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GALLSTONES Epidemiology and Pathogenesis

• Gallstone formation increases after age 50. • overall prevalence of gallstones of 7.9% in men and 16.6% in women. • Gallstones are formed because of abnormal composition. They are divided into two major types: stones and pigment stones. • Cholesterol stones account for >90% of all gallstones in Western industrialized countries. • Pigment stones are composed primarily of bilirubinate; they contain <20% cholesterol and are classified into “black” and “brown” types, the latter forming secondary to chronic biliary infection.

Diagnosis

• Ultrasonography of the is very accurate in the identification of cholelithiasis and has replaced oral cholecystography (OCG)

• Plain abdominal film may detect gallstones containing sufficient calcium to be radiopaque (10–15% of cholesterol and ~50% of pigment stones). Plain may also be of use in the diagnosis of emphysematous , , limey bile, and gallstone .

Symptoms of Gallstone Disease

• Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the or CBD. • The most specific and characteristic symptom of gallstone disease is biliary that is a constant and often long-lasting pain . • Obstruction of the cystic duct or CBD by a stone produces increased intraluminal pressure and distention of the viscus that cannot be relieved by repetitive biliary contractions. • The resultant is characteristically a severe, steady ache or fullness in the epigastrium or right upper quadrant (RUQ) of the with frequent radiation to the interscapular area, right scapula, or shoulder. • begins quite suddenly and may persist with severe intensity for 30 min to 5 h, subsiding gradually or rapidly. • It is steady rather than intermittent, as would be suggested by the word colic, which must be regarded as a misnomer, although it is in widespread use. • An episode of biliary pain persisting beyond 5 h should raise the suspicion of acute cholecystitis . • and vomiting frequently accompany episodes of biliary pain. • An elevated level of serum and/or alkaline phosphatase suggests a common duct stone. • or chills (rigors) with biliary pain usually imply a , that is, cholecystitis, , or cholangitis. • Biliary colic may be precipitated by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a normal meal; it is frequently nocturnal, occurring within a few hours of retiring. Natural History

• Sixty to 80% of persons with asymptomatic gallstones remain asymptomatic over follow-up periods of up to 25 years. • The probability of developing symptoms within 5 years after diagnosis is 2–4% per year and decreases in the years thereafter to 1–2%. • The yearly incidence of complications is about 0.1–0.3%. Patients remaining asymptomatic for 15 years were found to be unlikely to develop symptoms during further follow-up. • most patients who did develop complications from their gallstones experienced prior warning symptoms. • Similar conclusions apply to diabetic patients with silent gallstones. • Decision analysis has suggested that (1) the cumulative risk of death due to gallstone disease while on expectant management is small, and (2) prophylactic is not warranted. • Complications requiring cholecystectomy are much more common in gallstone patients who have developed symptoms of biliary pain. • Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients >60 years at the time of initial diagnosis. • Patients with mellitus and gallstones may be somewhat more susceptible to septic complications, but the magnitude of risk of septic biliary complications in diabetic patients is incompletely defined. TREATMENT

• In asymptomatic gallstone patients, the risk of developing symptoms or complications requiring surgery is quite small. Recommendation for cholecystectomy in a patient with gallstones should probably be based on assessment of three factors:

• (1) Presence of symptoms frequent enough or severe enough to interfere with patient’s general routine • (2) Presence of a prior complication of gallstone disease (acute cholecystitis, pancreatitis, gallstone fistula) • (3) Presence of underlying condition predisposing increased risk of gallstone complications (calcified or porcelain gallbladder and/or a previous attack of acute cholecystitis regardless of current symptomatic status) Other causes of prophylactic cholecystectomy in a silent gallstone

• Patients with very large gallstones (>3 cm in diameter) • Patients harboring gallstones in a congenitally anomalous gallbladder • Although young age is a worrisome factor in asymptomatic gallstone patients, few authorities would now recommend routine cholecystectomy in all young patients with silent stones. UDCA treatment for Gallstone disease

• patients with a functioning gallbladder and radiolucent stones <10 mm in diameter, complete dissolution can be achieved in ~50% of patients within 6 months to 2 years. • For good results within a reasonable time period, this therapy should be limited to radiolucent stones <5 mm in diameter. • Dose of UDCA should be 10–15 mg/kg per day. CHOLEDOCHOLITHIASIS

• Passage of gallstones into the CBD occurs in ~10–15% of patients with cholelithiasis. • Incidence of common duct stones increases with increasing age of the patient, so that up to 25% of elderly patients may have calculi in the common duct at the time of cholecystectomy. CHOLANGITIS

• Cholangitis may be acute or chronic, and symptoms result from inflammation, which usually is caused by at least partial obstruction to flow of bile. • Bacteria are present on bile culture in ~75% of patients with acute cholangitis early in symptomatic course. • Characteristic presentation of acute cholangitis involves biliary pain, , and spiking with chills (Charcot’s triad). CHOLANGITIS

• In suppurative acute cholangitis, however, presence of pus under pressure in a completely obstructed ductal system leads to symptoms of severe toxicity—mental confusion, bacteremia, and septic shock. • Response to antibiotics alone in this setting is relatively poor, multiple hepatic abscesses are often present, and mortality rate approaches 100% unless prompt endoscopic or surgical relief of the obstruction and drainage of infected bile are carried out. • Endoscopic management of bacterial cholangitis is as effective as surgical intervention. ERCP with endoscopic sphincterotomy is safe and preferred initial procedure for both establishing a definitive diagnosis and providing effective therapy. SCLEROSING CHOLANGITIS

• Primary or idiopathic sclerosing cholangitis (PSC) is characterized by a progressive, inflammatory, sclerosing, and obliterative process affecting extrahepatic and/or intrahepatic bile ducts. • Disorder occurs up to 90% in association with inflammatory bowel disease, especially ulcerative . It may also be associated with autoimmune pancreatitis. • (p-ANCA) is positive in about 65% of patients with PSC. Over 50% of patients with PSC also have (UC); accordingly, once a diagnosis of PSC is established, colonoscopy should be performed to look for evidence of UC. Immunoglobulin G4 (IgG4)–associated cholangitis • of unknown etiology presents with biochemical and cholangiographic features indistinguishable from PSC, often associated with autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts and liver tissue. • All newly diagnosed PSC patients should have a serum IgG4 level checked. In contrast to PSC, IgG4-associated cholangitis is not associated with inflammatory bowel disease • Glucocorticoids are regarded as initial treatment of choice. Relapse is common after steroid withdrawal, especially with proximal strictures. • Long-term treatment with glucocorticoids and/or azathioprine may be needed after relapse or for inadequate response PSC

• Patients with PSC often present with of chronic or intermittent biliary obstruction: RUQ , pruritus, jaundice, or acute cholangitis. • Late in the course, complete biliary obstruction, secondary biliary , hepatic failure, or with bleeding varices may occur. • Diagnosis is usually established by finding multifocal, diffusely distributed strictures with intervening segments of normal or dilated ducts, producing a beaded appearance on cholangiography PSC

• Independent predictors of a bad prognosis were advanced age, serum bilirubin concentration, and liver histologic changes. • was found in 8% of patients. • Small duct PSC is defined by the presence of chronic and hepatic histology consistent with PSC but with normal findings on cholangiography. Small duct PSC is found in ~5% of patients with PSC and may represent an earlier stage of PSC associated with a significantly better long-term prognosis PSC - Treatment

• Cholestyramine may help control symptoms of pruritus, and antibiotics are useful when cholangitis complicates the clinical picture. • Vitamin D and calcium supplementation may help prevent the loss of bone mass frequently seen in patients with chronic cholestasis. • Glucocorticoids, methotrexate, and cyclosporine have not been shown to be efficacious in PSC. • UDCA in high dosage (28–30 mg/kg) was not effective in prolonging survival. In cases where high-grade biliary obstruction (dominant strictures) has occurred, balloon dilatation or stenting may be appropriate. Only rarely is surgical intervention indicated. Efforts at biliary- • Enteric anastomosis or placement may be complicated by recurrent cholangitis and further progression of the stenosing process. • Four variables (age, serum bilirubin level, histologic stage, and splenomegaly) predict survival in patients with PSC PRIMARY BILIARY CHOLANGITIS

• Strong female preponderance and a median age of around 50 years • Characterized by portal inflammation and necrosis of cholangiocytes in small and medium-sized bile ducts. • Anti mitochondrial antibodies (AMA) are present in about 90% of patients with PBC. PRIMARY BILIARY CHOLANGITIS

• (UDCA) has been the only approved treatment that has some degree of efficacy by slowing the rate of progression of the disease.

• Obeticholic acid was approved for use in PBC patients with an inadequate response to UDCA. PRIMARY BILIARY CHOLANGITIS

• significant degree of fatigue • Pruritus is seen in ~50% of patients at the time of diagnosis. It might be intermittent and usually is most bothersome in the evening. • In some patients, pruritus can develop toward the end of , • Pruritus that presents prior to the development of jaundice indicates severe disease and a poor prognosis PRIMARY BILIARY CHOLANGITIS

• Laboratory findings in PBC show cholestatic liver enzyme abnormalities with an elevation in γ-glutamyl transpeptidase and alkaline phosphatase (ALP) along with mild elevation in aminotransferases (ALT and AST). • Immunoglobulins, particularly IgM, are typically increased. PRIMARY BILIARY CHOLANGITIS

• AMA testing may be negative, and it should be remembered that as many as 10% of patients with PBC may be AMA-negative. • Liver biopsy is most important in this setting of AMA-negative PBC. • In patients who are AMA-negative with cholestatic liver enzymes, PSC should be ruled out by way of cholangiography. PRIMARY BILIARY CHOLANGITIS

• UDCA has been shown to improve both biochemical and histologic features of disease. • Pruritus is treated with anti-histamines, narcotic receptor antagonists (naltrexone), and rifampin. • Cholestyramine, a bile salt–sequestering agent, has been helpful in some patients but is somewhat difficult to take. • Plasmapheresis has been used rarely in patients with severe intractable pruritus. • Increased incidence of osteopenia and osteoporosis in patients with cholestatic , and bone density testing should be performed. Treatment with a bisphosphonate should be instituted when bone disease is identified