Cholangitis
The term cholangitis refers to inflammation of the extrahepatic or intrahepatic biliary system. Acute cholangitis is most often a consequence of infection in the setting of biliary tract disease or obstruction. The diagnosis of cholangitis implies microbial colonization of the biliary tract, increased biliary pressure, and systemic signs of infection, although all of these findings are not present in all patients.
Acute biliary tract infection is rare in children and occurs most often in children with underlying disease. One specific pediatric population—children with biliary atresia and a hepatic portoenterostomy (HPE)—is particularly susceptible to cholangitis and its sequelae. This population and other patient groups at high risk of developing infectious cholangitis, such as patients with immunodeficiency states, congenital or acquired bile duct abnormalities, or liver transplants, are highlighted in this chapter. Biliary tract obstruction secondary to gallstone disease is discussed in the section on cholecystitis .
Etiology and Pathogenesis
The central mechanism leading to biliary tract infection is obstruction of normal bile flow. Bile typically is sterile due to mechanical flushing with normal bile flow, the anatomic gate of the choledochal sphincter, bacteriostatic properties of bile, and biliary IgA. When obstruction and stagnation occur, bacteria gain access either by ascending from the gut or via hematogenous spread. The exact route of bacterial invasion and spreading remains controversial. Ascent may occur from the duodenum, most commonly in the presence of abnormal function of the sphincter of Oddi. In addition, bacterial invasion may occur hematogenously via increased gut translocation across the intestine into the portal circulation, followed by flow across the gallbladder wall. Although the exact mechanism has not been firmly established, the consensus is that transient episodes of bactibilia combined with biliary obstruction may lead to higher concentrations of bacteria in the biliary tract. As biliary pressure increases, bacteria likely migrate from the bile ducts into lymphatic and blood vessels, resulting in bacteremia and clinical signs and symptoms of cholangitis. Iatrogenic introduction of bacteria into the biliary tract can occur during endoscopic retrograde cholangiopancreatography (ERCP) or with indwelling stents. More recently, challenges with endoscope cleaning in the duodenoscope elevator have led to infections, notably with carbapenem-resistant Enterobacteriaceae.
In adults, cholangitis typically occurs in the presence of biliary tract obstruction secondary to impaction of gallstones in the common bile duct leading to bile stasis and secondary infection. In approximately 85% of cases of cholangitis in adults, evidence of a common bile duct stone is present. In adults with documented gallstones in the common bile duct (choledocholithiasis), the incidence of positive bile cultures is 30% to 99%. Other causes of biliary obstruction in adults possibly leading to a more chronic or recurrent presentation include neoplasm of the biliary tree or head of the pancreas, other intrinsic or extrinsic strictures, parasitic disease, inflammatory conditions (e.g., primary biliary cirrhosis, primary sclerosing cholangitis [PSC]), and congenital bile duct anomalies. More recently, with improved imaging modalities and a better understanding of the pathogenesis of biliary lithiasis, it has become accepted that biliary sludge or microcalculi may be at the root of nonobstructive cholangitis and recurrent biliary infections.
In children, acute cholangitis occurs most frequently in patients with biliary atresia who have undergone HPE surgery, also known as a Kasai operation. HPE provides a permissive setup for cholangitis: poor bile flow combined with damaged intrahepatic bile ducts and obligate bacterial colonization with enteric flora in the intestinal conduit. In this setting, cholangitis is thought to arise from reflux of jejunal flora through the HPE (roux-en-Y loop), directly contiguous with the hepatic porta. Incidence is between 40% and 93% of patients and tends to occur more frequently within the first year after surgery. Decreased biliary and duodenal motility generally are accepted as being associated with a higher incidence of cholangitis, but most predictors and exacerbants for the development of cholangitis remain unknown.
Microbiologic evidence of biliary tract infection ideally should involve at least 10 4 organisms per milliliter of bile. Table 48.1 summarizes the frequencies of specific organisms found in adult and pediatric studies. Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and Enterococcus spp. are most commonly isolated from infected bile. Many cases of cholangitis are polymicrobial. Anaerobes, such as Bacteroides fragilis and Clostridium perfringens, also may play a significant role and have been identified in 40% of biliary tract infections. Specifically, the latter organism has been implicated in acute emphysematous cholecystitis. Despite these findings in bile, many patients with cholangitis have negative blood cultures, thus requiring clinicians to have a high index of suspicion for cholangitis in selected circumstances and patient populations.
| Organism | Keighley, 1975 ( n = 231) | Boey, 1980 ( n = 99) | Lewis, 1987 ( n = 23) | Brook, 1989 ( n = 123) | Rerknimitr, 2002 ( n = 69) |
|---|---|---|---|---|---|
| Escherichia coli | 65 | 46 | 15 | 71 | 16 |
| Klebsiella/Enterobacter spp. | 28 | 28 | 17 | 65 | 16 |
| Pseudomonas spp. | 1 | 17 | 0 | 2 | 6 |
| Proteus spp. | 13 | 8 | 0 | 15 | 0 |
| Enterococcus spp. | 22 | 14 | 0 | 42 | 15 |
| Staphylococcus spp. | 5 | 0 | 1 | 7 | 10 |
| Streptococcus spp. | 3 | 0 | 6 | 16 | 14 |
| Bacteroides spp. | 2 | 0 | 2 | 29 | 0 |
| Clostridium spp. | 11 | 0 | 9 | 27 | 0 |
| Other anaerobe | 7 | 0 | 0 | 14 | 4 |
| Other species | 7 | 23 | 10 | 8 | 3 |
In addition to bacterial infection, viral, fungal, and parasitic pathogens have been reported in cases of pediatric cholangitis, particularly in immunodeficient patients (primarily patients with human immunodeficiency virus [HIV]) and patients with environmental exposure to parasites in endemic settings. Cholangitis due to viral infection is most commonly associated with hepatocellular disease with hepatotropic viruses, primarily cytomegalovirus (CMV), hepatitis C, and hepatitis B. Depending on the clinical setting and age of the patient, CMV can have a markedly varied presentation, ranging from bile duct paucity seen in congenital CMV infection to hepatomegaly and jaundice in infants and children with primary CMV infection. The role of CMV hepatitis and cholangitis is significant in immunocompromised patients and solid organ transplant recipients.
Fungal cholangitis, specifically with Cryptococcus neoformans or Candida albicans, has been reported in immunocompromised and immunocompetent patients. Hepatobiliary dysfunction may be the initial manifestation of disseminated infection.
The biliary tree also is susceptible to parasitic infections in normal hosts. Nematodes— Ascaris and, rarely, Strongyloides —commonly cause biliary disease in endemic regions. Migrating Ascaris larvae may cause either a direct inflammatory response if they pass through the biliary system, or, more commonly, a high worm burden can cause an obstruction leading to secondary pyogenic cholangitis. Liver flukes, such as Clonorchis (now Opisthorchis ) sinensis, Opisthorchis viverrini, and Opisthorchis felineus, also may pass through the biliary system through their life cycle. Of these trematodes, Clonorchis is found frequently in cases of recurrent pyogenic cholangitis in Asian children. Similar to the worms, the migration of the flukes ( Fasciola hepatica ) through the biliary tree may induce primary inflammation and, later, a secondary bacterial infection. Echinococcal cholangitis has been described in the setting of obstruction secondary to cyst formation from infection with either Echinococcus granulosus or Echinococcus multilocularis. Although Cryptosporidium spp. typically are known to cause cholangitis in the immunocompromised host, one case of a child without a documented immunodeficiency has been reported. A thorough travel history should be obtained in all children presenting with new-onset cholangitis, in particular in patients in whom the most common causes are ruled out rapidly.
Finally several cases of Mycobacterium tuberculosis cholangitis mimicking cholangiocarcinoma in immunocompromised and immunocompetent hosts have been reported in the adult literature.
Clinical Presentation
The classic presentation of cholangitis first described by Charcot in 1877 and known commonly as the Charcot triad is reported in 50% to 70% of patients with cholangitis in most studies ( Box 48.1 ). It combines the clinical findings of fever, right upper quadrant pain, and jaundice. The Reynold pentad added septic shock and altered mental status to the Charcot triad. More recently the Tokyo guidelines updated diagnostic criteria for cholangitis to include laboratory evidence of an inflammatory response, abnormal liver test results, and imaging findings of biliary dilation or evidence of etiology of underlying disease. Studies in children show that fever is the most common presenting symptom, occurring in 100% of 105 patients with cholangitis after undergoing HPE. In addition, either acholic stools or an increase in serum bilirubin concentration occurs in 68% of patients. Older children and teenagers with cholangitis typically report abdominal pain that may or may not be associated with meals or localize to the right upper quadrant. Patients may report new-onset pruritus as a consequence of retained biliary constituents. Laboratory findings include elevated white blood cell count, C-reactive protein, bilirubin, and alkaline phosphatase.
Definitive Diagnosis
Clinical signs of infection and finding of purulent bile by
ERCP
Surgery
Percutaneous puncture
Charcot Triad (1877)
Fever
Right upper quadrant pain
Jaundice
Reynold Pentad (1959)
Fever
Right upper quadrant pain
Jaundice
Septic shock
Altered mental status
Tokyo Guidelines (2006)
Two of three Charcot triad criteria plus
Evidence of inflammatory response
Abnormal white blood cell count
Elevated C-reactive protein
Abnormal liver tests
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyltranspeptidase
Imaging evidence of etiology (e.g., stone, stricture, stent)
The findings of cholangitis may be markedly attenuated in infants and immunocompromised patients, suggesting that a low threshold for suspicion be employed in the evaluation of these children at risk. The presentation of cholangitis in an infant with biliary atresia, status post Kasai portoenterostomy, may be as varied as lethargy, increasing jaundice, abdominal tenderness, or fever alone. Finally, patients with ongoing hemolysis (e.g., patients with hemoglobin SS disease) are at high risk for developing cholecystitis and cholangitis from bilirubin stones, yet the symptoms may readily overlap with other causes of abdominal pain.
Diagnostic Evaluation
Physical examination may reveal a range of toxic appearances, with vital signs suggesting serious systemic infection in more advanced cases (fever, tachycardia, hypotension). Physical examination typically reveals icteric sclera and a distended abdomen, with tenderness localized to the mid or right upper quadrant. Palpation of the liver edge may reveal tenderness. Laboratory studies may reveal an elevated erythrocyte sedimentation rate (81%), leukocytosis or leukopenia (56%), and increased serum levels of conjugated bilirubin. Laboratory evaluations in children should include a complete blood count with differential and liver panel (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, γ-glutamyltransferase, and fractionated bilirubin [unconjugated and conjugated]). The differential diagnosis of fever, abdominal pain, and jaundice also should include sepsis and hepatitis. No single laboratory test or combination of tests can establish a diagnosis of cholangitis.
Attempts at identifying a microbiologic agent should be made. Blood and bile cultures should be performed at all available opportunities and drawn before antimicrobial therapy is initiated. Most cases are polymicrobial, with a predominance of gut-derived organisms (see Table 48.1 ). Some studies report positive blood cultures in 21% to 71% of patients with acute cholangitis. Other investigators have reported identification of organisms in blood in approximately 10% to 25% of patients, which is similar to our experience. In patients with a history of hepatobiliary surgery, aerobic and anaerobic cultures should be considered, and in virtually all cases of young children with abdominal pain and jaundice, a urine culture should be considered. In a study of 110 patients undergoing HPE, 58.4% of patients had serum bacterial DNA detection using the 16SrDNA method compared to 14.3% using the standard culture method.
The role of liver biopsy to evaluate the parenchyma for evidence of cholangitis is controversial, but occasionally this testing may have a place in the setting of negative blood cultures. When used along with blood cultures, hepatic cultures have been shown to increase the diagnostic yield of identifying a microbiologic organism to 75% of patients, whereas histologic confirmation of cholangitis may be the only firm evidence of biliary tract infection in some cases. In practice, liver biopsy is performed infrequently, and patients are treated empirically. In cases of gallstone-associated biliary tract obstruction with cholangitis that requires endoscopic or surgical decompression, bile should be obtained and cultured at the time of the procedure. In an adult study, 22 of 23 patients with gallstone-associated cholangitis were found to have positive bile cultures.
The initial and principal radiologic evaluation for suspected cholangitis is transabdominal ultrasound, with the primary goal being to search for evidence of biliary tract obstruction, usually associated with dilation of the common bile duct or intrahepatic ducts. Ultrasound examination may reveal anatomic biliary tract abnormalities (choledochal cyst), intrahepatic cysts or fluid collections, and hepatic or other intraabdominal masses. Other noninvasive imaging modalities include computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP), which provide increasingly detailed images of the intrahepatic and extrahepatic biliary anatomy.
Taken together, these noninvasive imaging techniques should be able to detect the presence of biliary tract obstruction and some congenital anatomic anomalies, although even experienced ultrasonographers still may miss small stones and sludge, especially in the common bile duct. It is important to recognize the technical limitations of the methodology and the possible presence of undetected stones or sludge in the gallbladder or common bile duct (choledocholithiasis) as a cause of biliary tract dilation. The sensitivity of ultrasound for choledocholithiasis is poor, ranging from 30% to 50%. Sensitivity improves to approximately 90% with CT and 95% to 99% with endoscopic retrograde cholangiopancreatography (ERCP).
Newer modalities, including endoscopic ultrasound, laparoscopic ultrasound, and helical CT cholangiography, may improve detection in certain patient populations. The 2002 National Institutes of Health State-of-the-Science Consensus conference regarded endoscopic ultrasound, MRCP, and ERCP as having comparable sensitivity and specificity in detecting common bile duct stones. In the hands of an experienced echoendoscopist, endoscopic ultrasound has been shown in adults to be the procedure of choice to identify small stones and sludge in the common bile duct. This method may prove useful in children as well and may prevent the unnecessary use of ERCP and the risk of its associated complications.
After HPE has been performed, imaging may be able to identify lakes of retained bile (bilomas), which may be a source of infection, in a patient with biliary atresia. Nuclear medicine (hepatobiliary iminodiacetic acid [HIDA]) scans have a limited role in the evaluation of cholangitis. HIDA scans may be most helpful in determining if a patient has a complete obstruction of the common bile duct or if an isolated obstruction of the cystic duct (e.g., cholecystitis) is present.
Because of the inherent risks associated with invasive procedures in these infants, percutaneous drainage of bilomas for culture or other purposes rarely is performed. Similarly percutaneous drainage is preferred to ERCP for anatomic reasons. Invasive imaging has a role, especially when it may be coupled with therapeutic decompression of an obstructed and potentially infected biliary tree. ERCP has proved to be extremely useful in the evaluation and management of biliary tract obstruction and should be considered in the management of a child with evidence of an obstructed common bile duct. The role of ERCP in infants and small children is limited by the number of trained pediatric gastroenterologists and also by limited availability of size-appropriate equipment. During ERCP bile for microbial and chemical analysis can be obtained and provides detailed imaging of the biliary tree. Significant technical advances have occurred in biliary endoscopy, such that direct visualization of the bile ducts (choledochoscopy) with the ability to obtain direct sampling is possible in children. Acute cholangitis alone is an indication for ERCP when there is a suspicion for choledocholithiasis.
Practically ERCP may detect (and remove) small stones and sludge that are missed by ultrasound, CT, or MRCP. ERCP is helpful in establishing the differential diagnosis of biliary tract diseases, such as PSC, which may manifest in a fashion similar to that of infectious cholangitis but have a characteristic radiographic appearance. In the future, as the use of endoscopic ultrasound in pediatrics increases, ERCP may be reserved for those patients in whom stones or sludge have been found by endoscopic ultrasound or in patients with a high pretest probability of having choledocholithiasis (e.g., patients with sickle-cell conditions). Any child with a first episode of cholangitis warrants a detailed investigation of a possible underlying biliary tract anatomic abnormality using at least one of the available diagnostic modalities.
Differential Diagnosis
The differential diagnosis for an acutely ill child with fever and clinical evidence of hyperbilirubinemia is broad; a thorough workup must include consideration of infectious and noninfectious etiologies ( Box 48.2 ). A thorough investigation for hepatic and biliary tract pathology with blood and radiologic studies must be initiated to evaluate for stones or other obstructive processes that may cause symptoms characteristic of the Charcot triad.
Cholangitis
Cholecystitis
Cholelithiasis
Sepsis
Hepatitis
Choledochal cyst
Pancreatitis
Urinary tract infection
Leptospirosis and other systemic infections with hepatic involvement
Spontaneous perforation of common bile duct
Biliary cyst
Appendicitis
Acute viral hepatitis may manifest in numerous ways but often begins with nonspecific signs: fever, headache, anorexia, and jaundice. Laboratory studies typically reveal a greater elevation of serum aminotransferase levels (ALT and AST) than the biliary tract enzymes alkaline phosphatase and γ-glutamyltransferase. In a child with no other evidence of biliary tract obstruction, screening assays for hepatitis infection are warranted.
Pyogenic liver abscesses and amebic abscesses tend to manifest with fever, abdominal pain, hepatomegaly, and focal right upper quadrant tenderness. Laboratory findings vary. CT is considered to be the most sensitive technique for evaluation of these diagnoses. Numerous bacterial, parasitic, and spirochetal infections also should be considered in the differential diagnosis, including but not limited to typhoid fever, brucellosis, leptospirosis, borreliosis, amebiasis, and malaria. It is beyond the scope of this chapter to expand on the systemic infections associated with hepatic involvement. Recurrent pyogenic cholangitis is another consideration, although it is rare in the Western Hemisphere and even more so in the pediatric population.
Jaundice may occur with sepsis of any etiology, more commonly in a critically ill infant or child. Clinical evaluation may show a predominantly direct (conjugated) hyperbilirubinemia usually accompanied by a modest elevation of γ-glutamyltransferase, although serum transaminase levels may not be elevated. These findings are caused by a hepatocellular cholestasis, owing to humoral mediators of sepsis (i.e., endotoxin and proinflammatory cytokines), but they can be exacerbated by biliary sludging that accompanies septicemia. Although sepsis-associated cholestasis historically was linked primarily to gram-negative sepsis, it can be seen in all forms of infection. In some cases, radiologic workup or biopsy is warranted to rule out ductal obstruction or biliary tract pathology. Jaundice may occur as the sole presentation of sepsis in infants and children; however, research into sepsis-induced cholestasis points to a complex, multifactorial etiopathogenesis.
Drug-induced cholestasis tends to occur acutely with the onset of jaundice, pruritus, and other symptoms that may mimic cholangitis. It rarely is associated with fever, however. Among the main classes of drugs commonly used in pediatric practice that may lead to significant hepatotoxicity are antimicrobials (mainly trimethoprim-sulfamethoxazole [TMP-SMX], amoxicillin-clavulanate, clindamycin, minocycline, nitrofurantoin, erythromycin, cephalosporins, isoniazid, rifampicin, fluconazole), anticonvulsants (phenytoin, carbamazepine, valproate, felbamate), nonsteroidal antiinflammatory drugs (aspirin, ibuprofen), antihypertensive agents (propranolol, diltiazem), and herbal remedies such as kava kava. Although rarely used in pediatric patients, statins may also lead to significant hepatotoxicity. If the offending agent is identified in time, removing it typically leads to rapid improvement. Ceftriaxone has been linked directly to cholangitis and cholecystitis, possibly as a result of its biliary concentration and precipitation, leading to sludge and stones. However, other third-generation cephalosporins also have been implicated in sludge and stone formation.
Other systemic illnesses may occur with fever and evidence of biliary tract pathology, and their presentations may overlap with presentations of infectious cholangitis. PSC is defined as a chronic inflammation of the intrahepatic or extrahepatic ducts leading to a range of biliary tract pathologies from dilation to obliteration and periductal fibrosis. PSC is seen most commonly in patients with inflammatory bowel disease and affects adolescent boys with inflammatory bowel disease more commonly than girls. Symptoms include systemic findings, such as fatigue, malaise, and weight loss, and evidence of cholangitis, including fever. PSC must be suspected in a jaundiced patient with inflammatory bowel disease or in an adolescent presenting for the first time with jaundice. Diagnosis is established best by ERCP or magnetic resonance cholangiography showing irregular narrowing and stricture of the hepatic and common bile ducts and the intrahepatic ducts. Patients with PSC are at risk of developing intrahepatic and common bile duct strictures, with subsequent obstruction, sludge or stone formation, cholangitis, and ultimately cholangiocarcinoma.
Treatment
Therapeutic goals in the treatment of cholangitis should include general support of the patient, early initiation of appropriate antibiotic therapy, and, in cases of obstruction by stones or stricture, decompression of biliary obstruction via ERCP or surgery. Consulting pediatric surgeons early in the course of evaluating a patient with suspected cholangitis generally is helpful. The importance of decompression and drainage of the bile tract in the face of systemic infection secondary to cholangitis cannot be overemphasized. Other potential etiologies of obstruction, such as choledochal cysts, ultimately require surgical consultation and repair.
Initial and conservative management should include appropriate inpatient monitoring, cessation of oral intake with intravenous fluid support, parenteral antibiotic therapy, and supportive management as warranted by the child’s clinical status. Antimicrobials are selected to cover suspected or documented organisms based on local or documented susceptibility patterns and the ability to achieve adequate serum and tissue concentrations. Currently no single antibiotic or combination is recognized universally as being the definitive therapy for cholangitis in children. Parenteral antibiotics are indicated in almost all cases of children with suspected biliary tract sepsis. Theoretically the ability to achieve high biliary concentrations ( Table 48.2 ) should be considered. However, clinical and experimental data are lacking to strongly support the recommendation for sole use of antimicrobials with excellent biliary penetration. Adequate serum levels may be sufficient.
| Antibiotic | Blood | Bile | Tissues |
|---|---|---|---|
| Aminoglycosides | +++ | + | + |
| Carbapenems | +++ | ++ | +++ |
| Cephalosporins a | +++ | +++ | ++ |
| Penicillins b | ++ | ++ | ++ |
| Quinolones | +++ | +++ | +++ |
| Trimethoprim-sulfamethoxazole | +++ | +++ | ++ |
a Anionic cephalosporins with molecular weight >500 such as cefpiramide, cefoperazone, ceftriaxone, cefotetan, cefixime.
Empiric antibiotics should cover the most commonly isolated enteric pathogens, including Escherichia coli, Klebsiella spp., and Enterococcus spp. Previously a combination of ampicillin or penicillin with an aminoglycoside was considered a standard regimen for cholangitis with a clinical cure rate of 40% to 95% in various adult studies. Multiple recent studies show equivalent effectiveness of newer agents including penicillin plus β-lactamase inhibitor combinations, third- and fourth-generation cephalosporins, and carbapenems.
The general recommendation for treatment of a pediatric patient with suspected cholangitis is a semisynthetic penicillin plus β-lactamase inhibitor combination or a third-generation cephalosporin with or without an aminoglycoside. The ureidopenicillins (e.g., piperacillin plus tazobactam) exhibit broad-spectrum activity against gram-positive streptococci, gram-negative bacilli, and many anaerobes. If a cephalosporin is used in a child with clinical sepsis, it is reasonable to consider the addition of metronidazole for anaerobic species, particularly Bacteroides spp . Rothenberg and colleagues reported a 63% success rate in the treatment of pediatric patients with cholangitis following HPE using imipenem-cilastatin or third-generation cephalosporins with or without aminoglycosides and a 58% success rate using semisynthetic penicillins with aminoglycosides. As mentioned previously, ceftriaxone probably should be avoided because it has been associated with biliary sludging and cholecystitis. Although carbapenems provide very broad-spectrum coverage of enteric organisms associated with bacterial cholangitis, these agents should be reserved for treatment of extended-spectrum β-lactamase producers or other multidrug-resistant pathogens. Antibiotic resistance is encountered more often in patients with repeated episodes of cholangitis. Empiric broad-spectrum treatment should be narrowed to target specific pathogens as soon as culture results are available to avoid emergence of antimicrobial resistance or overgrowth of flora leading to secondary infection (e.g., Clostridium difficile , yeast).
Antibiotic efficacy is determined by clinical and laboratory parameters such as defervescence and improvement in biliary excretion. Duration of antibiotic treatment in adult guidelines are as short as 2 to 3 days; however, a short course may result in recurrence in pediatric patients. The recommended course of therapy is 7 to 10 days, with longer duration recommended in special cases, such as recurrent or refractory cholangitis, and in the case of intrahepatic abscesses or hepatic surgery. Some experts recommend 14 to 21 days. Long-term administration of antibiotics without rationale should be avoided. Although oral antibiotic therapy generally has no place in the treatment of cholangitis in children, oral ciprofloxacin has been used in some adult populations.
Ultimately cholangitis or the risk thereof will not resolve in the presence of ongoing biliary obstruction. Although antibiotic therapy may treat septicemia, timely establishment of biliary drainage is imperative to relieve the obstruction and to increase biliary penetration of antibiotics. In 20% to 25% of adults with cholangitis, medical therapy is insufficient, and decompression via ERCP (or other drainage procedure) is indicated. Furthermore almost all patients who improve with medical therapy alone will ultimately require bile duct clearance to prevent recurrence of cholangitis. ERCP or percutaneous transhepatic cholangiography generally are recommended as first-line approaches because they pose a lower risk than does surgical intervention. While ERCP can be diagnostic in the case of biliary obstruction, it also provides therapeutic options with sphincterotomy, stone removal or destruction, or stent placement.
Treatment of parasitic cholangitis should include appropriate treatment of biliary parasites based on regional sensitivities in addition to antibiotic coverage of secondary bacterial infections. Endoscopic or surgical intervention may be required to remove worms or cysts from the biliary tree.
Prevention
Treatment of biliary obstruction is the primary means to prevent acute bacterial cholangitis. Long-term prophylactic antibiotics are not recommended. Although a few case reports and small case series have documented success with TMP-SMX, ciprofloxacin, and neomycin as prophylactic antibiotics, there are no data showing significant benefit compared to patients without prophylaxis in controlled studies. Moreover development of highly resistant bacteria selected by continuous use of antibiotics has been documented.
Antibiotics immediately prior to biliary tract surgery do play a role in prevention of wound infection rates. The role for antibiotic prophylaxis before endoscopic retrograde cholangiopancreatography is less clear. Antibiotics are recommended if biliary stone clearance is not anticipated during a single ERCP session; otherwise prophylaxis is unlikely to be useful.
Complications of Cholangitis
Regardless of the patient’s age at the time of presentation, cholangitis can be life-threatening. Other morbidities associated with cholangitis include biloma formation and pancreatitis. Because pediatric patients who present with cholangitis typically have underlying biliary or liver pathology, cholangitis may precipitate a rapid exacerbation of the underlying disease and potentiate cirrhosis, portal hypertension, severe gastroesophageal bleeding, or ongoing sepsis. In diseases such as biliary atresia, cholangitis may hasten the patient’s course toward requiring organ replacement. Cholangitis is an important determinant of long-term survival after HPE, but it is unclear if it is a determinant of transplant survival.
Specific Populations and Cholangitis
Cholangitis and Biliary Atresia
In pediatrics, cholangitis is encountered most frequently in the setting of a patient with biliary atresia who has undergone a Kasai procedure. In 1959, Kasai and Suzuki first reported relief of biliary obstruction in children with biliary atresia by HPE. The procedure, a roux-en-Y hepatic portoenterostomy, is considered to be standard first-line surgical therapy for infants with biliary atresia, and it is associated with the highest success rates and long-term survival when performed early, usually by 60 days of life. Without this procedure, 90% of patients with biliary atresia die before reaching age 3 years, at an average age of 19 months.
Cholangitis remains the most frequent complication of the Kasai procedure, occurring in 40% to 60% of patients. A subgroup of patients with the pathologic finding of cystic dilation of the intrahepatic bile ducts seems to have the highest risk of developing postoperative cholangitis. The development of cholangitis has been associated with a worsening in long-term prognosis of children with biliary atresia. Complications of cholangitis are severe, ranging from inflammation and scarring, to alterations in biliary flow, and eventually to biliary cirrhosis. Repeated bouts of cholangitis are associated with worsening liver function, impaired growth, and need for early transplantation. For this reason, early detection, appropriate management, and prompt intervention and treatment of cholangitis are important in this population.
Most cases of post–Kasai procedure cholangitis occur within 1 year postoperatively. In a 1976 review of 49 cases of children who underwent the procedure, 31 achieved good bile flow restoration. Of these, 20 subsequently developed cholangitis, 15 occurring within the first postoperative month and three within the second month. Likewise, in a study of 105 cases of cholangitis developing in 101 children after they underwent hepatic portoenterostomies, Ecoffey and colleagues showed that 63% of the cases occurred within 3 months after surgery, and 93% occurred within 1 year. Rarely late cholangitis may occur; this has been reported to occur several years after HPE.
The generally accepted mechanism for development of cholangitis after a Kasai procedure is ascending bacterial colonization. This theory is reinforced by reports of a higher incidence of cholangitis developing in patients with good or partial bile flow after the Kasai procedure (78%) than in patients with no obvious bile flow (13%). A 1978 study of 19 patients concluded that all bilioenteric conduits after the procedure were colonized within 1 month, correlating with the high incidence of symptomatic infection at this early stage. The retrograde bacterial colonization may be enhanced by overall changes in intestinal motility after the roux-en-Y loop. Over time, the intestinal conduit from hepatic porta to jejunum seems to “mature,” and the number of episodes of cholangitis diminishes. How this adaptation happens is unknown. Late episodes of cholangitis, occurring 1 to 2 years after a Kasai procedure, likely are related to mechanical obstruction, such as adhesions, and warrant investigation.
Gram-negative enteric organisms constitute most organisms causing ascending cholangitis after HPE. E. coli has been found in 50% of the first and second cholangitis episodes and in decreasing frequency in subsequent episodes. Anaerobes also are common findings and should be considered when selecting antibiotic treatment. Refractory or recurrent cases occurring after surgery may warrant consideration of fungal disease, principally Candida spp. Attempts to isolate an organism generally are made, but blood cultures typically have a low yield. Bile cultures tend to reflect the multiple enteric organisms that colonize the conduit but may not specify the true pathogens. Percutaneous liver biopsy has been used successfully to obtain cultures, but, as in other forms of cholangitis, it rarely is used for this purpose.
In the intraoperative and postoperative management of children with biliary atresia, attempts have been made to prevent the incidence of cholangitis. Various modifications in the surgical configuration of the intestinal conduit have been suggested to reduce enteric reflux. Initial studies have documented a reduced incidence of ascending cholangitis in the presence of a surgically placed antireflux valve. Despite the reduction of intestinal reflux in these cases, cholangitis continues to occur. Cases of refractory cholangitis may require surgical intervention, especially if obstruction of the conduit or porta hepatis is suspected. Absolute indications for reoperation after HPE are unclear; however, a recent series demonstrated positive outcomes with the primary indication of recurrent jaundice.
The role of corticosteroids in improving biliary drainage is controversial. Perioperative steroid pulses, typically a 3- to 5-day course of intravenous methylprednisolone, have been shown to be clinically beneficial by decreasing temperature, increasing bile flow, and improving liver biochemistries. In a recent, multicenter, randomized, double-blind, placebo-controlled study, there was no significant difference in bile drainage at 6 months between those treated with steroids and the control group. Additionally there were no differences in rates of cholangitis.
In addition, some centers advocate the use of prophylactic antibiotics, typically TMP-SMX. The benefits of this practice are not well established, however (see “ Prevention ”). In adults with recurrent cholangitis secondary to fixed obstruction, as in the case of malignancy, TMP-SMX and ciprofloxacin have been shown to be helpful in preventing episodes. When used, TMP-SMX is used as a first-line agent. In selected patients with recurrent episodes of cholangitis on TMP-SMX and a functional HPE, we have used oral ciprofloxacin successfully. Use of probiotics was recently studied in a Taiwanese cohort after HPE and compared to neomycin and a control group. Patients receiving Lactobacillus casei had fewer episodes of cholangitis compared to controls, and the probiotic was as effective at preventing cholangitis in patients with biliary atresia.
In patients with post–Kasai procedure biliary atresia, each episode of cholangitis is associated with a 1% mortality risk. In a recent longitudinal series, 30% of patients who died with biliary atresia without transplant had sepsis, several with suspected or proven cholangitis. Some studies suggest that no significant clinical difference exists in overall survival rates between patients who have undergone the Kasai procedure and have or have not had cholangitis. Previous studies suggest, however, an 88% mortality rate among patients who develop cholangitis within 1 month after undergoing the Kasai procedure and 16% in patients who develop it more than 1 month later. More recent studies suggest that the occurrence of cholangitis is related to early postoperative mortality, and the number of repeated episodes is inversely related to survival. Additionally in a series of 219 patients with biliary atresia from the Childhood Liver Disease Research and Education Network (ChiLDREN), 98% of these patients with native livers 5 or more years after HPE have evidence of chronic liver disease. Of this group, 136 patients (62.1%) experienced at least one episode of cholangitis post HPE. Multiple episodes occurred of cholangitis in 11 patients. Thus patients with recurrent episodes of cholangitis are considered for liver transplantation.
Cholangitis After Liver Transplantation
Infection remains the most common reason for morbidity and mortality after pediatric liver transplantation, accounting for 20% to 30% of postoperative deaths. Bacterial infection that develops after transplantation tends to occur within the first 2 months postoperatively and generally is of either respiratory tract or intraabdominal origin. Among patients with severe bacterial infections of intraabdominal origin, cholangitis and biliary tract infections commonly develop. Gram-negative aerobic bacteria are encountered most commonly in this setting. One adult study showed that 18% of 284 patients receiving liver transplantation had confirmed episodes of cholangitis. Pediatric data suggest that the rate of cholangitis after liver transplantation for biliary atresia is 5% to 11%.
Biliary tract disease frequently occurs after the post–liver transplantation complication of hepatic artery thrombosis. This complication was more prevalent in the early days of pediatric liver transplantation but decreased owing to the use of microsurgical techniques. Hepatic artery thrombosis eventually leads to damage of the bile duct because the biliary blood supply is exclusively arterial, whereas the hepatic parenchyma is vascularized by the portal vein and the hepatic artery. Biliary injury leads to altered biliary anatomy and drainage, increasing the risk of development of infection in these patients. Although the majority of pediatric liver transplant recipients have a roux-en-Y biliary–enteric anastomosis from the donor bile duct to the recipient bowel, ascending cholangitis is rare in this population. In patients with a duct-to-duct anastomosis, cholangitis secondary to stricture formation or intraductal lithiasis can be treated by ERCP.
Cholangitis that develops after liver transplantation may manifest with fever, jaundice, elevated aminotransferases, hyperbilirubinemia, and bacteremia. The variable nature of an immunocompromised patient’s response to infection renders the reliability of each of these signs and symptoms unique to each occurrence. Distinguishing these symptoms from the presentation of posttransplant rejection or infection (e.g., with CMV or Epstein-Barr virus) is important. For this reason, liver biopsy often is a necessary part of the evaluation of a posttransplant patient with fever and elevated liver tests.
Cholangitis in Immunocompromised Patients
Although biliary disease related to acquired immunodeficiency syndrome (AIDS) may be considered the most common cholangiopathy of immunocompromised hosts, it is not the most frequent one in pediatric practice. Cholangitis also may occur in children with non-AIDS immunodeficiency. Sclerosing cholangitis has been reported in cases of primary immunodeficiency, including familial T-cell deficiency, IgA/IgG deficiency, and X-linked hyper-IgM syndrome. Patients with sclerosing cholangitis often present with superimposed bacterial cholangitis because of poor biliary drainage. Opportunistic hepatobiliary infection also has been reported in children with leukemia.
AIDS-related cholangitis is a well-known complication of AIDS. It tends to occur late in the course of the illness and is more common in adults than in children. With the decline in the number of new AIDS cases in the United States, especially in pediatric patients, this diagnosis has become rare. In 1989, Cello described four distinct patterns of disease in AIDS-related cholangitis as seen on cholangiography: papillary stenosis, sclerosing cholangitis, combined papillary stenosis and sclerosing cholangitis, and long extrahepatic bile duct strictures. The pathogenesis of these changes is unknown and may be related to biliary inflammation secondary to immunodeficiency, infiltration of the mucosa by HIV itself, or opportunistic infection by known gut culprits in AIDS infection.
Opportunistic agents most commonly responsible are CMV, Cryptosporidium, Microsporida, and, uncommonly, Mycobacterium avium-intracellulare and Isospora . One report of unexplained cholangitis in a small cohort of HIV-positive men identified Enterocytozoon bieneusi in the bile of all of these patients. Although AIDS cholangiopathy is extremely rare in children, these pathogens can be found in pediatric patients with primary immunodeficiencies and associated PSC and with secondary immunosuppression after undergoing solid organ transplantation.
Clinical presentation is similar to that in non-HIV patients, with the exception of jaundice, which tends to be less common. In a series of 45 adults with AIDS-related cholangitis, abdominal pain was reported as the most common presenting symptom, occurring in 64% of patients, followed by diarrhea (22%), fever (20%), and jaundice (7%). Twenty percent of patients were asymptomatic and identified by routine blood work alone. A 1997 review reported that 90% of adults present with right upper quadrant or epigastric pain. Cholangitis has been reported as the initial presentation of HIV infection in a few patients.
Diagnostic steps include noninvasive imaging with sonography and CT, and ERCP. Abdominal ultrasound is abnormal in 75% of patients and typically shows dilation or wall thickening of the common bile duct. These findings, along with liver function studies, may be suggestive of the disease even in children. ERCP can show further characteristic changes in the biliary tract and has the added advantage of obtaining specimens for biopsy and culture and the possibility of therapeutic intervention. Although AIDS-related cholangitis typically is not directly associated with mortality, most patients with AIDS-related cholangitis die within 1 year of being diagnosed because cholangitis usually occurs in patients with end-stage disease. Therapy generally is symptomatic and should include coverage of bacterial cholangitis, which often is associated because of impaired biliary drainage.
Cholangitis in Association With Congenital Anatomic Abnormalities: Choledochal Cysts and Caroli Disease
Choledochal cysts occur in 1 in 15,000 births in Western nations and 1 in 1000 live births in Japan. Typically presenting signs suggest cholestasis and may include jaundice, dark urine, and acholic stools, or patients may present with abdominal masses with or without jaundice. If diagnosed late or left untreated, choledochal cysts may result in severe complications secondary to biliary tract obstruction, including cholangitis and pancreatitis. One series of 36 Indian patients reported 13 patients, more frequently children than infants, who presented with cholangitis. Cholangitis is more likely to be the presenting sign for choledochal cyst in adult patients.
Treatment of cholangitis associated with choledochal cysts involves supportive treatment of the patient, including appropriate antibiotic treatment. In the past, cyst-enteric drainage procedures were used as temporizing treatments, and this type of repair was associated with high rates of complications, including recurrent bouts of cholangitis, stones, and cholangiocarcinoma in the remnant duct. The current surgical goal is complete surgical excision; compared with internal drainage procedures, this approach is associated with lower rates of postoperative cholangitis and mortality. Five types of choledochal cysts have been identified, with solitary extrahepatic cysts (type I) being encountered most frequently. After this type of cyst has been excised, reconstruction of the biliary tract may involve a roux-en-Y choledochojejunostomy or hepatojejunostomy.
Patients who undergo this surgery also are at risk for developing postoperative ascending cholangitis, with an incidence of 8% to 19%. Although recurrent cholangitis may lead to chronic liver disease in the long term, antibiotic prophylaxis is not recommended routinely.
Caroli disease describes congenital dilation of the intrahepatic and extrahepatic biliary tree characterized by pure ductal ectasia. More commonly, dilation of the intrahepatic ducts is attributed to ductal plate malformation in association with congenital hepatic fibrosis. The association of ductal ectasia with congenital hepatic fibrosis is more common than without and is termed Caroli syndrome . Both of these diseases may manifest with clinical signs of liver disease or renal disease secondary to the associated condition of autosomal recessive polycystic kidney disease, or both. Dilation of the intrahepatic bile ducts results in biliary obstruction and places the patient at increased risk for development of intrahepatic stones and cholangitis, which significantly increases morbidity and mortality rates in Caroli disease and congenital hepatic fibrosis. Diagnosis is suspected in the case of recurrent cholangitis or portal hypertension of unknown etiology and can be confirmed by ultrasound or cholangiography (MRCP, ERCP, or PTC).
Surgical shunting is considered the treatment of choice because this condition typically does not progress to liver failure. Suspicion of cholangitis, whether owing to signs of infection or sepsis or laboratory results suggesting inflammation, should be confirmed via a diagnostic liver biopsy for culture. Treatment of cholangitis in the setting of Caroli disease may be difficult. Recurrent episodes may occur even after administration of intensive intravenous antibiotic therapy. In some cases, drainage procedures may be used for refractory or recurrent infections. Orthotopic liver transplantation is the treatment of choice in recurrent, life-threatening episodes of cholangitis.
Typically patients with Caroli disease or Caroli syndrome present with cholangitis because the biliary malformation communicates with the extrahepatic biliary tree. Rarely patients are seen with hepatic cysts associated with autosomal dominant polycystic kidney disease. These lesions are noncommunicating lesions and as such are not prone to infection. In the absence of a history of cholangitis, it is advisable that these rare patients not undergo invasive procedures of the biliary tree because of the risk of microbial seeding and subsequent suppurative cholangitis.
Cholangitis After Endoscopic and Other Biliary Procedures
The overall adverse event rate for pediatric ERCP is reported to be from 0% to 11%, and in adults cholangitis is a known risk of ERCP. In a series of 50 pediatric patients, low-grade fever, abdominal pain, nausea, and vomiting were reported as the most common complaints after undergoing ERCP; one patient was treated for mild cholangitis. Another group reported three cases of sepsis in adults caused by multidrug-resistant Pseudomonas aeruginosa after ERCP, ascribed to nosocomial transmission from the endoscope despite negative surveillance cultures. In adults, and rarely in children, biliary sphincterotomy with or without stent placement can be used to alleviate a common bile duct obstruction, most frequently malignant.
The major complication of biliary stents is obstruction and subsequent upstream infection. A Cochrane Review examined the role of antibiotics or ursodeoxycholic acid to maintain stent patency and demonstrated no conclusive evidence in favor of either one in the prevention of stent occlusion. In certain children and adolescents with a history of recalcitrant cholangitis, percutaneous transhepatic biliary drainage is used by experienced centers to decompress the biliary tree upstream of the stricture or to dilate the stricture. This procedure is used primarily in patients with PSC and in transplant patients with biliary stenoses secondary to ischemia or rejection. These patients may benefit from oral antibiotic prophylaxis, frequently ciprofloxacin for its excellent biliary penetration.
Cholecystitis
Cholecystitis and its related complications are most commonly associated with cholelithiasis (gallstones). However, it can occur without stone disease. An estimated 20 million individuals have gallbladder disease in the United States based on the National Health and Nutrition Examination Survey (NHANES) III report. Although gallbladder-related diseases occur less often in children, there is a trend toward increasing rates of disease. Gallstones accounted for 4 to 6 per 100,000 hospital discharges in children younger than 15 years. Recent data suggest that the obesity epidemic and related metabolic syndrome account for a greater proportion of gallstones in children. Despite the predominance of obesity-related disease, children with hemolytic disorders remain at high risk for gallstones and related comorbidities. Similarly, several studies have reported much higher rates of complicated gallbladder disease in children than in adults, with common bile duct obstruction and gallstone pancreatitis occurring in up to 30% of children.
Cholecystitis refers to inflammation of the gallbladder, which can occur in a variety of clinical scenarios. In adults, acute cholecystitis almost always is associated with gallstones—90% of adult cases occur secondary to gallstones. In contrast, 30% to 50% of pediatric cases are acalculous. Acalculous cholecystitis is discussed separately at the end of this section. The most likely cause of calculous cholecystitis is gallstone obstruction of the cystic duct, which leads to increased intraluminal pressure with gallbladder distention, mucosal damage, and release of inflammatory mediators. The end result is acute inflammation of the gallbladder. Any bacterial infection is likely a secondary occurrence to biliary obstruction.
Etiology and Pathogenesis
Gallstones are divided into cholesterol or pigmented stones (black or brown), although they often are mixed in constituents. Stone formation occurs secondary to precipitation of insoluble bile content (cholesterol, bile pigments, and calcium salts). Cholesterol stones are formed when the balance of cholesterol, lecithin, and bile salts is such that cholesterol in no longer soluble and becomes supersaturated. Black pigmented stones can form when there is supersaturated bile or a decrease in the bile salt pool. This process includes an increase in bilirubin anions (as seen in unconjugated hyperbilirubinemia), an increase in unbound Ca 2+ , or a decrease in other factors that solubilize calcium and bilirubin. Brown pigmented stones differ from black stones in that brown stones typically are more often related to infection and form within the common bile duct rather than the gallbladder in both children and adults. Opisthorchis sinensis and Ascaris lumbricoides are major sources of brown pigmented stones in rural Asian countries. Pigmented stones have been described with E. coli , Pseudomonas spp., Staphylococcus spp., Enterobacter spp., Citrobacter spp., and Salmonella enterica serovar Virchow. There is also a strong relationship to urinary tract infections. As discussed earlier, ceftriaxone as well as other third-generation cephalosporins have been associated with cholelithiasis and sludge in this population: up to 38% in one series of children with biliary tract disease in Israel.
The majority of data on children with pigmented stones come from patients with hemolytic disease (e.g., sickle-cell anemia and thalassemia). There is a significant population of patients with biliary disease secondary to hereditary spherocytosis and other red cell membrane defects, pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency, and autoimmune hemolytic anemia. The prevalence of pigment gallstones in hemolytic disease increases with age. In children younger than 10 years, the frequency is 12% to 14%; the frequency increases to 36% to 42% in individuals 10 to 20 years old.
Until recently pigmented stones were the predominant cause of gallstone disease and related morbidity in children, in which up to 72% were involved. However, in a recent 3-year report of more than 400 pediatric patients with gallbladder disease, there was more than a threefold difference in obese patients with cholesterol stones compared to those with hemolytic disease. This suggests a trend that children and adolescents are now more similar to adults with gallbladder disease than in years past.
Cholesterol stones are found most frequently in adults and have an increased prevalence in women from puberty to menopause and in obese patients. Although boys and girls exhibit an equal incidence in gallstones at young ages, the incidence in girls increases significantly after puberty, and female predominance of gallstone disease continues through menopause. Related risk factors for the presence of cholesterol stones in children and adolescents include ethnic background (Hispanic), obesity, pregnancy, and the use of oral contraceptives. In addition, conditions that are associated with decreased ileal bile salt resorption predispose to stone formation. This association includes patients who have undergone ileal resection or bypass and patients with Crohn disease.
Total parenteral nutrition remains a significant risk factor for children to develop biliary tract disease and in particular gallstone formation. This condition occurs more commonly in premature neonates, especially neonates with enteral diseases, in which prolonged fasting, sepsis, immaturity of the enterohepatic circulation of bile acids, small bowel bacterial overgrowth, and prolonged duration of total parenteral nutrition contribute to biliary stasis and increased prevalence of gallstones and sludge. The occurrence of gallstones secondary to total parenteral nutrition does not lead to increased prevalence of complications because many of these gallstones are clinically silent.
Gallstones in cystic fibrosis (CF) are common, with an estimated prevalence of gallstones in 10% to 30%. Symptomatic gallstones have been reported in 3.6% of affected pediatric patients. Gallstones in CF are predominantly composed of a mixed pigment and smaller amounts of cholesterol. Stone formation is multifactorial but is related to altered lipid composition and altered motility. Pathophysiology of pigmented stones in CF is also linked to deltaF508 mutations, with fecal bile loss and altered enterohepatic circulation as well as UGT1A1 mutations. Alterations in enterohepatic circulation have also been suggested as the mechanism for pigmented gallstone formation in Crohn disease. Finally children with chronic liver disease, and in particular cholestasis, are at increased risk for gallstone formation owing to a deficit of biliary excretion. Box 48.3 summarizes the pediatric patient populations at risk for the development of gallstones.
