Biliary Disease

Updated: May 02, 2018
Author: Annie T Chemmanur, MD; Chief Editor: BS Anand, MD 



A diverse spectrum of diseases affects the biliary system, often presenting with similar clinical signs and symptoms. These conditions include gallstones, acute calculus cholecystitis, acute acalculus cholecystitis, Mirizzi syndrome, chronic cholecystitis, cholangitis (recurrent pyogenic, primary sclerosing, primary biliary, autoimmune), biliary tract malignancies, biliary tract cysts, and others.

See the images below.

A normal postcholecystectomy cholangiogram. A normal postcholecystectomy cholangiogram.
Biliary disease. In a patient with persistent elev Biliary disease. In a patient with persistent elevation of liver-associated enzymes, the contrast medium entering the biliary ductal system preferentially enters the cystic duct.
Biliary disease. Even when the catheter is advance Biliary disease. Even when the catheter is advanced to the proximal common hepatic duct, contrast dye preferentially fills the cystic duct and gallbladder rather than allowing visualization of the intrahepatic ductal system (same patient as in previous image).
Biliary disease. In this image, the common bile du Biliary disease. In this image, the common bile duct is occluded with a balloon-tipped catheter. Contrast material fills the intrahepatic ductal system to reveal diffuse intrahepatic sclerosing cholangitis.

For patient education resources, see Digestive Disorders Center and Cholesterol Center, as well as Gallstones, Primary Biliary Cirrhosis (PBC), Cirrhosis (Liver, Symptoms, Stages, and Diet), and Primary Sclerosing Cholangitis.


Bile is produced by the liver and is channeled by the biliary ductal system into the intestinal tract for the emulsification and absorption of fats. Biliary disease is caused by abnormalities in bile composition, biliary anatomy, or function. The liver determines the chemical composition of bile, and this may be modified later by the gallbladder and the biliary epithelium. Cholesterol, ordinarily insoluble in water, comes into solution by forming vesicles with phospholipids (principally lecithin) or mixed micelles with bile salts and phospholipids.

When the ratio of cholesterol, phospholipids, and bile salts is outside an optimum range, cholesterol monohydrate crystals may come out of solution from multilamellar vesicles. Cholesterol supersaturation of bile appears to be a prerequisite for gallstone formation, which involves a variety of factors that affect the activity of low-density lipoprotein (LDL) uptake, hepatic 3-methylglutaryl coenzyme A reductase (HMG CoA), acyl cholesterol-lecithin acyltransferase, and 7-alpha hydroxylase.

By itself, cholesterol supersaturation is inadequate for explaining gallstone pathogenesis. Nucleation, the initial step in gallstone formation, is the transition of cholesterol from a soluble state into a solid crystalline form. Within the gallbladder bile, biologic molecules influence the process in a positive or negative fashion.

For example, mucus may function to promote nucleation, whereas bile-specific glycoproteins may function to inhibit nucleation. Mucin hypersecretion by the gallbladder mucosa creates a viscoelastic gel that fosters nucleation. Arachidonyl lecithin, which is absorbed from the alimentary tract and secreted into the bile, stimulates prostanoid synthesis by gallbladder mucosa and promotes mucus hypersecretion, while inhibitors of prostaglandin inhibit mucus secretion.

Finally, gallbladder hypomotility and bile stasis appear to promote gallstone formation and growth, which may be important in diabetes, pregnancy, oral contraceptive use in women, and prolonged fasting in critically ill patients on total parenteral nutrition.

More recent research suggests that elevated levels of four circulating interleukins (IL) (IL-6, IL-10, IL-12 [p70], IL-13) are associated with an increased risk of gallstones[1] and/or there may be a genetic predisposition that affects the supersaturation of bile with insoluble compounds (eg, cholesterol) thereby also raising the risk of gallstone disease.[2]



In about 80% of patients, gallstones are clinically silent. Approximately 20% of patients develop symptoms over 15-20 years, that is, about 1% per year, and almost all become symptomatic before complications develop. Biliary-type pain, the typical clinical presentation, is due to the obstruction of the bile duct lumen. The predictive value of other complaints (eg, intolerance to fatty food, indigestion) is too low to be clinically helpful. The incidence of gallbladder cancer developing in the setting of cholelithiasis is low, about 0.1% per year. Two main types of gallstones exist.

Cholesterol stones (85%)

These are divided into two subtypes—pure (90%-100% cholesterol) or mixed (50%-90% cholesterol).

Pure stones often are solitary, whitish, and larger than 2.5 cm in diameter. Mixed stones usually are smaller, multiple in number, and occur in various shapes and colors. They tend to be arranged in laminated layers of an alternating thicker whitish cholesterol and a thinner dark pigment in a concentric pattern around a pigmented center (similar to the rings visible on the cross section of a tree). These stones tend to occur in residents of Western countries, and they usually are found in the gallbladder.

The risk factors associated with the development of cholesterol gallstones include obesity, a high-calorie diet, clofibrate therapy, gastrointestinal disorders involving major malabsorption of bile acids, cystic fibrosis with pancreatic insufficiency, and female sex and the use of oral contraceptives and other estrogenic medications. Coffee and ascorbic acid have been shown to reduce the risk of symptomatic cholesterol gallstones.

Pigment stones (15%)

Pigment stones occur in 2 subtypes—brown and black.

Brown stones are made up of calcium bilirubinate and calcium-soaps. Bacteria are involved in their formation via secretion of beta glucuronidase and phospholipase. The bacterial glycocalyx aggregates with the bile pigment and precipitates out of solution. These stones are more common in Asia and tend to form within the bile ducts. They frequently are associated with periampullary duodenal diverticula.

Black stones typically form in the gallbladder and result when excess bilirubin enters the bile and polymerizes into calcium bilirubinate. These stones are more common in patients with chronic hemolysis, alcoholic cirrhosis, and advanced age.

Acute calculus cholecystitis

Acute calculus cholecystitis is an inflammation of the gallbladder that develops in the setting of an obstructed cystic or bile duct. It usually develops after 5 hours of biliary-type pain. The initial inflammation is caused by chemical irritation, and bacterial infection probably is a secondary event. A change in the perception of pain, classically a migration to the right upper quadrant, suggests transmural inflammation of the gallbladder, with involvement of the parietal peritoneum. Nausea and vomiting are common associated symptoms, and most patients are afebrile early in the course of the disease.

Mirizzi syndrome

Mirizzi syndrome refers to common hepatic duct obstruction caused by an extrinsic compression from an impacted stone in the cystic duct.[3] It has been estimated to occur in 0.7-1.4% of all cholecystectomies. It is often not recognized preoperatively, which can lead to significant morbidity and biliary injury, particularly with laparoscopic surgery.

Acute acalculous cholecystitis

Acute acalculous cholecystitis is the presence of an inflamed gallbladder in the absence of an obstructed cystic or common bile duct. It typically occurs in the setting of a critically ill patient (eg, severe burns, multiple traumas, lengthy postoperative care, prolonged intensive care) and accounts for 5% of cholecystectomies. Because abdominal pain, fever, and leukocytosis are relatively common in these patients and the signs and symptoms are not specific for acalculous cholecystitis, the physician must have a high index of suspicion to make the diagnosis. The etiology is thought to have an ischemic basis, and a gangrenous gallbladder may result. This condition has an increased rate of complications and mortality. An uncommon subtype known as acute emphysematous cholecystitis generally is caused by infection with clostridial organisms and occlusion of the cystic artery associated with atherosclerotic vascular disease and, often, diabetes.

Chronic cholecystitis

Chronic cholecystitis is a common disorder that frequently is associated with gallstones. The clinical features are nonspecific, and cholescintigraphy initially may suggest the diagnosis. The pathogenesis is poorly understood but may be due to abnormal bile composition leading to chemical injury of the gallbladder mucosa. Histologic evidence of a mononuclear infiltrate, fibrosis, and epithelial metaplasia confirms the diagnosis. A subset of patients develops dystrophic calcifications within the fibrosis, leading to a porcelain gallbladder, which is a risk factor for gallbladder carcinoma.


Cholangitis is an infection of the biliary system, complicating benign and malignant obstruction of the biliary tract. The clinical presentation is quite variable depending on the nature of the illness, patient age, and condition of the patient. Charcot triad (ie, fever, right upper quadrant pain, jaundice) occurs in only 20%-70% of cases. Hypotension and mental status changes also may accompany severe infection, a pentad described by Reynolds in 1959.[4]  The organisms typically identified are enteric in origin, notably Escherichia coli, Streptococcus faecalis, Clostridium species, Klebsiella species, Enterobacter species, Pseudomonas species, and Proteus species. They probably enter the biliary system via portal bacteremia. No correlation exists between the severity of the clinical manifestations and the presence or absence of pus in the biliary system; however, suppurative cholangitis is associated with a higher mortality rate.

Recurrent pyogenic cholangitis

Recurrent pyogenic cholangitis, also known as "oriental cholangiohepatitis," is prevalent in several parts of Asia and the Pacific Rim countries. It is limited to Asian immigrants in America, occurs in the second to fourth decades of life, and is associated with a lower socioeconomic class. It is initiated by parasitic infestation of the biliary ducts by Opisthorchis sinensis (formerly Clonorchis sinensis), in which the adult fluke may impair bile flow. In the setting of bile stasis and secondary bacterial infection, pigment stones form around ova and sets the stage for the intermittent obstruction leading to recurrent pyogenic cholangitis. Pathologic changes principally affect the intrahepatic bile ducts (curiously, more often the left duct).

Primary sclerosing cholangitis

PSC is a chronic cholestatic biliary disease characterized by nonsuppurative inflammation and fibrosis of the biliary ductal system. The cause is unknown but is associated with autoimmune inflammatory diseases, such as chronic ulcerative colitis and Crohn colitis (less commonly), and rare conditions, such as Riedel thyroiditis and retroperitoneal fibrosis. Most patients present with fatigue and pruritus and, occasionally, jaundice. The natural history is variable but involves progressive destruction of the bile ducts, leading to cirrhosis and liver failure. The clinical features of cholangitis (ie, fever, right upper quadrant pain, jaundice) are uncommon unless the biliary system has been instrumented.

Primary biliary cholangitis

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a progressive cholestatic biliary disease that presents with fatigue and itching or asymptomatic elevation of the alkaline phosphatase. The name change reflects the fact that cirrhosis occurs only in the late stage and therefore does not correctly identify patients with early-stage disease.[5]  Jaundice develops with progressive destruction of bile ductules that eventually leads to liver cirrhosis and hepatic failure. This autoimmune illness has a familial predisposition, in which even unaffected family members may have immunologic abnormalities, especially an increased serum immunoglobulin M (IgM) and an association with human leucocyte antigen (HLA)-DR8.[6, 7]

Although numerous autoantibodies have been identified, antimitochondrial antibodies (AMA) are present in 95% of patients. AMA is a family of antibodies; those directed against the inner mitochondrial membrane antigen M2 in the 2-oxo-acid dehydrogenase complex are most specific for PBC.[8]  Circulating immune complexes also have been identified but are unlikely to play a pathogenic role. Circulating T lymphocyte levels initially are within the reference range and decline as the disease progresses. The histologic appearance of the bile duct destruction resembles hepatic allograft rejection and graft-versus-host disease of the liver and appears to be mediated by cytotoxic T lymphocytes.

Autoimmune cholangitis

Autoimmune cholangitis represents a rare, distinct disease entity. While it shares some features with PBC, the results of tests for AMA are negative, the levels of gamma globulin and IgM are lower, and the results of tests for fluorescent antinuclear antibody (FANA) and anti–smooth muscle antibody (ASMA) are positive more commonly.

Neoplasms of the biliary tract

Carcinoma of the biliary system manifests with clinical symptoms of weight loss (77%), nausea (60%), anorexia (56%), abdominal pain (56%), fatigue (63%), pruritus (51%), fever (21%), malaise (19%), diarrhea (19%), constipation (16%), and abdominal fullness (16%). Symptomatic patients usually have advanced disease, with spread to hilar lymph nodes before obstructive jaundice occurs. It is associated with a poor prognosis.

Gallbladder cancer

This uncommon malignancy affects 2.5 individuals per 100,000 population. It represents 54% of biliary tract cancers, and more than 6500 patients die from this disease in the United States each year. Cancer that develops in the infundibulum (neck of the gallbladder) can produce hydrops of the gallbladder that is clinically indistinguishable from an obstructing stone.


Cholangiocarcinoma is an adenocarcinoma of the bile ducts.[9]  It may occur without associated risk factors, but it is associated more commonly with chronic cholestatic liver disease such as PSC, choledochal cysts, oriental cholangiohepatitis, and work-related handling of asbestos. Cholangiocarcinoma accounts for 25% of biliary tract cancers. Patients usually present with jaundice, a vague upper or right upper quadrant abdominal pain associated with anorexia, weight loss, and pruritus.

Ampullary cancer

Ampullary cancer accounts for 8% of biliary tract cancers. It most commonly presents with painless jaundice or acute pancreatitis.

Biliary tract cysts

Cystic dilatation of the biliary tree is an uncommon abnormality. About half of the patients present with some combination of jaundice, abdominal pain, and an abdominal mass. The presence of these cysts is often associated with an anomalous union of the pancreatic and biliary ductal system. This suggests that pancreatic juice enters the bile duct, causes a proteolytic and inflammatory injury to the duct wall, and leads to biliary cyst formation. The most commonly used classification scheme was proposed by Todani, which defines 5 cyst types, with groups I and IV having subtypes.

Type I involves a cystic dilatation of the extrahepatic biliary system. In subtype 1a (most common), the entire extrahepatic duct is diffusely involved. In subtype 1b (rare), a localized portion of the common bile duct is segmentally cystic. In subtype 1c (uncommon), the common bile duct is diffusely dilated.

Type II (rare) is a diverticulum of the extrahepatic bile duct.

Type III (uncommon) is a cystic dilatation of the intraduodenal portion of the common bile duct (sometimes referred to as a choledochocele).

Type IV has multiple cysts. Subtype IVa (uncommon) involves both the intrahepatic and extrahepatic biliary system, while subtype IVb (rare) has multiple cysts confined to the extrahepatic system.

Type V (rare) is characterized by single or multiple cysts involving the intrahepatic bile ducts (usually referred to as Caroli disease). Clinical symptoms usually are the result of associated complications such as cholangitis, choledocholithiasis, pancreatitis, hepatic abscess, cirrhosis, and biliary malignancy.


United States statistics

Gallstone disease is one of the most common and costly of all digestive diseases. The third National Health and Nutrition Examination Survey estimated that, in the United States, 6.3 million men and 14.2 million women aged 20-74 years have gallbladder disease.

The incidence of gallstones is 1 million new cases per year. The prevalence is 20 million cases among Americans.

Approximately 2-7 cases per 100,000 population of primary sclerosing cholangitis (PSC) exist. About 5% of patients with chronic ulcerative colitis develop PSC.

The incidence of gallbladder cancer is 2.5 cases per 100,000 population.

International statistics

The incidence of primary biliary cholangitis (PBC) is 5.8-15 cases per 1 million population. The incidence of PBC appears to be increasing, but the cause of the increase is unclear. However, the increase is possibly due to better detection and increased awareness rather than a true change in disease incidence.

According to an international multicenter study comprising 4805 patients with primary biliary cholangitis (primary biliary cirrhosis) over 44 years (1970-2014), there was an incremental increase in mean age at diagnosis: 2-3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P<0.001).<ref>10 </ref>In addition, although there were no significant changes in female predominance (female-male ratio of 9:1) and antimitochondrial antibody positivity (90%), increases in the incidence of mild biochemical disease and mild histologic stage at diagnosis were observed, as well as lower rates of decompensation and higher 10-year transplant-free survival with each decade forward.[10]

Race-related demographics

Mexican Americans and several American Indian tribes, particularly the Pima Indians in the Southwest, have very high prevalence rates of cholesterol gallstones. Decreased bile acid secretion is believed to be the common denominator in these ethnic groups.

Gallbladder cancer is the most common gastrointestinal malignancy in both Southwestern Native Americans and Mexican Americans. A prominent geographic variability exists in the incidence of gallbladder cancer that correlates with the prevalence of cholelithiasis. High rates of gallbladder cancer are also seen in South American countries, particularly Chile and Bolivia. These populations all share a high prevalence of gallstones and/or Salmonella infection, both recognized risk factors for gallbladder cancer.

Sex-related demographics

The prevalence of cholesterol gallstones is higher among females than males (lifetime risk of 35% vs 20%, respectively). This likely is due to endogenous sex hormones, which enhance cholesterol secretion and increase bile cholesterol saturation. Progesterone also may contribute by relaxing gallbladder smooth muscle and impairing gallbladder emptying. Note the following:

  • PSC: Males (primarily young to middle-aged[11] ) are affected twice as frequently as females.

  • PBC: Females are affected nine times as often as males.

Age-related demographics

Increased age is associated with lithogenic bile and an increased rate of gallstones. Note the following:

  • PSC: Mean age of onset is 40 years.

  • PBC: Among the autoimmune diseases, PBC is unique in that it never occurs in childhood and is rarely found before age 30 years. The onset is usually between the ages of 30-65 years, but the disease has been reported in women as young as 22 years and as old as 93 years.


In primary sclerosing cholangitis (PSC), several factors suggest a high risk of death. These include advancing age, serum bilirubin, serum albumin, presence or absence of inflammatory bowel disease, and histologic stage on liver biopsy.


Gallstones are a rare cause of mortality, accounting for 5000 of the 2.2 million deaths annually in the United States.

Primary biliary cholangitis (PBC) accounts for 0.6%-2% of deaths from cirrhosis worldwide. The median time of patient survival was 9.3 years from diagnosis. Independent predictors of survival include age and serum levels of alkaline phosphatase, albumin, and bilirubin. Liver failure develops in 26% of patients by 10 years after diagnosis. Neither the presence of antimitochondrial antibodies nor their titer affects disease progression or survival.

PSC is a leading reason for liver transplantation. Median survival without liver transplantation after diagnosis is approximately 12 years. Variables that appear to predict prognosis in PSC include age, histologic stage, hepatomegaly, splenomegaly, and serum alkaline phosphatase and serum bilirubin levels.


The complications common to all of the chronic cholestatic liver diseases, such as PSC and PBC, include fatigue, pruritus, steatorrhea, fat-soluble vitamin deficiencies (A, D, E, and K), metabolic bone disease, hypercholesterolemia, xanthomas, hypothyroidism, and anemia. There is a reported association of PBC with Sjögren syndrome, Raynaud phenomenon, and sicca symptoms.

Approximately 20% of patients with PSC develop a dominant stricture in the intrahepatic or extrahepatic biliary tree. Medical therapy to treat biliary strictures has been ineffective. Nonsurgical modalities to relieve biliary obstruction, such as endoscopically- or radiologically–guided balloon dilation of strictures or placement of prosthetic stents across strictures, should be attempted initially.

Choledocholithiasis and cholelithiasis due to cholesterol and/or pigment stones may be present in up to one third of patients with PSC. Bacterial cholangitis can occur in patients with PSC.

Cholangiocarcinoma eventually develops in about 20% of patients with PSC, principally late in the course of long-standing ulcerative colitis and the cirrhotic stage of biliary disease. About half of patients with PSC are diagnosed with cholangiocarcinoma within 2 years of the initial diagnosis, with an associated poor prognosis owing to advanced disease at the time of diagnosis.[12] This complication is difficult to detect, as evidenced by the finding of cholangiocarcinoma in 10% of patients undergoing liver transplantation for PSC.[13]

The incidence of hepatocellular carcinoma is increased in patients with PBC who have had stage IV disease for many years.[14]

Patients with both PSC and ulcerative colitis have an increased risk of colon cancer and progression of neoplastic transformation.




Biliary disease presents with some diversity, from no symptoms to a constellation of signs and symptoms of varying severity and combination. An accurate diagnosis, therefore, begins with listening closely to the patient. Reaching an accurate diagnosis is aided by clinical experience and often involves imaging studies.

When abdominal pain is the chief symptom, seek to determine when it began and the subsequent events. Clarify what the pain feels like to the patient; visceral pain is perceived as a vague, dull, gnawing, burning, or aching sensation, whereas parietal pain is sharper in quality and better localized. Psychological conditions (eg, anxiety, worry) may enhance pain perception, while impaired consciousness tends to blunt pain perception.

Biliary-type pain

Biliary disease often presents with upper abdominal pain. The pain quality is a penetrating, aching or tightness, typically severe and located in the epigastrium. The sensation usually is difficult to describe; it may develop suddenly, last for 15 minutes to several hours, and then resolve suddenly. Although the term biliary colic is used commonly, it is a misnomer because the pattern of pain is constant. The pain is caused by an obstruction to the flow of bile, with distension of the biliary lumen, and is clinically similar to when the obstruction occurs at the cystic duct or at another level of the common bile duct. As noxious visceral stimuli become more intense, referred pain may be experienced in the posterior scapula or right shoulder area and may be accompanied by nausea and vomiting.


Bilirubin metabolism and transport principally are handled by the hepatobiliary tract. A yellow discoloration of the skin begins to appear when the serum bilirubin rises above 3 mg/dL, and the yellow discoloration is termed jaundice. Abnormalities leading to jaundice may occur in various phases of the process.

Jaundice and abdominal pain

The combination of jaundice and abdominal pain suggests a subacute obstruction of the biliary ductal system. In elderly patients, however, biliary tract obstruction may be painless. Rarely, acute viral hepatitis can be confused with biliary-type pain.

Painless jaundice

The development of jaundice in the absence of abdominal pain is suggestive of a malignant obstruction of the bile duct. Here, the onset of jaundice is gradual and may be associated with anorexia; weight loss; and acholic, soft or loose stools. Nonbiliary causes should be considered, including increased bilirubin production (eg, from hemolysis, blood transfusions, or ineffective erythropoieses) and decreased bilirubin clearance due to hereditary defects (eg, unconjugated hyperbilirubinemia in Gilbert syndrome and Crigler-Najjar syndrome types I and II, conjugated hyperbilirubinemia in Dubin-Johnson syndrome and Rotor syndrome).


Itching is an unpleasant sensation in the skin associated with a strong desire to scratch. While several causes exist, itching is associated with cholestasis and may become the patient's most bothersome symptom. Itching may appear at first in the hands and feet, but it usually becomes generalized and typically is worse at night. Itching does not distinguish the cause of cholestasis as hepatic or biliary.


The insidious onset of fatigue, followed by pruritus and then jaundice, is observed to varying degrees in diseases of the intrahepatic bile ducts, such as primary biliary cholangitis, primary sclerosing cholangitis, and vanishing bile duct syndrome.

Weight loss

A history of weight loss is associated with more serious diseases of the biliary tract. The weight loss may be caused by inadequate nutrient intake (eg, anorexia) or malabsorption of fats (eg, a paucity of bile in cholestatic diseases or prolonged biliary obstruction).


Other symptoms, including fatty food intolerance, gas, bloating, and dyspepsia, do not reliably indicate the presence of biliary tract disease.

Physical Examination

The patient with acute biliary-type pain often is restless, anxious, and frustrated by unsuccessful attempts to find a comfortable position. Severe pain of acute onset usually is associated with facial grimacing. Writhing, diaphoretic patients usually are acutely and seriously ill; however, some patients with peritonitis may lie still, with a worried facial expression, and avoid being touched or jostled.

Vital signs

Vital signs may be normal. The presence of fever suggests the presence of inflammation or infection. Tachycardia and hypertension occasionally accompany pain. Tachycardia and hypotension suggests hypovolemia or the presence of sepsis.


In people with light skin, the skin color may suggest not only jaundice but also provide clues to the etiology; a yellow discoloration is associated with indirect hyperbilirubinemia, a more orange hue can be observed with hepatocellular jaundice, and a dark green tint may develop with prolonged biliary obstruction. Evidence of easy bruisability may indicate a coagulopathy associated with cirrhosis. Patients with cholestasis classically exhibit excoriation of the skin (from scratching, typically sparing the mid back), melanin pigmentation, and xanthomas of the eyelids and extensor surfaces.


Scleral icterus, a yellow discoloration of the whites of the eyes, results from hyperbilirubinemia. Although this term is in common use, it actually is a misnomer. The sclerae are relatively impervious to most compounds; the covering conjunctiva becomes permeated with unconjugated bilirubin, causing the yellow appearance. Approximately 58% of examiners are able to detect scleral icterus when the serum bilirubin rises above 2.5 mg/dL.


The abdomen should first be observed to determine if it is scaphoid, flat, distended, or asymmetric. Auscultation may reveal absent bowel sounds, suggesting an ileus, hyperactive bowel sounds (borborygmi), or high-pitched tinkling suggesting intestinal obstruction. The elicitation of pain and involuntary guarding during gentle palpation or jostling of the abdomen suggests peritonitis. Palpation may reveal a mass or fullness in the right upper quadrant.

In the patient with jaundice, an enlarged gallbladder is suggestive of malignant obstruction of the bile duct. In the absence of jaundice, the patient with a palpable mass in the right upper quadrant may have a gallbladder tumor or chronic obstruction of the cystic duct.

Gallbladder hydrops is a rare condition resulting from chronic common duct obstruction or mucosal inflammation, in which the gallbladder becomes grossly distended by an uninfected clear mucoid fluid. Although it usually requires cholecystectomy, when the condition is associated with a mucocutaneous lymph node syndrome (Kawasaki disease), it tends to be self-limited and resolve spontaneously.



Diagnostic Considerations

Important considerations

Choose the procedure that is appropriate for the patient. Know the limitations of the procedure. The presence of dense adhesions, advanced liver disease, unexpected cancer, or a severely inflamed gallbladder or encountering troublesome bleeding should prompt assessment of the need to convert a laparoscopic cholecystectomy to an open procedure.

Special concerns

Postcholecystectomy syndrome

The persistence, recurrence, or development of pain following the removal of the gallbladder is referred to as the postcholecystectomy syndrome. It occurs in 10%-15% of the 600,000 cholecystectomies performed annually in the United States.

A retained common duct stone can be identified in 0.3%-18% of cases. A history of recurrent biliary-type pain associated with nausea, vomiting, fever, and chills is suggestive of a retained common duct stone, and sonographic evidence of ductal dilation is supportive of this diagnosis. An intraoperative cholangiogram is very useful to exclude a retained common duct stone.

Biliary leaks or fistula occur in 0.1%-0.4% of all gallbladder operations. Leakage from the cystic duct stump is most common, but it may (1) emanate from accessory ducts along the gallbladder fossa, (2) be the result from an injury to a major extrahepatic duct, or (3) follow T-tube removal after open cholecystectomy and common bile duct exploration. In the past, these were associated with a mortality rate of about 30%.

Benign biliary strictures occur with a frequency of 0.1%-0.8% of all gallbladder operations. This usually is the result of an operative injury to the bile duct. The first type results from a surgical misadventure such as inadvertent duct ligation or placing clips on the bile duct. Only 10% of patients present with pain and jaundice in the first week, and another 60% present within 3 months of the surgery. The second type results either from ischemic injury or from crush injury from clamps. Many months or years may pass before mild cholestasis or symptoms develop when biliary sludge or stones form proximal to a stricture.

Cystic duct remnants are a rare and controversial cause of postcholecystectomy pain. The long cystic duct stump promotes bile stasis within which microlithiasis or stones may form. The passage of this material through the papilla is believed to cause intermittent biliary-type pain. In extremely rare instances, a neuroma or granuloma of the cystic duct stump can cause pain.

Sphincter of Oddi dysfunction

Sphincter of Oddi dysfunction is an uncommon, probably overdiagnosed, cause of biliary-type pain. The 2 subtypes are papillary stenosis and sphincter of Oddi dyskinesia. The former is a mechanical problem, and the latter is a functional problem.

Papillary stenosis is a mechanical problem involving an inflammatory stenosis of the duodenal papilla of Vater. It may be caused by choledocholithiasis, ascariasis, sclerosing cholangitis, pancreatitis, iatrogenic instrumentation of the duodenal papilla, peptic duodenitis, and Crohn disease involving the duodenum and cholesterolosis of the papilla. It is diagnosed manometrically when the sphincter of Oddi manometry reveals a basal sphincter pressure greater than 40 mm Hg that does not decrease in response to cholecystokinin (CCK) or amyl nitrate. It also may be diagnosed surgically via the inability to pass a #3 Bakes dilator through the sphincter or during endoscopic retrograde cholangiopancreatography (ERCP) via an inability to advance a 5F cannula retrograde over a wire placed into the bile duct.

Endoscopic sphincterotomy alleviates biliary-type pain in most, but not all, patients with papillary stenosis.

The term sphincter of Oddi dysfunction has been used to describe a clinical syndrome of biliary or pancreatic obstruction related to mechanical or functional abnormalities of the sphincter of Oddi.

Sphincter of Oddi dysfunction is diagnosed by a sphincter manometry study revealing a basal pressure greater than 40 mm Hg that is responsive to CCK or amyl nitrate. Other supportive features may include phasic wave contractions with a peak amplitude greater than 220 mm Hg, contraction duration greater than 8 seconds, and frequency of greater than 10 per minute. An increased percentage of retrograde contractions have also been cited. Abnormal sphincter motility is uncommon, identified in 1% of 454 patients following cholecystectomy; 14% of those were diagnosed with a postcholecystectomy syndrome.

HIV-associated cholangiopathy

Several biliary tract abnormalities are associated with human immunodeficiency virus (HIV) infection, but the CD4+ lymphocytes are usually below 100 cells per microliter before these problems develop. These include acalculous cholecystitis, papillary stenosis, and a sclerosing cholangitis–like picture. The causes include opportunistic infections, such as infection with cytomegalovirus, Cryptosporidium species, Enterocytozoon bieneusi, and Mycobacterium species, or neoplasms, such as Kaposi sarcoma and non-Hodgkin lymphoma. Liver-associated enzymes usually show a cholestatic picture, without significant hyperbilirubinemia, unless a neoplasm obstructs the bile duct. Medical therapy to date has been ineffective in treating opportunistic infections.

Ursodeoxycholic acid (UDCA) has been used in the treatment of primary sclerosing cholangitis, a disorder with similar intrahepatic changes to AIDS cholangiopathy. This observation has led to its experimental use in patients with acquired immunodeficiency syndrome (AIDS) cholangiopathy; results in a small number of patients have found an improvement in symptoms and a fall in the levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase. The authors recommend giving UDCA in a dose 300 mg 3 times daily, primarily in patients who have intrahepatic ductal disease and markedly elevated liver function test results.

Vanishing bile duct syndrome

This is a rare syndrome affecting the intrahepatic bile ducts. Most patients are asymptomatic, but some may present with pruritus and, rarely, jaundice. The alkaline phosphatase level usually is elevated, along with gamma-glutamyltransferase (GGT), which may exceed 600 IU/L. Obtaining a wedge liver biopsy often is necessary to make the diagnosis. The cause of ductopenia may be related to developmental abnormalities of the intrahepatic biliary system, as in Alagille syndrome. On physical examination, frontal bossing and triangular facies may be noted, and tests that are more specific can reveal butterfly vertebrae and posterior embryotoxon of the eye. Progressive familial intrahepatic cholestasis is another type, caused by a genetic mutation of the membrane transporter for phospholipids (MDR3).

Other types are acquired and are associated with cystic fibrosis, systemic mastocytosis, histiocytosis-X, Hodgkin disease, and drug-induced hepatotoxicity. Patients without a clear association are diagnosed with idiopathic adult ductopenia.

Differential Diagnoses



Laboratory Studies

Alkaline phosphatase

Alkaline phosphatase is a marker of cholestasis (ie, elevation of alkaline phosphatase occurs in more than 90% of patients with cholestasis) and suggests a reduction in bile flow. It also is elevated in infiltrative disorders or fungal infections of the liver, often quite strikingly, with levels above 1000 U/L.

Because isozymes are found in the liver, bone, placenta, leukocytes, and small intestine, an elevated alkaline phosphatase is not specific for the biliary tract. Although the source can be determined by measuring isozyme subtypes, these electrophoretic tests seldom are available clinically. A biliary source is inferred when the alkaline phosphatase is associated with an elevated gamma-glutamyl transpeptidase (GGT), 5'-nucleotidase, or leucine aminopeptidase.

An elevation of the hepatic alkaline phosphatase level involves an enzyme-induced secretory process, ie, it represents enzyme induction and accelerated de novo synthesis of alkaline phosphatase and backup into the circulation, not just a simple mechanical obstruction to flow. For this reason, an elevation of alkaline phosphatase may be delayed in the setting of acute obstruction.


Bilirubin is a breakdown product of heme, with 80% coming from senescent red blood cells and 20% coming from cytochromes and myoglobin. Unconjugated bilirubin is hydrophobic and transported in the blood reversibly bound to albumen. It is taken up by the hepatocyte, converted to conjugated bilirubin by glucuronyl transferase, and actively secreted into the biliary canaliculi.


In addition to the liver, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are found in cardiac and skeletal muscles and renal and cerebral nerve cells. The ALT is found predominantly in the cytosol of the hepatocyte, and an elevated ALT is more likely to suggest liver injury. The AST has both cytosolic and mitochondrial forms. Elevated aminotransferase levels are observed with hepatocellular injury (eg, viral hepatitis), usually sustained over weeks. A rapid rise and fall may be observed in acute posthepatic biliary obstruction or transient hepatic ischemia.

Antimitochondrial antibodies

More than 95% of cases of primary biliary cholangitis are associated with positive test results for antimitochondrial antibodies (AMA). The antigen that reacts with AMA is part of the 2-oxo-acid dehydrogenase multienzyme complex in the mitochondria, especially the E2 subunit of pyruvate dehydrogenase, located on the inner mitochondrial membrane.

Miscellaneous immunologic markers

An emerging role for immune markers in inflammatory bowel disease may have implications in the diagnostic evaluation of cholestatic liver disease. Just as AMA is an immunologic marker of primary biliary cholangitis (PBC), two markers are used in the evaluation of patients with suspected inflammatory bowel disease and primary sclerosing cholangitis (PSC). These are antineutrophil cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA). ANCA is strongly associated with ulcerative colitis (79%) and PSC (82%). Although ASCA is associated with Crohn disease, currently, no association with PSC exists. Multispecific ANCA with anti-nuclear antibodies (ANA) and anti-smooth muscle antibody (ASMA) may be potential markers for PSC.[15]

Tumor markers

Findings from a 2018 study indicated detection of a combination of serum tumor markers carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA-19-9 had the best clinical diagnostic value in patients with cholangiocarcinoma.[16] Optimal cutoff values were 2.85 U/mL for CEA, 23.85 U/mL for CA-125, and 46.75 U/mL for CA-19-9.

Imaging Studies


Ultrasonography uses technology similar to sonar. A two-dimensional image of echoes is created. Fluid appears black, solid organs appear hypoechoic, and structures with high amounts of fat or minimal water are hyperechoic.

Note that although ultrasonography is commonly used for the initial evaluation of patients with primary sclerosing cholangitis (PSC), it is not good at detecting small tumors in the heterogeneous liver.[12] However, contrast-enhanced ultrasonography can be useful for revealing cholangiocarcinoma by demonstrating rapid and marked washout.[12]

Right upper quadrant ultrasound

This is the principal study used to evaluate biliary-type pain and detect gallbladder disease and biliary dilatation. Gallstones appear as a highly echogenic focus with acoustic shadows and move to the dependent portion of the gallbladder. Right upper quadrant ultrasound can detect stones as small as 1-2 mm and has a sensitivity of 95% and a specificity of 97%. The presence of a thickened gallbladder wall, pericholecystic fluid, and a sonographic Murphy sign supports the diagnosis of cholecystitis. Because of interference by bowel gas, ultrasound does not reveal the common bile duct well, and ultrasound may miss 25%-40% of bile duct stones.

Endoscopic ultrasonography (EUS)

By placing a higher-frequency transducer into the gut adjacent to the hepatobiliary tract, endoscopic ultrasound provides more detailed images than a transcutaneous approach. Although no major advantage to examining the gallbladder exists, EUS can be used to detect intraductal stones with a sensitivity of 88%-97% and specificity of 97%. It also can be used to assess adjacent structures, such as porta hepatis nodes; malignancy is suggested by the presence of large (>1 cm), round, sharply demarcated hypoechoic nodes. By better defining the local anatomy of the ampullary tumors in relation to neighboring structures, information obtained with EUS can help guide the physician's selection of an appropriate intervention.

Abdominal computed tomography (CT) scanning

This imaging study usually is not very helpful in evaluating the biliary system. It may demonstrate dilated bile ducts and reveal the cause of a biliary obstruction. Relatively recent technologic advances, such as thin-section helical CT scanning, have increased the sensitivity for detection of bile duct stones from 60% to 90%.


Both endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) provide images of the biliary ductal system, which has an appearance similar to a deciduous tree in the wintertime. ERCP is an invasive endoscopic procedure in which radiopaque contrast is injected into the biliary ductal system under fluoroscopic guidance. MRCP is a noninvasive procedure that relies on heavily T2-weighted images to create an image of the fluid within the biliary and pancreatic ductal system. MRCP combined with magnetic resonance imaging (MRI) is able to demonstrate focal biliary anomalies and subtle liver lesions.[12]


On a cholangiogram, stones within the bile ducts appear as filling defects within the trunk or branches of the biliary tree. Depending on the type of stone and duration of the illness, they may be single or multiple, round or faceted, free-floating or adherent.

Primary sclerosing cholangitis

In PSC, the bile ducts are characterized by strictures and ectatic areas in an irregular, diffuse pattern. In some cases, the duct may resemble a string of beads due to alternating annular bandlike strictures separating areas of cholangiectasia. Diverticular outpouchings occur in 10% of cases and are observed exclusively in PSC, not cholangiocarcinoma. Specific radiologic patterns (ie, diffuse involvement versus intrahepatic versus extrahepatic) are not associated with differences in median survival.

Hepatobiliary scintigraphy

This test should be ordered when acute cholecystitis is suspected. Nonvisualization of the gallbladder supports the diagnosis of acute calculous cholecystitis with a sensitivity of 92%-98% and a specificity of 95%-98%. It also is used to confirm the presence of a biliary leak.

Although controversial, hepatobiliary scintigraphy occasionally is helpful in diagnosing chronic cholecystitis or gallbladder dyskinesia in patients with biliary-type pain and normal findings on right upper quadrant ultrasound. The test employs a 45-minute infusion of cholecystokinin (CCK) octapeptide to measure the gallbladder ejection fraction; values lower than 35% are considered abnormal. In some patients, an abnormal gallbladder ejection fraction may be associated with sphincter of Oddi dysfunction.


Hepatobiliary histology has emerged as an objective reference for staging primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In both, 4 stages are identified.

Primary sclerosing cholangitis

In PSC, stage 1 is characterized by portal tracts that are enlarged by edema, increased connective tissue, and proliferation of interlobular bile ducts. Periductal inflammation and fibrosis characterize stage 2. Connective tissue begins to encroach into the periportal parenchyma, and a fibrous-obliterative cholangitis is present. Stage 3 is defined by a discernible loss of interlobular bile ducts, and stage 4 is reached when cirrhosis is present.

Primary biliary cholangitis

In PBC, stage 1 is characterized by dramatic evidence of asymmetric destruction of septal and interlobular bile ducts by a mononuclear infiltrate (the typical appearance is referred to as a florid duct lesion). Occasionally, hepatic granulomas are observed. Diffuse periportal inflammation characterizes stage 2 and is accompanied by portal fibrosis, periportal liver cell necrosis, patchy ductopenia, and ductular proliferation. Stage 3 is defined by the presence of bridging fibrosis, and stage 4 is reached when cirrhosis is present.



Medical Care


Medical management of gallstone disease has decreased relatively recently with the advent of laparoscopic cholecystectomy. Cholecystectomy remains the preferred method because of its reduced cost, definitive nature, safety, and increased convenience to the patient.

Medical management may be an effective alternative to cholecystectomy in selected patients with symptomatic gallstone disease. Three methods used alone or in combination are available for the nonsurgical management of patients with gallstone disease, as follows: (1) oral bile salt therapy, primarily ursodeoxycholic acid, (2) contact dissolution, and (3) extracorporeal shock-wave lithotripsy. The method of choice depends upon the number, size, and composition of the stone(s); many symptomatic patients have stones that are not ideally suited for any of these methods, producing less than optimal results.

Several years of treatment may be necessary to completely dissolve a stone, and a 50% chance of stone recurrence over a period of 5 years exists. Some evidence supports using nonsteroidal anti-inflammatory drugs (NSAIDs) in the setting of recurrent biliary pain; inhibition of prostaglandins may arrest the inflammatory process and reduce the chance of developing acute cholecystitis.

There is consensus that incidentally discovered asymptomatic gallstones should not be treated. Once a patient develops symptoms or complications related to gallstones (eg, acute cholecystitis), treatment to eliminate the gallstones is recommended because the likelihood of subsequent symptoms or complications is high. The National Cooperative Gallstone Study demonstrated that the risk of recurrent symptoms was approximately 70% during the 2 years following the initial presentation.

Acute cholecystitis

Patients with a clinical diagnosis of acute cholecystitis should be admitted to the hospital, where they should have nothing by mouth (NPO) and be administered intravenous (IV) fluid hydration; correction of any associated electrolyte disorders is an important initial measure. In most cases, inflammation is initiated by mechanical obstruction of the cystic duct and mediated by a chemical irritation of the gallbladder mucosa (by lysolecithin).

However, in 20% of patients, bacterial infection complicates the picture. The most frequent isolates from the gallbladder or the common bile duct are Escherichia coli (41%), Enterococcus (12%), Klebsiella (11%), and Enterobacter (9%).

When poor clinical appearance, fever, and leukocytosis are prominent features of the illness, broad-spectrum antibiotics are indicated. Empiric antibiotic therapy should be directed at the organisms most frequently recovered. While the use of a second-generation cephalosporin, such as cefuroxime, is fairly common, cephalosporins do not treat Enterococcus. The combination of ampicillin (2 g IV q4h) and gentamicin (dosed according to weight and renal function) as empiric treatment can be used. The aminoglycoside is included for coverage of E coli and other gram-negative bacilli and also for synergy with ampicillin against Enterococcus. Routine coverage of anaerobic organisms is not required for acute cholecystitis since these organisms are recovered infrequently.

NSAIDs are useful in reducing inflammation, but narcotic analgesics often are needed to alleviate pain. Unless severe comorbid disease is a contraindication, these patients should undergo a cholecystectomy once their condition is stabilized.


The treatment of cholangitis is similar to that of acute cholecystitis, except that endoscopic intervention is indicated. The mainstays of therapy are antibiotics and the establishment of biliary drainage. Broad-spectrum antibiotics are indicated initially to cover gram-negative bacteria and Enterococcus. Antibiotics include ampicillin plus gentamicin, carbapenems (imipenem or meropenem), and fluoroquinolones (levofloxacin). Other agents that have good activity against intestinal anaerobes and lack the nephrotoxicity of aminoglycosides are piperacillin (4 g IV q6h), piperacillin-tazobactam (4/0.5 g IV q6-8h), ampicillin/sulbactam (3 g q6h), or ticarcillin-clavulanate (3.1 g q4h). Unlike acute cholecystitis, in patients with a more toxic appearance, metronidazole is often added to cover anaerobes, although the contribution of anaerobes to infection is low in patients who have not had previous biliary tract instrumentation or surgery.

Depending on the etiology of the cholangitis and the comorbid status of the patient, biliary drainage is established by endoscopic retrograde cholangiopancreatography (ERCP)–guided sphincterotomy and stone extraction or biliary stent placement. In a patient with sepsis, the least aggressive intervention to establish biliary drainage is often the best, with subsequent plans for definitive therapy (cholecystectomy) once the patient's condition is stabilized.

Percutaneous drainage should be considered when ERCP is unavailable, unsuccessful, or contraindicated. A percutaneous cholecystostomy tube may be an option in patients with an intact gallbladder.

Primary sclerosing cholangitis (PSC)

The two major goals of treatment in PSC are retardation and reversal of the disease process and management of progressive disease and its complications. A variety of immunosuppressive and anti-inflammatory agents have been studied in patients with PSC, including ursodeoxycholic acid (UDCA), corticosteroids, cyclosporine, methotrexate, azathioprine/6-mercaptopurine, tacrolimus, and D-penicillamine.

No effective medical treatment exists for PSC.

UDCA, a hydrophilic bile acid, is the most extensively studied of all medical treatments in PSC. However, its use is debatable and controversial. The American Association for the Study of Liver Diseases does not recommend UDCA for as a routine chemopreventive agent to reduce the risk of colorectal dysplasia in patients with PSC and ulcerative colitis[17] ; the European Association for the Study of the Liver (EASL) recommends oral UDCA as first-line pharmacotherapy in all patients with PSC (13-15 mg/kg/day), often continued for life.[18] The dosing regimen for UDCA is also under debate, including whether a low dose (15-20 mg/ kg/ day) or high dose (30 mg/kg/day) is optimal.

Ursodiol, used to create a less toxic population of bile acids, initially showed promise; however, subsequent clinical studies showed no difference in the time to treatment failure. It has also been hypothesized that UDCA given in higher than standard doses (20-30 mg/kg/d vs 13-15 mg/kg/d) may increase the benefit. Larger scale prospective studies of high-dose UDCA are currently underway.

Reduction of hepatic copper levels using D-penicillamine showed no benefits; immunosuppressives either failed or worsened patient status. Oral corticosteroids might help early stage disease with marked inflammatory changes as observed on biopsy specimens. Steroids administered by nasobiliary lavage complicated matters by introducing bacterial cholangitis.

While colchicine and steroids together improve laboratory test results, the development of cirrhosis is not diminished, and metabolic bone disease is aggravated, causing some patients to develop compression fractures. Colchicine alone showed no improvement in the symptoms, serum biochemistry, liver histology, or survival rate. While methotrexate decreased serum alkaline phosphatase levels, it produced no appreciable improvement in bilirubin, AST, ALT, or albumin levels, and it had minimal effect on symptoms or histologic progression. Cyclosporine decreased serum alkaline phosphatase levels but did not improve symptoms, histologic progression, or the development of complications.

Endoscopic therapy to dilate and/or stent dominant strictures is reasonable in centers with considerable expertise in therapeutic biliary endoscopy. An important potential clinical benefit is the relief of jaundice and pruritus, although a benefit on disease progression has not been clearly established.

Liver transplantation is now the treatment of choice for patients with advanced liver disease secondary to PSC.

Primary biliary cholangitis (PBC)

The management of this disorder has two goals, as follows: (1) the treatment of symptoms and complications that result from chronic cholestasis, and (2) the suppression of the underlying pathogenic process (ie, the destruction of small intralobular hepatic bile ducts). The complications that occur in PBC that require therapy include pruritus, metabolic bone disease, hypercholesterolemia/xanthomas, atherosclerosis, malabsorption, vitamin deficiencies, hypothyroidism, and anemia.

Data exist showing that medical therapy benefits patients with PBC. UDCA is the only treatment (aimed at modifying the natural history of the disease) currently recommended in the guidelines issued by the AASLD.[19] Oral UDCA alone (13-15 mg/kg/day) is recommended for patients with PBC and abnormal liver enzyme levels regardless of histologic stage. It is given in divided doses with meals and at bedtime. Blood tests are monitored every 3 months. If normalized within 6 months, UDCA is continued and liver biopsy is repeated within 18-24 months. If the biopsy result is stable or improved, UDCA is continued indefinitely and a liver biopsy is repeated after 2-3 years and then less often if still improved.[20]

In May 2016, the FDA approved obeticholic acid in combination with UDCA for PBC in adult patients with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.[21] Approval was based on the international phase 3 POISE trial of patients (n = 216) with PBC. The trial included patients who had not shown a reduction in alkaline phosphatase (ALP) levels with UDCA at optimal dosage for at least 1 year or as monotherapy in those who were intolerant to UDCA. The primary endpoint (ie, ALP <1.67 × ULN) was met in 47% of the obeticholic acid 10 mg group and 46% in the titration group (ie, 5-10 mg) compared to 10% in the placebo plus UDCA group (p <0.0001).<ref>22</ref>

In clinical studies, colchicine had no effect on symptoms, physical findings, or histology, but it improved levels of serum albumin, bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. One study showed improved mortality rates (21% vs 47%, P = 0.05). In a double-blind randomized clinical trial, azathioprine was well tolerated, slowed incapacitation, and improved actuarial survival by 20 months. However, the development of major complications or the need for liver transplantation was not influenced. In a small prospective randomized trial, chlorambucil reduced the inflammatory cell infiltrate, but it did not improve serum alkaline phosphatase levels, fibrosis, or histologic severity.

Methotrexate, used in pilot studies only, has been said to have beneficial effects on the symptoms and biochemical and histologic features of PBC. However, one randomized controlled trial of methotrexate therapy suggested that, even at low doses (2.5 mg 3 times per wk), methotrexate may be toxic over a 6-year period. Hence, at the present time, insufficient data support the use of immunosuppressive therapy for PBC.

Similar to the experience with PSC, corticosteroids worsened the metabolic bone disease and D-penicillamine induced serious adverse effects without providing a clinical benefit.

Liver transplantation in PBC is recommended for cases of liver failure. Liver transplantation may be recommended in appropriately selected patients for uncontrollable pruritus and severe osteoporosis.

Symptomatic treatment

The pruritus associated with cholestasis may respond to cholestyramine, rifampin, and even large-volume plasmapheresis. Naloxone also reduces the severity of itching but requires parenteral administration. Oral naltrexone may be an effective and well-tolerated alternative.


Patients with steatorrhea may benefit from pancreas enzyme supplements and fat-soluble vitamins A, D, E, and K.


When biliary disease associated with decreased bile flow causes steatorrhea, a diet low in neutral triglycerides often is prescribed. Supplementation with medium-chain triglycerides also is helpful.

Endoscopic management

Endoscopic management of biliary stones: Because choledocholithiasis frequently causes abdominal pain, pancreatitis, cholangitis, and secondary biliary cirrhosis, treatment is recommended once stones are identified. The standard approach is to perform endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy[23] and stone extraction using a balloon-tipped catheter or wire basket.[24] Clearance rates range from 80%-95%, depending on the experience of the endoscopist, with an associated morbidity rate of 5%-10% and a mortality rate of 0.5%.

Kageoka et al evaluated the long-term prognosis of 262 patients following endoscopic sphincterotomy for choledocholithiasis and the need for cholecystectomy post endoscopic sphincterotomy.[23] Patients were divided into four groups according to previous cholecystectomy (n = 18); those having a calculous gallbladder and who underwent cholecystectomy after endoscopic sphincterotomy (n = 129); those with a calculous gallbladder in situ (n = 46); and patients with an acalculous gallbladder in situ (n = 69).

Of the 262 patients, late complications occurred in 34 patients (13.0%), and recurrence of choledocholithiasis occurred in 29 patients (11.1%).[23] The group with a calculous gallbladder in situ had a late complication rate of 23.9% and a rate of recurrent choledocholithiasis of 17.4%, compared with a late complication rate of 23.9% and recurrent choledocholithiasis rate of 7.8% in the group with a calculous gallbladder that underwent cholecystectomy after endoscopic sphincterotomy.

Other findings included an association between pneumobilia after endoscopic sphincterotomy and choledocholithiasis recurrence, the presence of acute cholecystitis in 8 (7.0%) of 115 patients with an intact gallbladder, and 1 gallbladder carcinoma.[23] The investigators concluded that endoscopic sphincterotomy is a safe and effective procedure that should be used in patients with a calculous gallbladder.[23]

Intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment to preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy because IOES is as effective and safe as POES and results in a significantly shorter hospital stay.[25]

Refractory stones usually can be cleared using a mechanical lithotripsy device; however, electrohydraulic lithotripsy (EHL) and laser lithotripsy also can be used. Refractory biliary stones can be managed with biliary stent placement and ursodiol. In selected patients, percutaneous choledochoscopy can be used to remove intrahepatic stones using EHL or holmium laser lithotripsy (a holmium laser is used to fracture the stones).

Endoscopic management of benign biliary strictures: Benign postoperative strictures are managed successfully by endoscopic balloon dilation and stent placement on a quarterly basis for a period of a year. This approach has an 83% success rate, with 17% of cases eventually requiring surgical intervention. In patients with sclerosing cholangitis, mechanical dilation of dominant extrahepatic strictures decreases serum bilirubin levels but does not improve liver-associated enzymes. It primarily is helpful in preventing a dominant stricture from causing further damage to the liver, and it may delay the need for a liver transplant. Patients with a symptomatic or complicated distal biliary stricture caused by chronic pancreatitis usually are best managed surgically. In selected patients with high operative risk, placement of a metal mesh stent may be helpful; however, a tendency exists for biliary epithelial hyperplasia to obstruct these stents within several years.

Endoscopic management of malignant biliary strictures: The technical success rate of endoscopic dilation and stent placement for palliation of malignant biliary strictures is greater than 90%. It is associated with fewer complications than percutaneous transhepatic biliary drainage, and clinical studies show that the results are equal to that achieved with surgical bypass. Although the patency rate of metal mesh stents exceeds plastic stents, tumor ingrowth still may obstruct the stent and require subsequent procedures. Suppurative cholangitis can develop as a serious complication of an obstructed biliary prosthesis.

A retrospective review of percutaneous interventions performed from 1980-2005 at a tertiary-level hepatobiliary center by Castaing et al suggests that in complex biliary disease, the percutaneous approach is a feasible and safe therapeutic option and should be considered by experienced hepatobiliary teams.[26] Repeated interventions, prolonged biliary drainage, and optimal antibiotic therapy are necessary for this approach to be successful.

Surgical Care


Prophylactic cholecystectomy is not recommended for people with asymptomatic gallstones. It is recommended routinely for patients with symptomatic cholelithiasis (ie, biliary-type pain, complications), porcelain gallbladder, the finding of gallstones during a planned abdominal operation in patients with hemoglobinopathy, or in a child.

Laparoscopic cholecystectomy is the current standard of care[2] ; the stone clearance rate approaches 100%, the operative mortality rate is less than 1%, the morbidity rate is 2%-5%, and the disability time is 7 days, with minimal scarring.[27, 28, 29]

Open cholecystectomy occasionally is necessary and has a stone clearance rate of 100%, a mortality rate of less than 1%, a morbidity rate of about 6%, a disability time of about 30 days, and leaves a moderate scar. Retained common bile duct stones, (ie, those stones that elude detection during open cholecystectomy) occur in 5%-10% of patients.[29]

Patients with biliary-type pain and a gallbladder ejection fraction of less than 35% may have a 70-90% chance of achieving pain relief following cholecystectomy.

Transduodenal sphincteroplasty

This is a surgical procedure used to treat recurrent biliary-type pain due to papillary stenosis. F.G. Moody, who developed and refined the procedure, emphasizes the technical details of the procedure as the key to a successful outcome.[30] In his initial experience, 58% of patients remained totally free of pain and 26% had occasional pain not requiring narcotic analgesics when observed 5-15 years after operation. His subsequent experience was less favorable, with only 43% remaining pain free and 24% experiencing poor results. Based on these poor results, the presence of chronic pancreatitis is regarded as a contraindication to the procedure; however, patients with recurrent pancreatitis may achieve a good outcome.


This procedure is indicated in a patient with a tumor partially or completely obstructing the ampulla. Depending on clinical factors and local expertise, it can be performed by endoscopic or surgical techniques. Endoscopic snare excision is appropriate for relatively small lesions without evidence of severe dysplasia or malignancy and also is an option in periampullary malignancy in patients in whom pancreaticoduodenectomy is unsuitable because of underlying comorbid or metastatic disease.


This procedure is indicated in otherwise healthy patients with a periampullary adenoma harboring severe atypia, periampullary villous adenomas larger than 3 cm, or periampullary malignancy. Appropriately selected patients have a reasonably good outcome, and even those with malignancy achieve 5-year survival rates of 25%-30%.

Liver transplantation

In patients with end-stage cholestatic liver disease, liver transplantation continues to offer hope. Initial 1- and 2-year survival rates were 71% and 57%, respectively. However, 1-, 2-, and 5-year survival rates have reached 90%, 86%, and 85%, respectively.[31] Recurrent PSC or PBC develops within 5 years in 20%-25% of patients who undergo transplantation.[19, 17, 32] All patients in one study who were found to have unexpected cholangiocarcinoma at the time of liver transplantation experienced a recurrence within 6 months, and all had a significantly worse outcome.[31] In another study, the recurrence rate of PBC was 24.5% at 3 years, 39.3% at 5 years, and 45.8% at 6 years.[33] Active inflammatory bowel disease after liver transplantation was an independent risk factor for PSC recurrence.

Long-Term Monitoring

All patients with primary sclerosing cholangitis (PSC) should undergo surveillance for malignancy. Such monitoring includes the following:

  • Colonoscopy and biopsy to rule out inflammatory bowel disease (IBD)

  • Annual or biannual colonoscopy to rule out colorectal carcinoma in patients with PSC and IBD, even after liver transplantation

  • Serum CA 19-9 levels every 6-12 months for surveillance of cholangiocarcinoma

  • Annual ultrasonography to monitor for gall bladder cancer



Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Gallstone dissolution agents

Class Summary

Ursodeoxycholic acid is a naturally occurring bile acid used successfully in the dissolution of gallstones, microlithiasis, and in primary biliary cirrhosis. Some benefit may exist in patients with Caroli disease.

Ursodiol (Actigall)

Decreases cholesterol content of bile and bile stones probably by reducing the secretion of cholesterol from the liver and the amount reabsorbed by intestines. It is also used for PBC since it displaces endogenous bile acids from the enterohepatic circulation, stabilizes hepatocellular membranes, and reduces the abnormal expression of HLA class I and II molecules on the hepatocytes.

Farnesoid X Receptor Agonist

Class Summary

The farnesoid X receptor (FXR) is a nuclear receptor expressed in the liver, intestine, kidney, and adipose tissues that regulates a wide variety of target genes critically involved in the control of bile acid synthesis and transport, lipid metabolism, and glucose homeostasis.

Obeticholic acid (Ocaliva)

Farnesoid X receptor (FXR) agonist. FXR activation suppresses de novo synthesis of bile acids in hepatocytes as well as increases the transport of bile acids out of hepatocytes, thereby reducing exposure of the hepatocytes to bile acid. It is indicated for primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA for at least 1 y or as monotherapy in adults unable to tolerate UDCA.


Class Summary

Alleviation of itching associated with excessive bile acid levels.

Cholestyramine (Questran)

Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits the enterohepatic reuptake of intestinal bile salts.

Rifampin (Rifadin)

Antimycobacterial agent noted to alleviate pruritus in 79% of patients with primary biliary cholangitis. This effect may be a result of changed metabolism of liver bile acids or by altered bacterial metabolism by intestinal bacteria.

Naloxone (Narcan)

Opioid antagonist useful in the treatment of pruritus.