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 – 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

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 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