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Home , Biliary disease, Biliary dyskinesia, Cholescintigraphy, Gallbladder disease

REVIEW

DAVID P. VOGT, MD CME General and Transplant Surgery, Transplant CREDIT Center, and Department of , The Cleveland Clinic

Gallbladder disease: An update on diagnosis and treatment

■ ABSTRACT OR THE MANY PATIENTS who present with F acute or persistent symptoms of gallblad- This paper reviews the clinical presentation of der disease, current diagnostic techniques and disease, acalculous , biliary , and treatments offer results equal to or better than cancer, as well as how to make best use of those of earlier methods, are less invasive, and current diagnostic and treatment methods, particularly allow patients to recover faster. ultrasonography, , laparoscopic This paper reviews the evaluation and , and endoscopic retrograde treatment of , common duct cholangiopancreatography. stones, , gallbladder polyps, and .

■ KEY POINTS ■ CHOLELITHIASIS (GALLSTONES)

Although 10% to 15% of people in the United States About 20 million people in the United States develop gallstones, fewer than half of those with gallstones (10% to 15% of the adult population) develop have symptoms, and fewer than 10% develop potentially gallstones, and the incidence increases with life-threatening complications. age.1,2 Fewer than 50% of those with gall- stones actually have symptoms, and fewer than Ultrasonography and cholescintigraphy are the most helpful 10% develop potentially life-threatening com- imaging studies for the diagnosis of gallstone disease. plications.1 Cholescintigraphy is 95% accurate in the outpatient diagnosis of acute cholecystitis. Clinical presentations of cholelithiasis . From 60% to 70% of people with symptomatic cholelithiasis experience Laparoscopic cholecystectomy has replaced open episodes of biliary colic,1 typically described as cholecystectomy as the gold standard for treating postprandial epigastric or right upper quadrant symptomatic . pain, sometimes radiating to the back or up to the right shoulder. The pain may last from sev- Endoscopic retrograde cholangiopancreatography with eral minutes to several hours. Intense pain is sphincterotomy is the standard treatment of patients with often accompanied by and vomiting. common stones (choledocholithiasis). Occasionally, a patient may insist that the pain is in the left upper quadrant. Many Gallbladder cancer is relatively uncommon but often has a patients also complain of belching, bloating, dismal prognosis. dyspepsia, and flatulence, but unless these symptoms are associated with biliary colic, they are not likely to resolve after cholecystectomy. The physical examination may reveal mild epigastric or right upper quadrant ten- derness, but most patients do not have signif- icant physical findings.

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T ABLE 1 during inspiration often causes such severe discomfort that the patient stops inspiring (a The positive Murphy sign). Local peritoneal signs for prognosis in acute and fever are common. Signs on admission Gallstone pancreatitis. In 10% to 15% of Age > 55 years patients with symptomatic gallstones, the ini- Serum glucose level > 200 mg/dL tial presentation is a complication such as gall- Serum lactate dehydrogenase level > 350 U/L stone pancreatitis or a Aspartate aminotransferase level > 250 U/L stone.3 White blood cell count > 16,000 × 109/L Ninety percent of patients with gallstone Signs 48 hours after admission pancreatitis have a “mild” episode, defined as Hematocrit increase > 10 percentage points having no more than three of the 11 Ranson Blood urea nitrogen increase > 5 mg/dL criteria (TABLE 1).4 The symptoms are similar to Serum calcium < 8 mg/dL those of a severe episode of biliary colic. The Partial pressure of arterial oxygen < 60 mm Hg epigastric or right upper quadrant pain lasts for Base deficit > 4 mEq/L several hours and may be associated with nau- Estimated fluid sequestration > 6 L sea and vomiting. Physical examination usual- Mortality increases with the number of signs present; if fewer than ly reveals epigastric fullness and tenderness, three signs are present, the mortality rate is < 5%; if three or four but no peritoneal signs. For most patients, are present, it is 15% to 20% symptoms improve significantly over 3 to 4 days with supportive alone. ADAPTED FROM RANSON JHC, RIFKIND KM, ROSES DF, FINK SD, ENG K, SPENCER FC. PROGNOS- TIC SIGNS AND THE ROLE OF OPERATIVE MANAGEMENT IN . Patients with common bile duct stones SURG GYNECOL OBSTET 1974; 139:69–81. often have jaundice and fever in addition to pain.

The pain of biliary colic is from contrac- Laboratory tests for cholelithiasis tion of the gallbladder, which cannot empty Laboratory tests should include a complete Biliary colic is because the is obstructed by a blood count, liver function tests, and serum intermittent; stone. The gallbladder is stimulated to con- amylase and lipase levels. tract primarily by , which is In chronic, episodic biliary colic, most acute released from the small bowel mucosa. The patients have normal laboratory values, partic- cholecystitis is pain resolves after the gallbladder stops con- ularly if they have no symptoms at the time of tracting or when the cystic duct becomes their office visit. However, patients with acute persistent patent again. pain at the time of evaluation may have ele- Acute cholecystitis is the initial presenta- vated levels of liver enzymes (aspartate amino- tion of symptomatic gallstones in 15% to 20% transferase, alanine aminotransferase, alkaline of patients.3 phosphatase) and bilirubin, particularly if bile Patients with acute cholecystitis experi- duct stones are present. ence severe pain that persists for several hours, In gallstone pancreatitis, patients have until they finally seek help at a local emer- elevated levels of both serum amylase and gency room. lipase, as well as abnormal liver function tests. Whereas in biliary colic the cystic duct In acute cholecystitis, leukocytosis obstruction is transient, in acute cholecystitis should be expected, and up to 15% of patients it is persistent. Persistent cystic duct obstruc- may have mild elevations of aspartate amino- tion, in combination with chemical irritants transferase, alanine aminotransferase, alkaline in the bile, results in inflammation and edema phosphatase, and bilirubin if the stone is not of the gallbladder wall. Nausea and vomiting in the common bile duct. are common. Physical examination usually reveals Imaging studies for cholelithiasis marked tenderness in the right upper quad- Ultrasonography and cholescintigraphy are rant, often associated with a definite mass or the imaging studies most helpful and most fullness. Palpation of the right upper quadrant often used in the diagnosis of gallstone disease.

978 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 12 DECEMBER 2002 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. ■ Ultrasonography aids the diagnosis of gallstones Key findings of acute cholecystitis Thickened gallbladder wall include a thickened gallbladder wall and the presence of pericholecystic fluid Stone in cystic duct

Ultrasonic image of stones in the gallbladder Multifaceted stones in the gallbladder

Common bile duct Pancreatic duct

Distal

Ampulla Ultrasonic image of stones in the common bile duct

CCF ©2002

FIGURE 1

Ultrasonography is safe, fast, and relatively Cholescintigraphy is accurate in diagnos- inexpensive and involves no radiation expo- ing acute cholecystitis in ambulatory patients sure. It is the study of choice for patients with more than 95% of the time.6,7 When com- suspected biliary colic. Positive findings include bined with cholecystokinin injection, it is stones, thickening of the gallbladder wall, peri- helpful in assessing patients with possible bil- cholecystic fluid, and a positive Murphy sign on iary dyskinesia.8 contact with the ultrasonographic probe5 (FIG- Cholescintigraphy provides the function- URE 1). The latter three findings are particularly al information that the cystic duct is obstruct- indicative of acute cholecystitis. ed, which is a necessary component in the A drawback to ultrasonography is that it pathogenesis of calculous cholecystitis. How- is only as accurate as the person who performs ever, it has a false-positive rate of 30% to 40% and interprets it. in patients who have been hospitalized for

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other medical problems for several weeks, par- These patients should undergo laparo- ticularly if they have been on parenteral nutri- scopic cholecystectomy with intraoperative tion. In these patients, ultrasonography is within a month to prevent more accurate.5 further episodes of pancreatitis. They should Computed is not as accurate not undergo preoperative ERCP, as it may as ultrasonography in detecting gallstones and exacerbate the pancreatitis.9 If bile duct is therefore not a good screening study in eval- stones are found during cholecystectomy, uating patients with probable chronic biliary endoscopic sphincterotomy should be per- disease.5 In acute cases, however, it can show formed within the next few days. thickening of the gallbladder wall or peri- cholecystic fluid associated with acute chole- Outcomes of cholecystectomy cystitis.5 Cholecystectomy remains the best therapy for symptomatic gallstone disease. It is effective ERCP when choledocholithiasis is suspected and safe, with low rates of complications Patients suspected of having choledocholithi- (14%) and mortality (0.17%), particularly if asis (a stone in the common bile duct) may performed electively in patients younger than benefit from undergoing endoscopic retro- 65 years. grade cholangiopancreatography (ERCP), The number and severity of episodes of sphincterotomy, and stone extraction before a biliary colic vary considerably from patient to laparoscopic cholecystectomy. Factors that patient; some have relatively mild episodes for predict choledocholithiasis include: years, and others have a severe solitary attack. • Abnormal liver function tests, particularly Cholecystectomy is indicated across this spec- bilirubin and alkaline phosphatase levels trum of patients. However, when to perform • Common bile duct dilation of 8 mm or the procedure is ultimately determined by the greater patient. • Common bile duct stones identified with In patients with typical biliary colic, ultrasonography.9 symptoms resolve after cholecystectomy in Gallstone Another approach is simply to proceed more than 85% of cases.1 However, patients pancreatitis with laparoscopic cholecystectomy and to per- with gallstones who have atypical pain or form cholangiography intraoperatively. If nonspecific symptoms such as belching, bloat- resolves in 3–4 cholangiography demonstrates stones, these ing, and are less likely to have res- days with can sometimes be removed laparoscopically, or olution of their symptoms after the gallbladder the surgery can be converted to open surgical is removed. Therefore, these patients should supportive care exploration of the common bile duct. have further studies, which may include an alone However, in most cases, common bile duct upper contrast study, stones are removed via endoscopic sphinctero- , and . If the additional tomy within 1 or 2 days of cholecystectomy. studies are normal, the patient can be offered a cholecystectomy with the caveat that the Laparoscopic surgery for patients symptoms may not improve. with gallstone pancreatitis Most patients (90%) with gallstone pancre- Laparoscopic cholecystectomy: atitis have a mild episode. Their pain usually Advantages and disadvantages resolves promptly and their liver enzyme lev- Laparoscopic cholecystectomy is now the gold els (aspartate aminotransferase, alanine standard in the treatment of symptomatic gall- aminotransferase, alkaline phosphatase, bladder disease. More than 500,000 of these bilirubin, serum amylase, and serum lipase) procedures are performed every year in the decline within 3 to 4 days of admission to the United States.1 hospital with supportive care alone. Laparoscopic cholecystectomy is safe, and (Supportive care consists of giving nothing by compared with open cholecystectomy, the mouth and maintaining the patient on intra- previous gold standard, it is associated with venous hydration, parenteral analgesics, and less pain, fewer complications,10,11 and faster antibiotics.) recovery. Mortality rates for laparoscopic

980 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 12 DECEMBER 2002 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. cholecystectomy are 0.06% to 0.1%, vs 0 to increasing the risk of bile duct injury. If 0.4% for open cholecystectomy.10,11 The laparoscopic cholecystectomy is performed mean length of hospital stay after laparoscop- within 3 days of symptom onset, the conver- ic cholecystectomy is 1.6 days vs 4.3 days for sion rate is 23% to 27%; if performed after 3 open cholecystectomy, and patients return to days, the rate is 47% to 59%.13–16 Patients work in half the time (15 vs 31 days).11 with gangrenous cholecystitis have a conver- From 2% to 5% of elective laparoscopic sion rate of 35% to 49%.16,17 need to be converted to an open procedure, usually owing either to tube placement inflammation that obscures the distinction A cholecystostomy tube is indicated in some between the cystic and common bile duct or patients with acute cholecystitis. Historically, to bleeding that cannot be controlled laparo- surgeons used to place a tube when they start- scopically. ed an open cholecystectomy but could not Surgical complications. Significant com- complete it, either because the patient was plications, some resulting in death, can occur critically ill and was felt to be too unstable to with laparoscopic cholecystectomy, and intra- complete the planned procedure or because operative injuries that occur during laparo- the inflammation encountered precluded a scopic cholecystectomy are more likely to safe cholecystectomy. result in death than are those that occur dur- Now, for critically ill patients in intensive ing open cholecystectomy.10 Laparoscopic care, the accepted practice is for a radiologist cholecystectomy is also associated with a high- to place a cholecystostomy tube percuta- er incidence of bile duct injury than is open neously via the liver with guid- cholecystectomy (0.6% vs 0.1%–0.25%).10 ance. The procedure can be done safely at the More than half of patients with bile duct bedside without general anesthesia. The com- injury need operative repair, and up to 25% of plication rate is low, and mortality is related the repairs may need to be revised because of primarily to comorbidities.18 stricture formation.10–12 An analysis of data from a national survey The role of laparoscopic cholecystectomy Cholecystos- of almost 80,000 laparoscopic cholecystecto- in , diabetes, pregnancy tomy tubes can my procedures performed at 4,300 hospitals Cirrhosis. Mortality rates of 10%, mainly revealed that injury to the bowel or major ves- from and sepsis,19 have been be placed sels was associated with death rates of 8% and reported in patients with severe cirrhosis percutaneously 5%, respectively.10 (Child-Pugh grade C) who undergo cholecys- The rate of complications from laparo- tectomy.19 Laparoscopic cholecystectomy can at the bedside scopic cholecystectomy decreases as the num- be performed in patients with Child grade A ber of operations the surgeon has performed or B cirrhosis,20 but even in carefully selected increases: 21% if the surgeon has performed patients the complication rate is 32%.20 fewer than 10 procedures vs 12% if the sur- Diabetes alone is not a significant factor geon has performed more than 50.10 in patients with gallstones. Diabetic patients Conversion rates in patients with acute with asymptomatic gallstones do not require cholecystitis. Although laparoscopic chole- prophylactic cholecystectomy, as was advised cystectomy is the procedure of choice in 20 to 25 years ago. patients with acute cholecystitis, rates of con- Pregnant women can safely undergo version to an open procedure range from 5% laparoscopic cholecystectomy, particularly to 40%.13–16 In most cases of conversion, during the second trimester and with the help either was performed more than 3 of the obstetric team.21 days after the onset of symptoms or the gall- bladder was gangrenous. After 3 days, the ■ ACUTE ACALCULOUS CHOLECYSTITIS edema in the gallbladder progresses to a woody induration that obscures the anatomy The incidence of acute acalculous (ie, without in the area and makes it harder to distinguish stones) cholecystitis in the general population the cystic duct from the bile duct, thus ranges from 2% to 15%. In the past, nearly all

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patients with acute acalculous cholecystitis ■ BILIARY DYSKINESIA had previously sustained trauma or burns, undergone major surgery, or developed multi- Management of biliary dyskinesia is challeng- organ system failure. More recently, the inci- ing. Patients typically have chronic symptoms dence has been increasing in ambulatory consistent with biliary colic and an abnormal patients, particularly in elderly men with ath- gallbladder ejection fraction; however, ultra- erosclerosis or immunosuppression.6,22,23 sonography, even if repeated, does not Acute acalculous cholecystitis can rapidly demonstrate stones, nor does oral cholecys- progress to gangrene and perforation, since the tography. pathophysiologic process appears to be trans- mural infarction of the gallbladder wall rather Diagnosis than inflammatory changes associated with Evaluation of a patient with possible biliary stones.6,22,23 dyskinesia should include upper endoscopy and cholecystokinin-stimulated cholescintig- raphy. Endoscopic abnormalities such as gas- Most patients with acute acalculous cholecys- tritis, ulcer, or reflux should be treated before titis have , fever, and right considering cholecystectomy. upper quadrant tenderness or signs of local peritoneal irritation. Almost all have abnor- Treatment mal liver function tests and leukocytosis. If endoscopic testing is normal and the gall- bladder ejection fraction on cholescintigraphy Diagnosis is less than 35%, the patient may benefit from Imaging studies for acute acalculous cholecys- cholecystectomy. Several studies reported that titis include cholescintigraphy, ultrasonogra- 80% to 100% of carefully selected patients had phy, and computed tomography. Of these complete resolution of, or significant improve- three, ultrasonography and computed tomog- ment in, their symptoms.8,24,25 Pathologic raphy have higher specificity in critically ill examination of the of these Most patients patients.23 Cholescintigraphy is accurate in patients demonstrated acalculous chronic with acute about 95% of ambulatory patients, but the cholecystitis in 67% to 95%.8,24,25 false-positive rate is 30% to 40% in critically However, one report24 cautioned that an acalculous ill hospital patients, particularly those who are abnormal gallbladder ejection fraction does cholecystitis on hyperalimentation.5 not always indicate , since about 20% of patients studied had symptomatic res- have abnormal Treatment olution without cholecystectomy. liver function Treatments for acute acalculous cholecystitis include percutaneous cholecystostomy, open ■ GALLBLADDER POLYPS tests and cholecystostomy, and cholecystectomy. Even leukocytosis though acute acalculous cholecystitis may Approximately 4% of the general population result from infarction of the gallbladder wall, have gallbladder polyps.26 Most of these are decompression of the gallbladder by place- cholesterol polyps.27 Others include adeno- ment of a cholecystostomy tube may be suffi- mas, hyperplastic polyps, granulation, and cient to control the inflammatory process. .28 If cholecystectomy is necessary, the degree Cholesterol polyps are almost always less of inflammation and induration usually pre- than 10 mm in diameter, and often, more than cludes the laparoscopic approach. one is found.28 Adenomas tend to be larger The mortality rate is 50% if surgery is not (mean diameter 6 mm) and solitary.28 Almost performed.23 The mortality rate associated all malignant polyps are larger than 10 mm with surgical intervention in these patients and solitary.28 From 20% to 60% of patients ranges from 6% to 9%, which is significantly with polyps also have gallstones. higher than with calculous disease.22,23 The Although some polyps cause symptoms mortality is related primarily to the patient’s consistent with biliary colic, most are asymp- overall condition. tomatic and are found during ultrasonography

982 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 12 DECEMBER 2002 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. for investigation of nonspecific upper abdom- tomography, but neither demonstrates any inal discomfort. abnormalities if the cancer is in the early Patients with symptoms or with a 10 stages. These studies also cannot distinguish a mm or greater in diameter should undergo neoplasm from an extensive inflammatory cholecystectomy. Patients without symptoms process. However, if either study does demon- who have polyps smaller than 10 mm may strate a mass, particularly if the process undergo follow-up ultrasonography in 6 invades the liver parenchyma, an image-guid- months to monitor polyp growth. Enlargement ed biopsy should be performed. of a polyp may be an indication for cholecys- tectomy.28 Treatment If cancer is confirmed, no surgical interven- ■ GALLBLADDER CANCER tion is indicated. However, patients with jaundice and a gallbladder mass with or with- Gallbladder cancer is relatively uncommon out extension into the liver are candidates for and has a dismal prognosis. It is responsible for endoscopic or percutaneous stenting. about 6,500 deaths annually in the United Surgical management of gallbladder can- States, or approximately 4% of all cancer cer, especially radical resection, remains con- deaths.29 Eighty percent to 85% of patients troversial. In most cases, a patient undergoes with gallbladder cancer have cholelithiasis. cholecystectomy for symptomatic gallstones, Older studies suggested an association and cancer is only detected at the time of between calcium in the gallbladder wall pathologic analysis. (“”) and gallbladder can- The prognosis depends on the depth of cer: from 20% to 60% of patients with porce- invasion into the gallbladder wall and region- lain gallbladder had gallbladder cancer. al lymph node involvement. Patients with However, a more recent review30 demonstrat- stage 1 disease (involvement of the mucosa or ed no cancer in 15 specimens of porcelain of the mucosa and muscular layer) have an gallbladder, which represented 0.14% of 80% 5-year survival following simple chole- 10,741 cholecystectomies performed from cystectomy.31,32 Gallbladder 1955 to 1998. The management of advanced cancer is cancer often More than 90% of gallbladder cancers are controversial (gallbladder cancer is consid- adenocarcinomas, ranging from well differen- ered advanced if there is tumor penetration carries a dismal tiated to poorly differentiated. through the gallbladder wall, invasion into prognosis Patients with early-stage gallbladder can- adjacent organs, or positive regional nodes). cer have no symptoms, although if they have Should these patients undergo reexploration cholelithiasis they may have symptoms of bil- for more radical resection, such as liver resec- iary colic. Elderly patients with persistent, tion and extensive lymphadenectomy of the progressive right upper quadrant pain are like- porta hepatis? Although some experts advo- ly to have gallbladder cancer, particularly if cate very aggressive surgery, the 5-year sur- they develop jaundice and have a palpable vival rate is only about 10% in patients with mass. stage 2 disease (penetration through the wall of the gallbladder), and 0% in patients with Diagnosis regional lymph node involvement.33 Based on Laboratory studies are normal unless the bil- these data, our policy has been not to perform iary tree is obstructed. Useful imaging studies reexploratory surgery in patients found to include ultrasonography and computed have gallbladder cancer.

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ADDRESS: David P. Vogt, MD, Department of General Surgery, A110, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected].

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