Chronic pancreatitis Ermias D (MD)

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 – % - overestimates Retrospective studies – 3-9/100,000 Prospective data –among alcoholics – 8.2/yr/100,000; –overall prevalence /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

Etiologic factors ass. With CP: TIGAR-O

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 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, 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 %) – 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