2649 Diseases of the Gallbladder and Bile Ducts CHAPTER 346

Accordingly, considerable care should be taken to investigate the possible role of other factors in the production of postcholecystectomy

symptoms before attributing them to cystic duct stump syndrome.

SOD STENOSIS, SOD DYSKINESIA, AND BILIARY DYSKINESIA Symptoms of biliary colic accompanied by signs of recurrent, intermittent

biliary obstruction may be produced by acalculous cholecystopathy,

SOD stenosis, or SOD dyskinesia. SOD stenosis is thought to result

from acute or chronic inflammation of the papilla of Vater or from

glandular hyperplasia of the papillary segment. Five criteria have been

used to define SOD stenosis: (1) upper abdominal pain, usually RUQ

or epigastric; (2) abnormal liver tests; (3) dilatation of the CBD upon

MRCP or ERCP examination; (4) delayed (>45 min) drainage of contrast material from the duct; and (5) increased basal pressure of the

SOD. After exclusion of acalculous cholecystopathy, treatment consists

of endoscopic or surgical sphincteroplasty to ensure wide patency of

the distal portions of both the bile and pancreatic ducts. The greater the

number of the preceding criteria present, the greater is the likelihood

that a patient does have a degree of SOD sufficient to justify correction. The factors usually considered as indications for sphincterotomy

include (1) prolonged duration of symptoms, (2) lack of response to

symptomatic treatment, (3) presence of severe disability, and (4) the

patient’s choice of sphincterotomy over surgery (given a clear understanding on his or her part of the risks involved in both procedures).

Biliary SOD disorders are characterized by three criteria: (1) biliary

pain, (2) absence of bile duct stones or other abnormalities, and (3)

elevated liver enzymes or a dilated CBD, but not both. In this setting,

either hepatobiliary scintigraphy or SOD manometry can support the

diagnosis. Importantly, the presence of both elevated liver enzymes

and a dilated CBD should raise the question of obstruction. Proposed mechanisms to account for SOD dysfunction include spasm of

the sphincter, denervation sensitivity resulting in hypertonicity, and

abnormalities in the sequencing or frequency rates of the sphinctericcontraction waves. When thorough evaluation has failed to demonstrate another cause for the pain and when cholangiographic and

manometric criteria suggest a diagnosis of SOD dyskinesia, medical

treatment with nitrites or anticholinergics to attempt pharmacologic

relaxation of SOD has been proposed but not evaluated in detailed

studies. Endoscopic biliary sphincterotomy (EBS) or surgical sphincterotomy may be indicated in patients who fail to respond to a 2- to

3-month trial of medical therapy, especially if SOD pressures are elevated. Approximately 45% of such patients have long-term pain relief

after EBS. EBS has become the procedure of choice for removing bile

duct stones and for other biliary and pancreatic problems.

BILE SALT–INDUCED DIARRHEA AND GASTRITIS Postcholecystectomy

patients may develop symptoms of dyspepsia, which have been attributed to duodenogastric reflux of bile. However, firm data linking these

symptoms to bile gastritis after surgical removal of the gallbladder are

lacking. Cholecystectomy induces persistent changes in gut transit, and

these changes effect a noticeable modification of bowel habits. Cholecystectomy shortens gut transit time by accelerating passage of the fecal

bolus through the colon with marked acceleration in the right colon,

thus causing an increase in colonic bile acid output and a shift in bile

acid composition toward the more diarrheagenic secondary bile acids,

that is, deoxycholic acid. Diarrhea that is severe enough, that is, three

or more watery movements per day, can be classified as postcholecystectomy diarrhea, and this occurs in 5–10% of patients undergoing

elective cholecystectomy. Treatment with bile acid–sequestering agents

such as cholestyramine or colestipol is often effective in ameliorating

troublesome diarrhea.

■ THE HYPERPLASTIC CHOLECYSTOSES

The term hyperplastic cholecystoses is used to denote a group of disorders of the gallbladder characterized by excessive proliferation of

normal tissue components.

Adenomyomatosis is characterized by a benign proliferation of

gallbladder surface epithelium with glandlike formations, extramural

sinuses, transverse strictures, and/or fundal nodule (“adenoma” or

“adenomyoma”) formation.

Cholesterolosis is characterized by abnormal deposition of lipid, especially cholesteryl esters, within macrophages in the lamina propria of

the gallbladder wall. In its diffuse form (“strawberry gallbladder”), the

gallbladder mucosa is brick red and speckled with bright yellow flecks of

lipid. The localized form shows solitary or multiple “cholesterol polyps”

studding the gallbladder wall. Cholesterol stones of the gallbladder are

found in nearly half the cases. Cholecystectomy is only indicated in adenomyomatosis or cholesterolosis when biliary symptoms are present.

The prevalence of gallbladder polyps in the adult population is

1–4% with a marked male predominance. Types of gallbladder polyps

include cholesterol polyps, adenomyomas, inflammatory polyps, and

adenomas (rare). No significant changes have been found over a 5-year

period in asymptomatic patients with gallbladder polyps <6 mm and

few changes in polyps 7–9 mm. Cholecystectomy is recommended in

symptomatic patients as well as in asymptomatic patients >50 years

whose polyps are >10 mm or associated with gallstones or polyp

growth on serial ultrasonography.

DISEASES OF THE BILE DUCTS

■ CONGENITAL ANOMALIES

Biliary Atresia and Hypoplasia Atretic and hypoplastic lesions

of the extrahepatic and large intrahepatic bile ducts are the most common biliary anomalies of clinical relevance encountered in infancy.

The clinical picture is one of severe obstructive jaundice during the

first month of life, with pale stools. When biliary atresia is suspected

on the basis of clinical, laboratory, and imaging findings, the diagnosis is confirmed by surgical exploration and operative cholangiography. Approximately 10% of cases of biliary atresia are treatable with

Roux-en-Y choledochojejunostomy, with the Kasai procedure (hepatic

portoenterostomy) being attempted in the remainder in an effort to

restore some bile flow. Most patients, even those having successful

biliary-enteric anastomoses, eventually develop chronic cholangitis,

extensive hepatic fibrosis, and portal hypertension.

Choledochal Cysts Cystic dilatation may involve the free portion

of the CBD, that is, choledochal cyst, or may present as diverticulum

formation in the intraduodenal segment. In the latter situation, chronic

reflux of pancreatic juice into the biliary tree can produce inflammation and stenosis of the extrahepatic bile ducts, leading to cholangitis

or biliary obstruction. Because the process may be gradual, ~50% of

patients present with onset of symptoms after age 10. The diagnosis

may be made by ultrasound, abdominal CT, MRCP, or cholangiography. Only one-third of patients show the classic triad of abdominal

pain, jaundice, and an abdominal mass. Ultrasonographic detection

of a cyst separate from the gallbladder should suggest the diagnosis

of choledochal cyst, which can be confirmed by demonstrating the

entrance of extrahepatic bile ducts into the cyst. Surgical treatment

involves excision of the “cyst” and biliary-enteric anastomosis. Patients

with choledochal cysts are at increased risk for the subsequent development of cholangiocarcinoma.

Congenital Biliary Ectasia Dilatation of intrahepatic bile ducts

may involve either the major intrahepatic radicles (Caroli’s disease),

the inter- and intralobular ducts (congenital hepatic fibrosis), or both.

In Caroli’s disease, clinical manifestations include recurrent cholangitis,

abscess formation in and around the affected ducts, and, often, brown

pigment gallstone formation within portions of ectatic intrahepatic

biliary radicles. Ultrasound, MRCP, and CT are of great diagnostic

value in demonstrating cystic dilatation of the intrahepatic bile ducts.

Treatment with ongoing antibiotic therapy is usually undertaken in an

effort to limit the frequency and severity of recurrent bouts of cholangitis. Progression to secondary biliary cirrhosis with portal hypertension,

extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent

episodes of sepsis with hepatic abscess formation is common.

■ CHOLEDOCHOLITHIASIS

Pathophysiology and Clinical Manifestations Passage of gallstones into the CBD occurs in ~10–15% of patients with cholelithiasis.

2650 PART 10 Disorders of the Gastrointestinal System

The incidence of common duct stones increases with increasing age

of the patient, so up to 25% of elderly patients may have calculi in

the common duct at the time of cholecystectomy. Undetected duct

stones are left behind in ~1–5% of cholecystectomy patients. The overwhelming majority of bile duct stones are cholesterol stones formed in

the gallbladder, which then migrate into the extrahepatic biliary tree

through the cystic duct. Primary calculi arising de novo in the ducts

are usually brown pigment stones developing in patients with (1) hepatobiliary parasitism or chronic, recurrent cholangitis; (2) congenital

anomalies of the bile ducts (especially Caroli’s disease); (3) dilated,

sclerosed, or strictured ducts; or (4) an MDR3 (ABCB4) gene defect

leading to impaired biliary phospholipids secretion (low phospholipid–

associated cholesterol cholelithiasis). Common duct stones may remain

asymptomatic for years, may pass spontaneously into the duodenum,

or (most often) may present with biliary colic or a complication.

Complications  •  CHOLANGITIS Cholangitis may be acute or

chronic, and symptoms result from inflammation, which usually is

caused by at least partial obstruction to the flow of bile. Bacteria are

present on bile culture in ~75% of patients with acute cholangitis early

in the symptomatic course. The characteristic presentation of acute

cholangitis involves biliary pain, jaundice, and spiking fevers with chills

(Charcot’s triad). Blood cultures are frequently positive, and leukocytosis is typical. Nonsuppurative acute cholangitis is most common and

may respond relatively rapidly to supportive measures and to treatment

with antibiotics. In suppurative acute cholangitis, however, the presence

of pus under pressure in a completely obstructed ductal system leads

to symptoms of severe toxicity—mental confusion, bacteremia, and

septic shock. Response to antibiotics alone in this setting is relatively

poor, multiple hepatic abscesses are often present, and the mortality

rate approaches 100% unless prompt endoscopic or surgical relief of the

obstruction and drainage of infected bile are carried out. Endoscopic

management of bacterial cholangitis is as effective as surgical intervention. ERCP with endoscopic sphincterotomy is safe and the preferred

initial procedure for both establishing a definitive diagnosis and providing effective therapy.

OBSTRUCTIVE JAUNDICE Gradual obstruction of the CBD over a

period of weeks or months usually leads to initial manifestations of

jaundice or pruritus without associated symptoms of biliary colic or

cholangitis. Painless jaundice may occur in patients with choledocholithiasis but is much more characteristic of biliary obstruction secondary

to malignancy of the head of the pancreas, bile ducts, or ampulla of

Vater.

In patients whose obstruction is secondary to choledocholithiasis,

associated chronic calculous cholecystitis is very common, and the

gallbladder in this setting may be unable to distend. The absence of

a palpable gallbladder in most patients with biliary obstruction from

duct stones is the basis for Courvoisier’s law, that is, that the presence

of a palpably enlarged gallbladder suggests that the biliary obstruction

is secondary to an underlying malignancy rather than to calculous

disease. Biliary obstruction causes progressive dilatation of the intrahepatic bile ducts as intrabiliary pressures rise. Hepatic bile flow is

suppressed, and reabsorption and regurgitation of conjugated bilirubin

into the bloodstream lead to jaundice accompanied by dark urine (bilirubinuria) and light-colored (acholic) stools.

CBD stones should be suspected in any patient with cholecystitis

whose serum bilirubin level is >85.5 μmol/L (5 mg/dL). The maximum

bilirubin level is seldom >256.5 μmol/L (15.0 mg/dL) in patients with

choledocholithiasis unless concomitant hepatic or renal disease or

another factor leading to marked hyperbilirubinemia exists. Serum

bilirubin levels ≥342.0 μmol/L (20 mg/dL) should suggest the possibility of neoplastic obstruction. The serum alkaline phosphatase level

is almost always elevated in biliary obstruction. A rise in alkaline

phosphatase often precedes clinical jaundice and may be the only

abnormality in routine liver function tests. There may be a two- to

tenfold elevation of serum aminotransferases, especially in association

with acute obstruction. Following relief of the obstructing process,

serum aminotransferase elevations usually return rapidly to normal,

while the serum bilirubin level may take 1–2 weeks to return to normal.

The alkaline phosphatase level usually falls slowly, lagging behind the

decrease in serum bilirubin.

PANCREATITIS The most common associated entity discovered in

patients with nonalcoholic acute pancreatitis is biliary tract disease.

Biochemical evidence of pancreatic inflammation complicates acute

cholecystitis in 15% of cases and choledocholithiasis in >30%, and the

common factor appears to be the passage of gallstones through the

common duct. Coexisting pancreatitis should be suspected in patients

with symptoms of cholecystitis who develop (1) back pain or pain to

the left of the abdominal midline, (2) prolonged vomiting with paralytic ileus, or (3) a pleural effusion, especially on the left side. Surgical

treatment of gallstone disease is usually associated with resolution of

the pancreatitis.

SECONDARY BILIARY CIRRHOSIS Secondary biliary cirrhosis may

complicate prolonged or intermittent duct obstruction with or without recurrent cholangitis. Although this complication may be seen

in patients with choledocholithiasis, it is more common in cases of

prolonged obstruction from stricture or neoplasm. Once established,

secondary biliary cirrhosis may be progressive even after correction of

the obstructing process, and increasingly severe hepatic cirrhosis may

lead to portal hypertension or to hepatic failure and death. Prolonged

biliary obstruction may also be associated with clinically relevant deficiencies of the fat-soluble vitamins A, D, E, and K.

Diagnosis and Treatment The diagnosis of choledocholithiasis

is made by cholangiography (Table 346-3), either preoperatively by

endoscopic retrograde cholangiogram (ERC) (Fig. 346-2C) or MRCP

or intraoperatively at the time of cholecystectomy. As many as 15% of

patients undergoing cholecystectomy will prove to have CBD stones.

When CBD stones are suspected prior to laparoscopic cholecystectomy, preoperative ERCP with endoscopic papillotomy and stone

extraction is the preferred approach. It not only provides stone clearance but also defines the anatomy of the biliary tree in relationship to

the cystic duct. CBD stones should be suspected in gallstone patients

who have any of the following risk factors: (1) a history of jaundice or

pancreatitis, (2) abnormal tests of liver function, and (3) ultrasonographic or MRCP evidence of a dilated CBD or stones in the duct.

Alternatively, if intraoperative cholangiography reveals retained stones,

postoperative ERCP can be carried out. The need for preoperative

ERCP is expected to decrease further as laparoscopic techniques for

bile duct exploration improve.

The widespread use of laparoscopic cholecystectomy and ERCP

has decreased the incidence of complicated biliary tract disease and

the need for choledocholithotomy and T-tube drainage of the bile

ducts. EBS followed by spontaneous passage or stone extraction is the

treatment of choice in the management of patients with common duct

stones, especially in elderly or poor-risk patients.

■ TRAUMA, STRICTURES, AND HEMOBILIA

Most benign strictures of the extrahepatic bile ducts result from surgical

trauma and occur in about 1 in 500 cholecystectomies. Strictures may

present with bile leak or abscess formation in the immediate postoperative period or with biliary obstruction or cholangitis as long as 2 years

or more following the inciting trauma. The diagnosis is established by

percutaneous or endoscopic cholangiography. Endoscopic brushing of

biliary strictures may be helpful in establishing the nature of the lesion

and is more accurate than bile cytology alone. When positive exfoliative

cytology is obtained, the diagnosis of a neoplastic stricture is established. This procedure is especially important in patients with primary

sclerosing cholangitis (PSC) who are predisposed to the development of

cholangiocarcinomas. Successful operative correction of non-PSC bile

duct strictures by a skillful surgeon with duct-to-bowel anastomosis is

usually possible, although mortality rates from surgical complications,

recurrent cholangitis, or secondary biliary cirrhosis are high.

Hemobilia may follow traumatic or operative injury to the liver or

bile ducts, intraductal rupture of a hepatic abscess or aneurysm of the

hepatic artery, biliary or hepatic tumor hemorrhage, or mechanical

complications of choledocholithiasis or hepatobiliary parasitism. Diagnostic procedures such as liver biopsy, PTC, and transhepatic biliary

2651 Diseases of the Gallbladder and Bile Ducts CHAPTER 346

drainage catheter placement may also be complicated by hemobilia.

Patients often present with a classic triad of biliary pain, obstructive

jaundice, and melena or occult blood in the stools. The diagnosis is

sometimes made by cholangiographic evidence of blood clot in the

biliary tree, but selective angiographic verification may be required.

Although minor episodes of hemobilia may resolve without intervention, arteriography and transcatheter embolization or surgical ligation

of the bleeding vessel may be required.

■ EXTRINSIC COMPRESSION OF THE BILE DUCTS

Partial or complete biliary obstruction may be produced by extrinsic

compression of the ducts. The most common cause of this form of

obstructive jaundice is carcinoma of the head of the pancreas. Biliary

obstruction may also occur as a complication of either acute or chronic

pancreatitis or involvement of lymph nodes in the porta hepatis by

lymphoma or metastatic carcinoma. The latter should be distinguished

from cholestasis resulting from massive replacement of the liver by

tumor.

■ HEPATOBILIARY PARASITISM

Infestation of the biliary tract by adult helminths or their ova may produce a chronic, recurrent pyogenic cholangitis with or without multiple

hepatic abscesses, ductal stones, or biliary obstruction. This condition

is relatively rare but does occur in inhabitants of southern China and

TABLE 346-3 Diagnostic Evaluation of the Bile Ducts

DIAGNOSTIC ADVANTAGES DIAGNOSTIC LIMITATIONS CONTRAINDICATIONS COMPLICATIONS COMMENT

Ultrasound

Rapid

Simultaneous scanning of GB, liver,

bile ducts, pancreas

Accurate identification of dilated

bile ducts

Not limited by jaundice, pregnancy

Guidance for fine-needle biopsy

Bowel gas

Massive obesity

Ascites

Barium

Partial bile duct obstruction

Poor visualization of distal CBD

None None Initial procedure of choice in

investigating possible biliary tract

obstruction

Computed Tomography

Simultaneous scanning of GB, liver,

bile ducts, pancreas

Accurate identification of dilated

bile ducts, masses

Not limited by jaundice, gas,

obesity, ascites

High-resolution image

Guidance for fine-needle biopsy

Extreme cachexia

Movement artifact

Ileus

Partial bile duct obstruction

Pregnancy Reaction to iodinated contrast,

if used

Indicated for evaluation of

hepatic or pancreatic masses or

for assessing for complications

related to gallstones

(pancreatitis)

Procedure of choice in

investigating possible biliary

obstruction if diagnostic

limitations limit US

Magnetic Resonance Cholangiopancreatography

Noninvasive modality for

visualizing pancreatic and biliary

ducts

Has excellent sensitivity for bile

duct dilatation, biliary stricture,

and intraductal abnormalities

Can identify pancreatic duct

dilatation or stricture, pancreatic

duct stenosis, and pancreas

divisum

Cannot offer therapeutic

intervention

High cost

Claustrophobia

Certain metals (iron)

None First choice to assess for

choledocholithiasis given

comparable sensitivity and

specificity to ERCP

Endoscopic Retrograde Cholangiopancreatography

Simultaneous pancreatography

Best visualization of distal biliary

tract

Bile or pancreatic cytology

Endoscopic sphincterotomy and

stone removal

Biliary manometry

Gastroduodenal obstruction

Roux-en-Y biliary-enteric

anastomosis

Pregnancy

Acute pancreatitis

Severe cardiopulmonary

disease

Pancreatitis

Cholangitis, sepsis

Infected pancreatic pseudocyst

Perforation (rare)

Hypoxemia, aspiration

Cholangiogram of choice if there

is believed to be a need for

intervention:

Diagnosed or high clinical

probability of choledocholithiasis

Biliary stricture requiring

sampling and stenting

Need for sphincterotomy such as

Sphincter of Oddi dysfunction

Percutaneous Transhepatic Cholangiogram

Best when bile ducts dilated

Best visualization of proximal

biliary tract

May be used to obtain bile

cytology/culture

Allows for percutaneous

transhepatic drainage

Nondilated or sclerosed ducts Pregnancy

Uncorrectable

coagulopathy

Massive ascites

Hepatic abscess

Bleeding

Hemobilia

Bile peritonitis

Bacteremia, sepsis

Indicated for the drainage of

obstructed and infected ducts

when ERCP is contraindicated

or failed

Endoscopic Ultrasound

Most sensitive method to detect

ampullary stones and exclude

pathology in the head of the

pancreas

Excellent for detecting

choledocholithiasis

Abbreviations: CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography; GB, gallbladder; US, hepatobiliary ultrasound.

2652 PART 10 Disorders of the Gastrointestinal System

elsewhere in Southeast Asia. The organisms most commonly involved

are trematodes or flukes, including Clonorchis sinensis, Opisthorchis

viverrini or Opisthorchis felineus, and Fasciola hepatica. The biliary

tract also may be involved by intraductal migration of adult Ascaris

lumbricoides from the duodenum or by intrabiliary rupture of hydatid

cysts of the liver produced by Echinococcus spp. The diagnosis is made

by cholangiography and the presence of characteristic ova on stool

examination. When obstruction is present, the treatment of choice is

laparotomy under antibiotic coverage, with common duct exploration

and a biliary drainage procedure.

■ SCLEROSING CHOLANGITIS

PSC is characterized by a progressive, inflammatory, sclerosing, and

obliterative process affecting the extrahepatic and/or the intrahepatic

bile ducts. PSC is strongly associated with inflammatory bowel disease,

especially ulcerative colitis.

Immunoglobulin G4 (IgG4)–associated cholangitis is a biliary disease of unknown etiology that presents with biochemical and cholangiographic features indistinguishable from PSC, is often associated with

autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma

cells in bile ducts and liver tissue. All patients diagnosed with sclerosing cholangitis should have a serum IgG4 level checked to rule out

IgG4 disease as a cause of secondary sclerosing cholangitis, particularly

if they do not have inflammatory bowel disease. Glucocorticoids are

the initial treatment of choice. Relapse is common after steroid withdrawal, especially with proximal strictures. Long-term treatment with

glucocorticoids and/or steroid-sparing agents such as azathioprine may

be needed after relapse or for inadequate response (Chap. 348).

Patients with PSC often present with signs and symptoms of

chronic or intermittent biliary obstruction: RUQ abdominal pain,

pruritus, jaundice, or acute cholangitis. Late in the course, complete

biliary obstruction, secondary biliary cirrhosis, hepatic failure, or

portal hypertension with bleeding varices may occur. The diagnosis is

established by finding multifocal, diffusely distributed strictures with

intervening segments of normal or dilated ducts, producing a beaded

appearance on cholangiography (Fig. 346-2D). The cholangiographic

techniques of choice in suspected cases are MRCP and ERCP. When

a diagnosis of sclerosing cholangitis has been established, causes of

secondary sclerosing should be considered. Patients with PSC should

undergo testing for associated diseases, especially inflammatory bowel

disease, if that diagnosis has not already been established.

Small duct PSC is defined by the presence of chronic cholestasis and

hepatic histology consistent with PSC in a patient with IBD, but with

normal findings on cholangiography. Small duct PSC is found in ~5%

of patients with PSC and may represent an earlier stage of PSC associated with a significantly better long-term prognosis. However, such

patients may progress to classic PSC and/or end-stage liver disease with

consequent necessity of liver transplantation.

In patients with AIDS, cholangiopancreatography may demonstrate a broad range of biliary tract changes as well as pancreatic duct

obstruction and occasionally pancreatitis (Chap. 202). Further, biliary

tract lesions in AIDS include infection and cholangiopancreatographic

changes of sclerosing cholangitis. Changes noted include (1) diffuse

involvement of intrahepatic bile ducts alone, (2) involvement of both

intra- and extrahepatic bile ducts, (3) ampullary stenosis, (4) stricture

of the intrapancreatic portion of the CBD, and (5) pancreatic duct

involvement. Associated infectious organisms include Cryptosporidium, Mycobacterium avium-intracellulare, cytomegalovirus, Microsporidia, and Isospora. ERCP sphincterotomy can provide significant pain

reduction in patients with AIDS-associated papillary stenosis.

TREATMENT

Primary Sclerosing Cholangitis

There is no proven medical therapy for PSC. Therapy to treat pruritus associated with PSC includes cholestyramine, rifampin, and

naltrexone. Antibiotics are useful when bacterial cholangitis complicates the clinical picture. Vitamin D and calcium supplementation

Section 4 Disorders of the Pancreas

347

■ GENERAL CONSIDERATIONS

Globally, pancreatic disorders, including acute and chronic pancreatitis, pancreatic cysts, and pancreatic cancer, are challenging to manage

and associated with a high burden on health care resources. The relationships between these diseases continues to be poorly understood,

but there is encouraging progress. Acute pancreatitis is one of the most

common reasons for hospitalizations in gastroenterology, and there is

increasing evidence of long-term sequelae including diabetes, exocrine

pancreas insufficiency, and pancreas cancer. Chronic pancreatitis, an

irreversible disease of the pancreas, is associated with poor quality of

life, largely related to abdominal pain, and associated exocrine insufficiency. Pancreatic cysts, mostly incidental, are increasingly detected on

cross-sectional abdominal imaging studies. Although a small number

and specific types of pancreatic cysts can progress to pancreatic cancer,

diagnostic uncertainty can introduce unwanted anxiety to patients

and treating physicians. Meanwhile, with persistently high mortality

rates, the incidence of pancreatic adenocarcinoma is increasing and is

the seventh leading cause of cancer-related death in the industrialized

world and the third most common in the United States.

As emphasized in Chap. 348, the etiologies and clinical manifestations of pancreatitis are quite varied. Although it is well-appreciated

that acute pancreatitis is frequently secondary to biliary tract disease

and alcohol abuse, it can also be caused by drugs, genetic mutations, and trauma. In ~30% of patients with acute pancreatitis and

25–40% of patients with chronic pancreatitis, the etiology is initially

unexplained.

The global pooled incidence of acute pancreatitis is ~33.7 cases

(95% confidence interval [CI], 23.3–48.8) with 1.16 deaths (95%

CI, 0.85–1.6) per 100,000 person-years. The global pooled incidence

of chronic pancreatitis is ~9.6 cases (95% CI, 7.9–11.8) with 0.09

attributable deaths (95% CI, 0.02–0.5) per 100,000 person-years. In the

Approach to the Patient

with Pancreatic Disease

Somashekar G. Krishna,

Darwin L. Conwell, Phil A. Hart

may be used as initial therapy to help prevent the loss of bone mass

frequently seen in patients with chronic cholestasis. In cases where

high-grade biliary obstruction (dominant strictures) has occurred,

balloon dilatation is preferred over stenting due to the higher complication rate associated with stenting including pancreatitis and

cholangitis. Only rarely is surgical intervention indicated. PSC is a

progressive disease with a median survival of 12–18 years following

the diagnosis, regardless of therapy. Four variables (age, serum

bilirubin level, histologic stage, and splenomegaly) predict survival

in patients with PSC and serve as the basis for a risk score. PSC is a

common indication for liver transplantation.

■ FURTHER READING

Baron TH et al: Interventional approaches to gallbladder disease.

N Engl J Med 373:357, 2015.

Lindor K et al: American College of Gastroenterology (ACG) guidelines: Primary sclerosing cholangitis. Hepatology 51:660, 2010.

Ryl JK et al: Clinical features of acute acalculous cholecystitis. J Clin

Gastroenterol 36:166, 2003.

Strasberg S: Clinical practice. Acute calculous cholecystitis. N Engl J

Med 358:2804, 2008.

2653Approach to the Patient with Pancreatic Disease CHAPTER 347

United States, the number of patients admitted to the hospital with

acute pancreatitis is increasing, with estimated rates of almost 300,000

annually, whereas the number of patients hospitalized for chronic pancreatitis is decreasing, with recent estimates of ~13,000 admissions per

year. Chronic pancreatitis has an annual prevalence of 42–73 cases per

100,000 adults in the United States, although higher prevalence rates

(0.04–5%) have been noted among adults at autopsy. Together, acute

and chronic pancreatic disease costs an estimated $3 billion annually

in health care expenditures.

The diagnosis of acute pancreatitis is generally clearly defined

based on a combination of laboratory, imaging, and clinical symptoms. The diagnosis of chronic pancreatitis, especially in mild disease,

is hampered by the relative inaccessibility of the pancreas to direct

examination and the nonspecificity of the abdominal pain associated

with chronic pancreatitis. Many patients with chronic pancreatitis do

not have elevated blood amylase or lipase levels. Some patients with

chronic pancreatitis develop signs and symptoms of exocrine pancreatic insufficiency (EPI), and thus, objective evidence for pancreatic

disease can be demonstrated. However, there is a very large reservoir

of pancreatic exocrine function. More than 90% of the pancreas must

be damaged before maldigestion of fat and protein is manifested.

Noninvasive, indirect tests of pancreatic exocrine function (e.g., fecal

elastase) are much more likely to give abnormal results in patients

with obvious advanced pancreatic disease (i.e., pancreatic calcification,

steatorrhea, or diabetes mellitus) than in patients with occult disease.

Invasive, direct tests of pancreatic secretory function (e.g., secretin

stimulation test) are the most sensitive and specific tests to detect early

chronic pancreatic disease when imaging is equivocal or normal.

The increasing utilization of cross-sectional imaging modalities

with their improved resolution has contributed to a high prevalence

(2–5% with computed tomography [CT] scans, 20–30% with magnetic

resonance imaging [MRI]) of incidentally detected pancreatic cysts.

The most common cyst type encountered is an intraductal papillary

mucinous neoplasm (IPMN), which is classified as a precancerous

mucinous cyst. In the absence of high-risk features, radiographic

surveillance is typically recommended (Fig. 347-1). Mucinous cystic

neoplasms (MCNs) are a less commonly encountered mucinous cyst.

Among the neoplastic cysts, serous cystadenomas have a negligible

risk of progression to malignancy. Other infrequent neoplastic cysts

include neuroendocrine tumors and solid pseudopapillary neoplasms.

The most commonly encountered benign cyst is a pseudocyst, which

can occur in patients with a history of acute or chronic pancreatitis.

It is often difficult to accurately predict the risk of malignant transformation of precancerous pancreatic cysts, and there is an increasing

number of patients on imaging surveillance protocols burdening the

health care systems in the industrialized world.

A B C

FIGURE 347-1 A. Side-branch intraductal papillary mucinous neoplasm (magnetic resonance imaging [MRI] with magnetic resonance cholangiopancreatography [MRCP]).

T2-weighted MRCP image demonstrates a dominant, lobulated, hyperintense cystic structure (arrow) within the posterior body of the pancreas. The pancreatic duct

upstream from the cyst is dilated and irregular. Endoscopic ultrasound and fine-needle aspiration of cyst fluid were consistent with a mucinous cyst. Surgical histopathology

revealed an infiltrating moderately differentiated adenocarcinoma, 0.3 cm, arising in a background of an intraductal papillary mucinous neoplasm (IPMN). B. Mucinous

cystic neoplasm (computed tomography [CT] scan). In the tail of the pancreas, there is a well-circumscribed hypodense cyst (arrow) without any nodular enhancing

components. Endoscopic ultrasound and fine-needle aspiration of cyst fluid were suggestive of a mucinous cyst. Surgical histopathology revealed a mucinous cystic

neoplasm (3.4 cm) with low-grade dysplasia. The stroma of the cyst demonstrated diffuse positivity for progesterone receptor and focal positivity for CD10 (ovarian stroma),

confirming the diagnosis. C. Serous cystadenoma (MRI). A lobulated microcystic cyst (arrow) is observed in the tail of the pancreas. Neither a communication with the main

pancreatic duct nor intracystic soft tissue enhancing nodular components were observed. However, the cyst continued to increase in size and a distal pancreatectomy

was performed. Histopathology revealed a serous microcystic adenoma. (Courtesy of Dr. Z.K. Shah, The Ohio State University Wexner Medical Center; with permission.)

■ TESTS USEFUL IN THE DIAGNOSIS OF

PANCREATIC DISEASE

Several tests are of value in the evaluation of pancreatic disease. Examples of specific tests and their usefulness in the diagnosis of acute and

chronic pancreatitis are summarized in Table 347-1 and Fig. 347-2.

At some institutions, pancreatic function tests are available and performed if the diagnosis of chronic pancreatitis remains a possibility

after noninvasive tests (i.e., ultrasound, CT Scan, MRI with magnetic

resonance cholangiopancreatography [MRCP]) or invasive tests (i.e.,

endoscopic retrograde cholangiopancreatography [ERCP], endoscopic

ultrasound [EUS]) have given normal or inconclusive results. In this

regard, tests using direct stimulation of the pancreas with secretin are

the most sensitive.

Pancreatic Enzymes in Body Fluids The serum amylase and

lipase levels are widely used as screening tests for acute pancreatitis

in the patient with acute abdominal pain or back pain. Lipase is very

specific for the pancreas, and values greater than three times the upper

limit of normal (3× ULN) in combination with epigastric pain strongly

suggest the diagnosis of acute pancreatitis. In acute pancreatitis, the

serum amylase and lipase are usually elevated within 24 h of onset and

remain so for 3–7 days. Levels usually return to normal within 7 days

unless there is pancreatic ductal disruption, ductal obstruction, or

pseudocyst formation. Approximately 85% of patients with acute pancreatitis have threefold or greater elevated serum lipase and amylase

levels. The values may be normal if (1) there is a delay (2–5 days) before

blood samples are obtained, (2) the underlying disorder is chronic

pancreatitis rather than acute pancreatitis, or (3) hypertriglyceridemia

is present. Patients with hypertriglyceridemia and acute pancreatitis

have been found to have spuriously low levels of amylase and perhaps

lipase activity. In the absence of objective evidence of pancreatitis by

abdominal ultrasound, contrast-enhanced CT scan, MRI with MRCP,

or EUS, mild to moderate elevations of amylase and/or lipase are not

helpful in making a diagnosis of chronic pancreatitis.

It should be noted that the serum amylase can be elevated in other

conditions (Table 347-2), in part because the enzyme is found in many

organs. In addition to the pancreas and salivary glands, small quantities

of amylase are found in the tissues of the fallopian tubes, lung, thyroid,

and tonsils and can be produced by various tumors (carcinomas of the

lung, esophagus, breast, and ovary). Isoamylase determinations do not

accurately distinguish elevated blood amylase levels from pancreatic

or nonpancreatic sources. In patients with unexplained hyperamylasemia, the measurement of macroamylase can avoid numerous tests

in patients with this rare disorder.

Elevation of ascitic fluid amylase occurs in acute pancreatitis as well

as in (1) ascites due to disruption of the main pancreatic duct or a leaking

pseudocyst and (2) other abdominal disorders that simulate pancreatitis

2654 PART 10 Disorders of the Gastrointestinal System

(e.g., intestinal obstruction, intestinal infarction, or perforated peptic

ulcer). Elevation of pleural fluid amylase can occur in acute pancreatitis,

chronic pancreatitis, carcinoma of the lung, and esophageal perforation.

Lipase is the single best enzyme to measure for the diagnosis of acute

pancreatitis. It is important to acknowledge that levels are often mildly

elevated in the setting of renal disease, so determining whether a patient

with renal failure and abdominal pain has pancreatitis remains a challenging clinical problem. One study found that serum amylase levels

were elevated in patients with renal dysfunction only when creatinine

clearance was <0.8 mL/s (<50 mL/min). In such patients, the serum

TABLE 347-1 Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Neoplasms

TEST PRINCIPLE COMMENT

Pancreatic Enzymes in Body Fluids

Serum lipase Pancreatic inflammation leads to increased serum enzyme

levels

Enzyme measurement of choice for the diagnosis of acute pancreatitis;

increased specificity if the level is more than three times the upper limit

of normal (3× ULN)

Amylase

1. Serum Pancreatic inflammation leads to increased serum enzyme

levels

Simple; increased specificity if the level is >3× ULN; may be falsely

normal in patients with hypertriglyceridemic pancreatitis

2. Urine Renal clearance of amylase is increased in acute

pancreatitis

Infrequently used

3. Ascitic fluid Disruption of gland or main pancreatic duct leads to

increased amylase concentration

Can help establish source of ascites; false positives occur with intestinal

obstruction and perforated ulcer; can also measure lipase

4. Pleural fluid Exudative pleural effusion with pancreatitis False positives occur with carcinoma of the lung and esophageal

perforation

Studies Pertaining to Pancreatic Structure

Radiologic and radionuclide tests

1. Plain film of the abdomen or

upper gastrointestinal x-rays

Can demonstrate large calcifications in chronic

pancreatitis

Infrequently used

2. Ultrasonography (US) Can provide limited information on edema, inflammation,

calcification, pseudocysts, and mass lesions

Simple, noninvasive; sequential studies quite feasible; useful in diagnosis

of gallstones; pancreas visualization limited by interference from

overlying bowel gas

3. Computed tomography

(CT) scan

Permits detailed visualization of pancreas and

surrounding structures, pancreatic fluid collection,

pseudocyst; assessment of necrosis or interstitial disease

Useful in the diagnosis of pancreatic calcification, dilated pancreatic

ducts, and pancreatic tumors; may not be able to distinguish between

inflammatory and neoplastic mass lesions; multiphasic CT scans are the

preferred imaging modality for staging pancreatic cancer; IV contrast is

needed for characterization of most features

4. Magnetic resonance

imaging (MRI) and

cholangiopancreatography

(MRCP)

Permits noninvasive detailed evaluation of the pancreatic

parenchyma, biliary and pancreatic ducts, adjacent soft

tissues, and vascular structures.

Has mostly replaced ERCP for diagnostic assessment of the pancreatic

duct; more sensitive than CT scan for detection of mild pancreatitis,

necrosis, choledocholithiasis, pancreatic ductal abnormalities, and

cystic neoplasms; no exposure to ionizing radiation

5. Endoscopic ultrasonography

(EUS) and fine-needle

aspiration/biopsy (FNA/B)

High-frequency transducer used with EUS produces veryhigh-resolution images permitting focused evaluation of

pancreatic parenchyma and biliary and pancreatic ducts,

and FNA/B provides targeted tissue acquisition

Can be used to assess gallstones, choledocholithiasis, chronic

pancreatitis, pancreatic masses, and cystic neoplasms; FNA/B facilitates

diagnostic and therapeutic management of pancreatic diseases

6. Endoscopic retrograde

cholangiopancreatography

(ERCP)

Cannulation of pancreatic and/or common bile duct

permits visualization of pancreaticobiliary ductal system

Primarily a therapeutic procedure; invasive with risks for iatrogenic

complications

Tests of Exocrine Pancreatic Function

Direct stimulation of the pancreas with analysis of duodenal contents

1. Secretin test Secretin leads to increased output of pancreatic juice and

HCO3

–

; pancreatic secretory response is related to the

functional mass of pancreatic tissue; involves duodenal

intubation and fluoroscopic placement of gastroduodenal

tube

Sensitive to detect occult disease; poorly defined normal enzyme

response; large secretory reserve capacity of the pancreas; rarely

performed

2. Endoscopic pancreatic

function test (ePFT)

Secretin-stimulated collection of pancreatic juice

performed during upper endoscopy; replaces need for

tube placement in the duodenum

Sensitive to detect occult disease; high negative predictive value for

chronic pancreatitis; requires sedation

3. EUS-ePFT Combines endosonographic evaluation of the pancreas

and endoscopic collection of pancreatic juice

Single endoscopic evaluation of pancreatic structure and function

4. Secretin-stimulated MRCP Combines imaging evaluation of the pancreas and a

semiquantitative estimation of pancreatic juice output in

the duodenum

Improved visualization of pancreatic ductal anatomy; functional

evaluation is less accurate than ePFT; noninvasive

Measurement of intraluminal digestion products

1. Stool fat determination Lack of lipolytic enzymes brings about impaired fat

digestion; quantitative 72-h stool collection and estimation

are more reliable than qualitative analysis of a random

stool sample

Reliable reference standard for defining severity of fat malabsorption;

does not distinguish between pancreatic and nonpancreatic cause of

malabsorption

Measurement of pancreatic enzymes in feces

1. Fecal elastase Pancreatic secretion of proteolytic enzymes; not degraded

in intestine

Diagnostic accuracy is highest when the pretest probability is high

and the value is <100 μg/g; false positives will occur in patients with

nonformed stools

2655Approach to the Patient with Pancreatic Disease CHAPTER

amylase level was invariably <500 IU/L in the absence of objective

347

evidence of acute pancreatitis. In that study, serum lipase and trypsin

levels paralleled serum amylase values. With these limitations in mind,

the recommended screening test for acute pancreatitis in renal disease

is serum lipase, but a high index of clinical suspicion is needed based on

symptoms. Elevations in serum lipase >3× ULN due to nonpancreatic

etiology can be observed in hepatobiliary or gastrointestinal malignancies, septicemia, liver cirrhosis, systemic lupus erythematosus, severe

head injury, chronic alcoholism, diabetes mellitus, and post-ERCP

without any associated evidence of pancreatitis.

Studies Pertaining to Pancreatic Structure  •  RADIOLOGIC

TESTS Plain films of the abdomen rarely provide useful information related to pancreatic disease and have been superseded by more

detailed imaging studies (ultrasound, EUS, CT, and MRI with MRCP).

Ultrasonography (US) can provide important information in the

initial emergency ward evaluation of patients with acute pancreatitis,

chronic pancreatitis, pseudocysts, and pancreatic adenocarcinoma.

Sonographic changes can indicate the presence of edema, inflammation, and calcification (not obvious on plain films of the abdomen),

as well as gallstones, biliary dilation, pseudocysts, and mass lesions. In

acute pancreatitis, the pancreas is characteristically enlarged. In pancreatic pseudocyst, the usual appearance is primarily that of a smooth,

round fluid collection. Pancreatic adenocarcinoma distorts the usual

landmarks, and mass lesions >3.0 cm are usually detected as localized,

solid lesions. US is often the initial investigation for most patients with

suspected pancreatic disease. However, obesity and excess intestinal

bowel gas can interfere with pancreatic imaging, limiting its sensitivity.

CT with intravenous contrast is the best imaging study for the

assessment of complications of acute and chronic pancreatitis. It is

especially useful in the detection of pancreatic and peripancreatic

acute fluid collections, fluid-containing lesions such as pseudocysts,

walled-off necrosis (see Chap. 348, Figs. 348-1, 348-2, and 348-4),

and pancreatic neoplasms. Acute pancreatitis is characterized by (1)

enlargement of the pancreas, (2) distortion of the pancreatic contour

with peripancreatic stranding of adjacent fat tissue, and/or (3) the

presence of pancreatic fluid that has a different attenuation coefficient than normal pancreas. When possible, CT scans should ideally

be performed with oral and intravenous contrast to detect areas of

pancreatic necrosis. The major benefit of CT scan in acute pancreatitis

is the diagnosis of pancreatic necrosis in patients not responding to

conservative management within 72 h. It may take 48–72 h to develop

perfusion defects indicative of pancreatic necrosis. Therefore, if acute

pancreatitis is confirmed with serology and physical examination findings, CT scan in the first 3 days is not recommended to minimize risk

of contrast-induced nephropathy and unnecessary health care costs.

Improved imaging technology and increased resolution are facilitated

by multiphasic CT scans using multidetector technology (MDCT)

in which a pancreas protocol consisting of dual-phase scanning with

intravenous contrast is utilized for the detection and staging of pancreatic cancers. While the sensitivity of MDCT for detecting smaller

(≤2 cm) lesions is lower, the reported overall sensitivity for pancreatic

cancers is 76–97%. The contraindications to using intravenous contrast

include renal failure (serum creatinine >2 mg/dL) and a history of

severe allergic reaction to iodinated contrast agents. In situations where

EUS is not available, CT-guided percutaneous aspiration or biopsy of a

pancreatic mass can be performed. Prior to the major advance of EUSguided fine-needle aspiration (FNA), CT-guided biopsy was utilized in

the preceding decades and is regarded as a safe procedure.

MRI and MRCP provide excellent imaging of the bile duct, pancreatic duct, and pancreas parenchyma in both acute pancreatitis and

chronic pancreatitis. MRI is better than transabdominal US and CT

scans and comparable to EUS in the detection of choledocholithiasis.

Similar to CT, MRI can evaluate for the severity of acute pancreatitis.

Moreover, T2-weighted MRI of fluid collections can differentiate

necrotic debris from fluid in suspected walled-off necrosis, and T1

imaging can diagnose hemorrhage in suspected pseudoaneurysm

rupture. In chronic pancreatitis, secretin-enhanced MRCP is a method

to enhance the evaluation of major and minor ductal changes. While

imaging is comparable to CT for evaluating pancreatic mass lesions,

MRI with MRCP is the preferred imaging modality for evaluating

pancreatic cystic lesions. Nephrogenic systemic fibrosis has been

described in patients with chronic renal failure following exposure to

the gadolinium contrast, but incidence rates are extraordinarily low

with contemporary contrast agents.

EUS produces high-resolution images of the bile duct, pancreatic parenchyma, and pancreatic duct with a transducer fixed to an

Step 1

• Clinical signs and symptoms suggestive of chronic pancreatic disease: abdominal pain,

 nausea, weight loss, steatorrhea, malabsorption, history of alcohol abuse, recurrent

 pancreatitis, fatty-food intolerance

• Perform history, physical examination, review of laboratory studies; consider fecal elastase

 measurement

• Contrast-enhanced CT scan

• CP diagnostic criteria: calcifications in combination with atrophy and/or dilated duct

• Diagnostic criteria met; no further imaging needed

• Inconclusive or nondiagnostic results; continue to step 2

• MRI and MRCP, with or without secretin enhancement (sMRCP)

• CP diagnostic criteria: Cambridge class III,a dilated duct, atrophy of gland, filling

 defects in duct suggestive of stones

• Diagnostic criteria met; no further imaging needed

• Inconclusive or nondiagnostic results; continue to step 3

• Pancreas function test (with secretin)—endoscopic (ePFT) collection method

 preferred; consider combining ePFT with EUS

• CP diagnostic criteria: peak [bicarbonate] <80 mEq/L

• Diagnostic criteria met; no further imaging needed

• Inconclusive or nondiagnostic results require monitoring of signs and symptoms and repeat

 testing in 6 months–1 year

• EUS with quantification of parenchymal and ductal criteria

• CP diagnostic criteria: ≥5 EUS CP criteria

• Diagnostic criteria met; no further imaging needed

• Inconclusive or nondiagnostic results; continue to step 4

Step 2

Step 3

Step 4

FIGURE 347-2 A stepwise diagnostic approach to the patient with suspected chronic pancreatitis (CP). Endoscopic ultrasonography (EUS) and magnetic resonance

imaging (MRI) with secretin-stimulated magnetic resonance cholangiopancreatography (sMRCP/MRCP) are appropriate diagnostic alternatives to endoscopic

retrograde cholangiopancreatography (ERCP). CT, computed tomography; ePFT, endoscopic pancreas function test. a

Cambridge classification of pancreatic duct findings:

class 0: normal—visualization of complete normal ductal anatomy; class I: equivocal—normal main duct, 1–3 abnormal side branches; class II: mild—normal main duct,

>3 abnormal side branches; class III—dilated and irregular main duct, >3 abnormal side branches, small (<10 mm) cysts; class IV—irregular main duct, intraductal calculi,

strictures, obstruction with dilation, or large (> 10 mm) cysts.