Chronic pancreatitis
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INCLUDES DEFINITION, PREVALENCE, PATHOPHYSIOLOGY & ETIOLOGY, DIAGNOSIS, MANAGEMENT AND COMPLICATIONS OF DISEASE
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Chronic pancreatitis
- 1. CHRONIC PANCREATITIS Definition Prevalence Pathophysiology & Etiology Clinical features Diagnosis Management Complications
- 2. Definition: Chronic pancreatitis is a disease process characterised by irreversible damage to pancreas. and condition is defined by presence of histological abnormalities, including chronic inflammation, fibrosis and progressive destruction of both exocrine and eventually endocrine pancreatic tissue(atrophy) -Harrisons 20th Ed. Acute pancreatitis and chronic pancreatitis are assumed to be different disease processes, and most cases of acute pancreatitis do not result in chronic disease. PREVALANCE: 10-15/1,00,000 in western countries (alcohol misuse). 114-200/1,00,000 in southern India (severe chronic calcific pancreatitis in non-alcoholics, possibly due to malnutrition, deficient trace elements and nutrients and cassava consumption). Other causes are listed in next slide. Typical age 35-55
- 3. Etiologic factors associated With CP (mnemonic-TIGAR-O) Developed by Midwest multicenter pancreatic study group -Harrisons 20th Toxic –metabolic Alcohol, Hyperlipidemia, Tobacco smoking Chronic Renal Failure Hypercalcemia Medications/ toxins (Organotin compound) Idiopathic Tropical Early onset/ Late onset Genetic Cataionic trypsinogen (PRSS 1), Pancreatic secretory trypsin inhibitor gene(SPINK1) Cystic Fibrosis transamembrane conductance regulator gene (CFTR) Calcium-sensing receptor(CASR), Chymotrypsin C gene(CTRC), Autoimmune Type-1/Type-2 IgG4 systemic Recurrent and severe acute pancreatitis Recurrent acute pancreatitis Post-necrotic Obstructive Pancreas divisum Duct obstruction(tumor), Preampulary ductal wall cyst Post traumatic pancreatic ductal scar *Gall stones do not cause CP but may be observed as an incidental finding
- 4. TIGAR-O Risk factor classification system -British Journal of pain
- 5. Sentinel acute pancreatitis event hypothesis • According to this theory, First episode of acute pancreatitis is as a result of unregulated trypsin activation leads to massive inflammatory response divided into early and late phases. • Early phase response due to –inflammatory cells and cytokines(TGF-BETA1, IL-1, IL-6) –fibrosis and activation of pancreatic stellate cells. If no further exposure to noxious stimulus pancreas should heal and recover. If noxious stimulus persists then activated PSC will directly stimulate cytokines leading to fibrosis and CP. PSC pathway somehow unifies other theories and describes common pathway. • Recent studies also noted that PSC are also activated by its own intrinsic activation through macrophages this may be a reason for continuous process of inflammation and fibrosis of pancreas even after removal of noxious stimulus after diagnosis of CP.
- 6. • Chronic pancreatitis is a relapsing condition. • Predominant symptoms 1. Abdominal pain or maladigestion and weight loss. • Hall mark of CP is Abdominal pain, occurring in 95% of cases. Pain may be quit variable in location, severity and frequency and can be episodic, lasting hours to days, or it can persist for months or even years. • The pain is characteristically steady in the epigastrium also some patients describes it as stabbing pain, and it frequently radiates to the back. Importantly Eating may exacerbate pain , leading to fear of eating with consequent weight loss. • Chronic Diarrhea, Steatorrhea, fatigue. • Creatrorrhea in late stage of disease. • Patients with CP have significant morbidity. • Despite steatorrhea, clinically apparent deficiency of fat soluble vitamins are uncommon. Clinical features
- 7. Pathogenesis of pain • 1. Compartmental syndrome pain due to large and small duct obstruction. • 2. Neurogenic pain due to stretching of nerves. • 3. Pain due to ongoing inflammation due to release of local mediators like bradykinine, serotonin, tachykinine etc. • 4. Neuronal damage due to peripheral sensitization and resultant central sensitization fundamental to development of persistent and refractory pain in CP. • 5. Trypsin also having effect on sensory neurons. • 6. ‘Salutogenic response’ – Involvement of immune system-modulation of immune response by centres in brain. Abnormal immune response linked to brain mediated mechanisms, sustained the visceral inflammation and prolonged duration of pain-mal adaptive brain response. Which is treated by ‘Transcranial magnetic stimuli’.-IN TRIAL
- 8. Investigations Investigations To establish diagnosis 1. Ultra sound abdomen 2. CT- may show atrophy, ductal dilatation or calcification 3. Abdominal X-Ray-may show calcification 4. MRCP 5. Endoscopic USG Test to define pancreatic function 1. Collect of pure pancreatic juice after secretin injection(invasive test seldom used) 2. Faecal pancreatic elastase Test to demonstrate anatomy prior to surgery MRCP
- 9. PLAIN X-RAY ABDOMEN: Marked calcification in pancreas
- 10. CT FINDINGS: Pancreatic calcification, ductal dilatation and gland enlargement. Pancreatic Pseudocyst
- 12. Step wise approach to diagnose CP -Harrisons 20th Ed Initial imaging modality • Clinical signs and symptoms suggestive of CP disease: Abdominal pain, weight loss, steatorrhea, malabsorption, history of alcohol abuse, recurrent pancreatitis, fatty-food intolerance • History, physical examination, review of laboratory reports and consider local elastase measurement STEP-1 •CT Scan- CP Diagnostic criteria: calcification in combination with atrophy and/or dilated duct •Diagnostic criteria-No further imaging needed •Inconclusive/ no diagnostic results-continue step-2 STEP-2 •MRI/MRCP with secretin enhancement(s MRCP)- CP Diagnostic criteria: Cambridge class III, dilated duct, atrophy of gland, filling defect in duct s/o stones •Diagnostic criteria-No further imaging needed •Inconclusive/ no diagnostic results-continue step-3 STEP-3 • Endoscopic ultra sound(EUS) with quantification of parenchymal and ductal criteria- Diagnostic criteria: 5 or >5 EUS criteria • Diagnostic criteria-No further imaging needed • Inconclusive/ no diagnostic results-continue step-4 STEP-4 • Pancreas function test(with secretin)-gastroduodinal or endoscopic collection method- CP diagnostic criteria: <80 mmol/L • Diagnostic criteria-No further imaging needed • Inconclusive/ no diagnostic results-continue step-5 STEP- 5 •ERCP- Diagnostic criteria: Cambridge class III, dilated main pancreatic duct, and greater than 3 dilated side branch •Diagnostic criteria-No further imaging needed •Inconclusive/ no diagnostic results require monitoring of signs and symptoms and repeat testing in 6 months- 1year
- 13. Initial imaging modalities 1. X-ray Plain film of the abdomen. 2. Measurement of fecal pancreatic enzyme elastase Decreased Elastase 1 activity (FE-1) in stools is found in CP and Cystic Fibrosis FE-1 LEVEL >200 microg/g is normal <100microgm/gm considered as Pancreatic Exocrine Insufficiency. 3. Serum pancreatic enzymes-amylase, lipase
- 14. Tests for exocrine pancreatic function 1. Direct stimulation of pancreas by I/V infusion of secretin followed by measurement of duodinal contents (principle –the pancreatic secretory response is directly related to the functional mass of pancreas) *Bicarbonate concentration <80 mmol/L is considered abnormal secretory function and s/o CP. 2. Measurement of fecal pancreatic enzyme elastase *Decreased Elastase 1 activity (FE-1) in stools is found in CP and Cystic FibrosisFE-1 LEVEL >200 microg/g is normal <100microg/g considered as PEI.
- 15. Treatment • Aim – Lifestyle modifications, pain management, PERT and management of complications • 1. Lifestyle modifications: • Complete cessation of alcohol/tobacco smocking • Low fat meals • Regular exercises and nutrient rich food • 2. Pain management • Anti-pain medications– narcotics tramadol, codeine(addiction), pregalin • Surgical pain control : • Endoscopic treatment: Sphinctoretomy, dilatation of strictures, caliculi removal, duct stenting and drainage of pseudocyst. • Partial/total pacreatectomy • 3. Pancreatic enzyme replacement treatment (CREON, ULTRESA). Because of gastroparesis PERT fails to reduce pain therefore prokinetic drugs along with PPI are beneficial. • 4. Complications– acute pancreatitis, abscess, ductal damage
- 16. Complications of chronic pancreatitis include: Pancreatic Pseudocyst DM Obstructive jaundice Pancreatic cancer Pancreatic main duct stricture Duodenal stricture
- 17. Summary • CP and the pain associated with it, is a complex clinical syndrome that has devastating effect on those who are suffering from it. • It can also be described as a group of disorder with diverse etiologies and multiple pathological processes, leading to the physiological destruction of pancreas. • Management needs multidisciplinary approach includes-Primary care physician, Gastro-enterologist, Endocrinologist, Psychiatrists, Pancreatic surgeon, Anaesthetics. • Pathophysiology of CP disease is yet to be learned deeply IN PERTICULAR THE PATHOGENESIS OF PAIN. • CNS-HAS A ROLE IN GENERATING MODULATING AND MAGNIFYING THE PAIN OF CP.
- 18. •THANK YOU
Editor's Notes
- My topic of presentation is Chronic pancreatitis in which I will highlights it’s definition, prevalence, Pathophysiology & etiology, Clinical features, Treatment part and related complications of the disease. The reason why I selected this topic is 1. Presently we have two case of CP and 2. Severe morbidity especially due to continuous abdominal pain (which is very difficult to treat), which propelled them into frequent hospital admission. Patient’s general health, near cacchexic depriving them from leading normal life. Here in these cases I have also noticed their dependence on TAB. TRAMADOL for their pain - though results of this medicine are questionable.
- So Pancreas is a mixed type of gland and situated retro- peritoneal and in horizontal position at the level of L1. Its main function is to secrete digestive enzymes and aid in digestion of food in gut and regulation of metabolism by its endocrine hormone secretions. One of it’s disease is ‘Chronic pancreatitis’ It is a disease process characterized by irreversible damage to pancreas which is evident by histological abnormalities including chronic inflammation, fibrosis and progressive destruction of both exocrine and eventually endocrine pancreatic tissue. Please note, Acute and chronic pancreatitis are assumed to be different disease process and most cases of acute pancreatitis does not result in chronic pancreatitis. The depic-ed picture shows excised pancreas which is shrunk in size (i.e atrophied) with dilated pancreatic duct and also shows calcifications in pancreatic duct Now coming to its prevalence, in western countries it is 10-15/100000 population about 10 % of which is related to alcohol misuse. In southern India it is 114-200/100000 population and it is characterized by chronic calcific pancreatitis in non-alcoholics, possibly due to malnutrition, deficient trace elements & nutrients and cassava consumption. Other etiological factors are listed in next slide. C P usually occurs in the age group is 35-55 years and male are more affected than females (1:
- Alcohol is the most common cause in clinically apparent CP and Cystic fibrosis in children. About 25 % adults with CP is alcohol related. Recent study shows out of this 25 % about 15 % are of due to genetic defects. Smoking is an independent dose dependent risk factor for CP and recurrent acute pancreatitis. Genetic defects that affects the gene encoding for trypsinogen. The defect in gene prevents destruction of prematurely activated trypsin and allows it to be resistant to intracellular protective effect of trypsin inhibitor. This repeated and continuous activation of digestive enzyme within the gland leads to acute injury and finally chronic pancreatitis. There is documented mutation of CFTR gene. This gene functions as a cyclic AMP-REGULATED CHLORIDE channel, which leads to high concentration of macromolecules which can block the pancreatic duct. Combination of N34S SPINK1 pancreatic secretary trypsin inhibitor gene mutation along with CFTR mutation increase risk by 900 folds. Basically the gene defects which lead to failure of protective mechanism of pancreas from auto digestion will lead to chronic pancreatitis. Auto immune pancreatitis (AIP) is an uncommon disorder of presumed autoimmune causation with characteristic histopathological, laboratory and morphological findings. Two type AIP AND Idiopathic duct centric pancreatitis (IDCP). In AIP pancreas is involved as part bof IgG4 systemic disease- histological findings include lymphoplasmocytic infiltrate, storiform fibrosis and abundant IgG4 cells. In IDCP- granulocytic infiltrate of duct wall with out IgG4 positve cells and systemic invovement. The Myo clinic HISTORt criteria indicates that AIP can be diagnosed by the presence of one or more of the following Histology 2. imaging, 3. eleveted IgG4, 4. other organ involvement and 5. response to Glucocorticoid therapy.
- Alcohol and other risk factors may trigger chronic pancreatitis through multiple mechanisms. The first sentinel episode of acute pancreatitis initiates an inflammatory response involving T-helper cell (Th). Then ongoing exposure to alcohol or other risk stimuli drives further inflammation but this is modified by regulatory T-cells(Treg). Toxic metabolic risk – Direct toxic injury to ductal and acinar cells of pancreas and oxidative damage due to ethyl ester a by product of alcohol in acinar cell, predisposes acinal cells to destroy trypsinogen which leads to auto digestion of acinar cell. Also directly stimulate CholeCystoKinin(CCK) production (duodenal I cells) – activation of pro-inflammatory transcription factor. Genetic defects that affects the gene encoding for trypsinogen. The defect in gene prevents destruction of prematurely activated trypsin and allows it to be resistant to intracellular protective effect of trypsin inhibitor. This repeated and continuous activation of digestive enzyme within the gland leads to acute injury and finally chronic pancreatitis. Combination of N34S SPINK1 pancreatic secretary trypsin inhibitor gene mutation along with CFTR mutation increase risk by 900 folds. CFTR –cystic fibrosis trans-membrane conductance regulator -- associated with abnormalities of HCO3 secretion, ductal dilatation, ppt formation, pancreatic atrophy. PRSS1 –cationic trypsinogen gene -- Once trypsinogen is activated to trypsin, becomes resistant to inactivation and activate other proenzymes leading to episodes of acute pancreatitis. SPINK1 –serine protease inhibitor Kazal type -- Seen in pediatric Idiopathic CP, hereditary Pancreatitis, Tropical Pancreatitis, but not in chronic alcoholic pancreatitis Necrosis fibrosis hypothesis -- Repeated episodes of acute pancreatitis with cellular necrosis or apoptosis, healing replaces necrotic tissue with fibrosis. Ductal obstruction hypothesis – Toxic stimuli- Protein rich pancreatic juice low in volume and HCO3 - Formation of protein presipitates ppt -plug - Calcification of ppt-duct stone formation- Ductul obstruction- Parenchymal damage
- According to this theory, First episode of acute pancreatitis is as a result of unregulated trypsin activation leads to massive inflammatory response divided into early and late phases. Early phase response due to –inflammatory cells and cytokines(TGF-BETA1, IL-1, IL-6) –fibrosis and activation of pancreatic stellate cells. If no further exposure to noxious stimulus pancreas should heal and recover. If noxious stimulus persists then activated PSC will directly stimulate cytokines leading to fibrosis and CP. PSC pathway somehow unifies other theories and describes common pathway. Recent studies also noted that PSC are also activated by its own intrinsic activation through macrophages this may be a reason for continuous process of inflammation and fibrosis of pancreas even after removal of noxious stimulus after diagnosis of CP.
- Patients with CP seek medical attention predominantly because of two symptoms 1. abdominal pain or maldigestion and weight loss. Abdominal pain may be quit variable in location, severity and frequency. The pain can be constant or intermittent with frequent pain free intervals. Eating may exacerbate the pain, leading to a fear of eating with consequent weight loss. The spectrum of pain ranges for mild to quite severe, with narcotic dependence as frequent consequence. Pain may be releived by leaning forward or by drinking alcohol. Maldigestion is manifested as chronic diarrhea, steatorrhea, weight loss and fatigue. Steatorrhea occurs when more than 90 % of pancreas tissue has been destroyed.. Protein malabsorption develops only in the most advance case (creatorrhea) About 20 % patients will present with symptoms of maldigestion without h/o abdominal pain.. Despite steatorrhea apparent deficiency of fat soluble vitamins is surprisingly uncommon. Physical sign usually unimpressive, so there is disparity between the severity of abdominal pain and physical sign that usually consists of some mild tenderness. Physical examination reveals thin, malnourished patient with epigastric tenderness. There is no biomarker test for the disease. Incontrast to acute pancreatitis serum amylase and lipase levels are not strikingly elevated. Many patients may have IFG.The fecal elastase levels will be abnormal and small bowel biopsy will be normal in this patients. Fecal elastase level <100micro grmasgm of stools suggest severe pancreatic exocrine insufficiency.
- Compartmental syndrome pain due to large and small duct obstruction 2. Neurogenic pain due to strtching of nerves 3. Pain due to ongoing inflammation due to release of local mediators likebradykinine, serotonin, tachykinine etc. 4. Neuronal damage due to peripheral sensitization and resultant central sensitization fundamental to development of persistant and refractory pain in CP. 5. Trypsin also having efect on sensory neurons 6. ‘Salutogenic response’ – Invovement of immune system-modulation of immune response by centres in brain. Abnormal immune response linked to brain mediated mechanisms, sustained the visceral inflammation and prolonged duration of pain-mal adaptive brain response. Which is treated by ‘Transcranial magnetic stimuli’.-IN TRIAL
- Diagnosis of CP requires permanent histological irregularity with persistent pain, with clinical and functional impairment of pancreatic function. Patients disease history i.e. h/o abdominal pain or malabsorption, steatorrhea, weight loss and DM in late stages, shall give rise to suspicion of the underlining disease. These patient shall undergo initial imaging modalities to r/o CP. Investigations can be divided in to three parts i.e. to establish diagnosis 2. To define pancreatic function and 3. To demonstrate anatomy before surgery
- Patients history, clinical signs and symptoms (abdominal pain, weight loss steatorrhea, malabsorption, h/o alcohol abuse, recurrent pancreatitis, fatty food intolerance- s/o CP Initial imagining shall be done with review of laboratory reports and faecal elastase measurement shall be considered. STEP-01-CT Scan-which may shows pancreatic calcification with atrophy of pancreas tissue and dilated pancreatic duct. Inconclusive go for STEP-02 -MRI/sMRCP: Cambridge class III, dilated duct atrophy of gland and filling defects in duct. Inconclusive go for STEP-03- Endoscopic ultrasound (EUS) 5 or >5 EUS criteria, Inconclusive go for STEP -04 - Pancreas function test(with secretin)-gastroduodinal or endoscopic collection method- CP diagnostic criteria: <80 mmol/L. Inconclusive go for STEP-05 -ERCP- Diagnostic criteria: Cambridge class III, dilated main pancreatic duct, and greater than 3 dilated side branch
- This I have already mentioned shall be done when suspicion arises
- Already mentioned
- Currently available diagnostic and treatment options for chronic pancreas are unsatisfactory in terms of early detection and prevention of it’s progression. As CP is a slowly progressing and uncurable disease that continues to afflict patients life, treatments are relatively limited.4Oncetha patent is diagnosed we should actively support lifestyle modifications (mainly cessation of alcohol consumption and smoking). Pain control should be managed carefully to prevent drug addiction. Exocrine insufficiency shall be treated with pancreatic enzymes replacement (i.e.PERT) and strict control of DM to prevent secondary complications