Gi Pathophysiology Lecture 1: The Biliary Tract

Front 1

Primary bile duct stones

Back 1

Form in bile duct as a result of biliary stasis (e.g., above a stricture), around foreign material (e.g., suture or stent), or in association with infection. Primary bile duct stones are usually brown pigment stones and are very soft and like mud. They can be formed in extra- or intrahepatic bile ducts.

Front 2

Secondary bile duct stones

Back 2

Gallstones which have migrated from the gallbladder and into the bile duct. Their composition reflects the composition of gallstones.

Front 3

1. Biliary Pain.

a. Etiology:

Back 3

Sudden obstruction of the cystic duct by a stone produces increased intraluminal pressure and distention, leading to a visceral-type pain. The obstruction is intermittent.

Front 4

1. Biliary Pain.
b. Presentation:

Back 4

Discrete attacks may be precipitated by meals, but may occur at any time of the day or night. Their frequency may vary from weeks to years. The pain is steady, aching or pressure-type. Usually the pain is felt in the epigastrium or right upper quadrant, and can radiate to the right scapula. Characteristically, biliary pain begins suddenly and lasts for as little as 15 minutes to as long as 6 hours (generally 1-3 hours). Nausea is common and vomiting occurs occasionally. The pain subsides after the stone spontaneously falls back into the gallbladder or passes through the cystic duct into the common bile duct.

Front 5

1. Biliary Pain.
c. Laboratory:

Back 5

Hepatic injury labs, bilirubin, leukocyte count usually are normal.

Front 6

Biliary Pain
Clinical course:

Back 6

Several studies have prospectively evaluated outcomes of patients with biliary pain. Between one third and one half of patients per year will have recurrent biliary pain. However, up to one third who have one episode of pain do not have further episodes. The risk of developing biliary complications is approximately 1-2% per year. Because of this, elective cholecystectomy is usually offered to patients with recurrent biliary pain.

Front 7

2. Acute Cholecystitis.

a. Etiology:

Back 7

Caused by persistent obstruction of the cystic duct by a stone (calculous cholecystitis) in more than 90% of cases.

In order to cause gallbladder inflammation, a stone usually has to be impacted for many hours. Some patients, particularly the critically ill, may present with acalculous cholecystitis (gallbladder inflammation in the absence of stones). In calculous cholecystitis, the inflammation is thought to be caused mechanically by increased intraluminal pressure and ischemia. Subsequent bacterial superinfection can occur; enteric organisms have been cultured from 75% of patients with acute cholecystitis.

Front 8

2. Acute Cholecystitis.

b. Presentation:

Back 8

About 30% of patients have had no previous symptoms suggestive of cholelithiasis.

In contrast to biliary pain, this causes a peritoneal-type epigastric or right upper-quadrant pain that increases with jarring or respiration.

Consequently, patients frequently are motionless (in contrast to biliary pain).

Nausea is common and vomiting occurs occasionally. Fever, if present, usually is low grade (averaging about 38oC), and shaking chills do not occur.

Deep inspiration during palpation of the right upper quadrant produces increased tenderness and cessation of inspiration (Murphy's sign).

The gallbladder may be palpable (in about 25%).

Front 9

2. Acute Cholecystitis.

c. Laboratory:

Back 9

A white blood cell count of 10,000 to 15,000/mm3 with mostly polymorphonuclear leukocytes is common. Liver injury labs and bilirubin are usually normal or slightly abnormal. The bilirubin is almost always <4 mg/dL in the absence of complications. When jaundice is present, it should raise the suspicion for choledocholithiasis, cholangitis, or Mirizzi’s syndrome (all discussed below).

Front 10

2. Acute Cholecystitis.

d. Clinical Course:

Back 10

In about 75% of patients with acute cholecystitis, symptoms resolve spontaneously within 72 hours, after the stone presumably falls back into the gallbladder or passes through the cystic duct into the common bile duct. In the remaining 25%, the inflammation progresses to necrosis. Perforation or empyema of the gallbladder can develop unless cholecystectomy is performed. Clinical indications of progression are persistent symptoms, signs of peritonitis, or rising temperature, heart rate, and/or white blood cell count. In the elder patients, diabetic patients, or immunosuppressed patients (e.g., those taking corticosteroids), mild signs and symptoms may belie the severity of the inflammation. When surgery is not performed, cholecystitis recurs in 25% of patients within the first year of follow-up and in 60% of patients within 6 years. Cholecystectomy is the appropriate treatment for patients with this condition.

Front 11

B. Complications of Gallstones.

Back 11

1. Choledocholithiasis
2. Ascending cholangitis
3. Papillary stenosis
4. Choledochoduodenal fistula
a. Gallstone ileus
b. Bouveret’s syndrome
5. Acute pancreatitis (biliary pancreatitis)
6. Mirizzi’s syndrome
7. Gallbladder cancer

Front 12

Complications of Gallstones
1. Choledocholithiasis

Back 12

(stone passage into the common bile duct) occurs in 20% of patients with gallstones. Common bile duct stones can cause partial or complete obstruction which can be continuous or intermittent. Obstruction causes increased pressure in the bile duct. As a result, hepatic bile flow is suppressed and regurgitation of conjugated bilirubin into the blood stream causes jaundice, dark urine, and pale (acholic) stools. Serum alkaline phosphatase rises before serum bilirubin. In the acute setting, the most dramatic elevations may be in the transaminases (ALT and AST) and can go as high as 1000. Common bile duct stones may cause recurrent episodes of biliary pain or cholangitis.

Front 13

Complications of Gallstones
2. Ascending cholangitis

Back 13

with aerobic or aneaerobic organisms (most frequently E. coli) may result from prolonged obstruction (usually from choledocholithiasis). The classic presentation of fever, right upper quadrant pain, and jaundice (Charcot’s triad) occurs in 70% of patients. This is a medical emergency that requires prompt attention and decompression of the biliary tree by endoscopic, percutaneous, or surgical access.

Front 14

Complications of Gallstones
3. Papillary stenosis

Back 14

is the condition characterized by chronic inflammatory changes of the ampulla which result from recurrent passage of stones through the common bile duct and ampullary orifice.

Front 15

Complications of Gallstones
4. Choledochoduodenal fistula

Back 15

a connection between the bile duct and duodenum. This occurs by prolonged impaction of a stone in the wall of the bile duct which eventually erodes through the wall.

Front 16

Complications of Gallstones
Choledochoduodenal Fistula
a. Gallstone ileus

Back 16

results from impaction of large stones (which have passed through a choledochoduodenal fistula) at the ileocecal valve. Patients present with symptoms of small bowel obstruction (vomiting, abdominal distension, pain).

Front 17

Complications of Gallstones
Choledochoduodenal Fistula
b. Bouveret’s syndrome

Back 17

results from impaction of a gallstone in the duodenal bulb or descending duodenum. Causes symptoms of gastric outlet obstruction (vomiting). The vomiting is non-bilious if the stone is impacted proximal to the ampulla of Vater.

Front 18

Complications of Gallstones
5. Acute pancreatitis (biliary pancreatitis)

Back 18

occurs as the result of ampullary obstruction by a gallstone, sludge, or microlith. 30-75% of patients with acute pancreatitis have gallstones. Most patients with gallstone pancreatitis have passed their stone at the time of presentation.

Front 19

Complications of Gallstones
6. Mirizzi’s syndrome

Back 19

results from extrinsic compression of the common hepatic duct by a stone impacted in the cystic duct or neck of the gallbladder. The external compression can cause obstructive jaundice. The clinical presentation can mimic choledocholithiasis and cholangitis. Treatment is cholecystectomy, but ERCP with stent placement can be performed before surgery.

Front 20

Complications of Gallstones
7. Gallbladder cancer

Back 20

accounts for one third to one half of gallstone related death in the U.S. About 80% of patients with ________ have stones, and 1% of patients with gallstones at autopsy have ________. Cohort studies suggest that patients with symptomatic gallstones develop ________ at higher rates that do patients with asymptomatic stones. ________ occurs in 50% of patients with a calcified gallbladder wall (porcelain gallbladder), and in 3-5% of Native Americans, particularly if they have gallstones.

Front 21

C. Diagnosis of Gallstones.

Back 21

1. Transabdominal ultrasound (US):
2. 99mTc-labeled hydroxyl iminodiacetic acid (HIDA) scan
3. Computed tomography (CT)
4. Magnetic resonance cholangiopancreatography (MRCP)
5. Endoscopic ultrasound (EUS):

Front 22

1. Transabdominal ultrasound (US):

Back 22

US is considered one of the most sensitive (95%) and specific (95%) studies for the detection of gallstones and acute cholecystitis. US does not depend on gallbladder function, can be done even in the presence of jaundice, and without preparing the patient other than fasting. In addition to the presence of gallstones, US can detect signs of acute cholecystitis (GB wall thickening, pericholecystic fluid) and give information regarding the bile ducts (dilation, presence of stones). It can be done at the bedside and in patients with acute cholecystitis. It also allows for examination of the common bile duct and detects obstruction of the bile duct as well as stones. Its sensitivity for CBD stones is only 50%, but their presence can be inferred (75%) if there is ductal dilation. Therefore, US can confirm, but not exclude, the presence of CBD stones.

Front 23

2. 99mTc-labeled hydroxyl iminodiacetic acid (HIDA) scan:

Back 23

Relies upon uptake and excretion into bile of an intravenously administered radioactive compound. 80-90% sensitive for acute cholecystitis. A positive test is lack of GB filling 60 minutes after administration (indicating cystic duct obstruction). It is also useful for detecting CBD obstruction (lack of contrast passing into the duodenum). It can also measure gallbladder muscle function (gallbladder ejection fraction is measured after CCK administration), although a low ejection fraction is not per se pathologic. It has higher specificity and accuracy than US, but US is first test of choice due to ease of use and availability. Results are less reliable when patients are jaundiced (cholestasis interferes with biliary excretion of agents used in scintigraphy).

Front 24

3. Computed tomography (CT):

Back 24

CT scanning can be used to detect gallstones with some calcium content. Inflammatory changes around the gallbladder can also be identified. Cholesterol stones will not be seen on standard CT. Can also detect ductal dilation (indicating possible CBD stone).

Front 25

4. Magnetic resonance cholangiopancreatography (MRCP):

Back 25

MRI scanning can provide detailed imaging of the gallbladder and biliary tree. Calcified and non-calcified stones can be detected. MRI can also be used during pregnancy to image the common bile duct. MRCP is often the next test (before proceeding with ERCP) after a negative US if common bile duct stones are suspected.

Front 26

5. Endoscopic ultrasound (EUS):

Back 26

Primarily used in the detection of common bile duct stones. This is the most sensitive (93%) and specific (97%) test to detect choledocholithiasis. Its use is limited to patients in whom choledocholithiasis is highly suspected, but not confirmed on other imaging modalities.

Front 27

D. Treatment of Gallstones.

Back 27

1. Surgery
2. Endoscopic retrograde cholangiopancreatography (ERCP)
3. Percutaneous therapy:
4. Dissolution therapy:
5. Extracorporeal shockwave lithotripsy (ESWL):

Front 28

D. Treatment of Gallstones.
1. Surgery:

Back 28

This is the standard of care for symptomatic cholelithiasis and acute cholecystitis. The vast majority of cholecystectomies are now performed laparoscopically. Compared to open cholecystectomy (long right subcostal incision), it requires shorter hospital stay and recuperation time. Many “lap choles” are done as a same-day procedure. Post-operative pain is significantly reduced. Extensive abdominal scarring, unfavorable anatomy, or a complication may require conversion to an open cholecystectomy.

Laparoscopic removal of common bile duct stones through the cystic duct is possible though not routinely performed (see ERCP below). These are detected during an intraoperative cholangiogram (IOC) when the surgeon inserts a catheter into the cystic duct stump and injects contrast into the biliary tree. If stones are detected, the surgeon usually completes the operation, and the patient is sent post-operatively for an ERCP (see below). Alternatively, if CBD stones cannot be removed through the cystic duct, surgical exploration of the bile duct can be performed, but this is uncommon in situations where ERCP is available.

Front 29

D. Treatment of Gallstones.
2. Endoscopic retrograde cholangiopancreatography (ERCP):

Back 29

One of the main roles of ERCP in gallstone disease is to remove established common bile duct stones (choledocholithiasis) prior to or following laparoscopic cholecystectomy. If choledocholithiasis is confirmed pre-operatively, patients usually have an ERCP with stone extraction followed by cholecystectomy. ERCP is also performed preoperatively if common bile duct stones are highly suspected but not confirmed on imaging (i.e. jaundiced patient with dilated bile duct without obvious stones). With the advent of MRCP, purely diagnostic ERCPs are no longer performed and are not done routinely prior to cholecystectomy to “clear the bile duct” of stones if there is a low clinical suspicion of choledocholithiasis. If choledocholithiasis is confirmed intraoperatively (by intraoperative cholangiogram), ERCP is performed post-operatively and prevents a more involved surgery (common duct exploration).

Front 30

D. Treatment of Gallstones.
3. Percutaneous therapy:

Back 30

Percutaneous access, performed by interventional radiologists, is used to treat both gallbladder and bile duct stones. In addition to drainage of infected bile, it allows fragmentation or dissolution of stones. Percutaneous tracts can be dilated to allow passage of thin cholangioscopes with operating channels. Combined efforts with gastrointestinal endoscopists have been used to avoid operations in poor surgical candidates.

Front 31

D. Treatment of Gallstones.
4. Dissolution therapy:

Back 31

Reserved for non-surgical candidates. Even in this setting, however, dissolution therapy is rarely pursued. The risk of stone recurrence is possible if the gallbladder left in place. There are oral and contact dissolution agents. The most common oral agent is ursodeoxycholic acid (Ursodiol) which is a bile acid that reverses cholesterol supersaturation. The most widely investigated contact agent is methyl-tert-butyl ether (MTBE). This is instilled directly into the gallbladder and is very effective at dissolving stones, but it has systemic toxicity and spillage into the duodenum can cause severe inflammation.

Front 32

D. Treatment of Gallstones.
5. Extracorporeal shockwave lithotripsy (ESWL):

Back 32

ESWL was once used as a primary therapy for symptomatic cholelithiasis. While its use has been largely abandoned ESWL is still used for large, common bile duct stones that cannot be removed by other measures.

Front 33

A. Acquired Biliary Diseases.

1. Malignant.

Back 33

a. Pancreatic cancer:
b. Cholangiocarcinoma
c. Gallbladder cancer
d. Portal lymphadenopathy
e. Ampullary adenoma or cancer

Front 34

A. Acquired Biliary Diseases.
1. Malignant.
a. Pancreatic cancer:

Back 34

Cancer in the head of the pancreas can cause biliary obstruction. Usually this obstruction is at the level of the mid- to distal common bile duct. The obstruction is either due to external compression or direct invasion of the bile duct. Patients usually present with painless jaundice +/- pruritis (from cholestasis). If patients are not going directly for surgery (pancreaticoduodenectomy, or Whipple procedure), insertion of a plastic or metal stent via ERCP improves jaundice.

Front 35

A. Acquired Biliary Diseases.
1. Malignant.
b. Cholangiocarcinoma

Back 35

Rare cancer of the extra- or intrahepatic bile ducts. Patients with this type of tumor also present with painless jaundice. Tumors are classified by location and degree of involvement of the biliary tract (Bismuth classification). Klatskin tumors involve the common hepatic duct bifurcation. Partial hepatectomy can be curative. For non-operable lesions, patients receive chemotherapy and radiation. Jaundice can be treated with stenting which can sometimes be challenging for hilar or intraductal lesions.

Front 36

A. Acquired Biliary Diseases.
1. Malignant.
c. Gallbladder cancer:

Back 36

Can cause biliary obstruction by growth into bile duct. Can be treated with stenting.

Front 37

A. Acquired Biliary Diseases.
1. Malignant.
d. Portal lymphadenopathy

Back 37

can cause biliary obstruction by external compression. Can be treated with stenting

Front 38

A. Acquired Biliary Diseases.
1. Malignant.
e. Ampullary adenoma or cancer:

Back 38

can cause mechanical biliary obstruction at the level of the papilla. Presentation can be similar to pancreatic cancer. Ampullary adenomas can be removed endoscopically (ampullectomy) but invasive ampullary cancers require surgery (pancreatoduodenectomy=Whipple procedure). The prognosis for ampullary cancer is generally better than for pancreatic cancer.

Front 39

A. Acquired Biliary Diseases.
2. Benign.

Back 39

a. Inflammatory/infectious.
b. Post-surgical
c. Chronic pancreatitis
d. Sphincter of Oddi dysfunction

Front 40

A. Acquired Biliary Diseases.
2. Benign.
a. Inflammatory/infectious.

Back 40

(1) Primary sclerosing cholangitis (PSC): PSC is an inflammatory condition of the extra- and intrahepatic bile ducts of unknown etiology. The disease is generally diffuse and characterized by extensive focal scarring and dilation of the bile ducts. There is a high association with inflammatory bowel disease (70% of patients with PSC have inflammatory bowel disease). Treatment with high dose ursodiol (12-15 mg/kg/d) is variably successful. Superimposed bacterial cholangitis is treated with antibiotics. Patients may often develop “dominant strictures” in the CBD or common hepatic duct which require sampling (brush cytology obtained at ERCP) to rule out malignancy and stenting to palliate jaundice. There is an increased risk of cholangiocarcinoma (10-15% lifetime risk).
(2) Autoimmune pancreatitis/IgG4-associated cholangiopathy: Relatively recently recognized condition. Characterized by recurrent acute pancreatitis associated with elevated IgG4 levels. Can be associated with biliary strictures. Patients may present with jaundice and have a primary sclerosing cholangitis like cholangiogram. Treatment with steroids (prednisone) results in resolution of biliary and pancreatic duct strictures in approximately 50-60%.
(3) AIDS Cholangiopathy: Infectious condition usually associated with Cryptosporidium parvum but can also results from cytomegalovirus (CMV), microspora, or cyclospora infections. Seen in patients with CD4 counts well below 100. Patients typically present with RUQ/epigastric pain and diarrhea. Fever and jaundice are less common (10-20%). Causes sclerosing cholangitis-like cholangiogram. Severe abdominal pain indicates papillary stenosis. Treatment with antimicrobials does not alter the course of the disease. ERCP can be performed with stricture dilation, stenting, or sphincterotomy.

Front 41

A. Acquired Biliary Diseases.
2. Benign.
b. Post-surgical:

Back 41

Bile duct injuries can occur during cholecystectomy. Aberrent anatomy or inadequate visualization contributes to these injuries. The injuries vary from clipping of small intrahepatics to transection of the common bile duct. For complete transection, patients require biliary reconstructive surgery. Other strictures may be treated with biliary stenting.

Front 42

A. Acquired Biliary Diseases.
2. Benign.
c. Chronic pancreatitis:

Back 42

: Inflammation or fibrosis in the head of the pancreas can cause external compression on the bile duct resulting in biliary obstruction.

Front 43

A. Acquired Biliary Diseases.
2. Benign.
d. Sphincter of Oddi dysfunction:

Back 43

Typically seen in patients who have had a cholecystectomy. Causes recurrent biliary pain and is thought to be due to fibrotic stenosis and/or hypertension of the sphincter of Oddi.

(1) Type 1: Recurrent biliary pain, abnormal LFTs associated with pain, bile duct dilation >12 mm.

(2) Type 2: Recurrent biliary pain + one of the other criteria.

(3) Type 3: Recurrent biliary pain alone.

Front 44

B. Congenital Biliary Diseases.
1. Extrahepatic Biliary Atresia.

Back 44

a. 1:10,000-15,000 births.

b. 30% of neonatal jaundice.

c. Most common cause of death from liver disease and transplant referral in children.

d. Some types are surgically correctable, but extensive involvement requires transplantation.

e. Prognosis without correction is poor (death from liver failure w/in 2 years).

Front 45

B. Congenital Biliary Diseases.
2. Choledochal Cysts.

Back 45

a. Cystic dilation of intrahepatic and/or extrahepatic bile ducts.

b. 1:13,000-15,000 in Western countries; 1:1000 in Japan.

c. Clinical manifestations:

(1) Infants: 80% have cholestatic jaundice and acholic stools; may develop cyst rupture, portal hypertension, ascites.

(2) Older: epigastric pain most common symptom; intermittent jaundice.

(3) Classic triad: abdominal pain, jaundice, palpable abd mass (only 20%).

(4) Risk factor for cholangiocarcinoma.

d. Treatment: surgical excision of cyst and biliary reconstruction

Front 46

B. Congenital Biliary Diseases.
3. Paucity of Interlobular Bile Ducts.

Back 46

a. A.k.a. intrahepatic biliary atresia or intrahepatic biliary hypoplasia.

b. may be idiopathic or related to congenital infections such as rubella or cytomegalovirus (CMV).

c. cholangiogram reveals a sclerosing cholangitis-type picture (small, irregular ducts).

d. Alagille’s syndrome=syndromic form of the disease associated with congenital malformations such as facial abnormalities, butterfly vertebrae, and peripheral pulmonic stenosis.

Front 47

B. Congenital Biliary Diseases.
4. Cystic Fibrosis (CF).

Back 47

Mutation of the CFTR chloride transporter causes thick secretions which usually present in infancy. Pulmonary manifestations are usually the most profound (recurrent pneumonia). The exocrine pancreas is universally affected and most children have pancreatic insufficiency from birth. Bile may be thick and lead to focal obstruction and biliary cirrhosis in 2-5% of patients with CF.

Front 48

VI. Diagnosis of Biliary Diseases
A. Transabdominal US (US):

Back 48

US is often the initial study in the evaluation of jaundice. It provides excellent information regarding size of bile ducts (dilation) and frequently detects bile duct stones as discussed above. Masses in the pancreatic head or bile duct may be detected.

Front 49

VI. Diagnosis of Biliary Diseases
B. CT scan:

Back 49

CT scan: has a high diagnostic yield for jaundice caused by space-occupying lesions that either compress (liver metastasis, lymph nodes in the porta hepatis, pancreatic carcinoma) or arise from the biliary tract and invade the liver parenchyma (cholangiocarcinoma). Biliary dilation is an indirect sign of biliary tract obstruction. CT scan by itself is rarely able to assign a specific etiology to biliary dilation, but can help directing further evaluation by supplying important information about the surrounding tissues and organs.

Front 50

VI. Diagnosis of Biliary Diseases
C. MRCP:

Back 50

MRI and MRCP have largely replaced more invasive procedures (ERCP, PTC) for diagnostic imaging and is often used prior to therapy with the more invasive modalities listed below in order to map the biliary tree to improve targeted therapy with ERCP. MRI can be completed without the risks of bleeding or pancreatitis seen with invasive methods.

Front 51

VI. Diagnosis of Biliary Diseases
D. EUS:

Back 51

Since its development over 20 years ago, the role of EUS continues to expand from a diagnostic to a therapeutic modality in the evaluation and treatment of biliary disease. EUS is particularly useful in evaluating pancreatic masses and may be the most accurate noninvasive imaging study to assess vascular invasion and resectability. Fine needle aspiration (FNA) has been used to accurately detect neoplasms of the pancreas and biliary tree. Lymph nodes can also be sampled with this technique.

Front 52

VI. Diagnosis of Biliary Diseases
E. ERCP:

Back 52

Endoscopic procedure using sideviewing scope and catheters to gain access to biliary tree for diagnostic sampling and treatment. Becoming less and less of a diagnostic modality. Special brush catheter can obtain cytology specimen from stricture. Mostly used for treatment of biliary disorders (see below).

Front 53

VII. Treatment of Biliary Diseases
A. Surgery.

Back 53

1. Biliary reconstruction (e.g., choledochal cyst resection).

2. Partial hepatectomy (e.g., cholangiocarinoma involving the left lobe).

3. Transplantation (e.g., biliary atresia).

Front 54

VII. Treatment of Biliary Diseases
B. ERCP.

Back 54

1. Balloon dilation.
a. Strictures.

b. Stenotic papilla.
2. Stenting.

a. Plastic.

b. Metal: used for malignant strictures in patients who have inoperable disease.
3. Sphincterotomy.

a. Allows easy access to biliary tree for repeated procedures.

b. Performed if wide (metal) stent is being placed to prevent occlusion of pancreatic orifice (prevents pancreatitis).

c. Treatment for sphincter of Oddi dysfunction.
4. Risks: bleeding, infection, perforation, cholangitis, pancreatitis (3-5%).

Front 55

VII. Treatment of Biliary Diseases
C. Percutaneous transhepatic cholangiography (PTC):

Back 55

If ERCP is not successful or not available, PTC is an alternative and is performed by interventional radiologists. PTC is a more invasive alternative to ERCP (infection, bleeding, bile peritonitis), and its success rate is highest when the intrahepatic bile ducts are dilated. Cholangiography may be combined with internal or external drainage to treat obstruction.