Acute Pancreatitis

Acute Pancreatitis Epidemiology

Second most common principal inpatient GI diagnosis after cholelithiasis and acute cholecystitis Unreliable data due to misdiagnosis Estimated yearly incidence of 5-40/100,000 1998 data from the U.S. about pancreatic diseases

327,000 inpatient stays 78,000 outpatient hospital visits 195,000 ER visits 531,000 office visits

>2800 deaths due to acute pancreatitis in 2000 Estimated annual cost in 2000 was $2,500,000,000

Natural History

80% of cases are mild 20% are severe with organ failure and local complications

Estimated 25-33% mortality

Overall mortality estimates range from 2% to 10% Half of death occur within the first week, perhaps 25% to 33% of deaths occur within the first 48 hours Obese patients have higher rates of local complications, respiratory failure, severe acute pancreatitis and death from sterile necrosis than non-obese patients Older and multi-morbid patients have higher mortality rates

Definition

Acute inflammation of the pancreas Varying degree of regional tissue involvement and remote organ systems Classified as acute unless there is evidence of chronic pancreatitis, otherwise considered as exacerbation of inflammation superimposed on chronic pancreatitis

Pathology

Initial injury to peripheral acinar cells, fat necrosis and autodigestion Interstitial (edematous) pancreatitis:

Interstitial edema associated with inflammatory cells in the parenchyma Parenchymal necrosis is microscopic Focal macroscopic or diffuse necrosis Hemorrhage, vascular thrombosis Involvement of the main pancreatic duct

Necrotizing pancreatitis

Pathogenesis of Acute Pancreatitis

Trypsinogen to trypsin conversion in acinar cells overwhelms neutralization mechanisms Proenzymes (trypsinogen, elastase, phospholipase A2 (PLA2) and carboxypeptidase) are activated by trypsin Activation of complement and kinin systems Pancreatic autodigestion with self-sustaining cycle of proteolytic, etc. enzyme activation

Etiologies of Acute Pancreatitis

Obstructive Toxic Metabolic Infectious Vascular Trauma Iatrogenic Hereditary Controversial etiologies

Obstructive causes of AP

Gallstones/microlithiasis Tumors Parasites (those causing obstruction, e.g. Ascaris, Clonorchis) Duodenal diverticula Annular pancreas Choledochocele Celiac sprue? (chronic duodenal inflammation causing ampullary stenosis)

Toxic and Metabolic Etiologies

Toxic

Ethanol Methyl alcohol Scorpion venom (hyperstimulation of pancreas) Organophosphate insecticides (hyperstimulation of pancreas) Drugs Hypertriglyceridemia Hypercalcemia

Metabolic

Other Causes

Cardiovascular
Small vessel vasculitis Emboli to pancreatic vessels Hypotension

Blunt and penetrating abdominal traumas Iatrogenic

ERCP Surgery

Gallstone/Biliary Pancreatitis

40% of all cases of AP Risk of AP due to existing gallstones is greater in men, but overall incidence is lower as gallstones are more common in women Small stones (< 5 mm) are more likely to cause pancreatitis

Biliary Sludge

Viscous suspension of gallbladder bile that may contain tiny stones (< 3 mm) Usually composed of cholesterol monohydrate crystals, but also occurs with ceftriaxone-bile complexes Appears as a mobile, low-amplitude echo without shadow Biliary sludge often develops in acute pancreatitis Controversies about microlithiasis causing acute pancreatitis and effectiveness of cholecystectomy remain due to lack of prospective and controlled data

Alcohol

Causes 30% of cases Most but not all patients also have some degree of underlying chronic pancreatitis Proposed mechanisms:

Sphincter of Oddi relaxation & duodenal reflux Increased pancreatic duct permeability Sudden release of pancreatic enzymes with inappropriate activation Increased protein concentration in pancreatic juice leading to obstruction of small ductules Direct toxicity of ethanol on acinar cells

Hypertriglyceridemia

Third most common identifiable cause of AP Serum triglycerides > 1000 mg/dL Median serum TG concentration ~ 3-4K Mechanism?

Possibly, release of free fatty acids may cause pancreatic acinar or capillary endothelial damage

Important cause in children with inherited disorders of lipoprotein metabolism

Hypertriglyceridemia

Associated conditions in adults

Diabetes mellitus Alcohol abuse (chicken or the egg?) Obesity Hypothyroidism Pregnancy Estrogen therapy Types I & V hyperlipoproteinemia

Hypercalcemia

Rare, proposed mechanism is due to deposition of calcium in the pancreatic duct with activation of trypsinogen in the pancreatic parenchyma Chronic hypercalcemia less likely to induce pancreatitis than acute increases (animal data) Hyperparathyroidism causes < 0.5% of all cases of acute pancreatitis Incidence of acute pancreatitis in hyperparathyroidism is reportedly 02%-1.5% Rarely after metastatic cancer with bone involvement, TPN, sarcoidosis, vitamin D toxicity and following parenteral perioperative infusion of Ca in high doses (cardiopulmonary bypass surgery)

Tumors

Probably cause AP due to obstruction of the pancreatic duct Usually in older patients Most common with intraductal papillary mucinous neoplasm/tumor (IPMN/IPMT) of the pancreas Also possible with ampullary neoplasms Less commonly due to pancreatic adenocarcinoma Rarely due to pancreatic metastasis (e.g. from lung and breast cancer)

Drugs General Considerations

Over 80 drugs implicated based on unconvincing anecdotal reports Usually mild and self-limited after stopping drug Reliable causative etiology requires:

Exclusion of other etiologies Appropriate interval (usually 4-8 weeks) since initiation of therapy Clear mechanism of drug-induced pancreatitis Reproducible recurrence of pancreatitis following reintroduction of the culprit drug

Drugs Implicated

-Methyldopa Mesalamine Cimetidine Cytosine arabinoside Dexamethasone Ethinylestradiol/ lynestrenol Furosemide Isoniazid 6-Meraptopurine Metronidazole Norethindrone/mestranol

Pentamidine Perindopril Pravastatin Procainamide Stibogluconate Sulfamethizole Sulfasalazine Sulindac Tetracycline TMP/SMX Didanosine Valproic acid

Potential Mechanisms

Hypersensitivity reactions
Usually after 4-8 weeks of starting medication Not dose-related On rechallenge, recurrent pancreatitis occurs after a few days E.g. 6-MP/azathioprine, aminosalicylates, metronidazole, tetracycline

Potential Mechanisms (Contd)

Accumulation of toxic metabolites

Onset typically occurs after several months E.g. valproic acid, didanosine

Hypertriglyceridemia

Thiazides, tamoxifen, isotretinoin

Intrinsic toxicity
Pancreatitis can occur with overdose Acetaminophen, erythromycin

Diagnosis of AP

Clinical findings Laboratory findings Radiological findings

Clinical Findings

Usually acute onset of severe pain Epigastric, upper quadrants Radiation to back and chest (DDx myocardial ischemia) Nausea, vomiting, hematemesis Bowel obstruction Fever, tachypnea, shock Ecchymoses on the flanks (Turners sign) Periumbilical ecchymosis (Cullens sign)

Laboratory findings

2-3 fold elevations of pancreatic enzymes amylase and/or lipase Amylase

Cheap, fast and widely available Not 100% sensitive or specific (normal values in mild attacks, in the setting of chronic pancreatitis or even with fatal pancreatitis have been reported) False positive (as far as AP Dx is concerned) with:

Macroamylasemia (e.g. IG-bound amylase not cleared by kidneys) Parotitis (can also be EtOH induced, look for hamster cheeks!) Salpingitis/ectopic pregnancy Bowel obstruction and perforation Renal failure/dialysis (but no correlation with crea clearance, Hemodialysis > peritoneal dialysis) Ovarian cysts incl. papillary cystadenoma, lung cancer

Lipase

Sensitivity similar to amylase (85%-100%) Probably more specific (all pancreatic except a small amount of gastric lipase) Usually remains elevated longer than amylase False positive values in:
Renal insufficiency Macrolipasemia Bowel obstruction, perforation and enteritis (increased reabsorption)

Other Pancreatic Enzymes

Generally speaking, no significant clinical advantage over routine tests due to:

Similar dynamics Expense Unavailability

Phospholipase A2 Trypsin Caboxypeptidase A Colipase Elastase Ribonuclease Trypsin Activation Peptide (TAP)

Other Lab Findings

Nonspecific findings include

Leukocytosis LFT abnormalities CRP and other acute reactants Serum triglycerides Azotemia Hyperglycemia

Radiological Findings

Plain Films:

Localized segment of small intestine (sentinel loop) Generalize ileus Calcifications (stones, or pancreas with chronic calcific pancreatitis) Pneumobilia following stone passage and/or bilioenteric fistula formation Severe ascites Retroperitoneal gas (pancreatic abscess) 30% with CXR abnormalities (elevated hemidiaphragm, pleural effusion, basal atelectasis, pulmonary infiltrates)

CT and US

Cross-sectional imaging with more specific pancreatic changes (i.v. contrast is needed for detecting necrosis and tumors) US may show biliary dilation, stones, pancreatic calcifications, hypoechoic appearance of the pancreas with edema, pseudocysts and peripancreatic fluid collections, ascites, but often limited in the acute setting due to overlying intestinal gas

Differential Diagnosis

Biliary pain and acute cholecystitis Epigastric distress syndrome/non-ulcer dyspepsia Peptic ulcer disease and perforated hollow viscus Small bowel obstruction Inferior myocardial infarction Aortic dissection Ruptured ectopic pregnancy Acute appendicitis

Range of Severity

Mild
Minimal or no organ dysfunction Full recovery without complications

Severe
Local complications Organ failure death

Predictors of Severity

Ransons Score 2: Mortality 2.5%* Ransons Score 3: Mortality 62%* Limitations of Ransons Score:
Cumbersome Takes 48 hours to compute Not validated beyond 48 hours Cutoff of 3 has sensitivity of 40%-88% for detecting disease and specificity of 43% to 90%

* Obtained within the first 48 hours

Ransons Criteria
Parameter On Admission Age (years) WBC (cells/mm3) Glucose (mg/dL) LDH (IU/L) AST (U/L) During initial 48h in hct (%) BUN (mg/dL) Calcium (mg/dL) pO2 (mm Hg) Base deficit (mEq/L) Fluid seq. estimate (L) 1974 (Alcoholic) >55 >16,000 >200 >350 >250 >10 >5 <8 <60 >4 >6 1982 (Biliary) >70 > 18,000 >220 >400 >250 >10 >2 <8 NA >5 >4

Atlanta Criteria for Severe AP

ORGAN FAILURE

Shock
Pulmonary insufficiency Renal failure GI bleeding Necrosis Abscess Pseudocyst

SBP < 90 mm Hg
pO2 60 mm Hg Serum creatinine > 2 mg/dL >500 mL/24 hr LOCAL COMPLICATIONS

UNFAVORABLE EARLY PROGNOSTIC SIGNS 3 Ransons criteria APACHE II score 8

Approach to Patient

Triage

Prognosis Placement
Could affect the acute management I.v. fluid resuscitation Nutritional support Analgesia

Etiology

Supportive care

Further care

Observation for early detection of potential complications Treatment of complication Nutritional support (10% rate of TPN line infections in patients with severe pancreatitis)

Nutritional Support

TPN disadvantages

Expensive High complication rate Generally associated with higher morbidity and longer lengths of stay than enteral feeding via nasoenteric tubes In mild to moderate AP, enteral feeding was started within 48 hours of admission and was associated with faster improvement and shorter LOS than TPN In severe/necrotizing pancreatitis, LOS, ICU stay etc. similar, but septic complications are less frequent with enteral feeding vs. TPN

Specific Management

Based on (suspected) etiology Includes emergent and elective items Diagnostic strategy incorporates potential probabilities and associated risks of diagnostic tests Therapeutic strategy incorporates potential probabilities and associated risks of therapeutic interventions

Recommended reading
William S. Steinberg: Acute Pancreatitis, in Sleisenger & Fordtrans Gastrointestinal and Liver Disease, 8th Edition 2006, SaundersElsevier