INFECTIONS OF THE HEPATOBILIARY TRACT
Bacteriology of the Biliary Tract
Complications of Acute Cholecystitis
Biliary Tract Infections in Patients with HIV/AIDS
Pyogenic Hepatic Abscess
Infections of the hepatobiliary tract hold great potential for mortality and morbidity. Diagnosis may be difficult because of unusual presentations. Patients with advanced HIV and AIDS may present with hepatobiliary disease in which unusual pathogens (many nonbacterial) need to be considered, and for which management may differ significantly from that employed in other cases. Abdominal ultrasonography and computed tomography (CT) have favorably affected both diagnosis and treatment. Invasive radiologic procedures have emerged as an alternative to surgery in many instances.
Bacteriology of the Biliary Tract
The normal biliary tract is sterile. Approximately 80% of persons with cholelithiasis have biliary tract colonization; pathogenesis is unknown. Common bacteria include Escherichia coli, Proteus mirabilis, Klebsiella species, and enterococci and other streptococci. Anaerobes are less common than in other parts of the gastrointestinal tract, although the isolation of Clostridium perfringens is well described. Bacteroides fragilis may be noted as a colonizer in up to 41% of specimens obtained from elderly persons, but it is rarely pathogenic except in the presence of a stent.
Recent comparative studies demonstrate that the severity of the clinical condition is associated with the intensity of bacterial colonization. Likelihood of biliary colonization is higher when choledochlithiasis is present, and is essentially 100% with acute cholangitis. Age correlates with likely colonization, and in the presence of common duct stones, similar bacteria are recovered from common duct and gallbladder bile.
In the United States, most cases of acute cholecystitis are caused by cystic duct obstruction with subsequent proliferation of colonizing bacteria. Ischemia and tissue necrosis ensue, sometimes resulting in gangrene and perforation. The typical presentation of calculous cholecystitis includes right upper quadrant (RUQ) pain, nausea, and fever. In the elderly, presentation may be subtle, with blunted response to pain and absence of fever. In these situations, the diagnosis must be promptly suspected to avoid perforation, septicemia, and death.
The diagnosis of acute cholecystitis is usually suspected on clinical grounds and should be confirmed radiographically. Ultrasonography of the RUQ is generally considered the procedure of choice and may be able to predict the likelihood of perforation. If this test cannot be obtained for technical reasons, CT provides similar information. Routine blood studies often demonstrate leukocytosis with a left shift, but levels of hepatic enzymes and bilirubin may be normal. Elevation of serum bilirubin above 2 to 3 mg/dL suggests common duct obstruction and possible ascending cholangitis.
Management of acute cholecystitis consists of supportive care, appropriate antimicrobials, and surgery. Although the timing of surgical intervention remains controversial, most authorities recommend prompt cholecystectomy after initial medical stabilization. For patients who are too ill to tolerate major surgery, cholecystostomy may prove lifesaving and may be followed by removal of the gallbladder 4 to 6 weeks later. Patients who fail to stabilize within 24 hours or who demonstrate clinical deterioration should be operated on promptly.
Antimicrobial therapy is guided by the likely causative organisms. Although penetration of antimicrobials into the biliary tract has received attention in the literature, few clinical data confirm the importance of this. Additionally, most agents fail to penetrate the bile in the presence of total biliary tract obstruction. In all cases of acute cholecystitis, high-dose parenteral antimicrobials are initially indicated, as bacteremic disease is not unusual and may be polymicrobial. The regimen should be well tolerated, reasonably safe, and cover most enteric gram-negative bacilli, enterococci, and C. perfringens. Coverage for B. fragilis is controversial but is reasonable in the elderly. Single agents such as ticarcillin-clavulanate or imipenem-cilastatin are adequate for most cases. Recent investigations employing quinolones as monotherapy (either ofloxacin or ciprofloxacin) have also resulted in satisfactory outcomes. Therapy may be adjusted after the results of cultures become known. Severe sepsis with multiorgan failure or shock, for example, usually indicates a complication (gangrene, perforation) or complete cystic duct impaction.
Acute cholecystitis in the elderly patient is usually associated with higher morbidity and mortality. Up to 40% of the elderly have gangrene, perforation, or empyema at the time of surgical intervention. Fifteen percent have secondary intraabdominal abscesses. The reasons for these age-related differences are not understood. Often, diagnosis is delayed because of more subtle signs of disease. Elderly persons may be afebrile and fail to produce a prompt leukocytosis. Additionally, pain may be poorly localized and vaguely defined. Diagnosis should be suspected in the patient with vague abdominal pain of uncertain origin, and diagnostic studies should be undertaken promptly. Prompt surgical intervention may be necessary in uncertain circumstances.
In 2% to 15% of cases, cholecystitis is acalculous. Severe burns, other critical illnesses, residence within ICUs, and the postoperative state are contributory. Mortality is 30% to 50%, many times higher than that seen in calculous disease. The diagnosis of acalculous cholecystitis is often difficult, in part because of the severity of illness. Many patients cannot be carefully questioned and may be receiving medications that dull response. Fever, leukocytosis, and vague abdominal discomfort may be the sole presentation, and even these may not be simultaneously present. Diagnosis requires a high index of suspicion, and is generally made by RUQ ultrasonography. Laparoscopy can be definitive in selected cases and may obviate the need for formal laparotomy. Alternatively, a recent study employed follow-up sonography 24 hours after a nondiagnostic initial test result. Progressive thickening of the gallbladder wall correlated with acalculous cholecystitis. Therapy usually consists of percutaneous cholecystostomy, which may be curative. Antibiotics are given parenterally and should cover likely enteric flora of an ICU.
Biliary tract candidiasis has been recently reviewed. Approximately 1% of patients undergoing cholecystectomy demonstrate Candida as a significant pathogen. Many had uncomplicated cholecystitis. Risk factors include prior use of antimicrobials and corticosteroids. When disease is limited to the gallbladder, cholecystectomy without antifungal therapy is curative in patients who are not neutropenic patients.
Complications of Acute Cholecystitis
Gallbladder perforation is seen in 10% to 15% of cases and should be suspected in patients following delays in diagnosis and in men more than 70 years old. Clinical findings include RUQ mass, palpable gallbladder, and peritonitis. Three forms of perforation that occur are (a) free perforation into the peritoneal cavity, (b) rupture with local containment, and (c) rupture into an adjacent viscus. Generalized peritonitis, less common than localized and contained perforation, has the worst prognosis. The clinical presentation is similar to that seen when this disease has other causes, and identification of the gallbladder as the cause of peritonitis is usually made at laparotomy. Perforation with local containment often occurs several days after clinical cholecystitis is evident and usually presents as antimicrobial treatment failure. A palpable mass may become obvious. Rupture into an adjacent viscus, often the stomach, may be at first associated with dramatic clinical improvement. Management of perforation is surgical.
Emphysematous cholecystitis is an uncommon condition diagnosed by the presence of air in either the gallbladder wall or lumen. The clinical presentation is often that of “typical” acute cholecystitis, but with a higher rate of occurrence in male patients and a higher mortality rate (15% vs. 3% to 8%). C. perfringens is frequently implicated (45% vs. 10% to 15%). Early surgical intervention is necessary. Empyema of the gallbladder is documented at the time of operation and usually presents in the severely ill patient as RUQ discomfort. At the time of surgery, a pus-filled organ is demonstrated.
Ascending cholangitis results from infection within the common bile duct and is most often caused by an obstructing stone. It may also be noted as an uncommon complication of percutaneous biliary drainage, in the presence of intrahepatic stones, and in cases of AIDS. Fever (92%), chills (65%), and jaundice (67%) are generally observed, whereas RUQ pain (42%) is less commonly noted. Approximately 5% of patients present with septic shock. In the elderly, fever and pain may be subtle. Charcot’s intermittent fever is a syndrome of recurrent cholangitis, usually caused by a partially obstructing stone or a series of stones passing through the common duct. In a recent study, it was noted in fewer than 20% of patients with cholangitis.
Laboratory data may demonstrate elevations of both alkaline phosphatase and serum bilirubin. Levels of serum bilirubin above 3 mg/dL are unusual in uncomplicated acute cholecystitis. Leukocytosis is often observed but is nonspecific. Elevation of serum amylase is seen in approximately 40% of cases and does not necessarily imply pancreatitis.
Pathogens include enteric gram-negative bacilli, Enterococcus faecalis, and C. perfringens. B. fragilis and Candida albicans have been rarely noted. Rarely, parasites that include Ascaris lumbricoides, Clonorchis sinensis, and Echinococcus species have been identified. Ascending cholangitis is the most common cause of polymicrobial bacteremia, and the isolation of multiple pathogens from blood cultures should prompt the clinician to consider the biliary tract as the primary source. Overall, approximately 30% of patients with cholangitis will demonstrate positive blood cultures, and, of these, 25% will be polymicrobial.
Diagnosis can be confirmed by radiographic studies that include ultrasonography and CT. Generally, dilatation of the common duct more than 1.5 cm is noted. Cholangiography, generally by the endoscopic retrograde technique, is indicated in patients requiring urgent biliary decompression and those being prepared for surgery. Antimicrobial therapy is similar to that used for acute cholecystitis. Ticarcillin-clavulanate or imipenem-cilastatin cover most likely pathogens. Recent data demonstrate that parenteral quinolones are also effective. If combinations are to be employed, they should include an agent active against enterococci. Treatment should be continued for 7 to 10 days. Maintenance therapy with low-dose antibiotics has been studied in selected patients with recurrent cholangitis. Quinolones, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanate have been recommended, with suppression continued for 3 to 4 months before reassessment of need. The presence of yeast on Gram’s stain (from drainage) as the predominant flora or the heavy growth of Candida species on culture merits antifungal therapy. Amphotericin B remains the agent of choice, although newer data suggest a role for IV fluconazole.
Initial stabilization of the patient plus antimicrobials is always indicated. Up to 85% of patients respond favorably to such measures. Urgent drainage is necessary in patients who fail to respond rapidly. For persons who improve, drainage will often be necessary to prevent recurrence. Choice between surgery and endoscopy is dictated by availability and anatomic considerations.
Biliary Tract Infections in Patients with HIV/AIDS
Recognition of hepatobiliary complications in patients with AIDS dates back to the early 1980s, when patients with biliary tract cryptosporidiosis and obstruction were identified. Although typical bacterial diseases may develop in persons with HIV/AIDS as described above, two syndromes specific to this population are AIDS-related cholangiopathy syndrome and acalculous cholecystitis. However, a recent investigation of patients who underwent cholecystectomy demonstrated that about 25% had cholelithiasis.
Acalculous cholecystitis in this population generally presents with subacute or chronic RUQ pain and fever. Advanced AIDS is usually present. Noninvasive imaging depicts a thickening of the gallbladder wall, but the gallbladder is free of stones. The severity of imaging findings is out of proportion to clinical complaints. Laboratory data demonstrate significant elevations of alkaline phosphatase and absence of leukocytosis. Organisms implicated are usually Cryptosporidium or cytomegalovirus (CMV). Other opportunists that have been identified include Microsporidia, Isospora, and Pneumocystis carinii. Surgery is indicated and alleviates clinical complaints. However. life span is only about 7 months, owing to underlying advanced AIDS.
AIDS-related cholangiopathy is seen in patients with advanced AIDS; the typical CD4 count is less than 100/mm3. The presentation is subacute or chronic RUQ pain, but fever, nausea, and vomiting are seen in about 50% of cases. Jaundice is distinctly unusual. Pathogenesis is not known. The diagnosis should be suspected in patients with advanced AIDS and RUQ pain. Ultrasonography or CT are initially indicated and often suggest dilatation of ducts. Endoscopic retrograde cholangiopancreatography is the study of choice. It provides the best definition of ducts and strictures, tissues and materials can be sampled for culture and other microbiologic testing, and therapy with sphincterotomy is possible if indicated. Treatment is geared to relieving obstruction (sphincterotomy or stent placement). Up to 67% of patients will have some measurable relief. Therapy of specific pathogens has been unrewarding. Drugs for CMV have not had a major impact on CMV-related cholangiopathy, and therapy with paromomycin for cryptosporidiosis has also generally been unrewarding.
Pyogenic Hepatic Abscess
Cases of pyogenic hepatic abscess comprise only 0.016% of hospitalizations. Most cases now occur as a result of common bile duct obstruction. Other causes include (a) perforations of any portion of the gastrointestinal tract, (b) septicemia, (c) blunt trauma, and (d) contiguous spread from adjacent infected foci. However, many cases are cryptogenic. Such abscesses must be differentiated from other space-occupying lesions, including tumors, amebic abscesses, and cysts. Tumors are generally associated with longer prodromes, absence of known risk factors for abscess, and absence of fever and leukocytosis. Amebic abscess should be especially considered in younger patients (often male) with a history of diarrhea who are from underdeveloped countries and in patients with major pleuropulmonary manifestations. Serologic tests for amebiasis are reliable and clinically useful, with results available in only several days. In patients with AIDS, space-occupying lesions may be associated with Kaposi’s sarcoma, lymphoma, CMV, and opportunistic fungi and mycobacteria. The opinion of the author is that although in almost 50% of cases a diagnosis is obtained, it is rare to find a treatable etiology.
The clinical presentation of pyogenic hepatic abscess depends on the cause. When it is associated with generalized sepsis, hectic chills and fever may occur along with with RUQ tenderness and hepatomegaly. Localizing findings, however, may be absent. More commonly, hepatic abscess presents as vague RUQ discomfort in the absence of major constitutional complaints. Symptoms may last more than 1 month. Jaundice is unusual except with common duct obstruction. Between 20% and 30% of cases are associated with abnormalities of the right side of the chest, such as atelectasis or elevation of the right hemidiaphragm. Pneumonia may be the first consideration.
Routine hematologic and microbiologic studies are not generally useful except if blood cultures are positive. The most common clue is elevation of serum alkaline phosphatase, which in the proper clinical context suggests infiltrative disease of the liver. The diagnosis can be confirmed by CT or ultrasonography, which usually detects a space-occupying lesion. Results of these procedures are positive in more than 90% of cases, but they may miss lesions smaller than 1 cm in diameter.
Therapy consists of appropriate antimicrobials and drainage. The bacteriology of pyogenic abscess is often polymicrobial and includes enteric gram-negative bacilli, enterococci, and anaerobes (including B. fragilis). Septic metastatic complications, often involving the eye or lung, were recently reviewed and found to be associated with Klebsiella pneumoniae and underlying diabetes. Liver abscesses complicating bacteremia are often caused by Streptococcus pyogenes or Staphylococcus aureus.
Antimicrobials should be active against B. fragilis and enteric gram-negative bacilli. A potential advantage of clindamycin is its ability to penetrate hepatic tissue in therapeutic levels. No controlled studies have been done comparing various antimicrobial regimens. Therapy should be continued for at least 4 weeks with adequate drainage and for at least 8 weeks if drainage is not performed or is incomplete. Oral therapy has not been well studied. Drainage of all accessible abscesses should now be considered the standard of care. Percutaneous drainage is safe and effective and is generally preferred to surgical intervention when technically feasible. Surgery should be performed to eradicate a feeding focus. (R.B.B.)
Brandt CP, Priebe PP, Jacobs DG. Value of laparoscopy in trauma ICU patients with suspected acute acalculous cholecystitis. Surg Endosc 1994;8:361–364.
The authors assessed laparoscopic findings in nine patients with suspected acalculous cholecystitis. Diagnosis was essentially 100%. They consider it more accurate than noninvasive studies.
Csendes A, et al. Simultaneous bacteriologic assessment of bile from gallbladder and common duct in control subjects and patients with gallstones and common duct stones. Arch Surg 1996;131:389–394.
A recent study continues to demonstrate that the normal gallbladder is sterile. The presence of stones increases likelihood of colonization, and in these circumstance gallbladder and common duct bile harbor similar organisms.
Ducreux M, et al. Diagnosis and prognosis of AIDS-related cholangitis. AIDS 1995; 9:875–880.
Forty-five patients with AIDS-related cholangitis were identified. Several different patterns of disease were demonstrated by endoscopic retrograde cholangiopancreatography, and sphincterotomy was successful in alleviating pain in only about 33%. Survival rates were only 41% (1 year) and 8% (2 years). CMV and Cryptosporidium were the most commonly identified organisms.
Huang CJ, et al. Pyogenic hepatic abscess. Changing trends over 42 years. Ann Surg 1996;223:600–607.
An interesting retrospective study of 223 patients with hepatic abscess seen during a 42-year period. Apparent incidence rose from 13/100,000 hospitalizations (1973) to 20/100,000 hospitalizations (1993). Despite more patients documented with malignancy, mortality decreased substantially, and significantly more patients were treated with percutaneous drainage. This is one of several studies that claim better reduction of mortality with open surgical drainage than with percutaneous approaches.
Nash JA, Cohen SA. Gallbladder and biliary tract disease in AIDS. Gastroenterol Clin North Am 1997;26:323–335.
The authors review the principles of diagnosis and treatment of biliary tract syndromes unique to AIDS. They stress acalculous cholecystitis and cholangiopathy syndromes, and point out that most cases occur in patients with advanced AIDS, who have limited life spans. Drainage procedures are often indicated, but therapy targeted at offending opportunists is generally unrewarding.
Sung JJ, et al. Intravenous ciprofloxacin as treatment for patients with acute suppurative cholangitis: a randomized controlled clinical trial. J Antimicrob Chemother 1995;35:855–864.
One of several investigations published during the past several years that indicate the efficacy of fluoroquinolnes as monotherapy for acute bacterial cholangitis. In this study, ciprofloxacin was compared with ceftazidime, ampicillin, and metronidazole. Mortality was less than 5% in each group, and ciprofloxacin as monotherapy was considered equivalent to triple antibiotics.
van dan Hazel SJ, et al. Role of antibiotics in the treatment and prevention of acute and recurrent cholangitis. Clin Infect Dis 1994;19:279–286.
An excellent review of antibiotic choices and indications for the management of cholangitis. Of particular interest is the information regarding suppressive antibiotics for patients with recurrent disease.