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 the 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.
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 cholangitis
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. UDCA is the only treatment (aimed at modifying the natural history of the disease) currently 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 May 2016, the FDA approved obeticholic acid in combination with UDCA for primary biliary cholangitis (PBC) in adult patients with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.  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). 
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.
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 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.
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. [17, 18, 19]
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.
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.  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%.
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.
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