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  • 1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 1 3 JAUNDICE Jeffrey S. Barkun, M.D., F.A.C.S., Prosanto Chaudhury, M.D., and Alan N. Barkun, M.D. Approach to the Jaundiced Patient The term jaundice refers to the yellowish discoloration of skin, which are also known, respectively, as direct and indirect fractions sclerae, and mucous membranes that results from excessive depo- on the basis of their behavior in the van den Bergh (diazo) reac- sition of bilirubin in tissues. It usually is unmistakable but on occa- tion.3 If the patient has normal-colored urine and stools, unconju- sion may manifest itself subtly. It is generally held that jaundice gated bilirubin [see Sidebar Unconjugated (Indirect) Bilirubin] is develops when serum bilirubin levels rise above 34.2 μmol/L (2 predominant [see Table 1]. If the patient has dark urine, pale stools, mg/dl)1; however, the appearance of jaundice also depends on or any other signs or symptoms of a cholestatic syndrome (see whether it is conjugated or unconjugated bilirubin that is elevated below), the serum bilirubin fractionation usually indicates that and on how long the episode of jaundice lasts. conjugated bilirubin is predominant. Rarely, the clinical picture In what follows, we outline a problem-based approach to the may be secondary to a massive increase in both direct and indirect jaundiced patient that involves assessing the incremental informa- bilirubin production after the latter has overcome the ability of the tion provided by successive clinical and laboratory investigations, hepatocytes to secrete conjugated bilirubin. as well as the information obtained by means of modern imaging It is nearly always possible to distinguish between direct and modalities.We also propose a classification of jaundice that stress- indirect hyperbilirubinemia on clinical grounds alone.4 Our es the therapeutic options most pertinent to surgeons.We have not emphasis here is on direct hyperbilirubinemia, which is the type attempted a detailed review of bilirubin metabolism and the vari- that is more relevant to general surgeons. ous pediatric disorders that cause jaundice; such issues are beyond the scope of this chapter. Finally, we emphasize that modern deci- Cholestatic Syndrome sion making in the approach to the jaundiced patient includes not The term cholestasis refers to decreased delivery of bilirubin only careful evaluation of anatomic issues but also close attention into the intestine (and subsequent accumulation in the hepato- to patient morbidity and quality-of-life concerns, as well as a focus on working up the patient in a cost-effective fashion. For optimal treatment, in our view, an integrated approach that involves the surgeon, the gastroenterologist, and the radiologist is essential. Unconjugated (Indirect) Bilirubin The breakdown of heme leads to the production of unconjugated Clinical Evaluation and bilirubin, which is water insoluble, is tightly bound to albumin, and Investigative Studies does not pass into the urine. Excessive production of unconjugated bilirubin typically follows an episode of hemolysis. In the absence of concomitant liver disease or biliary obstruction, the liver can usually HISTORY AND PHYSICAL EXAMI- handle the extra bilirubin, and only a modest rise in serum levels is NATION observed. There is a substantial increase in bile pigment excretion, When a patient presents with a leading to large quantities of stercobilinogen in the stool. A patient skin discoloration suggestive of with hemolysis may therefore be slightly jaundiced with normal-col- ored urine and stools. Blood tests reveal that 60% to 85% of bili- jaundice, the first step is to con- rubin is indirect.124 firm that icterus is indeed present. To this end, the mucous mem- Possible causes of indirect hyperbilirubinemia include a variety of branes of the mouth, the palms, the soles, and the sclerae should be disorders that result in significant hemolysis or ineffective erythro- examined in natural light. Because such areas are protected from poiesis. The diagnosis of indirect hyperbilirubinemia attributable to the sun, photodegradation of bile is minimized; thus, the yellowish hemolysis is confirmed by an elevated serum lactate dehydrogenase discoloration of elastic tissues may be more easily detected. (LDH) level, a decreased serum haptoglobin level, and evidence of hemolysis on microscopic examination of the blood smear. Occasionally, deposition of a yellowish pigment on skin may mimic Disorders associated with defects in hepatic bilirubin uptake or jaundice but may in fact be related to the consumption of large conjugation can also produce unconjugated hyperbilirubinemia. The quantities of food containing lycopene or carotene or drugs such as most common of these, Gilbert syndrome, is a benign condition rifampin or quinacrine. In these cases, the skin is usually the only affecting up to 7% of the general population.125,126 It is not a single site of coloration, and careful inspection of sclerae and mucous disease but a heterogeneous group of disorders, all of which are membranes generally reveals no icteric pigmentation. In certain characterized by a homozygosity for a defect in the promoter controlling the transcription of the UDP glucuronyl transferase I cultures, long-term application of tea bags to the eyes may lead to gene.127 The consequent impairment of bilirubin glucuronidation a brownish discoloration of the sclerae that can mimic jaundice.2 presents as a mild unconjugated hyperbilirubinemia. The elevated bilirubin level is usually detected on routine blood testing, and affected DIRECT VERSUS INDIRECT HYPERBILIRUBINEMIA patients may report that their skin turns yellow when they are Once the presence of jaundice has been confirmed, further clin- fatigued or at stressful times (e.g., after missing meals, after vomiting, ical assessment determines whether the hyperbilirubinemia is pre- or in the presence of an infection). Other causes of an unconju- dominantly direct or indirect.This distinction is based on the divi- gated hyperbilirubinemia are beyond the scope of this chapter. sion of bilirubin into conjugated and unconjugated fractions,
  • 2. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 2 Approach to the Jaundiced Patient Patient has presumed posthepatic jaundice Patient has confirmed hepatic jaundice Obtain ultrasonogram to confirm posthepatic jaundice [See Sidebar Hepatic Jaundice.] and identify level of biliary obstruction. In some unusual clinical situations, ultrasonography may not detect the posthepatic cause of jaundice, and MRCP, ERCP, PTC, repeat ultrasonography, or EUS may be necessary. If all these situations are ruled out, seek a hepatic cause and consider liver biopsy. Patient has confirmed posthepatic jaundice Proceed according to clinical scenario present. Suspected cholangitis Suspected choledocholithiasis Choledocholithiasis is the most likely diagnosis. Perform preoperative MRCP or ERCP and laparoscopic Resuscitate, correct any coagulopathy, and give cholecystectomy. appropriate antibiotics. Alternatively, perform laparoscopic cholecystectomy Perform ERCP for definitive diagnosis and with intraoperative cholangiography. treatment. If ERCP cannot be done, consider transhepatic drainage or surgery.
  • 3. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 3 Patient presents with Perform clinical assessment skin discoloration suggestive of jaundice Perform physical exam and obtain history. Patient has indirect hyperbilirubinemia Confirm icterus by examining oral mucous membranes, palms, soles, [See Sidebar Unconjugated (Indirect) and sclerae in natural light. Bilirubin.] Distinguish indirect (unconjugated) from direct (conjugated) hyperbilirubinemia: • Normal-colored urine and stools suggest indirect hyperbilirubinemia Patient has direct hyperbilirubinemia • Dark urine, pale stools, and signs or symptoms of a cholestatic syndrome Distinguish hepatic (“medical”) jaundice from suggest direct hyperbilirubinemia posthepatic (“surgical”) jaundice. • Acute hepatitis, alcohol abuse, and physical Measure total serum bilirubin and • evidence of cirrhosis or portal hypertension percentage of conjugated bilirubin. • suggest hepatic jaundice • Abdominal pain, rigors, itching, and a • palpable liver > 2 cm below costal margin • suggest posthepatic jaundice Patient has presumed hepatic jaundice [See Sidebar Hepatic Jaundice.] Lesion appears unresectable, and surgical Suspected lesion other than choledocholithiasis palliation is not indicated The most common single cause is pancreatic cancer; Treat with ERCP or PTC and drainage. For many of the other possible causes also involve malignancy. advanced malignant disease, supportive care Perform spiral CT or MRI with MRCP to diagnose lesion alone may be indicated. and assess resectability. Consider EUS with biopsy for distal-third obstruction. Perform Doppler ultrasonography to stage lesion further; Lesion appears resectable, or surgical CT angiography or MRA may be considered if ultrasonogram palliation is indicated is abnormal. Perform MRCP to assess intrahepatic biliary system in Treat with surgical bypass or resection as patients with middle-third or upper-third obstruction. appropriate for level of obstruction. Perform laparoscopy to confirm resectability before laparotomy. Middle-third obstruction Lower-third obstruction Upper-third obstruction Palliation: bypass with left (segment III) Palliation: bypass with hepaticojejunostomy. Palliation: bypass with Roux-en-Y hepaticojejunostomy. Resection for cure: resection of tumor and choledochojejunostomy. Resection for cure: resection of tumor, reconstruction with hepaticojejunostomy. Resection for cure: resection of tumor possibly with hepatectomy or with pancreaticoduodenectomy or segmentectomy, and reconstruction local ampullary excision. with hepaticojejunostomy or cholangiojejunostomy.
  • 4. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 4 This model, however, despite its 96% sensitivity (greater than that of any single radiologic diagnostic modality), could not accurately Table 1 Causes of Unconjugated predict the level of a biliary obstruction. Other investigators have Hyperbilirubinemia reported similar findings,8,12,13 and most agree that strategies that omit ultrasonography are clearly inferior.17 Increased RBC breakdown In summary, a clinical approach supported by simple biochem- Acute hemolysis ical evaluation displays good predictive ability to distinguish hepat- Chronic hemolytic disorders ic from posthepatic jaundice; however, a clinical approach alone Large hematoma resorption, multiple blood transfusions does not accurately identify the level of biliary obstruction in a Gilbert syndrome patient with posthepatic jaundice. Decreased hepatic bilirubin conjugation The remainder of this chapter focuses primarily on manage- Gilbert syndrome ment of posthepatic jaundice; hepatic jaundice is less often seen Crigler-Najjar syndrome types I and II and dealt with by general surgeons [see Table 2 and Sidebar Hepatic Familial unconjugated hyperbilirubinemia Jaundice]. IMAGING Once the history has been cytes and in blood), irrespective of the underlying cause. When obtained and bedside and labora- cholestasis is mild, it may not be associated with clinical jaundice. tory assessments have been com- As it worsens, a conjugated hyperbilirubinemia develops that pre- pleted, the next step is imaging, sents as jaundice. The conjugated hyperbilirubinemia may derive the goals of which are (1) to con- either from a defect in hepatocellular function (hepatic jaundice, firm the presence of an extrahep- also referred to as nonobstructive or medical jaundice) or from a atic obstruction (i.e., to verify that blockage somewhere in the biliary tree (posthepatic jaundice, also the jaundice is indeed posthepatic rather than hepatic), (2) to referred to as obstructive or surgical jaundice). In this chapter, we determine the level of the obstruction, (3) to identify the specific refer to hepatic and posthepatic causes of jaundice, reserving the cause of the obstruction, and (4) to provide complementary infor- term cholestasis for the specific clinical syndrome that is attribut- mation relating to the underlying diagnosis (e.g., staging informa- able to a chronic lack of delivery of bile into the intestine.This syn- tion in cases of malignancy). drome is characterized by signs and symptoms that are related Of the many imaging methods available today, the gold stan- either to the conjugated hyperbilirubinemia or to chronic malab- dard for defining the level of a biliary obstruction before operation sorption of fat-soluble vitamins (i.e., vitamins A, D, E, and K): in a jaundiced patient remains direct cholangiography, which can jaundice, dark urine, pale stools, pruritus, bruising, steatorrhea, be performed either via endoscopic retrograde cholangiopancre- night blindness, osteomalacia, and neuromuscular weakness.5 atography (ERCP) [see 5:18 Gastrointestinal Endoscopy] or via per- HEPATIC VERSUS POSTHEPATIC cutaneous transhepatic cholangiography (PTC). Unlike other JAUNDICE imaging modalities, direct cholangiography poses significant risks to the patient: there is a 4% to 7% incidence of pancreatitis or Once the presence of direct cholangitis after ERCP,18,19 and there is a 4% incidence of bile hyperbilirubinemia is confirmed, leakage, cholangitis, or bleeding after PTC.20 There are also sever- the next step is to determine al risks that are particular to the manipulation of an obstructed bil- whether the jaundice is hepatic or iary system (see below). For these reasons, the role of ERCP and posthepatic. A number of authors PTC is increasingly a therapeutic one: therefore, it is important to have studied the reliability of clin- ical assessment for making this determination.6-17 The sensitivities of history, physical examination, and blood tests alone range from 70% to 95%,6-11 whereas the specificities are approximately 75%.10,11 The overall accuracy of clinical assessment of hepatic Table 2 Causes of Hepatic Jaundice133 and posthepatic causes of jaundice ranges from 87% to 97%.8,12 Clinically, hepatic jaundice is most often signaled by acute hepati- Hepatitis tis, a history of alcohol abuse, or physical findings reflecting cir- Viral rhosis or portal hypertension13; posthepatic jaundice is most often Autoimmune signaled by abdominal pain, rigors, itching, or a palpable liver Alcoholic more than 2 cm below the costal margin.14 Drugs and hormones By using discriminant analysis in a pediatric patient population, Diseases of intrahepatic bile ducts two investigators were able to isolate three biochemical tests that Liver infiltration and storage disorders differentiated between biliary atresia and intrahepatic cholestasis Systemic infections with an accuracy of 95%: total serum bilirubin concentration, alka- Total parenteral nutrition line phosphatase level, and γ-glutamyltranspeptidase level.15 Serum Postoperative intrahepatic cholestasis transaminase levels added no independent information of signifi- Cholestasis of pregnancy cance to the model. Another multivariate analysis model demon- Benign recurrent intrahepatic cholestasis strated that patients with posthepatic jaundice were younger, had Infantile cholestatic syndromes a longer history of jaundice, were more likely to present with fever, Inherited metabolic defects and had greater elevations of serum protein concentrations and No identifiable cause (idiopathic hepatic jaundice) shorter coagulation times than patients with hepatic jaundice.16
  • 5. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 5 Hepatic Jaundice Child-Pugh classification (see below), which correlates with individual Hepatic jaundice may be either acute or chronic and may be caused survival and has been shown to predict operative risk.131 Liver trans- by a variety of conditions [see Table 2 ]. plantation is the treatment of choice in most cases of end-stage liver Acute hepatic jaundice may arise de novo or in the setting of ongo- disease. ing liver disease. Historical clues may suggest a particular cause, such as medications or viral hepatitis. Physical examination usually The Child-Pugh Classification131 reveals little. In the presence of preexisting chronic liver disease, bed- Numerical Score (points) side stigmata (e.g., ascites, spider nevi, caput medusae, palmar ery- thema, gynecomastia, or Dupuytren contracture) may be present. Although specific therapies exist for certain clinical problems (e.g., Variable 1 2 3 acetylcysteine for acetaminophen ingestion and penicillin plus silib- inin for Amanita phalloides poisoning), treatment in most cases Encephalopathy Nil (0) Slight to mod- Moderate to remains supportive. Patients in whom encephalopathy develops with- erate (1, 2) severe (3–5) in 2 to 8 weeks of the onset of jaundice are usually classified as hav- Ascites Nil Slight Moderate to ing fulminant hepatic failure [see 8:9 Hepatic Failure]. Evidence of severe encephalopathy, renal failure, or a severe coagulopathy is predictive of poor outcome in this setting.128 The most common causes of fulmi- Bilirubin, mg/dl < 2 (< 34) 2–3 (34–51) > 3 (> 51) nant hepatic failure are viral hepatitis and drug toxicity. The mortality (μmol/L*) from fulminant hepatic failure remains high even though liver trans- plantation has favorably affected the prognosis.129 Albumin, g/dl > 3.5 (> 35) 2.8–3.5 < 2.8 (< 28) (g/L*) (28–35) In cases of chronic hepatic jaundice, the patient may have chronic hepatitis or cholestasis, with or without cirrhosis. The cause usually is Prothrombin > 70% 40%–70% < 40% determined on the basis of the history in conjunction with the results of index serology, biochemistry, viral DNA analysis, and, occasionally, histol- ogy. Causes include viral infection, drug-induced chronic hepatitis, Modified Child’s risk grade (depending on total score): 5 or 6 points, grade A; 7 to 9 points, grade B; 10 to 15 points, grade C. autoimmune liver disease, genetic disorders (e.g., Wilson disease and *Système International d’Unités, or Sl units. α1-antitrypsin deficiency), chronic cholestatic disorders, alcoholic liver disease, and steatohepatitis.130 Physical examination reveals the stig- mata of chronic liver disease and occasionally suggests a specific The Model for End-Stage Liver Disease (MELD) score is now used to cause (e.g., Kayser-Fleischer rings on slit-lamp examination in Wilson prioritize the allocation of organs for liver transplantation by the Unit- disease). Treatment, once again, is usually supportive, depending on ed Network for Organ Sharing.132 This score is based on the serum the clinical presentation; whether more specific therapy is needed and bilirubin and creatinine concentrations, the international normalized what form it takes depend on the cause of liver disease. Although ratio (INR), and the presence of hepatocellular carcinoma; it does physiologic tests have been developed to quantify hepatic reserve, not make use of some of the more subjective components of the the most widely used and best-validated prognostic index remains the Child-Pugh score (e.g., ascites and encephalopathy). gather as much imaging information as possible on the likely cause choledocholithiasis and some biliary tumors. In a patient with gall- of the jaundice before performing either investigation.21 We have stones, transient liver test abnormalities by themselves may suggest found the following approach to be an efficacious, cost-effective,22 an intermediate to high likelihood of common bile duct (CBD) and safe way of obtaining such information in a patient with pre- stones, even if there is no biliary ductal dilatation.25,26 If one of sumed posthepatic jaundice. these diagnoses is suspected, ultrasonography may be repeated The presence of ductal dilatation of the intrahepatic or extra- after a short period of observation (when clinically applicable); bil- hepatic biliary system confirms that a posthepatic cause is respon- iary ductal dilatation then generally becomes apparent. If all of sible for the jaundice. Ultrasonography detects ductal dilatation these unusual clinical situations have been ruled out, a hepatic with an accuracy of 95%, though results are to some extent oper- cause for the jaundice should be sought [see Table 2] and a liver ator-dependent.23 If ultrasonography does not reveal bile duct biopsy considered.27,28 dilatation, it is unlikely that an obstructing lesion is present. In Besides being able to identify the presence of extrahepatic duc- some cases, even though ductal dilatation is absent, other ultra- tal obstruction with a high degree of reliability, ultrasonography sonographic findings may still point to a specific hepatic cause of can accurately determine the level of the obstruction in 90% of jaundice (e.g., cirrhosis or infiltration of the liver by tumor). cases.29 For example, a dilated gallbladder suggests that the There are a few specific instances in which ultrasonography may obstruction is probably located in the middle third or the distal fail to detect a posthepatic cause of jaundice. For instance, very third of the CBD. early in the course of an obstructive process, not enough time may Some centers prefer CT to ultrasonography as the initial imag- have elapsed for biliary dilatation to occur. In this setting, a hepa- ing modality,30 but we, like a number of other authors,31 find ultra- to-iminodiacetic acid (HIDA) scan has often helped identify bile sonography to be the most expedient, least invasive, and most eco- duct blockage.24 The yield from this test is highest when the serum nomical imaging method for differentiating between hepatic and bilirubin level is lower than 100 μmol/L.1 Occasionally, the intra- posthepatic causes of jaundice, as well as for suggesting the level of hepatic biliary tree is unable to dilate; possible causes of such obstruction.32 Traditional imaging techniques, such as oral or inability include extensive hepatic fibrosis, cirrhosis, sclerosing intravenous cholangiography, have a negligible role to play in this cholangitis, and liver transplantation. If one of these diagnoses is setting because of their very poor accuracy and safety, especially in suspected, ERCP, magnetic resonance cholangiopancreatography jaundiced patients. (MRCP), or PTC will eventually be required to confirm the diag- MRCP [see Figure 1] and endoscopic ultrasonography (EUS) nosis of biliary obstruction. Occasionally, the biliary tree dilatation have been used to visualize the biliary and pancreatic trees in vari- may be intermittent; possible causes of this condition include ous populations of patients with obstructive jaundice.33-37
  • 6. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 6 Compared with direct cholangiography, both appear to be excel- a lent at diagnosing biliary obstruction and establishing its location and nature.38,39 MRCP exhibits more modest detection rates when diagnosing small CBD stones.40,41 Spiral (helical) CT scanning is also useful in diagnosing biliary obstruction and determining its cause, though concomitant oral or I.V. cholangiography is required to detect choledocholithiasis.42-44 In addition to their ability to detect choledocholithiasis, spiral CT, EUS, and MRCP in combination with abdominal magnetic resonance imaging (e.g., of the pancreas) are very useful in diag- nosing and staging biliopancreatic tumors.45-47 Cytology speci- mens are readily obtained via fine-needle aspiration (FNA) during CT or EUS.46 It is our current practice to employ these modalities as second- line tests after the initial abdominal ultrasonographic examination. To obtain a diagnosis, we favor EUS for periampullary pathologic conditions and MRI with MRCP for more proximal diseases of the biliary tree. In making the choice among the various available second-line tests, local expertise and cost-effectiveness become important con- siderations. Unfortunately, the reports on cost-effectiveness pub- lished to date have suffered either from limited assumptions (when the methodology involved decision modeling) or from the lack of an effectiveness-type design (when the methodology involved allo- cation of patients). Workup and Management of Posthepatic Jaundice Once ultrasonography has con- firmed that ductal obstruction is present, there are three possible b clinical scenarios: suspected chol- angitis, suspected choledocholi- thiasis without cholangitis, and a suspected lesion other than cho- ledocholithiasis. The direction of the subsequent workup depends on which of the three appears most likely. SUSPECTED CHOLANGITIS If a jaundiced patient exhibits a clinical picture compatible with acute suppurative cholangitis (Charcot’s triad or Raynaud’s pen- tad), the most likely diagnosis is choledocholithiasis. After appro- priate resuscitation, correction of any coagulopathies present, and administration of antibiotics, ERCP is indicated for diagnosis and treatment.48 If ERCP is unavailable or is not feasible (e.g., because of previous Roux-en-Y reconstruction), transhepatic drainage or surgery may be necessary. It is important to emphasize here that the mainstay of treatment of severe cholangitis is not just the administration of appropriate antibiotics but rather the establish- ment of adequate biliary drainage. SUSPECTED CHOLEDOCHOLITHIASIS WITHOUT CHOLANGITIS Choledocholithiasis is the most common cause of biliary obstruction.13,14 It should be strongly suspected if the jaundice is episodic or painful or if ultrasonography has demonstrated the presence of gallstones or bile duct stones. Patients with suspected Figure 1 ERCP (a) and corresponding MRCP (b) demonstrate choledocholithiasis should be referred for laparoscopic cholecys- presence of a stone in the distal CBD. tectomy with either preoperative ERCP, intraoperative cholan- giography, or intraoperative ultrasonography [see 5:21 Cholecystec- tomy and Common Bile Duct Exploration].49 We favor preoperative CBD of stones in 95% of cases. Decision analyses appear to con- ERCP in this setting of jaundice because its diagnostic yield is firm the utility of this strategy when laparoscopic CBD exploration high,50 it allows confirmation of the diagnosis preoperatively (thus is not an option.51-55 Many authors, however, favor a fully laparo- obviating intraoperative surprises), and it is capable of clearing the scopic approach, in which choledocholithiasis is detected in the
  • 7. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 7 OR by means of intraoperative cholangiography56,57 or ultra- lesion will not be resectable with an accuracy approaching 95%; sonography58-60 and laparoscopic biliary clearance is performed however, as many as 33% of tumors that appear to be resectable when choledocholithiasis is confirmed. Given that both the ERCP on CT are found to be unresectable at operation.64 approach and the fully laparoscopic approach have advantages MRI-based staging, along with MRCP, can further dictate the and limitations, the optimal approach in a particular setting subsequent choice of therapy.65-68 MRI may be particularly useful should be dictated by local expertise. for following up patients in whom clip artifacts interfere with a CT image.65 It also appears to be successful in detecting cholangiocar- SUSPECTED LESION OTHER cinoma spreading along the proximal biliary tree.69 Given the THAN CHOLEDOCHOLITHIASIS renewed interest in biliary contrast media and the availability of If no gallstones are identified, if software optimized for multidetector scanners, CT cholangiogra- the clinical presentation is less phy may soon rival MRCP for evaluation of the biliary tree in cases acute (e.g., constant abdominal or of suspected malignancy.70 back pain), or if there are associat- Only in a few very rare instances is traditional angiography used ed constitutional symptoms (e.g., to assess resectability or stage a hepatobiliary or pancreatic neo- weight loss, fatigue, and long- plasm. Increasingly, it is being replaced by CT angiography or standing anorexia), the presence of a lesion other than choledo- duplex Doppler ultrasonography, which can confirm the presence cholithiasis should be suspected. In such cases, another imaging of flow in the hepatic arterial or portal venous systems and occa- modality besides the ultrasonography already performed must be sionally can demonstrate invasion of these vessels by tumor.71 considered before the decision is made to proceed to cholangiog- Magnetic resonance angiography (MRA) has also been used with raphy or operation. excellent results. As yet, none of these noninvasive modalities has Possible causes of posthepatic obstruction (other than choledo- been shown to be clearly superior to any of the others.72 cholithiasis) may be classified into three categories, depending on the location of the obstructing lesion (as suggested by the pattern of gallbladder and biliary tree dilatation on the ultrasonogram): the upper third of the biliary tree, the middle third, or the lower (distal) Table 3 Causes of Posthepatic Jaundice third [see Table 3]. Once it has been determined that choledo- Upper-third obstruction cholithiasis is unlikely, the most common cause of such obstruction Polycystic liver disease is pancreatic cancer [see 5:9 Tumors of the Pancreas, Biliary Tract, and Caroli disease Liver].13,14 In adults, many of the other possible causes also involve Hepatocellular carcinoma malignant processes. Consequently, the next step in the workup of Oriental cholangiohepatitis the patient is typically the assessment of resectability and operabili- Hepatic arterial thrombosis (e.g., after liver transplantation or ty [see 5:22 Procedures for Benign and Malignant Biliary Tract Disease]. chemotherapy) Hemobilia (e.g., after biliary manipulation) Diagnosis and Assessment of Resectability Iatrogenic bile duct injury (e.g., after laparoscopic Assessment of the resectability of a tumor usually hinges on cholecystectomy) whether the superior mesenteric vein, the portal vein, the superior Cholangiocarcinoma (Klatskin tumor) mesenteric artery, and the porta hepatis are free of tumor and on Sclerosing cholangitis whether there is evidence of significant local adenopathy or extra- Papillomas of the bile duct pancreatic extension of tumor. Unfortunately, the majority of Middle-third obstruction lesions will be clearly unresectable, either because of tumor exten- Cholangiocarcinoma sion or because of the presence of hepatic or peritoneal metastases. Sclerosing cholangitis Many imaging modalities are currently used to determine Papillomas of the bile duct resectability, and several of these have been established as effective Gallbladder cancer alternatives to direct cholangiography because they involve little if Choledochal cyst any morbidity. Their accuracy varies according to the underlying Intrabiliary parasites pathology and the expertise of the user. They have been studied Mirizzi syndrome mostly with respect to the staging and diagnosis of pancreatic, peri- Extrinsic nodal compression (e.g., from breast cancer or lymphoma) Iatrogenic bile duct injury (e.g., after open cholecystectomy) ampullary, and biliary hilar cancers. Cystic fibrosis For determining resectability and staging lesions before opera- Benign idiopathic bile duct stricture tion, we rely mainly on spiral CT. The advent and widespread availability of multidetector CT have made this modality the dom- Lower-third obstruction inant second-line imaging method in cases of suspected pancreat- Cholangiocarcinoma ic masses. For optimal evaluation of the pancreas, a fine-cut dual- Sclerosing cholangitis phase (arterial phase and portal venous phase) scan should be Papillomas of the bile duct obtained. Oral administration of water allows better evaluation of Pancreatic tumors Ampullary tumors the duodenum and the ampulla.61,62 At present, spiral CT is con- Chronic pancreatitis sidered to be superior for the diagnosis and staging of lesions such Sphincter of Oddi dysfunction as pancreatic cancer.45,63,64 It exhibits a high negative predictive Papillary stenosis value and has a false positive rate of less than 10%; its sensitivity is Duodenal diverticula optimal for pancreatic lesions larger than 1.5 cm in diameter. Penetrating duodenal ulcer Ascites, liver metastases, lymph nodes larger than 2 cm in diame- Retroduodenal adenopathy (e.g., lymphoma, carcinoid) ter, and invasion into adjacent organs are all signs of advanced dis- ease.65 On the basis of these criteria, spiral CT can predict that a
  • 8. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 8 a b c Figure 2 (a) ERCP demonstrates missing liver segments. (b) Transhepatic cholangiography of segment 6 reveals the excluded liver ductal system. (c) MRCP shows the excluded liver segments, as well as the biliary system, which still communicates with the common hepatic duct. EUS is a highly sensitive method of imaging the pancreas and ence with FDG-PET is growing rapidly as this imaging modality the duodenum.46,73,74 In two large studies, it was found to be supe- becomes more readily accessible. rior to CT and standard ultrasonography in staging pancreatic When a biliary stricture is detected at cholangiography, brush and ampullary cancers.75,76 Subsequent studies indicated that cytology or biopsy is mandatory. Biliary cytology, however, has whereas EUS is superior to CT for detection and staging, it pro- been disappointing, particularly at ERCP: diagnostic accuracy vides similar information regarding nodal status and overall assess- ranges from 40% to 85%,85,86 mostly because the negative predic- ment of resectability.61,77 From a cost-minimization point of view, tive value is poor. Accuracy improves with multiple sampling and the optimal strategy is to begin with a dual-phase CT scan and to when a biliary rather than a pancreatic malignancy is detected. In follow up with EUS only in cases in which further information or addition, biopsy tends to be more accurate than brush cytology.85 a tissue diagnosis is required.78,79 In another large series, EUS was reported to be more accurate than CT in the comparative staging Nonoperative Management: of pancreatic and ampullary cancers. It has also been found use- Drainage and ful for identifying small (< 2 cm) pancreatic tumors, which may be Cholangiography suspected in a patient who has an obstruction of the distal third In the majority of patients with of the bile duct and whose CT scan is normal.74 Furthermore, malignant obstructions, treat- EUS is currently the dominant technique for staging ampullary ment is palliative rather than tumors.80 curative. It is therefore especially In patients with a suspected pancreatic tumor, direct FNA of important to recognize and mini- the lesion at the time of EUS has become the gold-standard mize the iatrogenic risks related to the manipulation of an method for obtaining a tissue diagnosis. In the case of potentially obstructed biliary system; this is why staging and cholangiography resectable lesions, however, this measure adds very little to the are currently being performed with EUS and MRCP. decision-making process.The limited data currently available sug- gest that assays of tumor markers in serum and pancreatic fluid are Cholangiography and decompression of obstructed bil- useful, particularly for cystic lesions of the pancreas.81 iary system As a rule, we favor ERCP, though PTC may be At this point in the evaluation, patients can be referred either for preferable for obstructions near the hepatic duct bifurcation. cholangiography (ERCP or MRCP) to clarify a still-unclear diag- Whichever imaging modality is used, the following four principles nosis or for biliary decompression (see below). MRI of the pancreas apply. with MRCP continues to improve rapidly. It is a noninvasive modal- ity that evaluates the pancreas, vasculature, and the pancreatobiliary 1. In the absence of preexisting or concomitant hepatocellular dys- ductal system in a single examination, with the additional benefit of function, drainage of one half of the liver is generally sufficient avoiding ionizing radiation and iodinated contrast agents.82 MRCP for resolution of jaundice.87 remains our test of choice for evaluation of middle- and upper-third 2. Because of its external diameter, a transhepatic drain, once lesions in cases in which decompression is not required. inserted, does not necessarily permit equal drainage of all seg- In the event that none of these modalities point to a diagnosis, ments of the liver, particularly if there are a number of intrahep- the use of 18F-fluorodeoxyglucose (FDG) positron emission tomog- atic ductal stenoses. Accordingly, some patients with conditions raphy (PET) may be considered to help differentiate benign pan- such as sclerosing cholangitis or a growing tumor may experience creatic conditions from malignant ones.83,84 Besides facilitating persistent sepsis from an infected excluded liver segment even diagnosis, FDG-PET provides information regarding occult me- when the prosthesis is patent [see Figure 2]. An excluded segment tastases and can be useful in detecting recurrent disease. Experi- may even be responsible for severe persistent pruritus.
  • 9. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 9 3. Any attempt at opacifying an obstructed biliary tree introduces Operative Management at a significant risk of subsequent cholangitis, even when appropri- Specific Sites: Bypass and ate antibiotic prophylaxis is provided. Accordingly, when one Resection elects to perform direct cholangiography, there should be a plan Surgical treatment of tumors for biliary drainage either at the time of ERCP or PTC or soon causing biliary obstruction is thereafter. determined primarily by the level 4. Even though jaundice is believed to be associated with multiple of the biliary obstruction. Current adverse systemic effects (e.g., renal failure, sepsis, and impaired evidence indicates that modern wound healing),88,89 routine preoperative drainage of an surgical approaches are resulting in lower postoperative morbidity obstructed biliary system does not benefit patients who will and, possibly, improved 5-year survival104; however, the prognosis is soon undergo resection.90,91 There is a growing body of evi- still uniformly poor, except for patients with ampullary tumors. In dence suggesting that in patients with either pancreatic92,93 or fact, the surgical procedure rarely proves curative, even after metic- hepatic94 malignancies, routine preoperative direct cholangiog- ulous preoperative patient selection. raphy with decompression is associated with a higher incidence At one time, there was considerable enthusiasm for routine use of postoperative complications when tumor resection is ulti- of staging laparoscopy; at present, however, selective use is recom- mately carried out. mended.105 The benefits of staging laparoscopy include more accu- When direct cholangiography is ordered, it should be thought of rate assessment of resectability and prevention of the prolonged as more than just a diagnostic test: it is the ideal setting for cytol- hospital stay and convalescence associated with an unnecessary ogy, biopsy, or even drainage of the obstructed bile duct via a laparotomy. Laparoscopy is used mostly to detect peritoneal carci- sphincterotomy, a nasobiliary tube, or a catheter or stent. Accord- nomatosis, liver metastases, malignant ascites, and gross hilar ingly, it is essential that the surgeon, the gastroenterologist, and the adenopathy.106,107 The main limitation of laparoscopy in this setting radiologist discuss the possible need for drainage well before it is appears to be that it does not accurately detect the spread of required. Early, open communication among all the members of tumors to lymph nodes or the vascular system.108 In several stud- the treating team is a hallmark of the modern management of bil- ies, a combined approach that included both laparoscopy and iary obstruction. laparoscopic ultrasonography was associated with shorter hospital stays and lower costs.105,107-109 Palliation in patients with advanced malignant disease When a patient has advanced malignant disease, drainage of the biliary system for palliation is not routinely indicated, because the risk of complications related to the procedure may outweigh the potential benefit. Indeed, the best treatment for a patient with asymptomatic obstructive jaundice and liver metastases may be supportive care alone.95 Biliary decompression is indicated if cholangitis or severe pruritus interferes with quality of life. We, like others,22 consider a stent placed with ERCP to be the palliative modality of choice for advanced disease, though upper- third lesions may be managed most easily through the initial place- ment of an internal/external catheter at the time of PTC. Metal expandable stents remain patent longer than large conventional plastic stents,96,97 but the high price of the metal stents has kept them from being widely used, and their overall cost-effectiveness has yet to be clearly demonstrated. Whether plastic biliary stents should be replaced prophylactically or only after obstruction has occurred remains controversial; however, results from a random- ized, controlled trial (RCT) favor the former approach.98 In anoth- er RCT, the use of prophylactic ciprofloxacin did not prolong stent patency but did reduce the incidence of cholangitis and improve quality of life scores.99 RCTs suggest that surgical biliary bypass should be reserved for patients who are expected to survive for 6 months or longer because bypass is associated with more prolonged palliation at the cost of greater initial morbidity.100 The role of prophylactic gastric drainage at the time of operative biliary drainage remains controversial,101,102 though two RCTs demonstrated a reduced incidence of subsequent clinical gastric outlet obstruction when this measure was employed. Jaundiced patients with unresectable lesions who also present with duodenal or jejunal obstruction should be referred for gastrojejunostomy at the time of biliary bypass surgery.There is evidence to suggest that when a pancreatic malignancy is present, intraoperative celiac gan- Figure 3 ERCP demonstrates extrinsic compression of the com- glion injection should be performed for either prophylactic or ther- mon hepatic duct by a stone in Hartmann’s pouch. A biliary stent apeutic pain control.103 has been inserted for drainage.
  • 10. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 10 In what follows, only the general principles of resection or bypass at each level of obstruction are discussed; operative technical details are addressed elsewhere [see 5:22 Procedures for Benign and Malignant Biliary Tract Disease]. Our preferred method of biliary anastomosis, for either reconstruction or bypass, involves the fash- ioning of a Roux-en-Y loop, followed by a mucosa-to-mucosa anas- tomosis. In all cases, a cholecystectomy is performed to facilitate access to the biliary tree. Upper-third obstruction Palliation. Because the left hepatic duct has a long extrahepatic seg- ment that makes it more accessi- ble, the preferred bypass tech- nique for an obstructing upper- third lesion is a left (or segment 3) hepaticojejunostomy. This opera- tion has superseded the Longmire procedure because it does not involve formal resection of liver parenchyma. Laparoscopic bypass techniques that make use of segment 3 have been developed, but their performance has yet to be formally assessed, and they cannot yet be incorporated into a management algorithm.110,111 Resection for cure. The hilar plate is taken down to lengthen the hepatic duct segment available for subsequent anastomosis. Often, a formal hepatectomy or segmentectomy is required to ensure an adequate proximal margin of resection. If the resection must be carried out proximal to the hepatic duct bifurcation, several cholan- giojejunostomies will have to be done to anastomose individual hepatic biliary branches. Frozen-section examination of the proxi- mal and distal resection margins is important because of the propensity of tumors such as cholangiocarcinoma to spread in a submucosal or perineural plane. The results of aggressive hilar tumor resections that included as much liver tissue as was necessary to obtain a negative margin appear to justify this approach.112 In cases of left hepatic involve- Figure 4 Jaundice has occurred after laparoscopic cholecystec- ment, resection of the caudate lobe (segments 1 and 9) is indicat- tomy as a result of bile leakage from a distal biliary tributary. A stent has been inserted to decrease bile duct luminal pressure and ed as well.113,114 foster spontaneous resolution. Middle-third obstruction Palliation. Surgical bypass of mid- dle-third lesions is technically sim- Lower-third obstruction pler because a hepaticojejunosto- Palliation. The preferred bypass my can often be performed distal technique for lower-third lesions is to the hepatic duct bifurcation, a Roux-en-Y choledochojejunos- which means that exposure of the tomy. Cholecystojejunostomy car- hilar plate or the intrahepatic ries a higher risk of complications ducts is unnecessary. and subsequent development of jaundice117; this remains true even Resection for cure. Discrete tumors in this part of the bile duct, when it is performed laparoscopically. Occasionally, it may be done though uncommon, are usually quite amenable to resection as a temporizing measure before a more definitive procedure in the along with the lymphatic chains in the porta hepatis. Resection context of an upcoming transfer to a specialized center. of an early gallbladder cancer may, on occasion, necessitate the concomitant resection of segment 5, though the value of resect- Resection for cure. Occasionally, an impacted CBD stone at the ing this segment prophylactically has not been conclusively duodenal ampulla mimics a tumor and is not clearly identified pre- demonstrated.115 Sometimes, jaundice from a suspected mid- operatively. Because of the growing use of EUS and MRCP, such dle-third lesion is in fact caused by a case of Mirizzi syndrome a situation is increasingly uncommon. Resection of a lower-third [see Figure 3]. In such cases, a gallstone is responsible for extrin- lesion usually involves a pancreaticoduodenectomy [see 5:24 sic obstruction of the CBD, either by causing inflammation Procedures for Benign and Malignant Pancreatic Disease], though of the gallbladder wall or via direct impingement. Proper treat- transduodenal ampullary resection may be an acceptable alterna- ment of this syndrome may involve hepaticojejunostomy in tive for a small adenoma of the ampulla [see 5:24 Procedures for addition to cholecystectomy if a cholecystocholedochal fistula is Benign and Malignant Gastric and Duodenal Disease]; local duode- present.116 nal resection without removal of the head of the pancreas has also
  • 11. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 3 Jaundice — 11 been described.118 For optimal results, pancreaticoduodenectomy ment of heart failure can lead to conjugated hyperbilirubinemia is best performed in specialized centers.119 within 5 to 10 days after operation.The hyperbilirubinemia may It has been suggested that postoperative adjuvant therapy may be associated with other end-organ damage (e.g., acute tubular improve the prognosis after resection of a pancreatic adenocarci- necrosis). In fact, any impairment of renal function causes a noma,104 but this debate falls outside the scope of our discussion. decrease in bilirubin excretion and can be responsible for a mild hyperbilirubinemia. • Jaundice may develop 7 to 10 days after operation in association Postoperative Jaundice with a medication-induced hepatitis attributable to an anesthet- A clinical scenario of particular pertinence to surgeons that we ic agent.This syndrome has an estimated incidence of 1/10,000 have not yet addressed is the development of jaundice in the post- after an initial exposure.122 More commonly, the jaundice is operative setting. related to the administration of antibiotics or other medications Jaundice develops in approximately 1% of all surgical patients used in the perioperative setting.122 after operation.120 When jaundice occurs after a hepatobiliary pro- • After the first week, jaundice associated with intrahepatic cedure, it may be attributable to specific biliary causes, such as cholestasis is often a manifestation of a septic response and usu- retained CBD stones, postoperative biliary leakage (through reab- ally presents in the setting of overt infection, particularly in sorption of bile leaking into the peritoneum) [see Figure 4], injury patients with multiple organ dysfunction syndrome. Gram-neg- to the CBD, and the subsequent development of biliary strictures. ative sepsis from an intra-abdominal source is typical; if it per- In most instances, however, the jaundice derives from a combina- sists, the outcome is likely to be poor. Jaundice may occur in as tion of disease processes, and only rarely is invasive testing or active many as 30% of patients receiving total parenteral nutrition treatment required.121 (TPN). It may be attributable to steatosis, particularly with for- A diagnostic approach similar to the one outlined earlier (see mulas containing large amounts of carbohydrates. In addition, above) is applicable to postoperative jaundice; however, another decreased export of bilirubin from the hepatocytes may lead to useful approach is to consider the possible causes in the light of the cholestasis, the severity of which appears to be related to the time interval between the operation and the subsequent develop- duration of TPN administration. Acalculous cholecystitis or even ment of jaundice. ductal obstruction may develop as a result of sludge in the gall- • Jaundice may develop within 48 hours of the operation; this is bladder and the CBD. An elevated postoperative bilirubin level most often the result of the breakdown of red blood cells, occur- at any time may also result from unsuspected hepatic or post- ring in the context of multiple blood transfusions (particularly hepatic causes (e.g., occult cirrhosis, choledocholithiasis, or with stored blood), the resorption of a large hematoma, or a cholecystitis). A rare cause of postoperative jaundice is the devel- transfusion reaction. Hemolysis may also develop in a patient opment of thyrotoxicosis. Another entity to consider (as a diag- with a known underlying hemolytic anemia and may be precip- nosis of exclusion) is so-called benign postoperative cholestasis, itated by the administration of specific drugs (e.g., sulfa drugs in a primarily cholestatic, self-limited process with no clearly a patient who has glucose-6-phosphate dehydrogenase deficien- demonstrable cause that typically arises within 2 to 10 days after cy).122 Cardiopulmonary bypass or the insertion of a prosthetic operation. Benign postoperative cholestasis may be attributable valve may be associated with the development of early postoper- to a combination of mechanisms, including an increased pig- ative jaundice as well. Gilbert syndrome [see Sidebar Hepatic ment load, impaired liver function resulting from hypoxemia and Jaundice] may first manifest itself early in the postoperative peri- hypotension, and decreased renal bilirubin excretion caused by od. Occasionally, a mild conjugated hyperbilirubinemia may be varying degrees of tubular necrosis.123 The predominantly con- related to Dubin-Johnson syndrome, which is an inherited dis- jugated hyperbilirubinemia may reach 40 mg/dl and remain ele- order of bilirubin metabolism.This condition is usually self-lim- vated for as long as 3 weeks.122 ited and is characterized by the presence of a melaninlike pig- • In the late postoperative period, the development of non-A, non- ment in the liver. B, non-C viral hepatitis after transfusion of blood products will • Intraoperative hypotension or hypoxemia or the early develop- usually occur within 5 to 12 weeks of operation. References 1. Schiff L: Jaundice: a clinical approach. Diseases 7. Lumeng L, Snodgrass PJ, Swonder JW: Final 61 proved cases. Am J Dig Dis 7:449, 1962 of the Liver, 7th ed. Schiff L, Schiff ER, Eds. JB report of a blinded prospective study comparing 12. 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