chronic pancreatitis ermias d (md). definition irreversible damage to the pancreas with histologic...
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Definition
• Irreversible damage to the pancreas with histologic evidence of inflammation, fibrosis, and destruction of exocrine (acinar) and endocrine (islets of Langerhans) tissue
• Etiologic classification – clinically useful– Histologic – accessibiliy of tissue
– Imaging – late morphologic changes
prevalence• Autopsy reports – 0.04-5% - overestimates
• Retrospective studies – 3-9/100,000• Prospective data
– among alcoholics – 8.2/yr/100,000;– overall prevalence - 27.4/100,000
• Japan overall prevalence – 28.5/100,000; – M:F =3.5:1
• Alcohol abuse – 2/3 of causes • Mortality 3.6X age matched control• Advanced age, alcoholism and smoking are poor
prognostic conditions
pathophysiology
• Incompletely understood
• Why 10% heavy alcoholics develop chronic pancreatitis and the rest not, or limited to asymptomatic pancreatic fibrosis
• Alcohol is the most studied
Ductal obstruction hypothesis• Chronic alcohol use • acinar and ductal cell
• protein rich pancreatic juice, low in volume and HCO3 • formation of protein precipitates – plug
• calcification of ppt – ductal stone formation• ductule obstruction
• parenchymal damage
• Pancreatic ductal stone are seen in alcoholic, tropical, hereditary, idiopathic
• Histologic changes of CP may be seen with out ductal obstruction
Toxic metabolic hypothesis
• (alcohol) Direct injurious effect on acinar and ductal cells
• Increased membrane lipid peroxidation (oxidative
stress), free radical production• Increase acinar cell sensitivity to pathogenic
stimuli• Stimulate CCK production (duodenal I cells) –
activation of proinflammatory transcription factors• Activation of pancreatic stellate cells (alcohol,
cytokines) – produce proteins of extracellular matrix
Necrosis fibrosis hypothesis
• Repeated episodes of acute pancreatitis with cellular necrosis or apoptosis, healing replaces necrotic tissue with fibrosis
• Evidence from natural history studies - more severe and frequent attacks
• More evidence from hereditary pancreatitis and animal models
• But some have evidence of chronic pancreatitis at time of first clinical acute attack
• CFTR – cystic fibrosis trans-membrane conductance regulator
– Cystic fibrosis is ass. with abnormalities of HCO3 secretion, ductal dilatation, ppt formation, pancreatic atrophy
– Seen in 50% of idiopathic CP, not common in alcoholic CP• PRSS1 – cationic trypsinogen gene
– Once trypsinogen is activated to trypsin, becomes resistant to inactivation and activate other proenzymes leading to
episodes of acute pancreatitis– like necrosis fibrosis theory
• SPINK1 - serine protease inhibitor Kazal type 1
– Seen in pediatric ICP, hereditary P, TP; but not in chronic alcoholic pancreatitis
– Trypsin inhibitor, mimic trypsinogen gene
Genetic forms
Disease modifying genes
• Polymorphisms that modulate immune response
• Cytokines – – transforming growth factors α, β, interleukin-
10, interferon gamma
TROPICAL PANCREATITIS
• Africa, India, Brazil; with in 30’ latitude• A disease of early childhood and youth• > 90% before age of 40yrs
• Prevalence in endemic areas: 1 in 500-800• Abdominal pain, malnutrition, exocrine and
endocrine insufficiency • Pancreatic caliculi – 90%
• Fibrocalculous pancreatic diabetes, tropical calcific pancreatitis
• 50% SPINK1 gene mutation (N34S)• Unclear environmental trigger – PEM, Cassava
Autoimmune pancreatitis• Confusing and evolving nomenclature• 5% of CP, more in males, middle age• 12 – 50% ass. With other autoimmune diseases• abdominal pain, weight loss, jaundice
• Imaging studies show focal or diffuse (sausage shaped) enlargement
• Pancreatogram – diffuse narrowing (thread like) or alternating pattern
• Dx – clinical, imaging, Ig, autoAb• Tx – glucocorticoids 1-2m and tappering in 3-4m
Diabetes mellitus• 1% of DM from CP• In DM - pancreas is smaller,
– abnormal duct in 40-50% , – abnormal pancreatic fn in 40-50%
• Insulin is a trophic factor for exocrine fn of the pancreas• Insulin def + microangiopathy of DM lead to pancreatic
damage• DM and CP cause effect r/n is not clear
• Increased risk of hypoglycemia due to glucagon deficiency when insulin therapy is initiated
• Glucagon like peptide infusion increases endogenous insulin
• Glucocorticoid tx for autoimmune cp reverses ass. DM
Idiopathic CP• 10-30% of acute pancreatitis• Early onset – 20yr mean age, m=f• 96% pain• Calcification, exocrine or endocine insufficiency
develop slowly over time – 25, 26 -27.5 yrs• CFTR, SPINK1 genes
• Late onset• Pain is less frequent 54%-75%
• Age of onset 56yrs, m=f• Exocrine and endocrine insuf. Upto 46 and 41%,
in 16.9 and 11.9yrs; 90% calcification
Clinical features
• Abdominal pain– Acute pancreatic inflammation– Increased intrapancreatic pressure– Alterations in pancreatic nerves
• Steatorrhea – lipase secretion <10%
• DM
diagnosis
• No single test is adequate
• Tests for function
• Tests for structure
• Both are more accurate in advanced disease
• Indicate large reserve functionally, late structural changes
• Big duct vs small duct disease
• Tests of function – hormone stimulation– Secretin/ secretin CCK test– Fecal elastase– Fecal chymotrypsin– Serum trypsinogen (trypsin)– Fecal fat– Blood glucose
• Tests of structure– Endoscopic US
– ERCP– MRI/MRCP
– CT– Abdominal US
– Plain abdominal film
Routine lab. tests
• Serum amylase and lipase– May be elevated in acute exacerbations– Also found increased in pseudocyst, ductal
stricture, internal pancreatic fistula
• Other chemistry and electrolytes depend on associated conditions
Classics of Chronic pancreatitis• Pancreatic calcification
• Steatorrhea
• Diabetes mellitus • Found in less than a third of pts with CP
• abnormal secretin stimulations test when >60 % affected
• Serum trypsinogen < 20ng/ml, fecal elastase < 100mcg/mg stool - severe
exocrine insuf.
US or CT grading system• Normal – no abnormality on good quality study• Equivocal – mild parenchymal duct dilatation (2-4mm)
– gland enlargement <2 fold
• Mild –moderate - + duct dilatation >4mm, » duct irregularity, » cavity < 10mm, » parenchymal heterogenity, » increased echo of duct wall, » irregular head and body, » focal parenchymal necrosis
• Severe - + cavity >10mm, » intraductal filling defects, » caliculi/ pancreatic calcification, » ductal obstruction/stricture, » severe ductal dilatation or irregularity, » contiguous organ invasion
complications• Cobalamin malabsorption
– Excess binding by cobalamin binding proteins other than intrinsic factor which were degraded by pancreatic enzymes
• DM – but end organ damages of DM and DKA are rare• Non DM retinopathy (peripheral) due to Vit A and Zn
defc.• Pleural, peritoneal and pericardial effusions with high
amylase• GI bleeding – PUD, gastritis, pseudocyst, varies (SV
thrombosis)• Cholestasis, icterus, cholangitis, biliary cirrhosis • Fistula – internal or external• Subcutaneous fat necrosis – tender red nodules on the
shins • Pseudocyst, obstruction • Pancreatic carcinoma – 4% life time risk• Narcotic addiction
treatment• Aim - Pain control and mx of maldigestion• Pain
– Avoid alcohol– Low fat meals– Antipain – narcotics (addiction)
– Surgical pain control• Resection (local - - - - 95%) – pancreatic insufficiency• Splanchinectomy, celiac ganglionectomy, nerve block
– Endoscopic tx• Sphinctorotomy, dilatation of strictures, caliculi removal, duct
stenting– Cpx – acute pancreatitis, abscess, ductal damage, death
– Pancreatic enzymes
• Abdominal pain – • R/o ddx – US (no mass) –
• secretin test (decreased HCO3 and volume) – • 3-4wk pancreatic enzyme –
• (4-8tablets at meals and at bed time) – • minimal change CP pt get relief of pain –
• if not, ERCP/EUS – • pseudocyst, obstruction, dilated duct –
surgery, octreotide –• If No response
• subtotal pancreatic resection
Tx of maldigestion• Pancreatic enzyme replacement
– 2-3 enteric coated or 8 conventional tablets with meals– adjuvants with conventional tablets – H2 blockers, PPI,
Na bicarbonate, – Ca carbonate and Mg OH may even ppt steatorrhea
• Steatorrhea can be abolished if 10 % of normal lipase amount can be delivered to the duodenum at the right time
• Limitations – Lipase is inactivated by gastric acid, – food and enzyme emptying from the stomach is
different, – variable enzymatic activity of the preparation, – high potency prep. And colonic stricture reports
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