Chapter 237. Infections of the Liver

Patients with infections of the liver generally present with nonspecific symptoms such as fever, abdominal pain, fatigue, or weight loss. The abdominal pain may be diffuse, be confined to the right upper quadrant, or radiate to the shoulder or back. Other symptoms may include adenopathy, arthralgias, and headache. The initial history should focus on travel, unprotected sex or drug use, anatomical anomalies or surgery that may affect the biliary tracts, a need for hemodialysis or blood products, and family history of hepatitis. Physical exam is often normal; some patients will have right upper quadrant or diffuse abdominal tenderness and hepatomegaly. Jaundice or stigmata of chronic liver disease is infrequent.1 For additional details regarding viral hepatitis, please refer to Table 237-1 and Chapter 308. Details regarding diagnosis and treatment of other organisms that infect the liver are provided in the relevant chapter in Section 17.

Laboratory findings of liver infections often consist of leukocytosis, elevated erythrocyte sedimentation rate (ESR) with variable elevation of bilirubin, aminotransferases (ALT/AST), alkaline phosphatase, and gamma-glutamyl transferase. Diagnosis of liver infections requires a high degree of clinical suspicion and should be considered in the context of patient age, chronicity of symptoms, disease epidemiology including geographic location or travel history, and associated conditions such as immune status. Liver ultrasound is useful in initial evaluation of the patient with suspected liver infection because it can screen for liver abscess or bile duct anomalies.

Cholangitis is an infection of the biliary tracts and is seen most commonly in patients with abnormal biliary tracts such as post-Kasai (portoenterostomy) for biliary atresia. Nearly 60% of patients have one or more episodes of cholangitis after portoenterostomy, with decreasing frequency over time.2 Other conditions that cause functional or mechanical obstruction of the bile ducts such as gallstones, congenital hepatic fibrosis, choledochal cysts, and primary sclerosing cholangitis (PSC) also increase the risk of cholangitis. When these patients present with fever and no obvious other source of infection, they should be evaluated for possible cholangitis. Cholangitis classically presents with jaundice, fever, and right upper quadrant pain (the Charcot triad); however, in children not all symptoms may be present. In patient status post-Kasai, fever is seen in nearly 100% of patients with cholangitis, usually with increased bilirubin or acholic stools and laboratory values showing either leukocytosis or leukopenia.2 Evaluation of cholangitis should include aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and blood and urine cultures, although blood cultures will be positive in less than 50% of cases.2-4 Imaging should also be undertaken by either ultrasound or CT scan to rule out the presence of abscess, calculi, ductal dilatation, or other anatomical lesions.3 If concern persists over the presence of a stone, a magnetic resonance cholangiogram (MRI) may be helpful in delineating the location, while endoscopic retrograde cholangiopancreatography (ERCP) provides therapeutic options in cases of obstruction. Liver biopsy can be used to support the diagnosis; however, the diagnostic value of the biopsy should be balanced with the risk of the procedure.

Therapy for cholangitis begins with ensuring that the patient is hemodynamically stable, with fluid resuscitation as needed. The patient may require nasogastric suction if an ileus is present. Antibiotics are given parenterally and should cover the most likely pathogens, based on local sensitivities, and have adequate biliary penetration. Cholangitis is most commonly caused by enteric pathogens such as E coli, Klebsiella, Enterobacter, and Enterococcus3; thus antibiotic coverage often involves a cephalosporin or broad-spectrum penicillin such as ampicillin-sulbactam in addition to an aminoglycoside. At times coverage should be expanded to include anaerobic bacteria, with a drug such as metronidazole. If the patient remains febrile, with evidence of obstruction, endoscopic retrograde cholangiopancreatography may be required to relieve the blockage;5 percutaneous drainage or surgical intervention is rarely needed. Patients should demonstrate response with defervescence and corresponding decrease in bilirubin, aminotransferases, and white blood cell count. Treatment should continue for 14 to 21 days.

Liver abscesses are usually classified as pyogenic (PLA) or amoebic based on etiology. The distinction is important because treatment varies substantially.

Pyogenic Liver Abscess

Pyogenic abscesses are commonly associated with trauma to the biliary tract6 or hematogenously spread through the portal vein in conditions such as appendicitis or inflammatory bowel disease.7 Other risk factors include pelvic inflammatory disease and altered immune status such as chronic granulomatous disease or leukemia. Important aspects of the patient’s history that suggest amoebic rather than pyogenic abscess include bloody diarrhea or travel to tropical areas preceding the illness. Signs and symptoms are usually nonspecific but commonly include fever, abdominal pain, right upper quadrant tenderness, weight loss, and hepatomegaly. A more fulminant presentation associated with septic shock may occur when multiple abscesses or a ruptured abscess occurs. Laboratory findings often demonstrate leukocytosis and an elevated erythrocyte sedimentation rate, but liver enzymes, alkaline phosphatase, and bilirubin may be normal or only mildly elevated. Diagnosis requires a high degree of suspicion and appropriate imaging.

Ultrasound or abdominal CT scans are the first line of imaging and may demonstrate abscesses as small as 1 cm. Abscesses appear as areas of hypoattenuation, with surrounding edema. Pyogenic abscesses are frequently multifocal. A solid appearance should suggest tumor. These findings are enhanced through the use of intravenous contrast. Amoebic abscesses, on the other hand, are usually single, most often in the right lobe, near the diaphragm; these tests, however, do not reliably distinguish between pyogenic abscess and amoebic abscess. As CT scans more accurately delineate abscess size, they allow further therapeutic guidance (see Fig. 237-1). The fluid should be obtained by either needle aspiration or placement of a drainage catheter, with specimens sent for gram stain and culture. Gram-positive bacteria are most common in children, although Gram-negatives and anaerobes are frequently involved and the specimen may grow more than one pathogen. Antibiotic therapy is aimed at covering the most likely pathogens and then refined based on culture susceptibilities. Treatment of 4 to 6 weeks is generally recommended.

Amoebic Abscess

Amoebic abscess presents similarly to pyogenic liver abscess but is caused by Entamoeba histolytica, which is reported to cause hepatic abscesses in up to 7% of invasive cases8 (see Chapter 341). Younger children and those living in or traveling from tropical regions such as Southeast Asia or Central or South America are most commonly affected. Jaundice is infrequently seen and diarrhea may be seen in less than half of patients at the time of presentation; however, a history of dysentery should raise the suspicion for this disease.

As with pyogenic liver abscess, the leukocyte count and erythrocyte sedimentation rate are usually elevated; and alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase are normal to mildly elevated. Imaging studies should include ultrasound or CT of the abdomen. Additional studies include evaluation of the stool for ova and parasites to evaluate the presence of trophozoites or cysts and serologic testing of the blood, which is positive in > 90% of patients.8 Many patients from endemic areas, however, will already have antibodies from previous exposure; the tests can also be falsely negative for the first 7 days of infection. Aspiration of the abscess may also be used to distinguish between pyogenic and amoebic liver abscess. In these cases, the fluid is classically sterile and reddish-brown in color; amoebic organisms will be seen in less than one third of cases.4

Treatment most often begins with metronidazole (50 mg/kg/day divided into 3 doses) for 10 days, with alternatives of tinidazole, ornidazole, and nitazoxanide, which can be given for shorter periods of time. This should then be followed by a luminal amoebicide such as paromomycin or iodoquinol for 10 or 20 days, respectively.9 This combination is effective at eradication in > 90% of patients. Surgery or invasive therapy usually is not needed. Aspiration may be indicated when fever and abdominal pain persist after 4 to 5 days of treatment and in large abscesses with imminent risk of rupture or abscesses with pulmonary or cardiac involvement.9 In these patients, repeated aspiration may be helpful in improving symptoms and speeding symptom resolution. Complications are generally related to delay in diagnosis or rupture of the abscess, which can cause peritonitis, as well as pulmonary or even cardiac involvement. Mortality is directly related with these findings.

A list of non-viral liver pathogens is shown in Table 237-2. Other bacterial infections also result in liver involvement as part of the systemic manifestations. Cat-scratch disease (CSD), caused by Bartonella henselae, is most often found in warm, humid climates and, in addition to lymphadenitis, can cause hepatitis, hepatosplenomegaly, and hepatic or splenic abscesses. Symptoms are nonspecific and similar to other liver infections previously discussed; in addition, patients often present with chronic adenopathy. The evaluation, therefore, should focus on a history of cat exposure, adenopathy, and seeking an inoculation site. Imaging studies may show multiple small lesions in both spleen and liver parenchyma, and antibody titers are typically elevated. Antibiotics may not be needed unless the patient is immunosuppressed; complete recovery is expected.10

Fitz-Hugh and Curtis syndrome is the common name for perihepatitis in association with salpingitis most often seen in young females. Rates range from 4% to 12% in most reports, but have been described in up to 27% of adolescents with salpingitis.11 Signs and symptoms generally include severe right upper quadrant pain at the lower costal margin with occasional radiation to the back or shoulder that increases with inspiration or deep palpation, in addition to a friction rub over the anterior costal margin. The most common organisms are those that cause pelvic inflammatory disease (N gonorrhea and C trachomatis), which can be identified in urine or cervical or rectal swabs. Laboratory values are not typically as helpful as the clinical picture taken in context. Treatment should cover the most likely bacteria.

Fungal liver infections are serious and a significant cause of morbidity and mortality most often seen in immunocompromised patients, especially neutropenic patients undergoing chemotherapy or post-transplant patients. Because of nonspecific symptoms, this condition should be suspected when a patient remains febrile without neutropenia, or when broad-spectrum antibiotics are administered and blood cultures have shown no growth. Fever, hepatomegaly, and splenomegaly are frequently seen with elevated alkaline phosphatase more often than bilirubin or liver enzymes. Ultrasound appears to be less sensitive than CT in the diagnosis of fungal liver infections. Different etiologies are listed in Table 237-2. Pertinent geographic clues include living or traveling in the southwestern United States or Mexico for Coccidioides, or living or traveling through the Ohio or Mississippi River valleys in the United States.4

The immunocompromised patient is susceptible to the same viruses and infections as immunocompetent individuals, but special attention should be given to opportunistic pathogens causing cholangiopathy, a condition with similar clinical and radiologic appearance to primary sclerosing cholangitis (see Chapter 420). Cholangiopathy is seen in patients with deficient cell-mediated immunity such as those who have AIDS, severe combined immunodeficiency (SCID), common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, MHC Class II deficiency, interferon-gamma deficiency, DiGeorge syndrome, or hyper-IgM syndromes.12,13 Signs and symptoms are similar to acute cholangitis with abdominal pain and fevers, but jaundice is less common. Other findings may include hepatomegaly and diarrhea. Laboratory values often demonstrate an elevated alkaline phosphatase with only mild elevation of bilirubin and mild to no change in liver enzymes. Mild hypoalbuminemia, anemia, or leukopenia may also be noted. Abdominal ultrasound may demonstrate mild dilation of the bile ducts, an enlarged gallbladder, and abnormal liver texture with possible splenomegaly. Detailed evaluation of the bile ducts may require magnetic resonance cholangiogram or endoscopic retrograde cholangiopancreatography. The most common pathogens include cryptosporidium and cytomegalovirus, but microsporidia and mycobacteria can also present. Treatment is more often aimed at prevention of the disease, as cholangiopathy often reflects an advanced disease stage and carries a poor prognosis. Therefore, in patients with AIDS, antiretroviral therapy remains the best option.12,14 With the introduction of highly active antiretroviral therapy and improved immune status, cholangiopathy is seen less frequently in HIV-infected patients. Patients with congenital immunodeficiencies may require bone marrow transplant.