Navid Madani, Acute Pancreatitis (March 2007)

7/30/2019 Navid Madani, Acute Pancreatitis (March 2007)

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Acute Pancreatitis Epidemiology

Second most common principal inpatient GI diagnosisafter 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


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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


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Definition

Acute inflammation of the pancreas

Varying degree of regional tissue involvementand remote organ systems

Classified as acute unless there is evidence ofchronic pancreatitis, otherwise considered asexacerbation of inflammation superimposed onchronic pancreatitis


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Pathology

Initial injury to peripheral acinar cells, fat necrosis andautodigestion

Interstitial (edematous) pancreatitis:

Interstitial edema associated with inflammatory cells in theparenchyma

Parenchymal necrosis is microscopic

Necrotizing pancreatitis

Focal macroscopic or diffuse necrosis Hemorrhage, vascular thrombosis

Involvement of the main pancreatic duct


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Pathogenesis of Acute Pancreatitis

Trypsinogen to trypsin conversion in acinar cellsoverwhelms neutralization mechanisms

Proenzymes (trypsinogen, elastase,phospholipase A2 (PLA2) and carboxypeptidase)are activated by trypsin

Activation of complement and kinin systems

Pancreatic autodigestion with self-sustainingcycle of proteolytic, etc. enzyme activation


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Etiologies of Acute Pancreatitis

Obstructive

Toxic

Metabolic

Infectious Vascular

Trauma

Iatrogenic Hereditary

Controversial etiologies


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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)


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Toxic and Metabolic Etiologies

Toxic

Ethanol

Methyl alcohol

Scorpion venom (hyperstimulation of pancreas) Organophosphate insecticides (hyperstimulation of pancreas)

Drugs

Metabolic

Hypertriglyceridemia

Hypercalcemia


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Other Causes

Cardiovascular

Small vessel vasculitis

Emboli to pancreatic vessels

Hypotension

Blunt and penetrating abdominal traumas

Iatrogenic ERCP

Surgery


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Gallstone/Biliary Pancreatitis

40% of all cases of AP

Risk of AP due to existing gallstones is greater inmen, but overall incidence is lower as gallstonesare more common in women

Small stones (< 5 mm) are more likely to causepancreatitis


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Biliary Sludge

Viscous suspension of gallbladder bile that may containtiny 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 acutepancreatitis and effectiveness of cholecystectomyremain due to lack of prospective and controlled data


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Alcohol

Causes 30% of cases

Most but not all patients also have some degree ofunderlying 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


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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 causepancreatic acinar or capillary endothelial damage

Important cause in children with inheriteddisorders of lipoprotein metabolism


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Associated conditions in adults

Diabetes mellitus

Alcohol abuse (chicken or the egg?)

Obesity

Hypothyroidism

Pregnancy

Estrogen therapy

Types I & V hyperlipoproteinemia


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Hypercalcemia

Rare, proposed mechanism is due to deposition of calcium in thepancreatic duct with activation of trypsinogen in the pancreaticparenchyma

Chronic hypercalcemia less likely to induce pancreatitis thanacute increases (animal data)

Hyperparathyroidism causes < 0.5% of all cases of acutepancreatitis

Incidence of acute pancreatitis in hyperparathyroidism isreportedly 02%-1.5%

Rarely after metastatic cancer with bone involvement, TPN,sarcoidosis, vitamin D toxicity and following parenteralperioperative infusion of Ca in high doses (cardiopulmonarybypass surgery)


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Tumors

Probably cause AP due to obstruction of the pancreaticduct

Usually in older patients

Most common with intraductal papillary mucinousneoplasm/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)


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DrugsGeneral Considerations

Over 80 drugs implicated based on unconvincinganecdotal 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 oftherapy

Clear mechanism of drug-induced pancreatitis

Reproducible recurrence of pancreatitis following

reintroduction of the culprit drug


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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


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Potential Mechanisms

Hypersensitivity reactions

Usually after 4-8 weeks of starting medication

Not dose-related

On rechallenge, recurrent pancreatitis occurs after afew days

E.g. 6-MP/azathioprine, aminosalicylates,

metronidazole, tetracycline


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Potential Mechanisms (Contd)

Accumulation of toxic metabolites

Onset typically occurs after several months

E.g. valproic acid, didanosine


Thiazides, tamoxifen, isotretinoin

Intrinsic toxicity

Pancreatitis can occur with overdose

Acetaminophen, erythromycin


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Diagnosis of AP

Clinical findings

Laboratory findings

Radiological findings


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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)


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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 beenreported)

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


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Lipase

Sensitivity similar to amylase (85%-100%)

Probably more specific (all pancreatic except asmall amount of gastric lipase)

Usually remains elevated longer than amylase False positive values in:

Renal insufficiency

Macrolipasemia Bowel obstruction, perforation and enteritis

(increased reabsorption)


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Other Pancreatic Enzymes

Generally speaking, no significant clinical advantage over routinetests due to: Similar dynamics Expense Unavailability

Phospholipase A2 Trypsin Caboxypeptidase A Colipase

Elastase Ribonuclease Trypsin Activation Peptide (TAP)


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Other Lab Findings

Nonspecific findings include

Leukocytosis

LFT abnormalities

CRP and other acute reactants

Serum triglycerides

Azotemia

Hyperglycemia


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Radiological Findings

Plain Films: Localized segment of small intestine (sentinel loop)

Generalize ileus

Calcifications (stones, or pancreas with chronic calcificpancreatitis)

Pneumobilia following stone passage and/or bilioentericfistula formation

Severe ascites

Retroperitoneal gas (pancreatic abscess) 30% with CXR abnormalities (elevated hemidiaphragm,

pleural effusion, basal atelectasis, pulmonary infiltrates)


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CT and US

Cross-sectional imaging with more specificpancreatic changes (i.v. contrast is needed fordetecting necrosis and tumors)

US may show biliary dilation, stones, pancreaticcalcifications, hypoechoic appearance of thepancreas with edema, pseudocysts andperipancreatic fluid collections, ascites, butoften limited in the acute setting due tooverlying intestinal gas


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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


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Range of Severity

Mild Minimal or no organ dysfunction

Full recovery without complications

Severe

Local complications Organ failure

death


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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 detectingdisease and specificity of 43% to 90%

* Obtained within the first 48 hours


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Ransons Criteria

Parameter 1974 (Alcoholic) 1982 (Biliary)

On Admission

Age (years) >55 >70

WBC (cells/mm3) >16,000 > 18,000

Glucose (mg/dL) >200 >220

LDH (IU/L) >350 >400

AST (U/L) >250 >250

During initial 48h

in hct (%) >10 >10

BUN (mg/dL) >5 >2Calcium (mg/dL) 6 >4


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Atlanta Criteria for Severe AP

ORGAN FAILURE

Shock SBP < 90 mm Hg

Pulmonary insufficiency pO2 60 mm Hg

Renal failure Serum creatinine > 2 mg/dL

GI bleeding >500 mL/24 hr

LOCAL COMPLICATIONS

Necrosis

Abscess

Pseudocyst

UNFAVORABLE EARLY PROGNOSTIC SIGNS

3 Ransons criteria

APACHE II score 8


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Approach to Patient

Triage Prognosis

Placement

Etiology Could affect the acute management

Supportive care I.v. fluid resuscitation

Nutritional support Analgesia


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Nutritional Support

TPN disadvantages Expensive

High complication rate

Generally associated with higher morbidity and longer lengthsof stay than enteral feeding via nasoenteric tubes

In mild to moderate AP, enteral feeding was started within 48hours of admission and was associated with fasterimprovement 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


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Specific Management

Based on (suspected) etiology

Includes emergent and elective items

Diagnostic strategy incorporates potentialprobabilities and associated risks of diagnostictests

Therapeutic strategy incorporates potentialprobabilities and associated risks of therapeuticinterventions


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Recommended reading

William S. Steinberg: Acute Pancreatitis, inSleisenger & Fordtrans Gastrointestinal and

Liver Disease, 8th Edition2006, Saunders-Elsevier

Documents

Navid Madani, Acute Pancreatitis (March 2007)