pathphysio

8/7/2019 Pathphysio

1/29

49

GALLSTONE PANCREATITIS

Overview

Responsible for 40-50%% of all cases of acute pancreatitis

3/4

th

of all cases involve women

The common channel concept- Caused by stone impaction at the ampulla of

vater-supported

by Acosta and Ledesma 1974 who found stones in feces of 94% of patients with

acute

gallstone pancreatitis

Uncertain if obstruction causes bile reflux into the pancreatic duct or if increased

duct

pressures in conjunction with continued enzyme secretion in the face of obstruction

Presentation/Diagnosis

Patients usually complain of epigastric pain radiating towards the back with

associated

nausea and vomiting.

Labs- CBC, LFTs (elevated Bilirubin/Alkaline Phosphatase, AST/ALT,

Amylase/Lipase)

KUB/CXR- rule out perforated viscus

CT Scan with contrast- for delineation of pancreatic necrosis/edema

U/S- Evidence of cholelithiasis, CBD dilation, choledocholethiasis- very difficult to

detect

stones in CBD

Predictors of Outcome

In the majority of cases, symptoms are mild and the pancreatitis resolves

10% of cases are severe, progressing to pancreatic necrosis/sepsis/death

8/7/2019 Pathphysio

2/29

Ransons Criteria- 11 variables in first 48hrs

Admission Within 48hrs

Age>70 HCT drop>10 2 or less- mortality18,000 BUN increase>2 3 - 5- mortality 10%

Glucose>220 Calcium400 Base deficit>5

AST>250 PaO24L50

Glasgow Scale

Age, Leukocyte count, glucose, BUN, PaO2, Calcium, albumin, LDH- all at 48hrs of

admission

APACHE II (Acute Physiology Score And Chronic Heath Evaluation)

Age points, Chronic health points, and lab values upon admission

Score>9 denotes severe acute pancreatitis

Management

Supportive care- NPO/Fluid resuscitation/Correction of electrolyte

imbalances/Analgesia/NGT for persistent vomiting

Antibiotics are not indicated in mild forms of pancreatitis. If there is evidence of

pancreatic

necrosis on CT scan- antibiotics have been shown to reduce morbidity/mortality.

Imipenem

is drug of choice.

In mild forms of pancreatitis, symptoms improve within 24-48 hrs with

improvement in

LFTs

Amylase and Lipase levels do not predict severity or outcome

ERCP- Controversial if ERCP is necessary in all cases of gallstone pancreatitis. In

mild

8/7/2019 Pathphysio

3/29

forms of pancreatitis, the stone usually passes from the CBD to the duodenum

within 24-48

hrs. Manipulation of the ampulla as well as introduction of air into the ductal

system

elevates pressures and may worsen pancreatitis.

However, if the attack is severe or if symptoms do not improve, ERCP may be

indicated.

The stone is removed and a sphincterotomy performed with stent placement.

4 randomized controlled trials

Study Predictor of

Severity

ERCP Conservative

Therapy

Complications of

ERCP group

Complication of

Conservative

Therapy

Length of

Hospitalization

UK 1988 Glasgow scale

0-2 Mild

3-8 Severe

At 72hrs N=59

Mild N=34

Severe N=25

N=62

8/7/2019 Pathphysio

4/29

Mild N=34

Severe N=28

Mild=12%

Severe=24%

Mild=12%

Severe=61%

ERCP-9.5

days

Conservative-

17

Overall mortality did not differ between ERCP vs Conservative therapy (2% vs 8%)

p=.23

Study Predictor of

Severity

ERCP Conservative

Therapy

Mortality Complications

HK 1993 Ransons Criteria

severe

N=64

Mild N=34

Severe N=30

N=63

Mild N=35

Severe N=28

2%vs8%(NS)

8/7/2019 Pathphysio

5/29

0%vs0%

12%vs22%

16%vs33% p=.03

18%vs17%

13%vs54%

Patients underwent ERCP within 24hrs of admission

Study Predictor of

Severity

ERCP Conservative

Therapy


German 1997 Glasgow Scale

0-2 Mild

3-8 Severe

N=126

Mild N=100

Severe N=26

N=112

Mild N=92

Severe N=20

16%vs9%(NS) 46%vs51%(NS)

Higher rate of complications, especially respiratory failure in the early ERCP group

Highly criticized study- 22 participating sites, operator variability, exclusion of

relevant patients51

Study Predictor of Severity ERCP Conservative

Therapy


8/7/2019 Pathphysio

6/29

Polish 1995 None N=178 N=102 2%vs13% 17%vs36

Published only in abstract form. No stratification of groups into mild vs severe

forms of

pancreatitis

*early ERCP (within 24 - 72hours) should only be performed in cases of severe acute

gallstone

pancreatitis

Patients should be started on oral feeds as soon as there is improvement in

symptoms and

evidence of resolution of ileus.

For mild pancreatitis patients should undergo cholecystectomy with intra-op

cholangiogram prior

to discharge as the risk of recurrence is high (30%).

Henry Lin, M.D.

Biliary Pancreatitis Symptoms

TEXT SIZE: A A | POST A COMMENT | PRINT

The pancreas is a gland that aids the digestive process by secreting

digestive juices into the first part of the small intestine via a tube that

is called the pancreatic duct. The digestive juices join with bile, which

is produced by the liver, to digest food. The pancreas also is

responsible for releasing insulin and glucagon into the bloodstream.

Pancreatitis is condition in which the pancreas becomes inflamed. In

biliary pancreatitis, pancreatic duct becomes obstructed. Digestive

juices that are normally released into the small intestine begin

attacking the pancreatic tissue that produced them.
http://tmp/svjgo.tmp/javascript:window.print()http://tmp/svjgo.tmp/javascript:window.print()

8/7/2019 Pathphysio

7/29

8/7/2019 Pathphysio

8/29

Buy the Book

PDA Download

Update Me

E-mail alerts

The Merck ManualMinute

Print This Topic

Email This Topic

Acute pancreatitis is inflammation of the pancreas (and, sometimes,

Acute Pancreatitis
http://www.merck.com/htbin/redirects/redirector.pl?url=http://www.merckbooks.com/redirect/mmpe1.htmlhttp://www.merck.com/htbin/redirects/redirector.pl?url=http://www.merckbooks.com/redirects/MM18-PDA.htmlhttp://www.merck.com/pubs/email_alert.htmlhttp://www.merckmanualminute.com/http://www.merckmanualminute.com/http://www.merckmanuals.com/professional/print/sec02/ch015/ch015b.htmlhttp://tmp/svjgo.tmp/javascript:emailpage();http://www.merck.com/htbin/redirects/redirector.pl?url=http://www.merckbooks.com/redirect/mmpe1.htmlhttp://www.merck.com/htbin/redirects/redirector.pl?url=http://www.merckbooks.com/redirects/MM18-PDA.htmlhttp://www.merck.com/pubs/email_alert.htmlhttp://www.merckmanualminute.com/http://www.merckmanualminute.com/http://www.merckmanuals.com/professional/print/sec02/ch015/ch015b.htmlhttp://tmp/svjgo.tmp/javascript:emailpage();

8/7/2019 Pathphysio

9/29

adjacent tissues) caused by the release of activated pancreatic

enzymes. The most common triggers are biliary tract disease and

chronic heavy alcohol intake. The condition ranges from mild

(abdominal pain and vomiting) to severe (pancreatic necrosis and a

systemic inflammatory process with shock and multiorgan failure).Diagnosis is based on clinical presentation and serum amylase and

lipase levels. Treatment is supportive, with IV fluids, analgesics,

and fasting.

Etiology

Biliary tract disease and alcoholism account for 80% of acute

pancreatitis cases. The remaining 20% result from myriad causes(see Table 1: Pancreatitis: Some Causes of Acute Pancreatitis ).

Table 1

Some Causes of Acute Pancreatitis

Cause Example

Drugs ACE inhibitors, asparaginase

, azathioprine

, 2, 3-dideoxyinosine, furosemide

, 6- mercaptopurine

, pentamidine

, sulfa drugs, valproate

8/7/2019 Pathphysio

10/29

Infectious Coxsackie B virus, cytomegalovirus, mumps

Inherited Multiple known gene mutations, including a small percentage of

cystic fibrosis patients

Mechanical/structural Gallstones, ERCP, trauma, pancreatic or periampullary cancer,

choledochal cyst, sphincter of Oddi stenosis, pancreas divisum

Metabolic Hypertriglyceridemia, hypercalcemia (including

hyperparathyroidism), estrogen use associated with high lipid

levels

Toxins Alcohol, methanol

Other Pregnancy, postrenal transplant, ischemia from hypotension or

atheroembolism, tropical pancreatitis

Pathophysiology

The precise mechanism by which obstruction of the sphincter of

Oddi by a gallstone or microlithiasis (sludge) causes pancreatitis is

unclear, although it probably involves increased ductal pressure.

Prolonged alcohol intake (> 100 g/day for > 3 to 5 yr) may cause the

protein of pancreatic enzymes to precipitate within small pancreatic

ductules. Ductal obstruction by these protein plugs may cause

premature activation of pancreatic enzymes. An alcohol binge in

such patients can trigger pancreatitis, but the exact mechanism is

not known.

A number of genetic mutations predisposing to pancreatitis have

been identified. One, an autosomal dominant mutation of the

cationic trypsinogen gene, causes pancreatitis in 80% of carriers;

an obvious familial pattern is present. Other mutations have lesser

penetrance and are not readily apparent clinically except through

genetic testing. The genetic abnormality responsible for cystic

fibrosis increases the risk of recurrent acute as well as chronic

pancreatitis.

Regardless of the etiology, pancreatic enzymes (including trypsin,

phospholipase A2, and elastase) become activated within the gland

itself. The enzymes can damage tissue and activate complement

8/7/2019 Pathphysio

11/29

and the inflammatory cascade, producing cytokines. This process

causes inflammation, edema, and sometimes necrosis. In mild

pancreatitis, inflammation is confined to the pancreas; the mortality

rate is < 5%. In severe pancreatitis, there is significant

inflammation, with necrosis and hemorrhage of the gland and asystemic inflammatory response; the mortality rate is 10 to 50%.

After 5 to 7 days, necrotic pancreatic tissue may become infected

by enteric bacteria.

Activated enzymes and cytokines that enter the peritoneal cavity

cause a chemical burn and third spacing of fluid; those that enter

the systemic circulation cause a systemic inflammatory response

that can result in acute respiratory distress syndrome and renal

failure. The systemic effects are mainly the result of increased

capillary permeability and decreased vascular tone, which result

from the released cytokines and chemokines. Phospholipase A2 is

thought to injure alveolar membranes of the lungs.

In about 40% of patients, collections of enzyme-rich pancreatic fluid

and tissue debris form in and around the pancreas. In about half,

the collections resolve spontaneously. In others, the collections

become infected or form pseudocysts. Pseudocysts have a fibrous

capsule without an epithelial lining. Pseudocysts may hemorrhage,

rupture, or become infected.

Death during the first several days is usually caused by

cardiovascular instability (with refractory shock and renal failure) or

respiratory failure (with hypoxemia and at times adult respiratory

distress syndrome). Occasionally, death results from heart failure

secondary to an unidentified myocardial depressant factor. Death

after the first week is usually caused by multiorgan system failure.

Symptoms and SignsAn acute attack causes steady, boring upper abdominal pain,

typically severe enough to require large doses of parenteral opioids.

The pain radiates through to the back in about 50 % of patients;

rarely, pain is first felt in the lower abdomen. Pain usually develops

suddenly in gallstone pancreatitis; in alcoholic pancreatitis, pain

develops over a few days. The pain usually persists for several

8/7/2019 Pathphysio

12/29

days. Sitting up and leaning forward may reduce pain, but coughing,

vigorous movement, and deep breathing may accentuate it. Nausea

and vomiting are common.

The patient appears acutely ill and sweaty. Pulse rate is usually 100to 140 beats/min. Respiration is shallow and rapid. BP may be

transiently high or low, with significant postural hypotension.

Temperature may be normal or even subnormal at first but may

increase to 37.7 to 38.3 C (100 to 101 F) within a few hours.

Sensorium may be blunted to the point of semicoma. Scleral icterus

is occasionally present. The lungs may have limited diaphragmatic

excursion and evidence of atelectasis.

About 20% of patients experience upper abdominal distention

caused by gastric distention or displacement of the stomach by a

pancreatic inflammatory mass. Pancreatic duct disruption may

cause ascites (pancreatic ascites). Marked abdominal tenderness

occurs, most often in the upper abdomen. There may be mild

tenderness in the lower abdomen, but the rectum is not tender and

the stool is usually negative for occult blood. Mild-to-moderate

muscular rigidity may be present in the upper abdomen but is rare

in the lower abdomen. Rarely, severe peritoneal irritation results in

a rigid and boardlike abdomen. Bowel sounds may be hypoactive.

Grey Turner's sign (ecchymoses of the flanks) and Cullen's sign

(ecchymoses of the umbilical region) indicate extravasation of

hemorrhagic exudate.

Infection in the pancreas or in an adjacent fluid collection should be

suspected if the patient has a generally toxic appearance with

elevated temperature and WBC count or if deterioration follows an

initial period of stabilization.

Diagnosis Serum markers (amylase, lipase)

Once diagnosed, CT usually done

Pancreatitis is suspected whenever severe abdominal pain occurs,

especially in a patient with significant alcohol use or known

gallstones. Conditions causing similar symptoms include perforated

gastric or duodenal ulcer, mesenteric infarction, strangulating

8/7/2019 Pathphysio

13/29

intestinal obstruction, dissecting aneurysm, biliary colic,

appendicitis, diverticulitis, inferior wall MI, and hematoma of the

abdominal muscles or spleen.

Diagnosis is made by clinical suspicion, serum markers (amylaseand lipase), and the absence of other causes for the patient's

symptoms. Thus, a broad range of tests is done, typically including

CBC, electrolytes, Ca, Mg, glucose, BUN, creatinine, amylase, and

lipase. Other routine tests include ECG and an abdominal series

(chest, flat, and upright abdomen). A urine dipstick for trypsinogen

2 has sensitivity and specificity of > 90% for acute pancreatitis.

Ultrasound and CT are not generally done specifically to diagnose

pancreatitis but are often used to evaluate acute abdominal pain

(see Acute Abdomen and Surgical Gastroenterology: Testing).

Laboratory tests: Serum amylase and lipase concentrations

increase on the first day of acute pancreatitis and return to normal

in 3 to 7 days. Lipase is more specific for pancreatitis, but both

enzymes may be increased in renal failure and various abdominal

conditions (eg, perforated ulcer, mesenteric vascular occlusion,

intestinal obstruction). Other causes of increased serum amylase

include salivary gland dysfunction, macroamylasemia, and tumors

that secrete amylase. Both amylase and lipase levels may remain

normal if destruction of acinar tissue during previous episodes

precludes release of sufficient amounts of enzymes. The serum of

patients with hypertriglyceridemia may contain a circulating inhibitor

that must be diluted before an elevation in serum amylase can be

detected.

Amylase:creatinine clearance ratio does not have sufficient

sensitivity or specificity to diagnose pancreatitis. It is generally used

to diagnose macroamylasemia when no pancreatitis exists. In

macroamylasemia, amylase bound to serum immunoglobulin falselyelevates the serum amylase level.

Fractionation of total serum amylase into pancreatic type (ptype)

isoamylase and salivary-type (stype) isoamylase increases the

accuracy of serum amylase. However, the level of ptype also

increases in renal failure and in other severe abdominal conditions

8/7/2019 Pathphysio

14/29

in which amylase clearance is altered.

The WBC count usually increases to 12,000 to 20,000/L. Third

space fluid losses may increase the Hct to as high as 50 to 55%,

indicating severe inflammation. Hyperglycemia may occur. SerumCa concentration falls as early as the first day because of the

formation of Ca soaps secondary to excess generation of free fatty

acids, especially by pancreatic lipase. Serum bilirubin increases in

15 to 25% of patients because pancreatic edema compresses the

common bile duct.

Imaging: Plain xrays of the abdomen may disclose calcifications

within pancreatic ducts (evidence of prior inflammation and hence

chronic pancreatitis), calcified gallstones, or localized ileus in the

left upper quadrant or the center of the abdomen (a sentinel loop

of small bowel, dilation of the transverse colon, or duodenal ileus).

Chest xray may reveal atelectasis or a pleural effusion (usually

left-sided or bilateral but rarely confined to the right pleural space).

Ultrasound should be done if gallstone pancreatitis is suspected

(and another etiology is not obvious) to detect gallstones or dilation

of the common bile duct (which indicates biliary tract obstruction).

Edema of the pancreas may be visualized, but overlying gas

frequently obscures the pancreas.

CT with IV contrast is generally done to identify necrosis, fluid

collections, or pseudocysts once pancreatitis has been diagnosed.

It is particularly recommended for severe pancreatitis or if a

complication ensues (eg, hypotension or progressive leukocytosis

and elevation of temperature). IV contrast facilitates the recognition

of pancreatic necrosis; however, it may cause pancreatic necrosis

in areas of low perfusion (ie, ischemia). Thus, contrast-enhanced

CT should be done only after the patient has been adequatelyhydrated.

If pancreatic infection is suspected, fluid obtained by percutaneous

CTguided needle aspiration of cysts or areas of fluid collection or

necrosis may reveal organisms on Gram stain or culture. The

diagnosis is supported by positive blood cultures and, particularly,

8/7/2019 Pathphysio

15/29

by the presence of air bubbles in the retroperitoneum on abdominal

CT. The advent of magnetic resonance cholangiopancreatography

(MRCP) may make the selection of pancreatic imaging simpler.

Prognosis

In edematous pancreatitis, mortality is < 5%. In pancreatitis with

necrosis and hemorrhage, mortality is 10 to 50%. In pancreatic

infection, mortality is usually 100% without extensive surgical

debridement or drainage of the infected area.

CT findings correlate with prognosis. If CT is normal or shows only

mild pancreatic edema (Balthazar class A or B), the prognosis is

excellent. Patients with peripancreatic inflammation or one area of

fluid collection (classes C and D) have a 10 to 15% incidence of

abscess formation; the incidence is over 60% in patients with two or

more areas of fluid collection (class E).

Ranson's prognostic signs help predict the prognosis of acute

pancreatitis. Five of Ranson's signs can be documented at

admission:

Age > 55 yr

Plasma glucose > 200 mg/dL (> 11.1 mmol/L)

Serum LDH > 350 IU/L

AST > 250 UL

WBC count > 16,000/L

The rest of Ranson's signs are determined within 48 h of admission:

Hct decrease > 10%

BUN increase > 5 mg/dL (> 1.78 mmol/L)

Serum Ca < 8 mg/dL (< 2 mmol/L)

PaO2 < 60 mm Hg (< 7.98 kPa)

Base deficit > 4 mEq/L (> 4 mmol/L) Estimated fluid sequestration > 6 L

Mortality increases with the number of positive signs: If < 3 signs

are positive, the mortality rate is < 5%; if 3 are positive, mortality is

15 to 20%.

The APACHE II index (see Table 4: Approach to the Critically Ill

8/7/2019 Pathphysio

16/29

Patient: Acute Physiologic Assessment and Chronic HealthEvaluation (Apache) II Scoring System* ), calculated on the

second hospital day, also correlates with prognosis.

Treatment Fluid resuscitation

Fasting

Drugs, including adequate analgesia and acid blockers

Antibiotics for pancreatic necrosis

Drainage of infected pseudocysts or areas of necrosis

Adequate fluid resuscitation is essential; up to 6 to 8 L/day of fluid

containing appropriate electrolytes may be required. Inadequate

fluid therapy increases the risk of pancreatic necrosis.

Fasting is indicated until acute inflammation subsides (ie, cessation

of abdominal tenderness and pain, normalization of serum amylase,

return of appetite, feeling better). Fasting can last from a few days

in mild pancreatitis to several weeks. To prevent malnutrition, TPN

should be initiated in severe cases within the first few days.

Pain relief requires parenteral opioids, which should be given in

adequate doses. Althoughmorphine

may cause the sphincter of Oddi to contract, this is of doubtful

clinical significance. Antiemetic agents (eg, prochlorperazine

5 to 10 mg IV q 6 h) should be given to alleviate vomiting. An NGTis required only if significant vomiting persists or ileus is present.

Parenteral H2 blockers or proton pump inhibitors are given. Efforts

to reduce pancreatic secretion with drugs (eg, anticholinergics,

glucagon, somatostatin, octreotide

8/7/2019 Pathphysio

17/29

) have no proven benefit.

Severe acute pancreatitis should be treated in an ICU, particularly

in patients with hypotension, oliguria, Ranson's score 3, APACHEII 8, or pancreatic necrosis on CT scan > 30%. In the ICU, vital

signs and urine output are monitored hourly; metabolic parameters

(Hct, glucose, and electrolytes) are reassessed every 8 h; ABG is

determined as needed; central venous pressure line or Swan-Ganz

catheter measurements are determined every 6 h if the patient is

hemodynamically unstable or if fluid requirements are unclear.

CBC, platelet count, coagulation parameters, total protein with

albumin, BUN, creatinine, Ca, and Mg are measured daily.

Hypoxemia is treated with humidified O2 via mask or nasal prongs.

If hypoxemia persists or adult respiratory distress syndrome

develops, assisted ventilation may be required. Glucose > 170 to

200 mg/dL (9.4 to 11.1 mmol/L) should be treated cautiously with sc

or IV insulin

and carefully monitored. Hypocalcemia generally is not treated

unless neuromuscular irritability occurs; 10 to 20 mL of 10% Ca

gluconate in 1 L of IV fluid is given over 4 to 6 h. Chronic alcoholics

and patients with documented hypomagnesemia should receive Mg

sulfate 1 g/L of replacement fluid for a total of 2 to 4 g, or until levels

normalize. If renal failure occurs, serum Mg levels are monitored

and IV Mg is given cautiously. With restoration of normal Mg levels,

serum Ca levels usually return to normal.

Heart failure should be treated (see Heart Failure: Treatment).

Prerenal azotemia should be treated by increased fluidreplacement. Renal failure may require dialysis (usually peritoneal).

Antibiotic prophylaxis with imipenem can prevent infection of sterile

pancreatic necrosis, although the effect on reducing mortality is

unclear. Infected areas of pancreatic necrosis require surgical

debridement, but infected fluid collections outside the pancreas may

8/7/2019 Pathphysio

18/29

be drained percutaneously. A pseudocyst that is expanding rapidly,

infected, bleeding, or likely to rupture requires drainage. Whether

drainage is percutaneous, surgical, or endoscopic depends on

location of the pseudocyst and institutional expertise. Peritoneal

lavage to wash out activated pancreatic enzymes and inflammatorymediators has no proven benefit.

Surgical intervention during the first several days is justified for

severe blunt or penetrating trauma or uncontrolled biliary sepsis.

Although > 80% of patients with gallstone pancreatitis pass the

stone spontaneously, ERCP with sphincterotomy and stone removal

is indicated for patients who do not improve after 24 h of treatment.

Patients who spontaneously improve generally undergo elective

laparoscopic cholecystectomy. Elective cholangiography remains

controversial.

Acute PancreatitisTyler Stevens

Darwin L. Conwell

CHAPTER SECTION LINKS

Definitions

Prevalence

Causes

Pathophysiology

Signs and symptoms

Diagnosis

Treatment

Outcomes

Summary

ShareThis
http://my.clevelandclinic.org/staff_directory/7/Staff_6435.aspxhttp://my.clevelandclinic.org/staff_directory/7/Staff_6435.aspx

8/7/2019 Pathphysio

19/29

DefinitionsAcute pancreatitis (AP) is an acute inflammatory condition of the pancreas that may

extend to local and distant extrapancreatic tissues. AP is broadly classified as mild or

severe. Mild AP is often referred to as interstitial pancreatitis, based on its radiographic

appearance. Severe AP implies the presence of organ failure, local complications, or

pancreatic necrosis. Interstitial pancreatitis implies preservation of pancreatic blood

supply; necrosis suggests the disruption of pancreatic blood supply, with resulting

ischemia.

Figure 1: Click to Enlarge

Different types of fluid collections develop in the setting of AP, including acute fluid

collections, acute pseudocysts, and pancreatic abscesses. Acute fluid collections occur

early in AP in the peripancreatic areas and are not encapsulated by a fibrous wall.

Acute pseudocysts are well-developed collections of pancreatic juice encapsu-lated by

a nonepithelialized wall of granulation tissue (Fig. 1). Pseudocysts typically form 4 to 6

weeks after an episode of AP. A pseudocyst that has become infected is a pancreatic

abscess. Pancreatic abscesses may also form through encapsulation of areas ofinfected pancreatic necrosis. The termspancreatic phlegmon and hemorrhagic

pancreatitis are no longer used in the current American College of Gastroenterology

(ACG) guidelines.

When acute pancreatitis occurs on two or more occasions (evidenced by elevation of

serum pancreatic enzyme levels), it is classified as acute recurrent pancreatitis. In some

cases, acute recurrent pancreatitis progresses to chronic pancreatitis, implying the

presence of parenchymal fibrosis and loss of glandular function.

Back to Top

Prevalence

The yearly incidence of AP in the United States is approximately 17 new cases per

100,000. Acute pancreatitis results in 100,000 hospitalizations per year. Eighty percent

of cases of AP are interstitial and mild; the remaining 20% are necrotizing and severe.

Approximately 2000 patients per year die from complications related to AP.
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/gastroenterology/acute-pancreatitis/images/acutepancreatitisfig1_large.jpghttp://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/gastroenterology/acute-pancreatitis/images/acutepancreatitisfig1_large.jpg

8/7/2019 Pathphysio

20/29

Back to Top

Causes

Gallstones and alcohol are the two most common causes of AP in western countries,

accounting for 80% of cases. Gallstone pancreatitis results from transient obstruction ofthe ampulla of Vater by small stones or edema. Clinical features include preceding

biliary colic, the presence of cholelithiasis or biliary dilation on gallbladder ultrasound,

and liver function test abnormalities. Gallstone pancreatitis typically does not recur after

cholecystectomy or endoscopic therapy (biliary sphincterotomy and stone extraction).

Alcohol is the second leading cause of AP, which typically occurs after episodes of

binge drinking. After recurrent episodes, most alcoholics go on to develop chronic

pancreatitis.

Numerous less common causes have been described (Box 1). Hypertriglyceridemia

produces acute pancreatitis if triglyceride levels are above 1000 mg/dL. Markedly

elevated triglyceride levels may be encountered in the setting of diabetes, alcoholism,

and inherited disorders of lipoprotein metabolism (Fredrickson types I, II, and V).

Hypercalcemia produces AP through calcium-mediated activation of trypsinogen and

subsequent glandular autodigestion. Hypercalcemia-associated AP may occur in the

setting of primary and secondary hyperparathyroidism, malignancy, and metabolic bone

disease. In recent years, numerous genetic mutations have been associated with the

development of pancreatitis. These include mutations of cationic trypsinogen (hereditary

pancreatitis), serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis

transmembrane regulator (CFTR) gene. Numerous case reports and case series have

implicated specific medications (e.g., sulfa drugs, 6-mercaptopurine, didanosine,

furosemide, valproate) as causes of acute pancreatitis; however, the strength of these

associations is variable.

Box 1: Causes of Acute Pancreatitis

Gallstones (45%)

Alcohol (35%)

Other (10%)

Medications

8/7/2019 Pathphysio

21/29

Hypercalcemia

Hypertriglyceridemia

Obstructive

Post-ERCP

Hereditary

Traumaviral, vascular-ischemic

Postcardiac bypass

Idiopathic (10%)

ERCP, endoscopic retrograde cholangiopancreatography.

Obstruction of the pancreatic duct may produce acute or chronic pancreatitis. Causes of

obstructive AP include ductal adenocarcinoma, ampullary tumors and polyps,

neuroendocrine and cystic pancreatic tumors, and intraductal papillary mucinous

tumors. Pancreatic tumors should be kept in the differential diagnosis, particularly in

older patients. Occasionally, congenital abnormalities of the pancreas, such as

pancreas divisum and annular pancreas, produce obstructive AP in adult patients.

Back to Top

PathophysiologyThe pathogenesis of AP has been studied extensively using animal models. Although

various causes produce distinct inciting events, the final common pathway is premature

activation of digestive enzymes within the acinar cells. Ordinarily, pancreatic

proenzymes become activated on release within the duodenum. Pancreatitis results

from early activation of pancreatic enzymes, producing autodigestion of the pancreas

and surrounding tissues. Exposure of trypsinogen to lysosomal enzymes such as

cathepsin B has recently been elucidated as a mechanism for early trypsin activation.

Digestive enzyme release is amplified as acinar cells lyse, leading to a vicious cycle of

inflammation and necrosis.

Back to Top

Signs and symptoms

Acute pancreatitis manifests with the sudden onset of epigastric pain radiating to the

back. The pain may be severe and characterized as deep and boring. Eating food

8/7/2019 Pathphysio

22/29

worsens pain; bending forward ameliorates pain. In AP precipitated by alcohol, pain

occurs from hours to days after binge drinking. Abdominal pain lasts for days and is

associated with anorexia, nausea, and vomiting. Most patients present to the

emergency department; however, occasional patients manage their symptoms at home

by minimizing oral intake for a few days.

Physical examination frequently reveals systemic signs such as fever, tachycardia, and

hypotension. Abdominal examination reveals epigastric tenderness, with localized

guarding and rebound. Sluggish or absent bowel sounds indicate coexisting ileus. Less

frequent findings signal complications, including Grey Turner's (flank ecchymosis) or

Cullen's (umbilical ecchymosis) signs suggestive of retroperitoneal hemorrhage, a

palpable mass suggestive of a pseudocyst, panniculitis suggestive of subcutaneous fat

necrosis, and dullness to percussion of lung fields suggestive of pleural effusion. The

differential diagnosis of upper gastrointestinal bleeding in acute pancreatitis includes

erosion of a pseudocyst into the splenic artery (hemosuccus pancreaticus) or bleeding

from gastric varices that arise secondary to splenic vein thrombosis.

Back to Top

Diagnosis

The diagnosis of AP is supported by an elevation of the serum amylase and lipase

levels in excess of three times the upper limit of normal. These enzyme levels are

elevated because of leakage from pancreatic acinar cells into the interstitial space and

subsequent absorption into the circulation. The amylase level becomes elevated withinhours of the development of pain and may remain elevated for 3 to 5 days. The

differential diagnosis for hyperamylasemia includes intestinal obstruction, visceral

perforation, tubo-ovarian abscess, renal failure, and salivary gland disease.

Macroamylasemia is a condition in which amylase is chronically elevated because of its

binding to an abnormal serum protein, leading to delayed clearance. Serum lipase has

higher specificity for pancreatic disease but its level may be elevated in other conditions

as well. The severity of pancreatitis does not correlate well with the magnitude of

elevation of the serum amylase and lipase levels. There is no value in following daily

trends of serum amylase and lipase levels, because they do not correlate with recoveryor prognosis.

Laboratory abnormalities encountered in AP include hyperglycemia, hypocalcemia,

leukocytosis, and mild elevations of liver function test results. Elevation of the serum

alanine aminotransferase level to higher than 80 U/mL is highly specific but poorly

sensitive for gallstone pancreatitis. Experimental biochemical markers that may hold

8/7/2019 Pathphysio

23/29

promise for assessing the severity of disease include trypsinogen activation peptide,

interleukin-6, interleukin-10, and C-reactive protein levels.

Simple plain films of the chest and abdomen are appropriate for the initial radiographic

assessment of AP. An abdominal radiograph is helpful for excluding other causes of

acute abdominal pain, such as obstruction and perforation. In AP, the abdominal

radiograph is frequently normal or may demonstrate ileus. A chest radiograph can

detect pulmonary complications of AP such as atelectasis, pleural effusions (most

commonly left-sided), or infiltrates suggestive of adult respiratory distress syndrome.

Although transabdominal ultrasound is poorly reliable for imaging the pancreas itself, it

is the best initial radiographic test for the evaluation of mild AP because of the following:

1. It detects gallstones as a potential cause,

2. It rules out acute cholecystitis as a differential cause of pain and hyperamylasemia, and

3. It detects biliary dilation suggestive of the need for early endoscopic retrograde

cholangiopancreatography (ERCP).


Contrast-enhanced computed tomography (CT) of the abdomen is the preferred test for

evaluating severe pancreatitis and detecting complications. CT features in interstitial

pancreatitis include homogenous contrast enhancement; diffuse or segmental

pancreatic enlargement; irregularity, heterogeneity, and lobularity of the pancreas; and

obliteration of the peripancreatic fat planes. CT detects areas of pancreatic necrosis

(Fig. 2), which significantly influences subsequent management. The presence of

necrosis confers a substantial increase in mortality compared with interstitial

pancreatitis. A CT should not be routinely ordered for all patients with AP; however, the

ACG practice guidelines state that a dynamic contrast-enhanced CT is recommended

at some point beyond the first 3 days in severe acute pancreatitis (on the basis of a high

APACHE score or organ failure) to distinguish interstitial from necrotizing pancreatitis.

A CT should also be considered for those in whom a localized pancreatic complication

is suspected (e.g., pseudocyst, splenic vein thrombosis, splenic artery aneurysm). CT is

also appropriate after resolution of AP to exclude a tumor if the cause of the attack is

unclear. It is highly controversial whether intravenous contrast worsens or precipitates

pancreatic necrosis, and abdominal CT should generally not be withheld on this basis.

Endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography

(MRCP) are emerging as potentially valuable tests in the evaluation of AP. Both are

helpful in detecting stones in the common bile duct and directly assessing the

8/7/2019 Pathphysio

24/29

pancreatic parenchyma. Magnetic resonance imaging is similar or superior to contrast

CT in its ability to stage AP and detect necrosis and complications, and it does not

require intravenous contrast. Operator dependence and expense limit the widespread

availability of EUS and MRCP.

Back to Top

Treatment

Supportive Care


The primary goals of therapy in AP are meticulous supportive care and prevention of

pancreatic necrosis, infection, and organ failure. The primary treatment is pancreaticrest and analgesia. Patients should be kept NPO, and intravenous fluids should be

given with careful attention to volume status. The ACG guidelines state, all patients

should receive close supportive care including pain control, fluid resuscitation, and

nutritional support. A therapeutic algorithm closely based on the ACG guidelines is

shown in (Fig. 3).

The importance of vigorous hydration to optimize outcomes has been increasingly

recognized. The ACG guidelines stress, Patients with evidence of significant third-

space losses require aggressive fluid resuscitation. Many patients sequester

substantial amounts of fluid into the retroperitoneal space, producing very high fluidrequirements. Intravascular volume depletion may lead to tachycardia, hypotension,

renal failure, hemoconcentration, and generalized circulatory collapse. More than 6 L of

fluid sequestration within the first 48 hours is considered a marker of increased severity,

according to the Ranson criteria (Table 1). Patients with evidence of hemoconcentration

resulting from intravascular water loss appear to be at increased risk for the

development of pancreatic necrosis and organ failure. In addition to maintenance fluid

requirements, the amount sequestered should be monitored and replaced with isotonic

fluids such as normal saline, with a goal of euvolemia and hemodilution. Some patients

may require as much as 250 to 350 mL/hr, particularly in the early phases of AP. Ofcourse, the aggressiveness of fluid replacement must be tempered in the presence of

underlying cardiac or renal disease.Table 1: Ranson Criteria for Severity of Acute Pancreatitis

At Admission At 48 hr

8/7/2019 Pathphysio

25/29

Age > 55 yr Hematocrit decrease > 10%

WBC > 16,000/mL BUN increase > 5 mg/dL

LDH > 50 IU/L Calcium < 8 mg/dL

AST > 250 IU/L PaO2 < 60 mm Hg

Glucose > 200 mg/dL Base deficit > 4 mg/dL Fluid sequestration > 6 L

AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; PaO2, partial pressure of

arterial carbon dioxide; WBC, white blood cell.

Oral intake should be severely limited initially and then carefully advanced as pain

subsides and hunger returns. Carbohydrate-containing foods are best for early

refeeding because they do not stimulate the pancreas as much as fat- and protein-

containing foods. A nasogastric tube is necessary only in the presence of vomiting or

ileus. Intravenous narcotics by injection or patient-controlled analgesia should be used

liberally during the attack and tapered as the diet is advanced to enable prompt bowel

recovery.

Nutritional support may be withheld in mild pancreatitis for several days. The ACG

guidelines advise nutritional support if NPO status is maintained for longer than 5 to 7

days. All patients with severe AP should receive nutritional support because of the

inherently high level of stress and hypercatabolism. Nasojejunal feeding past the

ligament of Treitz does not stimulate the pancreas and is preferred over parenteral

feeding because of decreased infection complication rates. Studies have shown

improved humoral and cellular immunity, decreased systemic inflammatory response,

and decreased bacterial translocation for enteral feeding compared with parenteral

nutrition. The presence of a severe intestinal ileus or delay in tube placement may limit

the use of enteral feeding. Many patients with AP develop gastric and colonic ileus but

maintain adequate small bowel motility, permitting enteral feeding.

Assessment of Severity

An important initial step in management is the assessment of severity by clinical and

radiographic criteria. Although AP is usually mild, a subset of patients develops a

severe course. Severe AP implies organ failure or pancreatic necrosis and carries a

mortality rate of 10% to 30%. Patients with severe AP should be administered close

8/7/2019 Pathphysio

26/29

supportive care in an intensive care unit (ICU) setting. According to the ACG guidelines,

severe pancreatitis is recognized on the basis of early clinical prognostic signs,

evidence of organ failure, or local complications (pancreatic necrosis or abscess). Early

recognition of severe pancreatitis improves outcomes by prompting aggressive fluid

resuscitation and transfer of the patient to an intensive care unit.Multiple clinical and radiographic severity scores have been proposed. Initially studied in

patients with alcoholic acute pancreatitis, the Ranson score comprises five clinical

criteria measured at admission and six clinical criteria measured at 48 hours (seeTable

1). The criteria measured at admission reflect the local inflammatory effects of

pancreatic enzymes; those measured at 48 hours represent the later systemic effects.

Three or more Ranson criteria predict a severe course and increased mortality and

should prompt ICU transfer and CT scanning to rule out pancreatic necrosis. The

APACHE II and III scores (acute physiology, age, chronic health evaluation) are

generated from multiple parameters and are considered highly accurate. Furthermore,APACHE scores allow prediction of severity from the day of admission and may be

recalculated on a daily basis. Unfortunately, because of the time-consuming and

cumbersome nature of the APACHE evaluation, it is rarely used in clinical practice.

In addition to formal scoring systems, patients should be followed closely for other

markers of increased severity, including signs of hemodynamic instability or organ

failure. Respiratory failure may occur through the development of large pleural effusions

or adult respiratory distress syndrome. Rarely, hemorrhage into retroperitoneal tissues

results in further hemodynamic compromise. Hypervigilance for these complications will

result in more timely and aggressive management and improved patient outcomes.

Preventive MeasuresPrevention of Infection

Because superinfection of pancreatic necrosis dramatically increases the mortality rate

of AP compared with sterile necrosis, a major goal in management is the prevention of

infection. Some randomized trials have suggested a benefit for early initiation of broad-

spectrum antibiotics in preventing pancreatic infection. Antibiotics with good pancreatic

tissue penetration, such as imipenem (500 mg IV every 8 hours), cefuroxime (1.5 g IV

every 8 hours), or ciprofloxacin (400 mg IV every 12 hours) are favored in this setting.Potential drawbacks of prophylactic antibiotics include the development of resistant

organisms and fungal infections. Although antibiotics have been shown to decrease

infection rates, they have not consistently demonstrated a mortality benefit. The ACG

guidelines recommend that in patients with necrotizing pancreatitis associated with

organ failure, it is reasonable to initiate treatment with antibiotics with good spectrum of

activity against aerobic and anaerobic bacteria.

8/7/2019 Pathphysio

27/29

Endoscopic Retrograde Cholangiopancreatography

Although the ACG guidelines state that patients with severe pancreatitis caused by

gallstones should undergo urgent ERCP, there has been much recent debate over the

benefit of early endoscopic removal of common bile duct stones in suspected gallstone

pancreatitis. There is strong evidence to suggest a benefit for ERCP with papillotomy

and stone extraction in the setting of stone impaction and cholangitis. However,

randomized trials of early ERCP in the management of all patients with suspected

gallstone pancreatitis have shown conflicting results. ERCP may further exacerbate

acute pancreatitis. Guidelines from the British Society of Gastroenterology advise that

severe gallstone pancreatitis in the presence of increasingly deranged liver function

tests and signs of cholangitis (fever, rigors, and positive blood cultures) require an

immediate and therapeutic ERCP. If there is only moderate suspicion of retained

stones, an MRCP is a no-risk alternative to ERCP, with excellent sensitivity for the

detection of common bile-duct stones.

Surgical Management

Surgical management of AP is indicated in two clinical settingsinfected pancreatic

necrosis and gallstone pancreatitis.

Pancreatic Necrosis

Confirmation of the diagnosis of infected pancreatic necrosis is critical because surgical

management is indicated. Unfortunately, clinical and radiographic criteria are not

sufficiently reliable for detecting pancreatic infection. Infection is confirmed through

ultrasound- or CT-guided aspiration of areas of pancreatic necrosis or suspected

pancreatic abscesses. This procedure is safe and reliable, and has been recommended

for all patients with CT criteria for pancreatic necrosis and evidence of sepsis or organ

failure.

The ACG guidelines differentiate necrotizing pancreatitis with and without clinical

improvement. Patients with evidence of slow clinical improvement may be managed

expectantly, without needle aspiration; however, in the absence of clinical

improvement, guided percutaneous aspiration should be performed. This ap-proach is

reasonable if the patient is hemodynamically stable and has not developed significantorgan failure or septic syndrome. It is important to obtain a surgical consultation before

consider-ation of this procedure, given the possible need for surgical dbridement.

In the setting of infected pancreatic necrosis, resection of all devitalized pancreatic and

surrounding tissue is performed. Multiple re-explorations, continuous irrigation, or

laparotomy formation may be required for adequate dbridement. Recent studies have

8/7/2019 Pathphysio

28/29

suggested that a delayed approach to surgical dbridement improves outcomes by

allowing time for adequate separation of necrotic and vital areas. Surgical necrectomy is

clearly indicated in the setting of infected necrosis; however, its benefit in sterile

necrosis is controversial. Cholecystectomy is indicated to prevent recurrence of

gallstone pancreatitis. In mild disease, an early cholecystectomy performed during thesame hospitalization is favored. In severe gallstone pancreatitis, cholecystectomy may

be delayed until clinical improvement or performed at the time of necrectomy.

Idiopathic Acute Pancreatitis

Ten percent of cases of acute pancreatitis are idiopathic acute pancreatitis (IAP).

Potential underlying causes of idiopathic pancreatitis include biliary microlithiasis,

sphincter of Oddi dysfunction, and undiagnosed genetic defects. Biliary microlithiasis

has been implicated as a common cause of IAP. Recurrent acute episodes of

pancreatitis may develop in the absence of gallstones on ultrasound, with or without

elevated liver enzyme levels. Repeat ultrasound examinations may eventually reveal

biliary sludge or small stones. The finding of cholesterol monohydrate or calcium

bilirubinate crystals on microscopic biliary analysis after cholecystokinin stimulation

strongly supports the diagnosis of microlithiasis; however, it is not completely sensitive.

Laparoscopic cholecystectomy prevents recurrence in patients with IAP and should be

considered in all patients with acute recurrent pancreatitis of unclear cause. Endoscopic

sphincterotomy or stone dissolution therapy with ursodiol (8 to 10 mg/kg/day, in two

divided doses) are valid options in patients with high surgical risk. Stone dissolution

therapy is effective only for noncalcified, cholesterol monohydrate stones smaller than 1

cm in diameter.


ERCP may be helpful in elucidating the cause of IAP. ERCP allows the detection of

ampullary tumors, mucinous ductal ectasia, common bile duct stones, pancreas

divisum, and pancreatic ductal adenocarcinoma. Biliary manometry allows the diagnosis

of sphincter of Oddi dysfunction. ERCP is most strongly indicated for patients who are

older than 40 years to rule out neoplasia. MRCP is a safer alternative to ERCP fordetection of diseases of the pancreatic duct; however, it is less sensitive for small duct

processes, and does not allow inspection of the ampulla or functional assessment of the

sphincter of Oddi. Genetic screening for cationic trypsinogen, SPINK1, or CFTR gene

mutations may be considered in some patients with IAP, although positive results are

unlikely to change management.

8/7/2019 Pathphysio

29/29

There are no published guidelines for the approach to recurrent IAP. Laparoscopic

cholecystectomy, ERCP-MRCP, and genetic screening each have their advocates as

the initial step in the diagnostic workup. Most clinicians do not favor extensive

evaluation for the first episode of IAP, because it does not recur in most patients after

the first episode; however, CT after resolution is probably reasonable for excludingpancreatic cancer. It is best to tailor the diagnostic approach individually based on

patient characteristics. We favor a laparoscopic cholecystectomy in any patient who

develops a second episode of IAP. One suggested approach to the patient with

idiopathic recurrent acute pancreatitis is demonstrated in Figure 4.

Back to Top

Outcomes

Mortality rates for hospitalized patients vary from 5% to 10% in most series. In patients

with interstitial pancreatitis, mortality is close to zero. Mortality is substantially increased

in necrotizing pancreatitis (less than 1% for interstitial pancreatitis, 10% for sterile

necrosis, 30% for infected necrosis).

pathphysio

Documents