Acute Pancreatitis
Normal Pancreas
Normal Pancreas
Abnormal Pancreas
Normal or Abnormal Pancreas
Chronic Pancreatitis
2
Dutta Gupta Pathology and pathogenesis
Chronic pancreatitis
Acute Pancreatitis
Normal Pancreas
Normal Pancreas
Normal or Abnormal Pancreas
Abnormal Pancreas
Chronic Pancreatitis
Non-Calcifying
Calcifying
Idiopathic
Obstructive
Hereditary
Tropical
Autoimmune
Alcoholic
Lymphoplasmacytic
Eosinophilic
Edema, inflammation Glandular atrophy Calcificatio
n Duct damage
Edema, inflammation Glandular atrophy Calcificatio
n Duct damage less severe
3
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4
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5
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6
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7
Dutta Gupta Pathology and pathogenesis
Trypsinogen activation
Block
Trypsin
Trypsin
Trypsinogen
Acinus
Duct
Duodenum
8
Dutta Gupta Pathology and pathogenesis
Cytokine factors
Upregulation of NF-kappa B (controls
transcription of inflammatory genes) Inhibition
of apoptosis Stimulation of Nitric oxide (iNOS)
and Cyclooxygenase (COX 2) Increased TNF alpha
Increased IL6 Shifts myeloid precursors to
macrophage phenotype Other cytokines TNF alpha
promotes fibrosis TGF beta stimulates
angiogenesis and cell proliferation Interleukins
IL1, IL8 Growth factors PDGF, EGF, IGF- 1
9
Dutta Gupta Pathology and pathogenesis
Ductal obstruction
Hydraulic Theory Experimental data (rats, dogs,
pigs) Obstruction of the duct is an important
cause Longer the obstruction, more serious are
the lesions Ductal obstruction results in
calculi in 50 of animals Complete obstruction
determines atrophy Restoration of outflow
prevents calculi and histological cahnges Large
duct lesions (Main pancreatic duct) Surgical
causes Small duct lesions (Secondary ducts)
Cystic fibrosis and other causes Hypersecretion
of protein from acinar cells Absence of fluids or
bicarbonates from ductal cells Precipitation of
plugs (Proteins, enzymes, glycoproteins,acid
mucopolysacharides, Lithostathine,
GP2) Calcification (Alcoholics ,Tropical
Calcific Pancreatitis) Ductal Hypertension
10
Dutta Gupta Pathology and pathogenesis
Protective inhibitors
Pancreatic secretory Trypsin Inhibitor
(PSTI) Serine protease Inhibitor Kazal Type I
(SPINK1)
Protease Activated Receptor (PAR-2)
Enterokinase
Trypsin
Trypsinogen
Trypsin
Duodenum
11
Dutta Gupta Pathology and pathogenesis
Development of pancreatitis
Ordinary state
Trypsinogen Trypsin PSTI
Inappropriate activation
Pancreatitis
Decreased PSTI Activity
Ordinary state
Stimulated state
Pancreatitis
12
Dutta Gupta Pathology and pathogenesis
Mutations
  • Cationic trypsinogen gene (Protease Serine 1
    Gene, PRSS 1)
  • Chromosome 7q35, Autosomal Dominant with 80
    penetrance
  • Mutation G to A (Arginine to Histidine R122H) and
    A to T (NN291)
  • Alters trypsin recognition sites preventing
    denaturation
  • Pancreatic Secretory Trypsin Inhibitor (PSTI) /
    Serine Protease
  • inhibitor Kazal Type 1 (SPINK 1)
  • Two exonic mutations identified N34S and R67C
  • Decreased activity of PSTI / SPINK 1 results in
    80 chance of pancreatitis
  • Cystic Fibrosis Transmembrane Conductance
    Regulator Gene
  • (CFTR gene)CFTRopathies
  • Chromosome 7q3.1, glycoprotein 1,70,000 molecular
    weight
  • Regulation of apical membrane chloride channel of
    epithelium
  • Common deletion(70) 3bpdeletion, loss of
    phenylalanine (?F508)
  • Highly viscous solution, inability to maintain
    luminal hydration

13
Dutta Gupta Pathology and pathogenesis
Hypertriglyceridemia and pancreatitis
Triglycerides
Chylomicrons
Pancreatic lipase
Free Fatty Acids
Clogs capillaries
Ischemia Acidosis
Activation of trypsinogen
Injury (Non-cacific)
14
Dutta Gupta Pathology and pathogenesis
Autoimmune pancreatitis
  • Instillation of tri-nitro-benzene sulfonic acid
    (TNBS) induces chronic pancreatitis in rats
    (Puig-Divi et al, 1996)
  • TNBS is a hapten, alters antigenic profile of
    duct epithelium, stimulates T-cell response
    (Similar results with instillation into bile
    ducts and colon)
  • Carbonic anhydrase I II (CA I II) antibodies
    identified in chronic pancreatitis
  • Aberrant HLA DR molecules by ductal epthelium
  • Presence of autoantibodies (ANA, ANCA,AMA, ASmA)
  • Chronic pancreatitis associated with other
    autoimmune diseases (Sjogrens, PSC, PBC, Crohns
    Disease, Ulcerative Colitis)
  • Histological examination shows intense plasma
    cell, lymphocytic and other inflammatory cell
    reaction
  • Response to steroids
  • Lymphplasmacytic sclerosing pancreatitis,
    sclerosing pancraetico cholangitis, non-alcoholic
    duct destructive chronic pancreatitis

15
Dutta Gupta Pathology and pathogenesis
Tropical calcific pancreatitis
  • Syn Tropical calcific pancreatitis, tropical
    pancreatic diabetes, nutritional pancreatitis,
    juvenile pancreatitis syndrome, Afro-Asian
    pancreatitits, tropical calculous pancreatopathy,
    fibrocalculus pancreatopathy
  • Early pre-diabetic stage Tropical chronic /
    calcific pancreatitis (TCP)
  • Diabetic stage Fibrocalcific pancreatic diabetes
    (FCDP)
  • Pathogenesis
  • Malnutrition? (Effect rather than cause)
    (Zuidema, 1959 Shaper 1960)
  • Cassava Toxicity (Cyanogen toxicity)
  • Cassava (Tapioca, Manihot esculanta) staple diet
    of poor
  • Rich in cyanogen glycosides linamarin and
    lotaustralin
  • Cyanide detoxified to thiocyanate in the presence
    of sulfur
  • S containing amino acids methionine and cysteine
    deficient
  • Malnutrition (High carbohydrate , low protein)
  • Familial and Genetic Factors
  • Familial aggregation in 8 cases (Mohan et al,
    1989)
  • HLA DQ beta insulin genes and SPINK 1 NS34S
    mutation
  • Oxidative stress and trace element deficiency
    states

16
Dutta Gupta Pathology and pathogenesis
Helicobacter pylori
H pylori inhibits secretion of stomatostatin by
gastric G cells Density of G cells and gastrin
levels increase Increased duodenal acid load
increases secretin induced pancreatic
secretion Gastrin also has weak CCK-like
effect Experimental studies with vac toxin of H
pylori H pylori DNA sequences in pancreatic juice
(Italian study, De Campli et al , 2000) H pylori
may have an associated role with other factors
17
Dutta Gupta Pathology and pathogenesis
DNA microarray studies
(Frei et al, 2001) Six genes identified in
comparison to normal and carcinoma
pancreas Notable Cartilage oligomeric matrix
protein (COMP) Thrombospondin family, acinar cell
degeneration dedifferentiation Cystein rich
protein 3 (CRISP 3) Acinar cells, defence
molecule of mammals Tryptase Mast cells, induces
synthesis of Type I collagen
18
Dutta Gupta Pathology and pathogenesis
Progression from acute to chronic pancreatitis
Acute Pancreatitis
Alcoholic
Biliary
Hereditary
Idiopathic
Tropical
Autoimmune
Early onset
Late onset
Main Duct Scars
ARP
AP
Oddi Sphincter Pathology
ARP
ARP
AP
Non Progression
Obstruction
Chronic Pancreatitis
19
Dutta Gupta Pathology and pathogenesis
Conclusions
Obstruction is an important factor Recent
insights suggest molecular pathways Multifactorial
pathogenesis most likely Histological features
generally similar irrespective of
etiology Certain unique features identified in
some specific histological types
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