Cholelithiasis

Description
 The presence of cholesterol, pigment, or mixed stones (calculi) within the gallbladder
 Synonym(s): gallstones

Epidemiology
Incidence
 Increased in Native Americans and Hispanics
 Increases with age by 1–3% per year; peaks at 7th decade; 2% of the U.S. population develops gallstones annually.

Prevalence
 Population: 8–10% of the United States; gallstones present in 20% >65 years of age
 Predominant sex: female > male (2 to 3:1)

Etiology and Pathophysiology

 Gallstone formation is a complex process mediated by genetic, metabolic, immune, and environmental factors. Gallbladder
sludge (a mixture of cholesterol crystals, calcium bilirubinate granules, and mucin gel matrix) serves as the nidus for gallstone
formation.
 Production of bile supersaturated with cholesterol (cholesterol stones) precipitates as microcrystals that aggregate and expand.
Stone formation is enhanced by biliary stasis or impaired gallbladder motility.
 Decrease in bile content of either phospholipid (lecithin) or decreased bile salt secretion
 Excess unconjugated bilirubin in patients with hemolytic diseases; passage of excess bile salt into the colon with subsequent
absorption of excess unconjugated bilirubin in patients with inflammatory bowel disease (IBD) or after distal ileal resection
(black or pigment stones)
 Hydrolysis of conjugated bilirubin or phospholipid by bacteria in patients with biliary tract infection or stricture (brown stones
or primary bile duct stones; rare in the Western world and common in Asia)

Risk Factors
 Age (peak in 60s to 70s)
 Female gender, pregnancy, multiparity, obesity, and metabolic syndrome
 Caucasian, Hispanic, or Native American descent
 High-fat diet rich in cholesterol
 Cholestasis or impaired gallbladder motility in association with prolonged fasting, long-term total parenteral nutrition (TPN),
s/p vagotomy, long-term somatostatin therapy, and rapid weight loss
 Hereditary (p.D19H variant for the hepatic canalicular cholesterol transporter ABCG5/ABG8)
 Short gut syndrome, terminal ileal resection, IBD
 Hemolytic disorders (hereditary spherocytosis, sickle cell anemia, etc.), cirrhosis (black/pigment stones)
 Medications (birth control pills, estrogen replacement therapy at high doses, and long-term corticosteroid or cytostatic therapy)
 Viral hepatitis, biliary tract infection, and stricture (promotes intraductal formation of pigment stones)
General Prevention
 Ursodiol (Actigall) taken during rapid weight loss prevents gallstone formation.
 Regular exercise and dietary modification may reduce the incidence of gallstone formation.
 Lipid-lowering drugs (statins) may prevent cholesterol stone formation by reducing bile cholesterol saturation.

Commonly Associated Conditions

90% of people with gallbladder carcinoma have gallstones and chronic cholecystitis.

Diagnosis
History
 Mostly asymptomatic (80%): 2% become symptomatic each year. Over their lifetime, <50% of patients with gallstones develop
symptoms.
 Episodic right upper quadrant or epigastric pain lasting >15 minutes and sometimes radiating to the back (biliary colic—due
to transient cystic duct obstruction), usually postprandial; pain sometimes awakens the patient from sleep; most patients
develop recurrent symptoms after a first episode of biliary colic.
 Nausea, vomiting; indigestion or bloating sensation; fatty food intolerance

Physical Exam
 Physical exam is usually normal in patients with cholelithiasis in the absence of an acute attack.
 Epigastric and/or right upper quadrant tenderness (Murphy sign) is traditional physical finding—associated with acute
cholecystitis.
 Charcot triad: fever, jaundice, right upper quadrant pain
 Reynold pentad: fever, jaundice, right upper quadrant pain, hemodynamic instability, mental status changes; classically
associated with ascending cholangitis
 Flank and periumbilical ecchymoses (Cullen sign and Grey-Turner sign) in patients with acute hemorrhagic pancreatitis
 Courvoisier sign: palpable mass in the right upper quadrant in patient with obstructive jaundice most commonly due to
malignant tumors within the biliary tree or pancreas

Differential Diagnosis
 Peptic ulcer diseases and gastritis
 Hepatitis
 Pancreatitis
 Cholangitis
 Gallbladder cancer
 Gallbladder polyps
 Acalculous cholecystitis
 Biliary dyskinesia
 Choledocholithiasis

Diagnostic Tests & Interpretation: No lab study is specific for cholelithiasis.

Initial Tests (lab, imaging)

 Leukocytosis and elevated C-reactive protein level are associated with acute calculus cholecystitis.
 Ultrasound (US) is the preferred imaging modality. US detects gallstones in 97–98% of patients.
 Thickening of the gallbladder wall (≥5 mm), pericholecystic fluid, and direct tenderness when the probe is pushed against the
gallbladder (sonographic Murphy sign) are associated with acute cholecystitis.
 CT scan has no advantage over US except in detecting distal common bile duct (CBD) stones.
 MR cholangiopancreatography (MRCP) is reserved for cases of suspected CBD stones. MRCP is recommended as a secondary
imaging study if ultrasonography does not clearly demonstrate acute cholecystitis or gallstones.
 Endoscopic US is as sensitive as endoscopic retrograde cholangiopancreatography (ERCP) for detection of CBD stones in
patients with gallstone pancreatitis.
 Hepatobiliary iminodiacetic acid (HIDA) scan is useful in diagnosing acute cholecystitis secondary to cystic duct obstruction.
It is also useful in differentiating acalculous cholecystitis from other causes of abdominal pain. False-positive tests can result
from a fasting state, insufficient resistance of the sphincter of Oddi, and gallbladder agenesis.
 Cholecystokinin (CCK)-HIDA is specifically used to diagnose gallbladder dysmotility (biliary dyskinesia).
 10–30% of gallstones are radiopaque calcium or pigment-containing gallstones that are more likely to be visible on plain x-
ray. A “porcelain gallbladder” is a calcified gallbladder, visible by x-ray; associated with chronic cholecystitis and gallbladder
cancer

Test Interpretation
 Pure cholesterol stones are white or slightly yellow.
 Pigment stones may be black or brown. Black stones contain polymerized calcium bilirubinate, most often secondary to
cirrhosis or hemolysis; these almost always form within the gallbladder.
 Brown stones are associated with biliary tract infection, caused by bile stasis, and as such may form either in the bile ducts or
gallbladder.

Treatment
General Measures
 Treat symptomatic cholelithiasis.
 Conservative therapy is preferred during pregnancy. Surgery in the 2nd trimester if necessary.
 Prophylactic cholecystectomy for patients with calcified (porcelain) gallbladder (risk for gallbladder cancer), patients with
large stones (≥3 cm), patients with sickle cell disease, patients planning an organ transplant, and patients with recurrent
pancreatitis due to microlithiasis
 In morbidly obese patients, cholecystectomy may be performed in combination with bariatric procedures to reduce subsequent
stone-related comorbidities.
 Prophylactic cholecystectomy is recommended for gallstones discovered incidentally during open abdominal surgery.

Medication
First Line
 Analgesics for pain relief
o NSAIDs are the first-choice treatment for pain control equivalent to opioid therapy.
o Opioids are an option for patients who cannot tolerate or fail to respond to NSAIDs.
 Antibiotics for patients with acute cholecystitis
 Prophylactic antibiotics in low-risk patients do not prevent infections during laparoscopic cholecystectomy (LC)

Issues For Referral

Patients with retained or recurrent bile duct stones following cholecystectomy should be referred for ERCP.

Surgery/Other Procedures
 Surgery should be considered for patients who have symptomatic cholelithiasis or gallstone-related complications (e.g.,
cholecystitis) or in asymptomatic patients with immune suppression, calcified gallbladder, or family history of gallbladder
cancer. Open and LC have similar mortality and complication rates. LC offers less pain and quicker recovery. In well-selected
patients, single-incision LC (SILC) and robotic LC are novel methods for the treatment of symptomatic cholelithiasis. SILC
has not been shown to be superior to conventional multiport LC in terms of pain and risk of complications. Natural orifice
transluminal endoscopic surgery (NOTES) is investigational. Surgery-related complications include CBD injury (0.2%), right
hepatic duct/artery injury, retained stones, duct leak, biloma formation, and bile duct stricture.
o Conversion to open procedure is based on clinical judgment. Male gender, previous upper abdominal surgery, thickened
gallbladder wall, and acute cholecystitis increase the likelihood of need to convert to an open procedure.
o In 10–15% of patients with symptomatic cholelithiasis, CBD stones are detected by intraoperative cholangiogram (IOC).
CBD stone(s) can be removed by laparoscopic CBD exploration or postoperative ERCP.
o IOC helps delineate bile duct anatomy when dissection is difficult. Routine use of IOC is debatable but may be associated
with decreased incidence and severity of bile duct injury.
 Early LC (<24 hours after diagnosis of biliary colic) decreases hospital stay and operating time.
 For patients with acute cholecystitis, early LC (<7 days of clinical presentation) is safe and may shorten the total hospital stay
versus delayed LC (>6 weeks after index admission with acute cholecystitis).
 Percutaneous cholecystostomy (PC) is used in high-risk patients with cholecystitis or gallbladder empyema. Interval
cholecystectomy is advisable.
 Symptomatic patients who are not candidates for surgery or those who have small gallstones (5 mm or smaller) in a functioning
gallbladder with a patent cystic duct are candidates for oral dissolution therapy (Actigall). However, the recurrence rate is
>50% once the medication is discontinued.
 Extracorporeal shock wave lithotripsy is a noninvasive therapeutic alternative for symptomatic patients who are not candidates
for surgery. It helps break down large bile duct stones before ERCP. Complications include biliary pancreatitis, hepatic
hematoma, incomplete ductal stone clearance, and recurrence.

Inpatient Considerations
For patients with symptomatic cholelithiasis, LC is typically an outpatient procedure. For patients with complications (i.e.,
cholecystitis, cholangitis, pancreatitis), inpatient care is necessary.
 Acute phase: NPO, IV fluids, and antibiotics
 Adequate pain control with narcotics and/or NSAIDs

Gallbladder and Biliary Tract Disease

David S. Barnes, MD
Gallbladder diseases

Gallbladder diseases considered here include gallstones, tumors, and acute acalculous cholecystitis.
Gallstones and Cholecystitis
Definition and Etiology

Gallbladder stones are an extremely common disorder and are usually asymptomatic. Some patients experience biliary colic, an
intermittent and often severe pain in the epigastrium or right upper quadrant, and at times between the scapula because of temporary
obstruction of the cystic duct with a gallstone. If the cystic duct obstruction persists, the gallbladder becomes inflamed and the
patient develops cholecystitis, an acute inflammation and infection of the gallbladder.

Prevalence and Risk Factors

It is estimated that there are 20.5 million cases of gallbladder disease in the United States, 14.2 million of whom are in women.
More than 600,000 cholecystectomies per year are performed in the United States, most of which are for symptomatic gallstone
disease. Epidemiologic studies have shown variations in the prevalence of gallstones in different ethnic populations, with
particularly high rates in Native Americans. In addition to ethnic background, other risk factors for the development of gallstones
include diabetes, rapid weight loss, morbid obesity, cirrhosis, and conditions associated with infrequent gallbladder emptying, such
as total parenteral nutrition.

Pathophysiology and Natural History

Most gallstones are composed primarily of cholesterol, with smaller amounts of mucus, calcium bilirubinate, and protein. Pigment
stones, a result of hemolysis, are less common and are made primarily of calcium bilirubinate. Symptoms occur with gallstones
when the gallbladder contracts, often after a meal, resulting in occlusion of the cystic duct with a stone that produces symptoms,
typically pain.

Signs and Symptoms

The vast majority of patients with gallstones are asymptomatic. Symptomatic gallstones typically manifest with right upper
quadrant abdominal pain, often accompanied by nausea and vomiting. The pain is often severe, may abate over several hours
(biliary colic), or may progress to cholecystitis, with persistent pain and fever. On examination, there is pain to palpation in the
right upper quadrant (Murphy's sign).

Diagnosis

The imaging study of choice is a right upper quadrant ultrasound, which, in the presence of cholecystitis, typically shows the
presence of gallstones, a thickened gallbladder wall, and pericholecystic fluid. In those patients with symptomatic gallstones and a
negative ultrasound examination, endoscopic ultrasound may be helpful. To confirm the suspicion of cholecystitis, a
hydroxyiminodiacetic acid (HIDA) scan can be useful. The radionuclide material is concentrated in the liver and excreted into the
bile but does not fill the gallbladder because of cystic duct obstruction.

Summary: Acute Cholecystitis

 Right upper quadrant abdominal pain, nausea, and vomiting

 Ultrasound reveals
 Thickened gallbladder wall
 Pericholecystic
 HIDA scan reveals nonvisualized gallbladder

Treatment

The primary treatment for symptomatic gallstone disease is cholecystectomy. Prophylactic cholecystectomy for silent gallstones is
not warranted. Most cholecystectomies in the United States are done laparoscopically. A patient with an acute episode that resolves
should see a surgeon within a few weeks and elective cholecystectomy should be considered. Patients who have persistent right
upper quadrant tenderness and develop fever or an elevated white blood cell count should be seen more urgently.

Common bile duct stones can accompany acute cholecystitis in up to 10% of cases. These stones can be removed endoscopically
before or after cholecystectomy, or surgically at the time of laparoscopic or open cholecystectomy.
Most good-risk patients who undergo elective laparoscopic cholecystectomy are sent home within 24 hours. Patients who undergo
open cholecystectomy may require hospitalization for several days. It is estimated that 95% of patients experience relief of pain
after cholecystectomy. The remaining patients probably had symptoms not related to gallbladder disease before surgery.

Practice guidelines for the treatment of gallstones and gallbladder disease are available from the Society for Surgery of the
Alimentary Tract (SSAT). These guidelines (available at http://www.ssat.com/cgi-bin/guidelines.cgi) review the symptoms and
diagnosis of gallstone disease and make treatment recommendations regarding surgical consultation and indications for surgery.
They review the risks of cholecystectomy, both laparoscopic and open, and the expected outcomes. There are also recommendations
for the treatment of common duct stones.

Gallbladder Tumors

Benign and malignant tumors can occur in the gallbladder. Benign tumors consist of papillomas, adenomyomas, or cholesterol
polyps. Malignant tumors of the gallbladder are uncommon. The most common malignant tumor of the gallbladder is
adenocarcinoma, although squamous cell carcinoma, cystadenocarcinoma, and adenoacanthomas have been reported.
Adenocarcinoma of the gallbladder is associated with chronic cholecystitis; exposure to rubber or petroleum products has also been
suggested as a cause. It occurs more commonly in women and those older than 50 years.

Patients with small gallbladder tumors may present with symptoms suggesting cholecystitis (e.g., abdominal pain, fever), whereas
larger tumors may manifest late with jaundice and an abdominal mass. Computed tomography (CT) or ultrasound scans will reveal
a gallbladder mass and, in the case of larger tumors, a mass in the liver and evidence of biliary obstruction. Patients with the
incidental finding of gallbladder carcinoma at the time of cholecystectomy have a good prognosis. Otherwise, the 5-year survival
rate of patients with gallbladder cancer is only about 5%.

Special mention should be made of the finding on ultrasound of polypoid lesions of the gallbladder, gallbladder polyps.
Histologically, there are four types of polypoid lesions, including cholesterol polyps, adenomas, adenomyomatous hyperplasia, and
malignant polyps. Although polyp size (larger than 10 mm) and patient age (older than 60 years) are more suggestive of malignancy,
no radiologic test can distinguish benign from malignant polyps in the absence of metastatic or invasive cancer. 4Although there are
no firm guidelines, cholecystectomy for patients with polyps larger than 10 mm seems warranted.4,5 Regular follow-up ultrasound
examination for patients with polyps smaller than 10 mm has been suggested, but prospective studies confirming the benefit of
such a surveillance program have not been done.4

Acute Acalculous Cholecystitis

Acute acalculous cholecystitis is an acute inflammatory disease of the gallbladder not associated with gallstones. About 10% of
the 500,000 cholecystectomies performed each year in the United States are for acalculous cholecystitis. The pathogenesis is
believed to be an ischemic injury to the gallbladder wall, compounded by chemical injury caused by bile acids. It is often seen in
patients hospitalized for trauma or burns who have a superimposed sepsis and are on mechanical ventilation. It is also associated
with patients with vascular disease and immunodeficiency.

Clinical manifestations can be similar to those seen with calculous cholecystitis (right upper quadrant pain, fever, and a positive
Murphy sign [pain during inspiration associated with palpation of the right upper quadrant]) but are typically subtler in a ventilated
patient in the intensive care unit, in whom usual clinical clues are absent. When acalculous cholecystitis is being considered,
ultrasound is the diagnostic test of choice and shows a thickened gallbladder wall, pericholecystic fluid, and a sonographic Murphy's
sign. Cholecystectomy, open or laparoscopic, is the definitive therapy. In patients who are a prohibitively high surgical risk, an
ultrasound-guided percutaneous cholecystostomy tube provides drainage of the gallbladder without surgery. Another nonsurgical
approach is transpapillary endoscopic drainage of the gallbladder.6 The outcome of patients with acalculous cholecystitis depends
to a large extent on the underlying illness, but mortality can be as high as 30% when perforation of the gallbladder occurs as a
complication.7

Biliary tract diseases

Choledocholithiasis
Definition and Causes

One of the most common causes of extrahepatic biliary obstruction is choledocholithiasis, with one or more stones in the common
bile duct or common hepatic duct causing biliary obstruction.
Prevalence and Risk Factors

Up to 10% of patients with gallstones have common bile duct stones. Common bile duct stones have been discovered days to
several years after surgery in as many as 5% of patients who have undergone cholecystectomy. It is believed that the stones
represent retained stones or stones that have formed de novo after the operation.

Pathophysiology and Natural History

Stones in the bile duct can cause biliary obstruction and cholestasis. This can lead to infection in the bile duct (bacterial cholangitis),
which requires urgent medical therapy. The long-standing presence of stones in the bile duct can lead to secondary biliary cirrhosis.
Choledocholithiasis can also lead to gallstone pancreatitis.

Signs and Symptoms

Most patients with choledocholithiasis report upper abdominal pain, although some patients may remain asymptomatic. Because
complete obstruction of the bile duct by the stone may be intermittent, patients may report episodic jaundice.

The initial manifestation of choledocholithiasis can also be heralded by an episode of cholangitis. Gallstone pancreatitis manifests
with typical features of pancreatitis, including epigastric pain, nausea, and vomiting.

Diagnosis

Several diagnostic tools can be used when evaluating patients suspected of having choledocholithiasis. Ultrasound is the preferred
initial screening test because it is usually less expensive than CT or magnetic resonance imaging (MRI), does not use ionizing
radiation, and is highly accurate in detecting gallbladder stones and bile duct dilation. MR cholangiography has gained acceptance
as a tool for diagnosing choledocholithiasis. Its accuracy in detecting bile duct stones approaches that of endoscopic retrograde
cholangiography. Abdominal CT scanning can also be helpful in evaluating patients with obstructive jaundice. It is as accurate as
ultrasound in detecting common duct stones and may help localize the level of obstruction in the biliary tree.

Once biliary dilation or the presence of a common duct stone is noted on an imaging study, or biliary obstruction is strongly
suspected on clinical grounds despite negative imaging studies, endoscopic retrograde cholangiopancreatography (ERCP) is
recommended. ERCP provides a means of visualizing the biliary tree and the opportunity for therapy. Percutaneous transhepatic
cholangiography can be a useful alternative when ERCP is not successful, although it is sometimes not successful in the absence
of dilated bile ducts. Practice guidelines from the Society for Surgery of the Alimentary Tract for the treatment of gallstone and
gallbladder diseases can be found online (www.ssat.com/cgi-bin/chole7.cgi).

Treatment

The goals of therapy for choledocholithiasis are to remove the stones from the biliary tree and to decompress the biliary tree urgently
if bacterial cholangitis is present. Stone extraction can be accomplished with ERCP, often preceded by an endoscopic
sphincterotomy. In the presence of bacterial cholangitis, when a stone cannot be removed for technical reasons—for example,
because of its large size—an endoscopically placed biliary stent can be useful for decompressing the biliary tree. An alternative to
ERCP for the treatment of choledocholithiasis is percutaneous transhepatic cholangiography (PTHC). PTHC can be used for
emergent drainage of the biliary tree in the presence of cholangitis. Passage of a wire into the duodenum via a percutaneous
approach can also help guide an endoscopist when performing an ERCP with stone extraction if ERCP had previously failed
because of technical factors.

Cholangiocarcinoma
Definition

Cholangiocarcinoma is an adenocarcinoma of the intrahepatic or extrahepatic bile duct.

Prevalence and Risk Factors

There are 2000 to 3000 new cases per year of cholangiocarcinoma in the United States, accounting for 10% to 15% of all primary
hepatobiliary malignancies. It is most common in middle-aged men. Primary sclerosing cholangitis (PSC) is a major risk factor for
the development of cholangiocarcinoma. In a large Swedish study, 8% of patients with PSC developed cholangiocarcinoma over a
mean follow-up period of 5 years. However, this study might have underestimated the actual incidence of PSC-associated
cholangiocarcinoma. Other diseases associated with the development of cholangiocarcinoma include choledochal cysts and
infection with liver flukes, including Opisthorchis (formerly Clonorchis) sinensis, O. felineus, and O. viverrini.
Pathophysiology and Natural History

Cholangiocarcinoma is a malignant transformation of the bile ducts, including the ducts in the intrahepatic, perihilar, or extrahepatic
biliary tree. A commonly used classification system for cholangiocarcinoma is based on the anatomic location of the tumor.13 The
natural history is one of progression, with a poor 5-year survival rate, lower than 5%. A tissue diagnosis is often difficult to obtain
and, in the absence of obviously metastatic disease or extensive local spread, surgical exploration is the only way to determine
resectability.

Signs and Symptoms

Patients typically present with jaundice and pruritus and more generalized symptoms, such as weight loss, anorexia, and fatigue.
Cholangiocarcinoma should always be suspected in a previously stable patient with PSC who has a rapid clinical decline.

Diagnosis

Initial diagnostic testing for cholangiocarcinoma is similar to that used for other causes of cholestasis. Laboratory testing typically
shows an elevated level of alkaline phosphatase of liver origin, with or without an elevation of the bilirubin level. Ultrasound
examination, MRI, or CT scanning may reveal areas of focal biliary dilation. MRI is the optimal imaging study when
cholangiocarcinoma is suspected. Direct cholangiography with ERCP or PTHC cholangiography with brush cytology of the biliary
tree can be useful for diagnosis, although the sensitivity for detecting malignancy with brush cytology is less than 75%.

Blood testing for cancer antigens, particularly CA19-9, has been shown to be useful in detecting cholangiocarcinoma, as has an
index using CA19-9 and carcinoembryonic antigen (CEA). Neither method is highly sensitive or specific but can help confirm
suspected cholangiocarcinoma.

Treatment

Surgical resection of cholangiocarcinoma has resulted in a 5-year survival rate of 16% to 44%.Liver transplantation for
cholangiocarcinoma is not offered by most transplantation centers because of a high recurrence rate after transplantation. Some
centers have had a more favorable outcome with radiation and chemotherapy followed by liver transplantation in patients with
early-stage disease. Palliative therapy includes percutaneously or endoscopically placed biliary stenting. Photodynamic therapy has
also been used with some success.

Miscellaneous Conditions Causing Biliary Tract Obstruction

Benign Tumors

Although most bile duct tumors are malignant, some benign biliary lesions result in biliary obstruction and cholestasis. These
include papillomas, adenomas, and cystadenomas.

Ampullary Tumors

Tumors of the ampulla of Vater can be benign (adenomas) or malignant (ampullary carcinoma). Either can result in biliary
obstruction and can be confused with cholangiocarcinoma and pancreatic adenocarcinoma. At presentation, patients are often
jaundiced and may have a palpable gallbladder because of bile duct obstruction distal to the cystic duct. Laboratory findings
typically show an elevation of alkaline phosphatase and bilirubin levels.

Imaging studies of the biliary tree will often show dilation, suggesting a distal bile duct obstruction. Further investigation with a
side-viewing duodenoscope will reveal the presence of the ampullary tumor. Ampullary adenomas, often seen with familial
adenomatous polyposis, can be treated with surgical excision of the ampulla. Whipple's procedure is the treatment of choice for
those with resectable ampullary carcinoma.

The 5-year survival rate is as high as 60% in patients with tumor-free surgical margins. For patients who are not surgical candidates,
ERCP with sphincterotomy can provide palliation for what are often slow-growing tumors.

Pancreatic Disorders

Carcinoma of the head of the pancreas can manifest with painless jaundice caused by obstruction of the bile duct as it passes through
the head of the pancreas. Weight loss, fatigue, and other constitutional symptoms often accompany the cholestasis. CT scanning or
ultrasound typically reveal biliary ductal dilation to the level of the pancreatic head and a pancreatic mass.
Cholestasis can also result from benign pancreatic disorders such as chronic pancreatitis resulting in pancreatic fibrosis leading to
common duct narrowing and cholestasis or a pancreatic pseudocyst causing compression of the biliary tree.

Mirizzi's Syndrome

Mirizzi's syndrome is caused by an impacted cystic duct stone, leading to gallbladder distention and subsequent compression of
the extrahepatic biliary tree. Occasionally, the gallstone erodes into the common hepatic duct, producing a cholecystocholedochal
fistula. The original classification of Mirizzi's syndrome has been expanded to include hepatic duct stenosis caused by a stone at
the junction of the cystic and hepatic ducts or as a result of cholecystitis, even in the absence of a obstructing cystic duct stone.

Patients present with jaundice, right upper quadrant, pain and fever. Ultrasound or CT scanning reveals biliary dilation above the
cystic duct. ERCP may reveal the obstructing stone, which can occasionally be removed, but the definitive treatment is usually
surgical, consisting of cholecystectomy with surgical repair of the bile duct, if necessary.

AIDS Cholangiopathy

Cholestasis can be seen in AIDS as a result of biliary ductal changes seen on a cholangiogram that resemble primary sclerosing
cholangitis. The ductal strictures are believed to be caused by infections, including Cryptosporidium spp, cytomegalovirus,
microsporidian, and Cyclospora spp.

Patients present with right upper quadrant pain and laboratory tests suggesting cholestasis. A wide variety of other hepatobiliary
abnormalities may also occur in those with HIV infection, including granulomatous liver disease from mycobacteria, fungi, or
drugs, bacterial abscesses, neoplasms such as Kaposi's sarcoma or lymphoma, and drug toxicity. Initial evaluation should include
ultrasound and ERCP if the ultrasound is abnormal. ERCP should also be carried out despite a normal ultrasound if there is evidence
of severe abdominal pain. Endoscopic therapy is useful in certain circumstances. Endoscopic sphincterotomy is useful for those
patients with symptoms of papillary stenosis (e.g., abdominal pain, jaundice, cholangitis). Endoscopic stenting of the dominant
structure of the biliary may also be helpful.

Parasites

Extrahepatic biliary obstruction has been seen with various parasitic infections, such as Strongyloides and Ascaris spp, and liver
flukes, such as Opisthorchis sinensisand Fasciola hepatica.

Congestive Hepatopathy
Moderate or severe right-sided heart failure increases central venous pressure, which is transmitted to the liver via the
inferior vena cava and hepatic veins. Chronic congestion leads to atrophy of hepatocytes, distention of sinusoids, and centri zonal
fibrosis, which, if severe, progresses to cirrhosis (cardiac cirrhosis). The basis for liver cell death is probably sinusoidal
thrombosis that propagates to the central veins and branches of the portal vein, causing ischemia. Most patients are
asymptomatic. However, moderate congestion causes right upper quadrant discomfort (due to stretching of the liver capsule)
and tender hepatomegaly. Severe congestion leads to massive hepatomegaly and jaundice. Ascites may result from the
transmitted central venous hypertension; infrequently, splenomegaly results. With transmitted central venous hypertension, the
hepatojugular reflex is present, unlike in hepatic congestion due to Budd-Chiari syndrome.

Diagnosis: Congestive hepatopathy is suspected in patients who have right-sided heart failure, jaundice, and tender
hepatomegaly. Laboratory test results are modestly abnormal: unconjugated hyperbilirubinemia (total bilirubin < 3 mg/dL),
elevated (usually < 2- to 3-fold) aminotransferases, and prolonged PT/INR. Ascitic fluid, if present, has a high albumin content
(typically > 2.5 g/dL). In contrast, only 10% of patients with cirrhotic ascites have ascitic albumin levels that high. There is
also a high serum-to-ascites albumin concentration gradient, which is the serum albumin concentration minus the ascitic albumin
concentration. Gradients ≥ 1.1 g/dL are relatively specific for ascites due to portal hypertension (including cirrhosis), but
in congestive hepatopathy, values tend to be even higher.
Because the laboratory abnormalities are nonspecific, recognition of congestive hepatopathy is ultimately clinical.
The liver disorder is more important as an index of the severity of heart failure than as a diagnosis by itself.

Acute Pancreatitis
Gallstones cause about 40% of cases of acute pancreatitis. The precise mechanism of gallstone pancreatitis is unknown
but likely involves increased pressure in the pancreatic duct caused by obstruction at the ampulla secondary to a stone or ed ema
caused by the passage of a stone. Ductal hypertension results in aberrant activation of digestive enzymes from acinar cells. The
toxic effects of bile acid itself on acinar cells might also be a mechanism. Gallstone pancreatitis is rare in pregnancy and occurs
most commonly in the 3rd trimester.
Pathogenesis: Regardless of the etiology, the initial step in pathogenesis of acute pancreatitis is intra -acinar activation of
pancreatic enzymes (including trypsin, phospholipase A 2, and elastase), leading to the autodigestive injury of the gland itself.
The enzymes can damage tissue and activate the complement system and the inflammatory cascade, producing cytokines and
causing inflammation and edema. This process causes necrosis in a few cases. Acute pancreatitis increases the risk of infecti on
by compromising the gut barrier, leading to bacterial translocation from the gut lumen to the circulation. Activated enzymes
and cytokines that enter the peritoneal cavity cause a chemical burn and third spacing of fluid; those that enter the systemi c
circulation cause a systemic inflammatory response that can result in acute respiratory distress syndrome and acute kidney
injury. The systemic effects are mainly the result of increased capillary permeability and decreased vascular tone, which result
from the released cytokines and chemokines. Phospholipase A 2 is thought to injure alveolar membranes of the lungs. In mild
pancreatitis, inflammation is confined to the pancreas. Patients do not have organ failure or systemic or local complications .
The mortality rate is < 5%. In severe pancreatitis, there is persistent single or multiorgan failure (after about 48 h). Most patients
have one or more local complications. The mortality rate is > 30%.

Signs and Symptoms: n 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. Pain usually develops suddenly i n
gallstone pancreatitis; in alcoholic pancreatitis, pain develops over a few days. The pain usually persists for several 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 100 to 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 because of obstruction of the bile duct by a gallstone or
inflammation and swelling of the pancreatic head. The lungs may have limited diaphragmatic excursion and evidence of
atelectasis. Patients may have an ileus resulting in decreased bowel sounds and abdominal distention. Marked abdominal
tenderness occurs, most often in the upper abdomen. Rarely, severe peritoneal irritation results in a rigid and b oardlike abdomen.
Pancreatic duct disruption may cause ascites (pancreatic ascites). The Grey Turner sign (ecchymoses of the flanks) and the
Cullen sign (ecchymoses of the umbilical region) indicate extravasation of hemorrhagic exudate, occur in < 1% of ca ses, and
portend a poor prognosis. Infection in the pancreas or in an adjacent fluid collection should be suspected if the patient has a
generally toxic appearance with fever and an elevated WBC count or if deterioration follows an initial period of stabil ization.
Patients with severe disease can manifest multiorgan failure (cardiovascular, renal, and respiratory).

Primary Sclerosing Cholangitis

Although the cause is unknown, PSC is associated with inflammatory bowel disease, which is present in 80% of
patients. About 5% of patients with ulcerative colitis and about 1% with Crohn disease develop PSC. This association and the
presence of several autoantibodies (eg, anti–smooth muscle and perinuclear antineutrophilic antibodies [pANCA]) suggest
immune-mediated mechanisms. T cells appear to be involved in the destruction of the bile ducts, implying disorder ed cellular
immunity. A genetic predisposition is suggested by a tendency for the disorder to develop in multiple family members and a
higher frequency in people with HLAB8 and HLADR3, which are often correlated with autoimmune disorders. An unknown
trigger (eg, bacterial infection, ischemic duct injury) probably causes PSC to develop in genetically predisposed people.

Signs and Symptoms: Onset is usually insidious, with progressive fatigue and then pruritus. Jaundicetends to develop later.
About 10 to 15% of patients present with repeated episodes of right upper quadrant pain and fever, possibly due to ascending
bacterial cholangitis. Steatorrhea and deficiencies of fat-soluble vitamins can develop. Persistent jaundice harbingers advanced
disease. Symptomatic gallstones and choledocholithiasis tend to develop in about 75% of patients.
Some patients, asymptomatic until late in the course, first present with hepatosplenomegaly or cirrhosis. PSC tends to slowly
and inexorably progress. The terminal phase involves decompensated cirrhosis, portal hypertension, ascites, and liver failure.
The time from diagnosis to liver failure is about 12 yr.
Despite the association between PSC and inflammatory bowel disease, the two diseases tend to run separate courses. Ulcerative
colitis may appear years before PSC and tends to have a milder course when associated with PSC. Similarly, total colectomy
does not change the course of PSC.
The presence of both PSC and inflammatory bowel disease increases the risk of colorectal carcinoma, regardless of whether
a liver transplantation has been done for PSC. Cholangiocarcinoma develops in 10 to 15% of patients.

Drug-Induced Liver Injury

Pathophysiology: The pathophysiology of DILI varies depending on the drug (or other hepatotoxin) and, in many cases, is not
entirely understood. Drug-induced injury mechanisms include covalent binding of the drug to cellular proteins resulting in
immune injury, inhibition of cell metabolic pathways, blockage of cellular transport pumps, induction of apoptosis, and
interference with mitochondrial function.

 Hepatocellular: Hepatocellular hepatotoxicity generally manifests as malaise and right upper quadrant abdominal pain,
associated with marked elevation in aminotransferase levels (ALT, AST, or both), which may be followed by
hyperbilirubinemia in severe cases. Hyperbilirubinemia in this setting is known as hepatocellular jaundice and,
 according to Hy’s law, is associated with mortality rates as high as 50%. If hepatocellular liver injury is accompanied
by jaundice, impaired hepatic synthesis, and encephalopathy, chance of spontaneous recovery is low, and liver
transplantation should be considered. This type of injury can result from drugs such asacetaminophen and isoniazid.
 Cholestatic: Cholestatic hepatotoxicity is characterized by development of pruritus and jaundice accompanied by
marked elevation of serum alkaline phosphatase levels. Usually, this type of injury is less serious than severe
hepatocellular syndromes, but recovery may be protracted. Substances known to lead to this type of injury
include amoxicillin/clavulanateand chlorpromazine. Rarely, cholestatic hepatotoxicity leads to chronic liver disease
and vanishing bile duct syndrome (progressive destruction of intrahepatic bile ducts).
 Mixed: In these clinical syndromes, neither aminotransferase nor alkaline phosphatase elevations are clearly
predominant. Symptoms may also be mixed. Drugs such as phenytoin can cause this type of injury.

Diagnosis: Identification of characteristic patterns of laboratory abnormalities; Exclusion of other causes. Presentation varies
widely, ranging from absent or nonspecific symptoms (eg, malaise, nausea, anorexia) to jaundice, impaired hepatic synthesis,
and encephalopathy. Early recognition of DILI improves prognosis. Identification of a potential hepatotoxin and a pattern
of liver test abnormalities that is characteristic of the substance (its signature) make the diagnosis likely.

Choledocholithiasis/Cholangitis:
Choledocholithiasis is the presence of stones in bile ducts; the stones can form in the gallbladder or in the ducts
themselves. These stones cause biliary colic, biliary obstruction, gallstone pancreatitis, or cholangitis (bile duct infection and
inflammation). Cholangitis, in turn, can lead to strictures, stasis, and choledocholithiasis. Diagnosis usually requires visualization
by magnetic resonance cholangiopancreatography or ERCP. Early endoscopic or surgical decompression is indicated.

Stones may be described as

 Primary stones (usually brown pigment stones), which form in the bile ducts
 Secondary stones (usually cholesterol), which form in the gallbladder but migrate to the bile ducts
 Residual stones, which are missed at the time of cholecystectomy (evident < 3 yr later)
 Recurrent stones, which develop in the ducts > 3 yr after surgery
In developed countries, > 85% of common duct stones are secondary; affected patients have additional stones located in the
gallbladder. Up to 10% of patients with symptomatic gallstones also have associated common bile duct stones.
After cholecystectomy, brown pigment stones may result from stasis (eg, due to a postoperative stricture) and the subsequent
infection. The proportion of ductal stones that are pigmented increases with time after cholecystectomy.Bile duc t stones may
pass into the duodenum asymptomatically. Biliary colic occurs when the ducts become partially obstructed. More complete
obstruction causes duct dilation, jaundice, and, eventually, cholangitis (a bacterial infection). Stones that obstruct the ampulla
of Vater can cause gallstone pancreatitis. Some patients (usually the elderly) present with biliary obstructio n due to stones that
have caused no symptoms previously.
In acute cholangitis, bile duct obstruction allows bacteria to ascend from the duodenum. Most (85%) cases result from common
bile duct stones, but bile duct obstruction can result from tumors or other conditions (see table Causes of Bile Duct Obstruction).
Common infecting organisms include gram-negative bacteria (eg, Escherichia coli,Klebsiella sp, Enterobacter sp); less
common are gram-positive bacteria (eg, Enterococcus sp) and mixed anaerobes (eg, Bacteroides sp, Clostridia sp). Symptoms
include abdominal pain, jaundice, and fever or chills (Charcot triad). The abdomen is tender, and often the liver is tender and
enlarged (often containing abscesses). Confusion and hypotension predict about a 50% mortality rate and high morbidity.
Recurrent pyogenic cholangitis (Oriental cholangiohepatitis, hepatolithiasis) is characterized by intrahepatic brown pigment
stone formation. This disorder occurs in Southeast Asia. It consists of sludge and bacterial debris in the bile ducts.
Undernutrition and parasitic infestation (eg, Clonorchis sinensis, Opisthorchis viverrini) increase susceptibility. Parasitic
infestation can cause obstructive jaundice with intrahepatic ductal inflammation, proximal stasis, stone formation, and
cholangitis. Repeating cycles of obstruction, infection, and inflammation lead to bile duct strictures and biliary cirrhosis. The
extrahepatic ducts tend to be dilated, but the intrahepatic ducts appear straight because of periductal fibrosis.
In AIDS-related cholangiopathy or cholangitis, direct cholangiography may show abnormalities similar to those in primary
sclerosing cholangitis (PSC) or papillary stenosis (ie, multiple strictures and dilations involving the intrahepatic and
extrahepatic bile ducts). Etiology is probably infection, most likely with cytomegalovirus, Cryptosporidium sp,
or microsporidia.

Diagnosis: Common duct stones should be suspected in patients with jaundice and biliary colic. Fever and leukocytosis further
suggest acute cholangitis. Elevated levels of bilirubin and particularly alkaline phosphatase, ALT, and gamma-
glutamyltransferase are consistent with extrahepatic obstruction, suggesting stones, particularly in patients with features o f
acute cholecystitis or cholangitis. Ultrasonography may show stones in the gallbladder and occasionally in the common duct
(less accurate). The common duct is dilated (> 6 mm in diameter if the gallbladder is intact; > 10 mm after a cholecystectomy).
If the ducts are not dilated early in the presentation (eg, first day), stones have probably passed. If doubt exists, magnetic
resonance cholangiopancreatography (MRCP) is highly accurate for retained stones. ERCP is done if MRCP is equivocal; it
can be therapeutic as well as diagnostic. CT, though less accurate than ultrasonography, can detect liver abscesses.
For suspected acute cholangitis, CBC and blood cultures are essential. Leukocytosis is common, and aminotransferases may
reach 1000 IU/L, suggesting acute hepatic necrosis, often due to microabscesses. Blood cultures guide antibiotic choice.

Cholangiocarcinoma/ Gallbladder cancer

Cholangiocarcinomas and other bile duct tumors are rare (1 to 2/100,000 people) but are usually malignant.
Cholangiocarcinomas occur predominantly in the extrahepatic bile ducts: 60 to 70% in the perihilar region (Klatskin tumors),
about 25% in the distal ducts, and the rest in the liver. Risk factors include primary sclerosing cholangitis, older age, infestation
with liver flukes, and a choledochal cyst.
Gallbladder carcinoma is uncommon (2.5/100,000). It is more common among American Indians, patients with large
gallstones (>3 cm), and those with extensive gallbladder calcification due to chronic cholecystitis (porcelain gallbladder).
Nearly all (70 to 90%) patients also have gallstones. Median survival is 3 mo. Cure is possible when cancer is found early (eg,
incidentally at cholecystectomy).

Signs and Symptoms: Most patients with cholangiocarcinomas present with pruritus and painless obstructive jaundice,
typically at age 50 to 70 yr. Early perihilar tumors may cause only vague abdominal pain, anorexia, and weight loss. Other
features include fatigue, acholic stool, a palpable mass, hepatomegaly, or a distended gallbladder (Courvoisier sign, with distal
cholangiocarcinoma). Pain may resemble that of biliary colic (reflecting biliary obstruction) or may be constant and
progressive. Sepsis (secondary to acute cholangitis), although unusual, may be induced by ERCP.
Manifestations of gallbladder carcinoma may range from incidental findings at cholecystectomy done to relieve biliary pain to
cholelithiasis to advanced disease with constant pain, weight loss, and an abdominal mass or obstructive jaundice.