Pancreas Tavassoli,Alireza

نام درس :بيمار يهاي پانكراس اهداف نام درس :بيمار يهاي پانكراس اهداف 1-بيماري هاي پانكراس رابشناسد 2-عوامل سبب زاي بيماري هاي پانكراس را بشناسد 3- راه هاي پيشگيري بيماري هاي پانكراس را بداند. 4- نحوه مراقبت بيماري هاي پانكراس را فراگيرد. (Surveillance) 5-عوامل خطرزاي بيماري هاي پانكراس را بداند 6- ويژگي هاي اپيدميولوژيك بيماري هاي پانكراس را بشناسد . 7-روش هاي تشخیصی بيماري هاي پانكراس رابشناسد. 8- روش هاي درمان را بداند.

Normal Anatomy & Physiology neutralize chyme digestive enzymes hormones The pancreas lies in the retroperitoneum nestled in the C-loop of the duodenum and posterior to the stomach. Physiologic function of the pancreas. The human pancreas has three general functions: (1) neutralizing the acid chyme entering the duodenum from the stomach; (2) synthesis and secretion of digestive enzymes after a meal; and (3) systemic release of hormones that modulate metabolism of carbohydrates, proteins, and lipids.

Exocrine Function pancreatic enzymes common bile duct pancreatic duct BODY common bile duct TAIL HEAD ampulla pancreatic duct To understand pancreatitis, you need a basic understanding of pancreatic exocrine function UNCINATE pancreatic enzymes

Enzyme Secretion acinus pancreatic duct microscopic view The pancreatic acinar cells are specialized cells which synthesize, store, and secrete digestive enzymes These digestive enzymes are stored in zymogen granules (shown in blue) which serve as a compartment for inactive pro-enzymes thus preventing auto-activation. pancreatic duct microscopic view of pancreatic acini duodenum

Enzyme Secretion Neural Hormonal Secretin (hormonal) acetylcholine VIP GRP Hormonal CCK gastrin Enzyme secretion is stimulated by neural pathways or by hormones with 2 most potent stimulators being CCK and secretin. The pancreatic fluid is rich in bicarbonate which makes it alkaline and the total daily volume is approx. 2.5 L. Secretin (hormonal) H2O bicarbonate

Digestive Enzymes in the Pancreatic Acinar Cell PROTEOLYTIC LIPOLYTIC ENZYMES ENZYMES Lipase Trypsinogen Prophospholipase A2 Chymotrypsinogen Carboxylesterase lipase Proelastase Procarboxypeptidase A NUCLEASES Procarboxypeptidase B Deoxyribonuclease (DNAse) Ribonuclease (RNAse) AMYOLYTIC ENZYMES Amylase OTHERS Procolipase Trypsin inhibitor There are several different classes of digestive enzymes secreted by the pancreatic acinar cells. Most of these enzymes are proenzymes which are inactive with the exceptions of amylase and lipase. Protein Starch and glycogen Fat Amino acids Other

Exocrine Stimulation The more proximal the nutrient infusion…the greater the pancreatic stimulation (dog studies) stomach – maximal stimulation duodenum – intermediate stimulation jejunum – minimal / negligible stimulation Elemental formulas tend to cause less stimulation than standard intact formulas intact protein > oligopeptides > free amino acids Intravenous nutrients (even lipids) do not appear to stimulate the pancreas

Acute Pancreatitis

Clinical Case A man with acute onset abdominal pain h/o alcohol intake Or Gall stone A 32-year-old man is admitted to the hospital with acute onset abdominal pain of presumed pancreatic origin.

Acute Pancreatitis Definition Acute inflammatory process involving the pancreas Usually painful and self-limited Isolated event or a recurring illness Pancreatic function and morphology return to normal after (or between) attacks Here are the details…

Acute Pancreatitis Etiology

Acute Pancreatitis Associated Conditions Cholelithiasis Ethanol abuse Idiopathic Medications Hyperlipidemia ERCP Trauma Pancreas divisum Hereditary Hypercalcemia Viral infections Mumps Coxsackie virus End-stage renal failure Penetrating peptic ulcer

Acute Pancreatitis Causative Drugs AIDS therapy: pentamidine ,didanosine Anti-inflammatory: sulindac, salicylates Antimicrobials: metronidazole, sulfonamides, tetracycline, nitrofurantoin Diuretics: furosemide, thiazides IBD: sulfasalazine, mesalamine Immunosuppressives: azathioprine, 6-mercaptopurine Neuropsychiatric: valproic acid Other: calcium, estrogen, tamoxifen,

Pancreas divisum

Hereditary Pancreatitis Autosomal dominant with 80% phenotypic penetrance Recurrent acute pancreatitis, chronic pancreatitis, and 50-fold increased risk of pancreatic cancer

Pancreatitis Background Potentially fatal Mortality – 10-15% Necrosis determines the prognosis Acute pancreatitis is a potentially fatal disease, with reported mortality rates ranging from zero to almost 25%, depending on severity. Severity itself depends greatly on whether or not pancreatic necrosis is present. Since majority of the patients with mild acute pancreatitis recover without any short term complications or long term sequelae. So majority of the studies have focussed on management of acute necrotizing pancreatitis. I would also

Background Mild AP (no necrosis) – 0% Sterile necrosis – 10% Infected necrosis – 25% Overall mortality: 10-15% Since majority of the patients with mild acute pancreatitis recover without any short term complications or long term sequelae. So majority of the studies have focussed on management of acute necrotizing pancreatitis. I would also

What do you think? Amylase or lipase Ultrasound or CT scan If yes, When? ICU or medical ward Enteral nutrition or TPN Antibiotics ERCP Surgery

Epidemiology of acute pancreatitis There appears to be an increase in the incidence of acute pancreatitis. This rise attributed to increased alcohol consumption No seasonal or weekly Men are affected much more than women Main age group affected is 40–60 year olds.

Acute Pancreatitis Pathogenesis acinar cell injury failed protective mechanisms premature enzyme activation talk about failure of compartmentalization, premature activation, and overwhelming or absence of inhibitors

Acute Pancreatitis Pathogenesis premature enzyme activation autodigestion of pancreatic tissue local vascular insufficiency activation of white blood cells release of enzymes into the circulation local complications distant organ failure

Acute Pancreatitis Pathogenesis SEVERITY Mild Severe STAGE 1: Pancreatic Injury Edema Inflammation STAGE 2: Local Effects Retroperitoneal edema Ileus STAGE 3: Systemic Complications Hypotension/shock Metabolic disturbances Sepsis/organ failure Three stages of pathophysiology of acute pancreatitis The pathophysiology of acute pancreatitis can be considered as involving three stages. The first stage is pancreatic injury with edema, inflammation, necrosis of pancreatic fat, and variable degrees of necrosis of pancreatic secretory cells. The second stage is spread of the inflammatory process to surrounding tissues, with development of retroperitoneal edema, peripancreatic fat necrosis, and an ileus, with ;third spacing; of fluid and electrolytes in the gastrointestinal tract resulting in hemoconcentration (increased hematocrit). The third stage involves systemic complications, such as hypotension/shock, multiorgan system failure (eg, respiratory, renal), metabolic disturbances, such as hypoalbuminemia and hypocalcemia, and sepsis.

Pathophysiology of necrosis infection

Pancreatitis Clinical Presentation Pain: Steady & severe in nature; located in the epigastric or umbilical region; may radiate to the back. Worsened by lying supine; may be lessened by flexed knee, curved-back position. Vomiting: Varies in severity, but is usually protracted, worsened by ingestion of food or fluid. Does not relieve the pain. Usually accompanied by nausea.

Pancreatitis con’t…… Fever: Rarely exceeds 39 C. Abdominal Finding: Rigidity, tenderness, guarding, distended Abd, decreased or absent peristalsis and paralytic ileus.Fatty stools-(steatorrhea) Laboratory Finding: Elevation of WBC count- 20-50,000. lipase and amylase(5 to 40 times); elevated(glucose, bilirubin, alkaline phosphatase.,Urine amylase).Abnormal low serum CA, Na & Mg.-due to dehydration. Binding of Ca in areas of fat necrosis.

Acute Pancreatitis

Acute Pancreatitis

Acute Pancreatitis

Acute Pancreatitis

Acute Pancreatitis Differential Diagnosis Choledocholithiasis Perforated ulcer Mesenteric ischemia Intestinal obstruction Ectopic pregnancy

Acute Pancreatitis Diagnosis Symptoms & Signs Abdominal pain Laboratory Elevated amylase or lipase > 3x upper limits of normal Imaging Abnormal sonogram or CT

Acute Pancreatitis Diagnosis EtOH: history Gallstones: abnormal LFTs & sonographY Hyperlipidemia: lipemic serum, Tri>1,000 Hypercalcemia: elevated Ca Trauma: history Medications: history

Abdominal Exam Skin Exam Abdominal tenderness and rigidity Bowel sounds decreased Palpable upper abdominal mass Acute fluid collections and pseudocysts Skin Exam Erythematous skin Nodule (Subcutaneous Fat Necrosis) Cullen's Sign (periumbilical discoloration) Turner's Sign (flank discoloration) * due to exudation of blood-stained fluid into the subcutaneous tissue, usually 72 h into the illness.

Acute Pancreatitis Clinical Manifestations PANCREATIC PERIPANCREATIC Adjacent viscera: SYSTEMIC Mild: edema, inflammation, fat necrosis Severe: phlegmon, necrosis, hemorrhage, infection, abscess, fluid collections Retroperitoneum, perirenal spaces, mesocolon, omentum, and mediastinum ileus, obstruction, perforation Cardiovascular: hypotension Pulmonary: pleural effusions, ARDS Renal: acute tubular necrosis Hematologic: disseminated intravascular coag. Metabolic: hypocalcemia, hyperglycemia

Diagnosis: Biochemical Serum Amylase elevated Nonspecific Returns to normal in 48-72 hours Normal amylase does not exclude pancreatitis Level of elevation does not predict disease severity Serum Lipase elevated Specific for pancreatic disease Returns to normal in 7-14 days

Diagnosis: Biochemical White Blood Cells increased to 15k-20k Hypertriglyceridemia (15%) liver Function Tests (ALP) (AST) ,elevated (LDH) elevated (Poor prognosis) Hyperglycemia Albumine (Poor prognosis) Serum Electrolytes Hypocalcemia (25%)

Acute Physiology And Chronic Health Evaluation Another criteria often used to assess the severity of pancreatitis is the (APACHE-II) . Acute Physiology And Chronic Health Evaluation age and vital signs Specific laboratory parameters, Chronic health status The main advantage is the immediate assessment of the severity of pancreatitis. A score of eight or more at admission is usually considered indicative of severe disease

Predictors of Severity Why are they needed? Appropriate triage & therapy compare results of studies of the impact of therapy When are they needed? optimally, within the first 24 hours Which is the best?

Ranson Criteria Alcoholic Pancreatitis AT ADMISSION Age > 55 years WBC > 16,000 Glucose > 200 AST > 250 IU/L LDH > 350 IU/L WITHIN 48 HOURS HCT drop > 10% BUN > 5 Arterial PO2 < 60 mm Hg Base deficit > 4 mEq/L Serum Ca < 8 Fluid sequestration > 6L Number <2 1% 3-4 16% 5-6 40% 7-8 100% Mortality

Glasgow Criteria Non-alcoholic Pancreatitis WBC > 15,000 Glucose > 180 BUN > 16 Arterial PO2 < 60 mm Hg Ca < 8 Albumin < 3.2 LDH > 600 U/L AST or ALT > 200 U/L

Balthazar et al. Radiology 1990. CT Severity Index appearance normal enlarged inflamed 1 fluid collection 2 or more collections grade A B C D E score 1 2 3 4 necrosis none < 33% 33-50% > 50% score 2 4 6 So, even if we can’t identify severe cases sooner, the CT index appears to be the best way to judge severity. score morbidity mortality 1-2 4% 0% 7-10 92% 17% Balthazar et al. Radiology 1990.

Useful markers of severe disease. Pleural effusion BMI (High body mass index) Necrosis on contrast-enhanced CT-SCAN CRP level greater than 150 mg/L at 48 h Infection of the necrotic tissue after the first week of illness is the major determinant of later outcome.

Pancreatic necrosis

CT-guided percutaneous fine-needle aspiration of the pancreatic tail

Immediate assessment Clinical assessment including great care to assess respiratory, cardiovascular and renal compromise. Organ failure ? BMI?. There is considerable risk (> 30 kg/m2) or much greater risk > 40 kg/m2 Chest X-ray. Is there a pleural effusion present? CT.Scan Is there more than 30% of the volume of the pancreas malperfused? Scoring. Is it high score or low?

Resuscitation Transudation of fluid from the intravascular space to the peritoneum is the principle cause of hypovolemia in AP. Assessment of the patient’s volume status determined by heart rate, blood pressure, urine output and CVP line.

Treatment of Mild Pancreatitis Pancreatic rest Supportive care fluid resuscitation – watch BP and urine output pain control NG tubes ,H2 blockers ,PPIs helpful?? Refeeding (usually 3 to 7 days) bowel sounds present patient is hungry nearly pain-free (off IV narcotics) amylase & lipase not very useful here mild panc – support is all that’s needed hypotension probably predisposes to necrosis (poor microcirculation)

Treatment of Severe Pancreatitis Pancreatic rest & supportive care fluid resuscitation* – may require 5-10 liters/day careful pulmonary & renal monitoring – ICU maintain hematocrit of 26-30% pain control – PCA pump correct electrolyte derangements (K+, Ca++, Mg++) Rule-out necrosis contrasted CT scan at 48-72 hours prophylactic antibiotics if present surgical debridement if infected Nutritional support may be NPO for weeks, TPN *common serious error to underestimate volume needs may need SG catheter – lookout for ARF or ARDS we have impacted the early mortality by better support…late mortality still problem

Analgesia Severe pain should be treated with meperidine 50 to 100 mg IM q 3 to 4 h prn in patients with normal renal function (morphine causes the sphincter of Oddi to contract and should be avoided).

Antibiotic prophylaxis Infectious complications are still regarded as the primary cause of mortality in severe pancreatitis.Thus, it is essential to identify the presence of pancreatic necrosis and take measures to prevent infection. The current recommendation is the use of a systemic antibiotic such as imipenem-cilastatin 500 mg three times a day for 2 weeks in patients with documented pancreatic necrosis.

Role of ERCP in pancreatitis 1-Gallstone pancreatitis Cholangitis Obstructive jaundice 2-Recurrent acute pancreatitis Structural abnormalities Neoplasm Bile sampling for microlithiasis 3-Sphincterotomy in patients not suitable for cholecystectomy

Reduced Oral Intake in Acute Pancreatitis Abdominal pain with food Nausea and vomiting Gastric atony Ileus Partial duodenal obstruction

Summary 1-The overall mortality ranges from 2 to 10%. The incidence in males is usually 10–30% higher than in females. 2-The commonest cause is gallstones with alcohol being the next most common cause. 3-Patients with acute pancreatitis present with upper abdominal pain and/or different degrees of organ failure. 4-The diagnosis is suspected by a typical clinical presentation and supported by raised serum amylase. Atypical presentations may require confirmation by CT imaging. 5-Immediate management comprises analgesics, intravenous fluids and monitoring.

6-Acute pancreatitis, severity best defined by failure of one or more organ systems and/or the Acute Physiology and Chronic Health Evaluation, (APACHE II) score of 8 or more. 7-Gallstone etiology is usually identified by early routine abdominal ultrasonography. 8-The majority of patients have mild pancreatitis and recover without additional treatment. 9-In 20%, the disease is severe and is associated with a mortality of about 20%. 10-Patients with severe pancreatitis require management in a high dependency or intensive care setting; this may require transfer to a specialized unit. 11-Clinical severity is paralleled by the degree of pancreatic and peripancreatic tissue necrosis as defined by dynamic CT. 12-Antibiotic prophylaxis is advised in patients with greater than 30% necrosis and imipenem is recommended currently.

12- Enteral nutrition probably retains the integrity of the intestinal mucosal barrier and hence early mesenteric feeding is recommended. Parenteral nutrition is rarely indicated. 13- In patients with severe gallstone pancreatitis, early endoscopic retrograde cholangiography is indicated and, where appropriate, a sphincterotomy and clearance of the bile duct. 14--Where infection of pancreatic necrosis is proved by the presence of positive FNA or free gas in the area of necrosis, surgical intervention is indicated. 15--In sterile necrosis, continued conservative management is justified. 16--Patients with gallstone pancreatitis should either undergo cholecystectomy or endoscopic sphincterotomy and bile duct clearance prior to discharge. 17--Acute fluid collections are a feature of severe acute pancreatitis and often resolve spontaneously. 18--Pancreatic and peripancreatic abscesses, symptomatic pseudocysts and other ductal disruptions require interventional treatment.

Factors Differentiating Mild from Severe Pancreatitis Parameter Mild Pancreatitis Severe Admissions 80% 20% Pancreatic necrosis No Yes Oral diet within 5 days 0% Morbidity 8% 38% Mortality 3% 27%

Total Enteral Nutrition in Severe Pancreatitis may start as early as possible when emesis has resolved ileus is not present nasojejunal route preferred over nasoduodenal likely decreases risk of infectious complications by reducing transmigration of colonic bacteria

Conclusions ( MOUSE CLICK) Acute pancreatitis is a self-limited disease Most cases are mild. Gallstones and alcohol are the leading causes of acute pancreatitis. In mild pancreatitis, nutritional support is usually not required In severe pancreatitis, nutritional support will likely be required with the enteral route preferred over TPN because of both safety and cost.

Evidence A. Proven B. Possible/ Probable C. Consensus > 2 well designed trials, randomized B. Possible/ Probable 1 well designed study, randomized C. Consensus agreed opinion with no supportive evidence