A diverse spectrum of disease affects the biliary system, often presenting with similar clinical signs and symptoms. See the images below.
A normal postcholecystectomy cholangiogram.
Biliary disease. In this patient with persistent elevation of liver-associated enzymes, the contrast entering the biliary ductal system preferentially....
Biliary disease. Even when the catheter is advanced to the proximal common hepatic duct, contrast dye preferentially fills the cystic duct and gallbla....
Biliary disease. In this image, the common bile duct is occluded with a balloon-tipped catheter. Contrast fills the intrahepatic ductal system to reve....
Bile is produced by the liver and 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 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 gallbladder bile, biologic molecules influence the process in a positive or negative fashion.
For example, mucus may function to promote nucleation, while 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.
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 had 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.
The incidence of primary biliary cirrhosis (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.
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.
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 smooth muscle and impairing gallbladder emptying.
Increased age is associated with lithogenic bile and an increased rate of gallstones.
Biliary disease presents with some diversity, from no symptoms to a constellation of signs and symptoms of varying severity and combination. 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.
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.
Hepatobiliary histology has emerged as an objective reference for staging PBC and PSC. In both, 4 stages are identified.
Medical management of gallstone disease has decreased in recent years 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 to 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 initial presentation.
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 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 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.
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 of PSC. 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 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 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.
The management of this disorder has 2 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. The only approved treatment is UDCA, which is the only treatment (aimed at modifying the natural history of the disease) recommended in the guidelines issued by the American Association for the Study of Liver Diseases (AASLD). UDCA alone (13-15 mg/kg/d is given in divided doses with meals and at bedtime) in asymptomatic patients with stages I-III disease. 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.
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 histological 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 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.
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.
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 an ERCP with biliary sphincterotomy and stone extraction using a balloon-tipped catheter or wire basket. 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 shincterotomy. Patients were divided into 4 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 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%). 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. The investigators concluded endoscopic sphincterotomy is a safe and effective procedure that should be used in patients with a calculous gallbladder.
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.
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 bilirubin 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. Repeated interventions, prolonged biliary drainage, and optimal antibiotic therapy are necessary for this approach to be successful.
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.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Decreases cholesterol content of bile and bile stones probably by reducing secretion of cholesterol from the liver and the amount reabsorbed by intestines.
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.
Clinical Context: Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits enterohepatic reuptake of intestinal bile salts.
Clinical Context: Antimycobacterial agent noted to alleviate pruritus in 79% of patients with primary biliary cirrhosis. Effect may be a result of changed metabolism of liver bile acids or by altered bacterial metabolism by intestinal bacteria.
Clinical Context: Opioid antagonist useful in treatment of pruritus.
Alleviation of itching associated with excessive bile acid levels.
This 92-year-old woman had recurrent abdominal pain and jaundice. A right upper quadrant ultrasound showed a dilated biliary duct with no stones. She had a previous Roux-en-Y surgery that made endoscopic retrograde cholangiopancreatography (ERCP) impossible. Critical aortic stenosis that increased the risk of most interventions. This percutaneous cholangiogram, performed under conscious sedation in the operating room, revealed a large stone missed by the ultrasound. It was removed successfully with percutaneous choledochoscopy and electrohydraulic lithotripsy.
Biliary disease. This patient had malignant strictures of the biliary system that were palliated with metal mesh stents. Unfortunately, the tumor has grown through the metal mesh to reobstruct the biliary system. After a wire is passed through the lumen, a balloon-dilating catheter is passed into the metal mesh stents and inflated to enlarge the lumen.
Biliary disease. This patient had malignant strictures of the biliary system that were palliated with metal mesh stents. The tumor has grown through the metal mesh to reobstruct the biliary system. After a wire was passed through the lumen, a balloon-dilating catheter was passed into the metal mesh stents and inflated to enlarge the lumen. In this image, 2 plastic stents were passed into the intrahepatic ductal system to again palliate the obstruction.