BILIARY PROBLEMS
| TREATMENT OF PATIENTS WITH SCLEROSING CHOLANGITIS —Henry A. Pitt, MD, Vice Chairman, Department
of Surgery, Indiana University School of Medicine, Indianapolis
|
| Primary sclerosing cholangitis (PSC): patients usually have diffuse intra- and extrahepatic bile duct strictures; more
likely to be men and relatively young; two thirds have inflammatory bowel disease (IBD); management includes steroids,
colchicine (for hepatic fibrosis), and immunosuppressive agents (eg, cyclosporine, methotrexate), but none delays need for
liver transplantation or prolongs life; ursodeoxycholic acid (UDCA) improves liver function tests and some symptoms; majority
of patients eventually require liver transplantation; cholangiocarcinoma major issue related to timing of transplantation and
proper management
|
Biliary Malignancy and PSC
| Johns Hopkins study: late 1990s; 139 patients with PSC; 25 developed biliary malignancies; no differences in age and
sex in those who had biliary malignancies and those who did not; patients with cholangiocarcinoma more likely to have
IBD (80% vs 60%); minority had cirrhosis at time of analysis; many had jaundice, with cholangiocarcinoma patients having
higher bilirubin levels; Mayo Clinic risk score—higher the score, more advanced the disease, and more likely patient
has cirrhosis; 2 patient groups had Mayo risk scores of 3.5 (with cirrhosis, score 5 or 6); serum CA 19-9—levels
higher in patients with biliary malignancy; mortality—majority of patients presented within 1 yr or 18 mo of diagnosis;
most of mortality occurs in first 2 yr; 40% of mortality at 10 yr due to biliary malignancy, and 60% of these patients require
transplantation; 9 of 25 biliary malignancy patients managed with resection, 8 had operative palliation, and 8 nonoperative
palliation; those resected had longer-term survival, but most eventually died; points—high serum CA 19-9
predicts cholangiocarcinoma; survival prolonged by resection or transplantaton; cholangiocarcinoma leading cause of
death in patients with PSC; early liver transplantation not likely to prevent cholangiocarcinomas, but in select subgroup,
aggressive surgical approach to hilar and extrahepatic strictures might provide treatment or prevent biliary malignancy
|
| Aggressive surgical approach to PSC: Pitt et al, 1982 (Longmire group)—small subset of patients with PSC
have dominant distal stricture, with abnormal but unstrictured proximal ducts; biliary-enteric anastomosis performed
on 17 of these patients, and 82% alive at 5 yr; Cameron et al, 1988—in patients with predominant extrahepatic biliary
strictures and dilated intrahepatic ducts, resection of extrahepatic duct bifurcation and removal of gallbladder removed
areas most likely to develop cancer; speaker’s series—of 125 patients, 50 had extrahepatic biliary resection,
54 had nonoperative biliary dilation (endoscopically in 35 and percutaneous in 19), and 21 had liver transplantation; 3
groups similar in age, sex, incidence of IBD, and previous biliary surgery; jaundice more frequent in resection and
transplant patients; Mayo risk score highest in transplant patients; mortality initially high (8%) in resection group;
morbidity and mortality—high with percutaneous management; morbidity even higher in transplant patients; morbidity
and mortality lowest with endoscopic management; overall survival best in patients managed surgically, compared
to balloon dilation; differences in transplant-free survival even greater
|
 | Results based on Mayo risk score: low-risk—those who had surgery (resection) did as well as predicted by score, while
balloon-dilated patients did worse than predicted; moderate-risk—surgery patients did better than predicted and balloon-dilated
patients did worse (transplant-free survival), due to development of cancer not detected early;
cholangiocarcinoma—none of 50 resection patients or those in percutaneous group developed cholangiocarcinoma
over 8- to 10-yr median follow-up; cholangiocarcinoma rate 10% with balloon dilation; high-risk—patients with established
cirrhosis should undergo transplantation and do better than Mayo risk score predicts
|
| Conclusions: selected noncirrhotic patients with PSC who have primary disease at bifurcation and extrahepatic ducts do
better with early surgery than early transplantation; if cirrhosis present, patient should undergo transplantation early (prevents
few cholangiocarcinomas that develop over 5 yr, does not improve 5-yr survival, and more costly)
|
| SPHINCTER OF ODDI DYSFUNCTION: NONCALCULOUS BILIARY PAIN —Walter J. Hogan, MD, Professor of
Medicine and Radiology, Medical College of Wisconsin, Milwaukee
|
| Biliary dyskinesia: definition—functional biliary disorder caused by dysmotility and/or hyperalgesia of gallbladder or
sphincter of Oddi (SO); clinical relevance—postcholecystectomy symptoms occur in 5% to 10%; patient with right
upper quadrant (RUQ) or epigastric pain and normal gallbladder on ultrasonography (US) could have irritable bowel
syndrome or SO dysfunction (SOD)
|
| Rome III criteria—episodes of pain located in epigastrium and RUQ; characteristics include 1) episodes last 30 min; 2)
symptoms recur at variable intervals (not daily); 3) episodes have occurred on >1 occasion within last 12 mo; 4) pain
builds to steady level; 5) pain moderate to severe enough to interrupt daily activities; 6) no evidence of structural abnormalities;
first suspect gallbladder; test for gallbladder ejection fraction (GBEF)
|
| Studies: Yap et al, 1991—patients stratified according to GBEF (>40% considered abnormal) and randomized into cholecystectomy
or none; used predetermined histopathologic criteria for chronic cholecystitis; in cholecystectomy group, all patients
pain-free for several years; in nonsurgical group, only 1 of 10 patients pain-free; Utsunomiya et al, 2000—18 postcholecystectomy
patients, some with pain for 19 yr; 10 postcholecystectomy control patients pain-free; if group given intravenous (IV)
morphine, migrating myoelectric contractions in GI tract caused spasm of SO, with increased pain and SO pressure in 78% of
patients and 3% of controls; if IV cerulein given, spasm aborted due to relaxation of sphincter, and pain and pressure relieved
in 13 of 14 patients and 2 of 3 controls; after endoscopic sphincterotomy (ES), all patients with pain better, and SO pressures
absent or markedly decreased
|
| SO dysfunction: modified Milwaukee classification, type 1—biliary pain, normal liver function tests (LFTs), dilated
common bile duct, and probable structural etiology; type 2—pain and 1 or 2 of above; type 3—pain only; basal SO
pressure—amount above ductal pressure minus duodenal pressure; ablated during sphincterotomy; parameters in SO
manometry—basal pressure, amplitude of contraction, sequence of contraction (antegrade, simultaneous, or retrograde),
whether chole-cystokinin (CCK) inhibits or causes contraction; stenosis—basal pressure abnormally high (>40 mm Hg);
dyskinesia—possible abnormal pressure, increased frequency of contractions, intermittent increase in basal pressure,
retrograde contractions, parodoxic response to CCK
|
| Markers for SOD: none; concept based on experience, eg, paradoxic response to CCK, pancreatic duct (PD) stenting,
botulinum toxin type A (Botox) injection; speaker’s study— 5 of 38 patients given CCK during manometry had abnormal
contractions of SOD; if CCK given to normal individual, lower esophageal sphincter (LES) relaxes; if given to patient
with achalasia, LES contracts; electroacupuncture and SO—acupoint GB34 (supposedly connects to biliary tract)
stimulated in 11 patients; all SO manometry parameters decreased, and CCK plasma levels increased; when stimulation
stopped, everything reversed (due to inhibition or neurohormonal activity?); Botox injection—22 patients with type III
SOD; 11 of 12 responded to Botox up to 6 mo, and all improved after ES; 8 of 10 had no response to Botox and had no
improvement after ES; Botox response had 100% positive and 85% negative predictive value
|
| Diagnosis: quantitative hepatobiliary scan (QHBS; some with morphine augmentation); fatty-meal US; CCK-stimulated
magnetic resonance cholangiopancreatography (MRCP); imaging combinations; QHBS—look for duodenal appearance
time and hilum to duodenum transit time; study—20 asymptomatic postcholecystectomy patients; QHBS had specificity
of ≈60% when true negative defined as 2 negative examinations; poor reliability for screening in suspected dyskinesia; SO
manometry compared to QHBS or fatty-meal US—accuracy not enhanced; abnormal manometry sometimes validated
reason for performing sphincterotomy; not effective in singling out which patients would respond to treatment; CCK scintigraphy
vs SO manometry—biliary scan ≈25% sensitive and 86% specific; speaker’s recommendations—good history;
careful clinical monitoring; perform GBEF, and if abnormal and indications present, perform surgery; if not
abnormal, consider SO manometry; if manometry elevated, may perform sphincterotomy, but chances of patient getting
better 30% to 50%; if not elevated, look elsewhere; in long term, sleeve catheter (back-perfused; can monitor SO) may be
used
|
| MANAGEMENT OF HEPATOBILIARY TUMORS —Thomas N. Wang, MD, PhD, Associate Professor of Surgery,
Medical College of Georgia, Augusta
|
Gallbladder Cancer
| Epidemiology: more common in women; etiology unknown; risk factors—cholelithiasis; adenomatous gallbladder polyps;
choledochal cysts; anomalous pancreaticobiliary duct junction; chemical carcinogens (eg, azotoluene); chronic Salmonella
typhi infection; obesity; estrogen; most have presentation similar to benign stone disease (symptomatic
cholelithiasis), including RUQ pain, anorexia, and nausea; when patients present with advanced disease (eg, fatigue,
weight loss, jaundice, RUQ fixed mass, duodenal obstruction), usually too late
|
| Diagnosis: imaging studies; laboratory studies not helpful; tumor markers (CA 19-9 and CEA) nonspecific; if suspicion
high based on history and imaging, plus elevated CA 19-9, make diagnosis; abdominal US helpful but nonspecific and
difficult to read; computed tomography (CT) gold standard, allowing look at primary disease and assessment for metastatic
disease within liver and lymph nodes; magnetic resonance imaging (MRI) and MRCP helpful, especially in planning
surgery or if diagnosis suspicious; CT used first; endoscopic US completes metastatic work-up and allows
performance of US-guided biopsy; positron emission tomography (PET)—presently not used in work-up; used more
as follow-up after resection, to look for metastatic disease; technology evolving; in more advanced gallbladder cancer,
presence of metastatic disease as high as 50%
|
| Staging system: 6th edition from American Joint Committee on Cancer (AJCC); stage 0— carcinoma in situ; stage
Ia—T1 lesion; stage Ib—T2 lesion (has invaded through perimuscular connective tissue); T3 lesion perforated into adjacent
organs; T2 and T3 originally part of stage III, but now moved into stages Ib and IIa; stage II—separated into a and
b, with end disease present only in stage IIb; stage III—includes only T4 lesions (invasion into main portal vein, common
hepatic artery, or multiple extrahepatic organs); stage IV—metastatic disease; general—only stages III and IV
considered highly unresectable; all stages moved down to lesser stage because of better prognosis gained with better resection
|
| Treatment: stages 0 and Ia—simple cholecystectomy if margins negative; if duct margin positive, common bile duct excision
with hepaticojejunostomy (good 5-yr survival); stage Ib—T2 lesion invading into dissection plane; simple cholecystectomy
that leaves behind cystic plate leaves cancer, with 15% to 50% rate of lymph node spread; first do staging
work-up with imaging study; diagnostic laparoscopy paramount because of high incidence of metastatic disease; CT and
MRI can show evidence of liver and other hematogenous metastases (eg, to lungs), but cannot pick up small peritoneal disease;
treatment radical cholecystectomy and regional lymphadenectomy; 5-yr survival 80% to 90% if algorithm followed
|
| Radical cholecystectomy: performed if cancer invades liver; removal of Couinaud segments V and IVb and extensive
lymph node dissection (all lymph nodes from hilum to superior edge of pancreas, medially as far as celiac axis and laterally
to gallbladder; dissection of all lymph node-bearing soft tissue on right side of left hepatic artery, cleaning out portal
vein and bile duct, then removal en bloc with gallbladder and segments IV and V)
|
| Stage II, T3 disease: in stage IIb, lymph nodes involved; preoperative imaging important to determine whether metastatic
disease present; diagnostic laparoscopy important; perform right hepatectomy or extended right hepatectomy, ie,
cannot perform radical resection only; 5-yr survival 25% to 50%; terminology for liver resection—“right or left lobectomy”
now termed “left or right hepatectomy”; extended right resection now called “right sectionectomy”; in advanced
disease, right portal triad often involved; therefore, right hepatectomy most likely procedure necessary; if disease
progresses to left side, perform extended right hepatectomy or right sectionectomy
|
| Stages III and IV: unresectable disease with invasion of portal vein, common hepatic artery, and multiple organs (distant
metastases); in some institutions where study protocols and trials ongoing, right hepatectomy, radical cholecystectomy,
and pancreaticoduodenectomy performed
|
| Algorithm for treating suspected gallbladder cancer in patients undergoing laparoscopic cholecystectomy:
if evidence of gross gallbladder disease at time of surgery, convert to open procedure; if locally advanced disease
demonstrated, chemotherapy, chemoradiation, and palliation; if T2 or T3 disease present with no distant metastases,
can proceed to radical resection, radical cholecystectomy, and lymphadenectomy; if gross disease not seen at time of surgery,
must send gallbladder for frozen sections; if evidence of T2 or T3 disease present, radical cholecystectomy; if evidence
of tumor in situ or T1 disease, only simple cholecystectomy needed; if ambiguous, wait for final pathology; if
pathology positive for gallbladder cancer, patient needs radical cholecystectomy; if T2 lesion not involved, nothing more
needed; if disease advanced, chemotherapy or chemoradiation and palliation
|
Cholangiocarcinoma
| Epidemiology: etiology unknown; associated risk factors include bacterial or parasitic infection, anatomic anomalies, irradiation,
and PSC; intrahepatic—most rare; occurs above bifurcation, usually above second radicals of liver bile ducts;
perihilar—most common; extends from hilum from division of hepatic ducts (right and left) to cystic duct; distal—
treated with pancreaticoduodenectomy
|
| Presentation: usually painless jaundice; intrahepatic type not associated with jaundice; weight loss, fatigue, and abdominal
pain, usually indicative of advanced disease; some have elevations in bilirubin, alkaline phosphatase, and γ-glutamyl
transpeptidase (GGT), especially in hilar disease, due to obstruction of bile ducts; demonstrated occasionally by abdominal
US; CT gold standard; MRI and MRCP utilized for planning and diagnosis; preoperative pathologic diagnosis—
not always necessary if high suspicion for malignant biliary tumor present; required only if patient inoperable with several
comorbid problems or if cancer unresectable and pathology needed for medical oncologist
|
| Intrahepatic cholangiocarcinoma: important to ensure lesion not metastatic; 3 subtypes; periductal infiltrating—
has worst prognosis because it invades around ducts into surrounding blood vessels, making it unresectable, or has
higher propensity for developing metastatic disease throughout liver; mass-forming—better prognosis but also higher
incidence of lymph node disease; intraductal growth type—grows through bile ducts and extends for several millimeters
or centimeters
|
| Hilar cholangiocarcinoma: criteria for resectability include, patient factors (those medically unfit for resection and
those with cirrhosis or portal hypertension should not be resected); local factors, eg, whether hepatic duct involved to
second radicals; unresectable if involved bilaterally, encasement or occlusion of main portal vein makes it unresectable;
atrophy—indicates unresectability; signifies obstruction of portal vein or biliary ducts; unresectability also defined as
distant disease; liver resection for cholangiocarcinoma important because majority of patients have liver involvement;
necessary to reach negative margins (only 5-yr survivors); positive margin occurs because liver resection not done; gallbladder
cancer and cholangiocarcinoma surgical diseases; if not resected, 5-yr survival 0%
|
Suggested Readings
Alazmi WM et al: Chemotherapy-induced sclerosing cholangitis: long-term response to endoscopic therapy. J Clin Gastroenterol
40:353, 2006; Bistritz L et al: Sphincter of Oddi dysfunction: managing the patient with chronic biliary pain.
World J Gastroenterol 12:3793, 2006; Cameron JL et al: Resection of hepatic duct bifurcation and transhepatic stenting
for sclerosing cholangitis. Ann Surg 207:614, 1988; Elsayes KM et al: MR and MRCP in the evaluation of primary sclerosing
cholangitis: current applications and imaging findings. J Comput Assist Tomogr 30:398, 2006; Freeman ML et
al: Predictors of outcomes after biliary and pancreatic sphincterotomy for sphincter of oddi dysfunction. J Clin Gastroenterol
41:94, 2007; Gordon F: Recurrent primary sclerosing cholangitis: Clinical diagnosis and long-term management issues.
Liver Transpl 12:S73, 2006; Hemming AQ et al: Surgical management of hilar cholangiocarcinoma. Ann Surg
241:693, 2005; LaRusso NF et al: Primary sclerosing cholangitis: summary of a workshop. Hepatology 44:746, 2006;
Martins EB et al: Sclerosing cholangitis. Curr Opin Gastroenterol 17:458, 2001; Peter SA et al: CCK1 antagonists:
are they ready for clinical use? Dig Dis 24:70, 2006; Pitt et al: Primary sclerosing cholangitis: results of an aggressive surgical
approach. Ann Surg 196:259, 1982; Rubens DJ: Hepatobiliary imaging and its pitfalls. Radiol Clin North Am 42:257,
2004; Sgouros SN et al: Systematic review: sphincter of Oddi dysfunction--non-invasive diagnostic methods and long-
term outcome after endoscopic sphincterotomy. Aliment Pharmacol Ther 24:237, 2006; Siegel JH et al: Pull or push pancreatic
sphincterotomy for sphincter of Oddi dysfunction? A conundrum for experts only. Gastrointest Endosc 64:723, 2006;
Utsunomiya N et al: Pain associated with phase III of the duodenal migrating motor comples in patients with postcholecystectomy
biliary dyskinesia. Gastrointest Endosc 51:528, 2000; Vauthey JN et al: is extended hepatectomy for hepatobiliary
malignancy justified: Ann Surg 239:722, 2004; Vittal H et al: Botulinum toxin for gastrointestinal disorders: therapy
and mechanisms. Neurotox Res 9:149, 2006; Yap L et al: Acalculous biliary pain: cholecystectomy alleviates symptoms in
patients with abnormal cholescintigraphy. Gastroenterology 101:786, 1991.
Educational Objectives
| The goal of this program is to improve treatment outcomes of patients with sclerosing cholangitis and sphincter of
Oddi (SO) dysfunction and improve management of hepatobiliary tumors. After hearing and assimilating this program,
the clinician will be better able to:
|
| 1. Review the association between primary sclerosing cholangitis and biliary malignancies.
|
| 2. Treat biliary dyskinesia and SO dysfunction.
|
| 3. Describe the diagnostic tests for SO dysfunction.
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| 4. Summarize the staging system and algorithm for the treatment of gallbladder cancer.
|
| 5. Differentiate the 3 types of cholangiocarcinoma.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this issue, the faculty reported nothing to disclose.
Acknowledgements
Drs. Pitt and Hogan were recorded at Advances in Hepatic, Biliary and Pancreatic Surgery, held June 14-17, 2006, in
Minneapolis, MN, and sponsored by the Department of Surgery, Continuing Medical Education of the University of Minnesota
Medical School. Dr. Wang was recorded at Medical and Surgical Approaches to GI Disorders, held July 10-14,
2006, in Kiawah Island, SC, and sponsored by the Medical College of Georgia, Division of Continuing Education and
School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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