Pathophysiology: 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.
Frequency:
- In the US: 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.
- Internationally: 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.
Mortality/Morbidity:
- Gallstones are a rare cause of mortality, accounting for 5000 of the 2.2 million deaths annually in the United States.
- 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 included age and alkaline phosphatase, serum albumin, and bilirubin levels. Liver failure developed 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, histological stage, hepatomegaly, splenomegaly, and serum alkaline phosphatase and serum bilirubin levels.
Race: 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 GI 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: 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.
- PSC: Males are affected twice as frequently as females.
- PBC: Females are affected 9 times as often as males.
Age: Increased age is associated with lithogenic bile and an increased rate of gallstones.
- 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.
Medical Care:
b>Gallstones
edical 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.
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 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.
Cholangitis
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 often is 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
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.
Primary biliary cirrhosis
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.
ata 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.
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.
Steatorrhea
Patients with steatorrhea may benefit from pancreas enzyme supplements and fat-soluble vitamins A, D, E, and K.
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 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%. 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.
Surgical Care:
- Cholecystectomy: 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; 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.
- 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.
- 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 (1991), who developed and refined the procedure, emphasizes the technical details of the procedure as the key to a successful outcome. 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.
- Ampullectomy: 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.
- Pancreaticoduodenectomy: 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. Recently, 1-, 2-, and 5-year survival rates have reached 90%, 86%, and 85%, respectively. Recurrent PSC developed in 20% of patients. In those patients found to have unexpected cholangiocarcinoma at the time of liver transplantation, all experienced a recurrence within 6 months and had a significantly worse outcome. In a recent study, the recurrence rate of PBC was 18% at 5 years and 30% at 10 years.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Gallstone dissolution agents -- 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.
| Drug Name | Ursodiol (Actigall) -- Decreases cholesterol content of bile and bile stones probably by reducing secretion of cholesterol from the liver and the amount reabsorbed by intestines. |
|---|---|
| Adult Dose | Gallstone dissolution: 8-10 mg/kg/d PO divided tid Primary biliary cirrhosis: 10-15 mg/kg/d PO divided tid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; calcified cholesterol stones; radiopaque stones; bile pigment stones |
| Interactions | Decreased effect with aluminum-containing antacids, cholestyramine, colestipol, clofibrate, and oral contraceptives |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in patients with a nonvisualizing gallbladder |
| Drug Name | Cholestyramine (Questran) -- Forms a nonabsorbable complex with bile acids in the intestine, which in turn inhibits enterohepatic reuptake of intestinal bile salts. |
|---|---|
| Adult Dose | 4 g 2-6 times/d mixed in 4 oz water or juice; not to exceed 24 g/d |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; complete biliary obstruction; hyperlipidemia types III, IV, or V |
| Interactions | Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, phenobarbital, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, cephalexin, and metronidazole; thiazide diuretics; valproic acid; troglitazone; coadministration with pravastatin increases effects |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Documented hypersensitivity; caution in constipation and phenylketonuria; chronic use may lead to insufficiency of fat-soluble vitamins and contribute to bleeding. |
| Drug Name | Rifampin (Rifadin) -- 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. |
|---|---|
| Adult Dose | 300 mg PO bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in liver impairment and adrenal insufficiency; perform LFTs before and during treatment, may increase alkaline phosphatase levels |
| Drug Name | Naloxone (Narcan) -- Opioid antagonist useful in treatment of pruritus. |
|---|---|
| Adult Dose | 0.4 mg IV bolus initial, followed by continuous infusion of 0.2 mg/kg/min |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Decreases analgesic effects of narcotics; increases effects of clonidine |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in cardiovascular disease; may precipitate withdrawal symptoms in patients addicted to opiates |
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