Schiff’s Diseases of the Liver
10th Edition

Chapter 50
Bacterial and Systemic Infections
Stuart C. Gordon
A variety of bacterial, fungal, and rickettsial infections affect the liver, either as the result of direct hepatocellular or biliary invasion or through the production of toxins. In addition, systemic infectious processes frequently cause jaundice or nonspecific liver biochemical abnormalities through mechanisms that are less defined. The jaundice of bacterial pneumonia has been long recognized (1,2), and both jaundice and aminotransferase abnormalities have been associated with other systemic infections, including appendicitis (3), bacteremia in infants (4,5), and other extrahepatic infections (6,7). Most descriptions of liver dysfunction during systemic infection were reported several decades ago, whereas recent research has focused on the mechanisms of the jaundice of sepsis. Reports of the hepatobiliary manifestations of specific infectious agents come from around the world; newly recognized manifestations, diagnostic modalities, and treatment regimens shed new light on the clinical relevance of these conditions. Anecdotal case reports emphasize the need for clinicians to consider the possibility of such infectious agents and entities when encountering unusual cases of hepatitis or cholestasis.
Bacterial Infection and Jaundice
The observation that extrahepatic bacterial infection can cause jaundice has been attributed to Garvin (8). Osler (9) in 1892 found that in patients with pneumonia, jaundice might occur. The syndrome of septic jaundice is highly variable and may range from nonspecific

biochemical cholestasis to deep jaundice. Sepsis as a cause of jaundice in the hospitalized patient is often an overlooked entity (10). A disproportionate elevation of serum bilirubin in comparison with serum alkaline phosphatase and aminotransferase levels should suggest underlying sepsis, even in the absence of fever or leukocytosis (11). Accordingly, early medical or surgical intervention may reduce morbidity and mortality (11).
In more than one third of patients with sepsis, hyperbilirubinemia associated with bacteremia with or without an increase in serum alkaline phosphatase level may occur 1 to 9 days before the initial positive blood culture result is obtained. Although gram-negative bacteria, especially Escherichia coli, have been implicated as the predominant causative agent in most series, infection with nonhepatic gram-positive organisms, especially Staphylococcus aureus (12,13) also have been cited.
The mechanisms by which bacterial infection causes cholestasis and jaundice are not clear, but endotoxemia appears to be the likely cause. Lipopolysaccharide (LPS), or endotoxin, is contained within the outer membranes of gram-negative bacteria and is a potent inducer of cytokines. Endotoxemia may occur in the absence of documented sepsis (14), and increased levels of tumor necrosis factor α and other cytokines occur in alcoholic hepatitis and in jaundice associated with total parenteral nutrition. Accordingly, endotoxin-mediated cytokine release may be the basis for the jaundice of many disorders, including sepsis (15,16).
Early studies showed a reduction in bile flow and biliary excretion after administration of endotoxin to isolated, perfused rat liver. Pretreatment with dexamethasone, which blocks endotoxin-mediated release of the cytokines tumor necrosis factor α and interleukin-1, largely prevented this reduction in bile flow (11,17). The cholestasis of sepsis has long suggested an impaired hepatocyte transport of bile acids and organic anions. Studies have shown that canalicular bile acid and organic anion transport are markedly impaired in endotoxemia (18). Therefore, endotoxemia severely impairs the transport of organic anions at both the sinusoidal and canalicular membrane. Because of impaired hepatic organic anion transport, both bile acid–dependent and bile acid–independent components of bile flow decrease with the administration of endotoxin. Li et al. (19) recently demonstrated that LPS administration decreases organic anion transport mRNA levels in mice, and that this decrease is mediated through toll-like receptor 4 (TLR4).
The jaundice of sepsis was historically described as occurring in pediatric patients, but its presence in adults is increasingly observed. Marked elevations in direct and total serum bilirubin concentrations occur in bacteremic adults (20,21). In a review of 100 consecutively enrolled adult and pediatric patients with positive results of blood cultures (4), 54% had elevated serum bilirubin levels, and 34% had values of 2.0 mg/dL or greater. The condition may be more prevalent among patients with preexisting liver disease, whereas only 6% of patients without preexisting hepatobiliary disease had jaundice in another series (22).
The molecular pathogenesis and pathophysiology of cholestasis has been reviewed (23,24). Secretion of bile depends on the adequate functioning of many membrane transport systems in both hepatocytes and cholangiocytes, and various molecular defects in hepatocellular membrane transporters are associated with cholestatic liver disease in humans. At present, ursodeoxycholic acid (ursodiol) is used in many cholestatic liver diseases, presumably because it replaces toxic hydrophobic bile salts in serum, liver, and bile. At present, however, ursodiol has no accepted role in the cholestasis of sepsis. A better understanding of the molecular mechanisms involved in cholestatic syndromes should unfold the potential for newer therapies (23).
Specific Bacterial Infections
Salmonella Hepatitis (Typhoid Fever)
Both Salmonella typhi and Salmonella paratyphi cause the acute systemic disease enteric fever. It has been estimated that 16 million cases occur per year, with at least 600,000 deaths, making typhoid fever a major public health problem in less developed regions of the world (25). Although clinical hepatitis is unusual (probably fewer than 25% of all cases), liver involvement is present in almost all cases (26).
The term salmonella hepatitis refers to liver injury caused by infection with either S. typhi or S. paratyphi, and the disease has been documented in both endemic and nonendemic areas. Among the 150 cases of salmonella hepatitis reported to date, most occurred in patients with typhoid infection. The disease affects people of all ages, and those with immune deficiency are particularly at risk. Among persons with human immunodeficiency virus (HIV) infection, the most commonly isolated serotypes are Salmonella enteritidis and Salmonella typhimurium (25). Alcoholism has been identified as a predisposing factor for severe forms of S. enteritidis infection in cases in which no other underlying disease has been evident (27,28,29).
The mechanism by which the organism causes hepatitis is not established. It may be related to either direct hepatic damage from endotoxin or the inflammatory process or to immune mechanisms. In a rodent

model of Salmonella infection, the organism invaded and multiplied extensively in hepatocytes. Thereafter destruction of infected hepatocytes by inflammatory phagocytes was followed by a release of bacteria into the extracellular space. The findings suggested that lysis of infected hepatocytes by phagocytic cells was an important early-defense strategy against liver infection with S. typhimurium (30). Similar mechanisms of infection occurred with Francisella tularensis and Listeria monocytogenes (see subsequent text). There is also evidence to suggest that the severity of the hepatitis in typhoid fever correlates with the virulence of the infecting organism (31,32).
The liver histology of salmonella hepatitis is nonspecific. Ballooning degeneration with vacuolation has been reported. Reticulum endoplasmic dilatation, mitochondrial alterations, and biliary canaliculus injury have been described. Occasionally, S. typhi organisms are found in the liver cells, as are lobular aggregates of Kupffer cells, lesions known as typhoid nodules (33,34). Such nodules simulate granuloma formation and represent hyperplasia of the reticuloendothelial system. This hyperplasia reportedly causes hepatic enlargement in patients with enteric fever (35).
The clinical presentation of salmonella hepatitis resembles that of viral hepatitis, but certain features help in differentiating the two diseases. In particular, high fever (often >40°C) and bradycardia (inappropriate response of heart rate to degree of fever) seem to be more common among patients with salmonella hepatitis. In addition, the biochemical profile is markedly different from that of viral hepatitis and suggests the presence of an infiltrative process rather than hepatitis. In a comparison of 27 cases of salmonella hepatitis with acute viral hepatitis, El-Newihi et al. (36) found that patients with salmonella hepatitis were more likely to have a disproportionately increased serum alkaline phosphatase level and that serum aminotransferase values were far lower than with acute viral hepatitis. Also unlike viral hepatitis, salmonella hepatitis was associated with fever and a left shift of white blood cells (37). Jaundice is unusual, and many cases of salmonella hepatitis are anicteric. In untreated patients, jaundice may be delayed appearing in the second to the fourth week of the illness. Among patients with jaundice, and presumably more severe disease, glomerulonephritis (characterized by increased blood urea nitrogen and serum creatinine levels, proteinuria, and urinary sediment red cell casts) has been more common (38,39). In the more severe cases, in addition to glomerulonephritis, complications include liver abscess, cholangitis, encephalitis or neuropsychiatric manifestations, myocarditis, or bleeding diathesis. Disseminated intravascular coagulation with extensive gangrene of the extremities and rhabdomyolysis has been described (27).
Establishing a diagnosis of salmonella hepatitis may be difficult in developing countries, because the manifestations are similar to those of other forms of acute hepatitis, including viral hepatitis, leptospirosis, and malaria. The biochemical profile described earlier helps to differentiate the various entities. The alanine aminotransferase (ALT) to lactate dehydrogenase (LDH) (ALT/LDH) ratio usually is less than 4.0 in salmonella hepatitis. A ratio greater than 5.0 is reported in acute viral hepatitis, and a ratio less than 1.5 occurs in cases of central zonal injury, such as hepatic ischemia or acetaminophen injury (36).
Prompt diagnosis and early intervention with appropriate antibiotics assure a good prognosis. Because of salmonella resistance to the so-called first-line antibiotics (chloramphenicol, trimethoprim-sulfamethoxazole, and amoxicillin), antibiotic sensitivity testing is advised. A 5-day course of fluoroquinolone is the therapy of choice for uncomplicated enteric fever. Some experts have advocated the addition of intravenous dexamethasone (40). Because the organism can enter the bile and reside in the gallbladder, shedding for long periods can cause the chronic carrier state. Follow-up stool cultures are advised for all patients with typhoid fever to ensure that they are not carriers, and long-term fluoroquinolone therapy may help eradicate the carrier state (35). The prognosis for salmonella hepatitis is excellent; death has occurred among patients with malnutrition and immunodeficiency.
There has been a renewed interest in tuberculous infection of the liver because of the increasing incidence of extrapulmonary tuberculosis related to acquired immunodeficiency syndrome. In such cases, Mycobacterium avium-intracellulare is often the cause of liver dysfunction (see Chapter 51). Classically, however, hepatic tuberculosis (infection with Mycobacterium tuberculosis) as a part of miliary disease may occur in as many as 80% of all patients dying of pulmonary tuberculosis (41). The original description of hepatic tuberculosis classified the disease as (a) miliary, a part of generalized disease, or (b) local, with focal involvement of the liver. The terms that have led to confusion over the years included tuberculous pseudotumor, atypical hepatic tuberculosis, tuberculous cholangitis, and tuberculous liver abscess (42).
One classification scheme (42) separates hepatic tuberculosis into three categories: Miliary, granulomatous, and localized hepatic. The miliary form, which is part of generalized miliary disease, usually does not involve the liver. Granulomatous disease, that is, hepatitis due to tuberculosis, is defined by the finding of typical caseating granulomas at liver biopsy and response to appropriate antimicrobial therapy. Finally,

localized hepatic tuberculosis is further classified into disease that is either (a) without bile duct involvement (e.g., solitary or multiple hepatic nodules or tuberculous abscess) or (b) with bile duct involvement due to either compression of the bile duct by lymph nodes or actual involvement of the ductal epithelium by the tuberculous process. Therefore, the term hepatobiliary tuberculosis refers to a distinct clinical entity of localized hepatic disease with characteristic clinical features.
The portal of entry of M. tuberculosis organisms into the biliary tract and the liver is the hematogenous route or, less commonly, the portal vein or lymphatic vessels (43). Therefore disease that is isolated to the liver is considered rare, even in the absence of documented disease elsewhere; often inactive pulmonary tuberculosis is found at autopsy. One variant form of hepatic tuberculosis without active pulmonary or miliary disease is the so-called “nodular form,” which presents as an isolated liver tumor or abscess (44,45). In most cases, the clinical presentation is that of neoplasm, with solitary liver lesions of variable size and imaging features, raised alkaline phosphatase values, weight loss, and so on, in the absence of known previous tuberculosis. In one recent series, PCR assay of the liver tissue in five cases established the etiologic diagnosis of M. tuberculosis, with postoperative histologic diagnoses only showing chronic granulomatous inflammation. Such cases underscore the difficulty in reaching the correct diagnosis of hepatic tuberculosis, the value of PCR technology in establishing this diagnosis, and the need for a high index of suspicion (44).
The clinical manifestations of hepatobiliary tuberculosis are those of the extrahepatic disease; hepatic involvement usually produces no symptoms (46). Nevertheless, cases of fulminant hepatic failure have been reported, among both immunosuppressed and immunocompetent persons (47,48). In one summary of cases of gastrointestinal tuberculosis in California, patients with hepatic involvement usually had right upper quadrant pain or fever of unknown origin (49). Nonspecific abdominal pain may be present in patients with chronic tuberculosis, whereas fever and weight loss are common in cases of tuberculous abscess. The most common physical finding is hepatomegaly, which probably occurs in most cases (46,50). A disproportionately increased serum alkaline phosphatase level is a consistent finding (51), which suggests the presence of an infiltrative hepatic process, whereas nonspecific aminotransferase elevations do not aid in diagnosis (52). The presence of jaundice suggests biliary involvement, and the biochemical profile may simulate that of extrahepatic biliary obstruction (53).
An unusual manifestation of tuberculosis involves the development of portal hypertension caused by the compression of the portal vein by tuberculous lymph nodes, followed by the rupture of esophageal varices and hematemesis (54). Isolated pancreatic tuberculosis may manifest in a manner very similar to that of a pancreatic neoplasm, including a mass lesion of the pancreatic head (55). Similarly, gallbladder tuberculosis is reportedly increasing in incidence and may manifest as biliary colic and acute cholecystitis (56).
Another unusual but increasingly reported variant of hepatobiliary tuberculosis is obstructive jaundice caused by the involvement of the bile duct, pancreas, or gallbladder. Compression of the biliary tree by involved lymph nodes or possibly by direct involvement of the biliary epithelium or rupture of a caseating granuloma into the lumen of the bile duct may cause jaundice and biochemical cholestasis. Intrahepatic bile duct obstruction may result from granulomatous involvement, often as part of miliary tuberculosis. The entity of bile duct tuberculosis (57) may manifest as bile duct dilatation and common hepatic duct strictures. Biliary cytologic findings from endoscopic cholangiography may yield the diagnosis (58). Such patients have painless jaundice and weight loss that mimics malignant disease of the pancreas or cholangiocarcinoma, and dilated bile ducts are found at imaging studies. Experience with therapeutic biliary stenting has been variable, and in unsuccessful cases, percutaneous biliary drainage decompresses the obstruction (59,60).
Imaging studies may help rule out other conditions. Plain radiographs may show hepatic calcifications in patients with chronic tuberculosis, and both ultrasonography and computed tomography (CT) may show complex masses, either solitary or multiple. Such masses, common in patients with tuberculous liver abscesses, cannot be differentiated from malignant tumors and necessitate aspiration or biopsy for further investigation. One patient with cirrhotic hepatitis C and end-stage renal disease presented with multiple hyperechoic hepatic lesions on ultrasound, without pulmonary involvement (61). Blind percutaneous liver biopsy may be useful in the diagnosis of the miliary form, whereas direct-guided biopsy with laparoscopy results in a higher diagnostic yield. At laparoscopy, a cheesy white appearance of irregular nodules, often resembling malignant tumor, has been described (42,62). Although the finding of caseating granuloma is highly suggestive of tuberculosis (Fig. 50.1), similar pathologic findings occur in brucellosis, coccidioidomycosis, and Hodgkin’s disease. Caseation is commonly associated with tuberculosis, but in some series it occurs less frequently. The finding of acid-fast bacilli at biopsy occurs infrequently, fewer than 35% of cases, and the yield of a positive culture result for M. tuberculosis itself is even less common.
Molecular techniques establish the diagnosis of hepatic tuberculosis. Akcan et al. (63) and Alcantara-Payawal et al. (64) reported very high sensitivity (overall assay positivity of 88% in one series) with

low false-negativity among control patients, from a PCR assay on the liver tissue of patients with infection.
▪ Figure 50.1 Tuberculosis. Caseating hepatic granuloma in a patient with fever of unknown origin.
The management of hepatic tuberculosis involves the use of at least four antituberculous drugs, usually including isoniazid, rifampicin, pyrazinamide, and ethambutol (65). Although therapy traditionally lasts at least 6 months, multidrug resistant organisms require alternative chemotherapies, and there is a genuine need for new agents. It is anticipated that implementation of the recently developed molecular assays for M. tuberculosis will serve to assess response to therapy and allow individualized treatment duration.
Legionnaires Disease
Although most forms of pneumonia may cause derangements in liver function, Legionnaires disease, pneumonia characterized by multisystemic involvement, is particularly likely to cause abnormal results of liver tests. In one large review (66) both aminotransferase levels (up to 15 times the upper limit of normal) and alkaline phosphatase levels (up to 9 times the upper limit of normal) accompanied the pneumonia. Fifteen percent of patients also had hyperbilirubinemia. Therefore, the finding of markedly abnormal liver biochemical values in the presence of obvious pneumonia may be a clue to the appropriate diagnosis. The organism can be found with direct immunofluorescence or other techniques (Fig. 50.2) (67). Deranged liver biochemistries may represent the main manifestation (68).
Three species of Brucella affect humans: Brucella melitensis, Brucella abortus, and Brucella suis. Brucellosis is an occupational disease that affects food handlers, and organisms enter the body through the skin or oropharynx and spread to regional lymph nodes. The disease can also be airborne and transmitted to personnel in microbiology laboratories.
▪ Figure 50.2 Legionella pneumophila serogroup 3. Antigenic material within sinusoidal lining cells in the liver (direct immunofluorescence, 512×). (Courtesy of John Watts, MD.)
The involvement of the liver in human brucellosis may occur with infection by both B. melitensis and B. abortus. The incidence of liver disease in brucellosis depends on the definition. Colmenero et al. (69) proposed that the concept of hepatic complication of systemic brucellosis be reserved for patients with obvious hepatic dysfunction, including jaundice or abscess. Defined in these terms, only 2.4% of 530 patients with B. melitensis infection had hepatic complications, whereas the presence of hepatic granuloma in the absence of overt hepatitis may be more common. In a study of 905 patients with brucellosis, Ariza et al. (70) found 16 cases of chronic hepatosplenic suppurative brucellosis (14 in the liver and 2 in the spleen) among 15 patients. One half of the patients had previous remote brucellosis. Although hepatic abscess formation after acute infection is unusual, mild nonspecific liver enzyme abnormalities may be detected in approximately 50% of patients with brucellosis. In addition to hepatic involvement, spontaneous bacterial peritonitis can occur in the absence of obvious hepatic involvement (71,72). Febrile and fatal hepatitis with hepatic abscess and endotoxic shock has been described (73).
Carazo et al. recently described the imaging features in cases of hepatosplenic brucelloma, and noted that on ultrasound, the lesion appears iso- or hypoechogenic with the liver, with focal calcifications. Contrast-enhanced CT scans showed predominantly solid masses with irregular borders, rarely with transdiaphragmatic lung invasion (74).
Histologic examination of the liver in brucellosis usually shows nonspecific portal and lobular inflammation, and small noncaseating granulomas are often associated with reactive hepatitis (Fig. 50.3). The finding of granuloma is constant when the duration of the

disease is less than 100 days but is infrequent after this time (75). The predominant biochemical derangement in clinically apparent disease is an increase in serum alkaline phosphatase level. This finding suggests the presence of an infiltrative process. The organism can be isolated from the blood in acute states, but cultures may take 3 weeks to turn positive. Agglutinating antibodies generally appear after the second week of illness, and the diagnosis usually is established by the demonstration of increasing titers. Therefore, the presence of acute infection may be established by isolation of the microorganism or by appropriate serologic findings. These diagnostic criteria may not be helpful, however, for chronic forms of the disease, which may have evolved over long periods.
▪ Figure 50.3 Brucella melitensis. Nonspecific lymphoplasmacytic inflammatory infiltrate in patient with brucellosis (hematoxylin and eosin, 510×). (Courtesy of John Watts, MD.)
The more serious form of the disease therefore involves hepatic abscesses, and imaging studies show large calcium densities within the liver. Many such patients had known brucellosis many years earlier and were free of symptoms before the development of the abscess. However, even among patients without previous brucellosis, the finding of hepatic calcium deposits when the patient first arrives for evaluation strongly suggests that this entity represents a local reactivation of a previous undocumented brucellosis, as in tuberculosis (70). In the United States, the manifestation of brucellosis among children as hepatosplenic abscess may cause diagnostic confusion, particularly among immigrants and travelers from countries where brucellosis is endemic (76).
Unlike patients with acute brucellosis, patients with hepatic abscess (chronic hepatosplenic suppurative brucellosis or “brucelloma”) tend not to have either leukopenia or relative lymphocytosis, and biochemical abnormalities are minor (68,75). The differential diagnosis includes neoplasm, hydatid disease, pyogenic or amebic abscess, and other granulomatous infections, including tuberculosis and histoplasmosis (77). Such patients often have had very low titers of agglutinating antibody that have delayed appropriate diagnosis.
The drugs administered for therapy for acute infection are tetracycline and rifampicin. In cases of chronic suppurative disease, percutaneous or surgical drainage should be performed (70,78).
Infection with F. tularensis, the causative agent of tularemia, occurs after exposure to jackrabbits and hares, the main animal reservoir in North America and Europe. Hunters are at risk and may acquire the disease from tick or deer-fly bites in the summer months. In Sweden, the lemming is responsible for this disease (“lemming fever”), whereas in Russia the water rat and muskrat may spread tularemia. The disorder usually affects the lungs, and the usual manifestation is a flu-like syndrome occurring between 1 and 10 days after exposure. Liver involvement is rare, and when it does occur, only modest aminotransferase abnormalities are found (79). Tularemia also manifests as obstructive jaundice with fever, suggesting the presence of cholangitis. A cholestatic biochemical profile may cause a diagnostic dilemma in such cases (80).
Early diagnosis and management of tularemia probably account for the rarity of hepatic dissemination, but hepatic tularemia may also manifest as a solitary hepatic abscess early in the course of disease (81). Histologic examination of the liver in cases of tularemia shows multiple focal areas of coagulative necrosis with a surrounding chronic inflammatory infiltrate (82). The diagnosis can be established serologically with demonstration of agglutinating antibodies. Enzyme-linked immunosorbent assay (ELISA) tests are available, but a PCR test for F. tularensis should enable rapid confirmation of the clinical diagnosis of tularemia (83). Treatment consists of streptomycin or gentamicin.
L. monocytogenes is an organism found mostly in rodents. It is widely distributed in nature, including soil and plant material. It usually causes meningoencephalitis or pneumonitis, although hepatic involvement is reported. The liver disease of listeriosis is more common in neonates, but in adults, it may manifest as signs and symptoms of viral hepatitis, usually with high fever (84). Patients are often immunosuppressed or have underlying malignant disease (85). The onset may be gradual over several weeks or immediate fulminant hepatitis. Aminotransferase levels may be high, and jaundice may be present. The presence of high fever and leukocytosis tends to differentiate this condition from viral hepatitis, and the diagnosis is confirmed by the isolation of the organism from blood or cerebrospinal

fluid. The disease may also manifest as a liver abscess, in which case the diagnosis is established by culturing aspirated abscess material (86).
Melioidosis is endemic to northeastern Thailand but is also found throughout Southeast Asia and northern Australia. It is a potentially fatal infection caused by the bacterium Burkholderia pseudomallei (formerly Pseudomonas pseudomallei). The organism is ubiquitous in many parts of the tropics, and is found in damp soil and freshwater. The usual mode of acquisition is through inhalation or through minor skin abrasions. The mortality may be high, averaging 45%, and in cases of acute septicemia, death occurs within the first 3 days after hospital admission. The disease has protean manifestations, and histopathologically it mimics tuberculosis and catscratch disease. Early diagnosis and proper antibiotic therapy (parenteral ceftazidime was provided for 4 weeks in the report of Ben et al. (87)) are crucial.
Melioidosis may present with pulmonary infection, tonsillitis, localized abscess or fulminant septicemia (87). Liver involvement in melioidosis is common, but the increase in aminotransferase and serum bilirubin values is similar to that among patients with other forms of bacteremia. Visceral organ abscesses are common and usually involve the spleen, liver, and kidney. Granulomas may be found. The sonographic appearance of these multiple, small, discrete abscesses is target-like, and larger multiloculated abscesses are common (88). The differential diagnosis of melioidosis includes other forms of liver abscess, tuberculosis, and other bacterial causes of sepsis. Immunohistochemistry plays a useful diagnostic role, and polyclonal antibodies applied to formalin-fixed, paraffin-embedded tissue help establish the diagnosis earlier than the traditional but less reliable culture techniques (89).
Spirochetal Infections
Professor Weil of Heidelberg first made the classic description of febrile headache, jaundice with renal failure, and severe muscle pain, which is now known as Weil disease. Yet only a small percentage of patients infected by spirochetes of the genus Leptospira have this most severe of manifestations, and most descriptions of liver pathology in this disease come from autopsy series. Early recognition, with administration of appropriate antibiotics, has resulted in a very low incidence of hepatic manifestations.
Leptospirosis has a worldwide distribution. It results from direct or indirect exposure to the urine of infected animals, usually rodents. The most common serotypes are Leptospira icterohaemorrhagiae, carried by rats, and Leptospira canicola, carried by dogs. The organism enters the body through wounds on the skin and through intact mucous membranes and can directly penetrate the skin. Therefore the disease often results from occupational exposure, as among persons who work in sewers, mines, and construction sites and among food workers who may be exposed to rodent-infested environments. Leisure activities that include swimming, white-water rafting, or fishing in rivers or ponds contaminated with infected urine from wild animals also have resulted in leptospiral infection (90). In Thailand, risk factors include walking through water, applying fertilizer or plowing wet fields (91). Eating uncooked rice has been reported as a risk factor because of contamination with rat urine (90).
Although usually considered a disease of developing nations, cases occur in the United States and may cause a diagnostic dilemma. Among immunosuppressed HIV-infected patients, homelessness in large cities may result in exposure to rodent urine and resultant urban leptospirosis (92). The usual manifestations are acute fever and a flu-like illness, often with cough and chest pain, that occur after a 7- to 10-day incubation period. The abdominal pain of the acute phase may simulate surgical abdomen and may manifest as biliary colic. At a recent triathlon in Illinois, which included swimming in a freshwater lake, two athletes had clinically suspected acute cholecystitis and underwent cholecystectomy. An immunohistochemical test for leptospirosis applied to these gallbladders showed bacterial antigens and intact bacteria (93). Central nervous system symptoms of headaches and confusion may occur in the acute stage.
A second phase occurs during the second week of illness. The patient may have a milder recurrence of the aforementioned symptoms. This is the so-called icteric stage and may be caused by the effects of an activated immune system (90,94). Muscle pain may become severe, especially in the lower extremities. Marked conjunctival congestion (suffusion) occurs within the first few days of the illness and may persist into the second stage. Jaundice may or may not be present at this stage. Renal function worsens during this second phase, and a progressive increase in serum creatine kinase level reflects the presence of myositis.
The third, or convalescent, stage starts in the third week with progressive improvement in mental status and renal function and relief from jaundice. The so-called classic Weil disease is actually a recurrence of the fever after termination of the first stage of the illness, and the initial biphasic course is bypassed. Hepatic involvement is usually self-limited, and “microcirculatory abnormalities” (95) have been implicated as a cause of high bilirubin values. One recent report from Japan (96) described a case of simultaneous hepatitis E

infection and leptospirosis, with prolonged cholestasis and jaundice lasting several months.
Doxycycline may be effective prophylaxis of leptospirosis (97). Once the disease has developed, early intensive care and administration of doxycycline may be lifesaving (98), and therefore early diagnosis is important. During the first phase, leptospires can be isolated from the cerebrospinal fluid and blood; in the second phase, they are isolated from the urine. Dark-ground microscopic examination of plasma has been found to be a simple and rapid form of early diagnosis of leptospirosis with hepatorenal involvement (99). PCR based on the flaB gene of Leptospira has been found to be an efficient tool for the rapid detection and identification of Leptospira from clinical specimens (100).
Syphilis is a multisystemic disease caused by the spirochete Treponema pallidum subsp. pallidum, and is a microaerophilic gram-negative bacterium. Like tuberculosis, syphilis, once a disease affecting primarily homosexual men, has been increasingly reported among heterosexuals in the urban areas of the United States. The disease spans several stages, from congenital involvement to tertiary disease, and derangements in liver function may occur in all stages. In the congenital form of the disease, liver manifestations generally occur between the ages of 2 and 15 years, with hepatic gummas. Biochemical hepatitis with jaundice may occur, and therefore a wide differential diagnosis can produce a diagnostic dilemma. A positive result of an ELISA test for immunoglobulin G (IgG) antibodies against treponemal antigen and the fluorescent treponemal antibody (FTA)-immunoglobulin M (IgM) help establish the correct diagnosis.
In a 1917 paper on the subject (101), jaundice was reported to occur in as many as 12% of cases of secondary syphilis, probably owing to inflammation of hepatocytes. The pathologic findings generally include lymphocytic and neutrophilic infiltrates in the portal tracts; pericholangiolar inflammation has also been described. Spirochetes are infrequently seen (10% in one series); identification of treponemes in the liver is even less common. Therefore, direct hepatotoxicity by the organism is probably a less likely pathogenesis of hepatitis than are immune-mediated mechanisms. Invasion of the portal venous system through the rectal portal entry in homosexual men with primary anal or rectal lesions may explain a reportedly higher frequency of syphilitic hepatitis in this population.
The clinical manifestations may be subtle in an anicteric patient, who may have anorexia, weight loss, and hepatomegaly. The initial signs and symptoms may include pruritus and proteinuria (102,103). The rash of secondary syphilis usually is present, whereas the primary chancre usually is no longer present. In the absence of jaundice, biochemical cholestasis with a disproportionately increased serum alkaline phosphatase level may provide a clue to the diagnosis (104,105,106). Syphilitic hepatitis may coexist with nephrotic syndrome due to syphilitic membranous glomerulonephritis (107). However, because many of the reported cases of presumed syphilitic hepatitis occurred before the advent of viral hepatitis serologic tests, Veeravahu (105) suggested that the evidence to implicate T. pallidum as a liver pathogen in early syphilis is not convincing. Nevertheless, the occurrence of acute cholestatic syphilitic hepatitis in the era of viral hepatitis testing has been described (108).
Additional laboratory studies of the syphilitic hepatitis of secondary-stage disease include a hemagglutination test for T. pallidum and an FTA absorption (FTA-ABS) test. Liver imaging studies may reveal focal liver lesions as large as 3 cm in diameter. In an unusual case from France, Maincent et al. (109) reported a case of tertiary hepatic syphilis that manifested as multinodular hepatic metastasis. This case shows that the entity of hepatic syphilis may manifest in a variety of misleading ways.
Liver involvement in cases of tertiary syphilis usually is discovered at the postmortem examination. The gummas of the liver may resemble metastatic disease at autopsy or may resemble cirrhosis because of the nodular configuration of the liver in the later stages. Hepar lobatum refers to the lobulation of the liver because it appears to be divided into several smaller lobes by deep furrows. The lobulation originates from the resorption of gummas in the tertiary stages of the disease (110). Focal liver lesions with filling defects on CT scans may similarly mimic metastatic disease in a patient with weight loss. Diagnostic liver biopsy is therefore essential (109) (Fig. 50.4). Appropriate intervention with proper antimicrobial therapy may reduce the size of the liver lesions.
The incidence of primary and secondary syphilis, as noted in the preceding text, has increased in the United States in recent years, especially among HIV-positive individuals (111). Regarding the involvement of the liver, the last large review of syphilitic hepatitis that was described in the medical literature was 30 years ago (112) until the recent report of seven such cases among HIV-infected patients (113). These individuals presented with rash and predominant alkaline phosphatase elevations, with symptomatic and biochemical improvement following antibiotic therapy. The authors noted that high rapid plasma reagin (RPR) titers were more likely to be present if CD4+ cell counts were higher. These cases emphasize the importance of entertaining the diagnosis of syphilitic hepatitis as a cause of otherwise unexplained high alkaline phosphatase levels among HIV-infected patients.
▪ Figure 50.4 Hepar lobatum. A: Diffuse pericellular sinusoidal fibrosis in congenital syphilis of liver (hematoxylin and eosin, 485×). B: Numerous spirochetes layered in periphery of sinusoids adjacent to hepatocyte cords (Dieterle, 1,200×). (Courtesy of John Watts, MD.)

Lyme Disease
One of the less recognized manifestations of multisystemic Lyme disease is hepatitis, yet hepatic involvement appears to be common. It has been suggested that Lyme disease resembles syphilis, in that a spirochete organism causes both diseases (in the case of Lyme disease, a zoonosis, the tick-borne Borrelia burgdorferi), and both diseases may develop as an acute or chronic multisystemic inflammatory disease (114). The mechanism by which liver injury occurs is not known. Direct invasion of the liver by the organism and immune-complex deposition have been proposed. In one case of Lyme disease–related hepatitis in a human, the organism was found in the liver with Dieterle staining, and the patient’s condition improved with doxycycline therapy. This result suggests that borrelial invasion may cause direct hepatocyte damage (115).
Lyme disease has both an early, acute stage and a chronic phase (116). Involvement of the liver is more common in the early stage. Histologic examination shows portal inflammation, ballooning of hepatocytes, considerable mitotic activity, hyperplasia of Kupffer cells, prominent microvesicular fat, and sinusoidal mononuclear and neutrophil cell infiltration (115). Clinically, in addition to other features of erythema chronicum migrans, hepatosplenomegaly and biochemical hepatitis may persist for several weeks. The acute phase may manifest as a febrile illness with jaundice and mixed hepatitic and cholestatic abnormalities (117).
In a review of the cases of 115 patients with erythema migrans, the characteristic rash of early Lyme disease, approximately one third of the patients were found to have abnormal serum ALT values. Among those with early disseminated Lyme disease, two thirds of the patients had abnormal liver biochemical values (118). The investigators concluded that liver function test abnormalities are common among patients with erythema migrans but that these abnormalities are generally mild and improve with antibiotic therapy. Zaidi and Singer recently reviewed biochemical abnormalities of the liver in patients with Lyme disease (118a).
Rickettsial Infections
Q Fever
The causative rickettsia of Q fever is Coxiella burnetii. It was first described in Australia in the 1930s after an outbreak of an undiagnosed febrile illness among workers at an abattoir in Brisbane; the Q represents query. The source of infection is infected sheep, goats, or cattle, and the infection may be transmitted through contact with unpasteurized milk or contact with livestock. The organism has been identified in ticks, and the disease has a worldwide distribution. Liver involvement is common.
The typical presentation of Q fever is a febrile, flu-like illness with pneumonitis. The usual epidemiologic risk factors of exposure to sheep, cattle, and goats may be lacking in many cases, and often the disease goes undiagnosed (119). Hepatitis is common (120), and the disease may manifest as hepatitis in the absence of pulmonary manifestations (121). In a report of 63 sporadic cases of Q fever in an urban adult population in Spain (122), approximately 50% of patients had accompanying hepatitis.
Three main hepatic manifestations of Q fever have been proposed: A clinically acute hepatitis-like illness without respiratory involvement (the most common form of hepatic involvement); an incidental finding of increased liver biochemical values in a patient with known acute Q fever; or fever of unknown origin with characteristic hepatic granulomas (123,124,125). After an incubation period of 14 to 26 days, patients have a fever and flu-like symptoms, often with a dry cough.

Bradycardia may be present. Liver biochemical abnormalities are common but nonspecific and may manifest as anicteric hepatitis. In an appropriate setting, the disease mimics several other conditions, including other fungal infections of the liver, other granulomatous diseases, drug reactions, and so on. A 70-year-old man with cancer presented with low-grade fever and fatigue following a vacation in the Canary Islands, an area endemic for Q fever. His illness progressed to jaundice and fatal liver failure; the following year, after considering the diagnosis, an indirect microimmunofluorescence test for C. burnetii IgG and IgM antibodies were strongly positive, therefore confirming acute Q fever (126).
The classic doughnut granuloma of Q fever—a central clear space in the center of the granuloma—is not pathognomonic for the disease and may be seen in Hodgkin’s disease and infectious mononucleosis (Fig. 50.5). The granulomas have been shown to disappear over a period of 3 months after appropriate antibiotic therapy (127). The granuloma is a dense fibrin ring surrounded by a central lipid vacuole and is composed of neutrophils, monocytes, eosinophils, and occasional multinucleated giant cells. Kupffer cells are hypertrophied and there may be a lymphocytic portal inflammation with erosion of the limiting plate (128).
The disease may be prolonged, may affect children exposed to farm animals (129), and one third of patients may have jaundice. The diagnosis is established when an increase in complement fixation is detected or the result of an immunofluorescent antibody titer to C. burnetii is positive (123). PCR can be used to amplify C. burnetii DNA from tissue (130,131). Tetracycline is considered the treatment of choice, although the less effective erythromycin may be an appropriate alternative in the treatment of children. A recently developed vaccine may be efficacious in persons at high risk (132).
▪ Figure 50.5 Section shows classic doughnut granuloma. The characteristic lesion of Q fever is a doughnut granuloma similar to that shown here (hematoxylin and eosin, 780×). (Courtesy of John Watts, MD.)
Ehrlichiosis is a rickettsial infection that occurs in animals and humans, and is caused by microorganisms of the genus Ehrlichia. The pathogenesis and comparative pathology and immunohistology of ehrlichiosis have been reviewed (133). Human infection with Ehrlichia canis, a tick-borne infection common among dogs, was first reported in 1987. Recent molecular characterization, however, has suggested that taxonomic reorganization will more accurately define the Ehrlichia species. Therefore, Ehrlichia chaffeensis causes human granulocytic ehrlichiosis, and the major tick vector is a member of the genus Ixodes (134).
Involvement of the liver in human ehrlichiosis is largely anecdotal, but it can be a multisystemic disease with intense cholestasis. In one case following a documented tick bite, a 56-year-old man had multisystemic disease with sepsis and renal failure complicated by deep jaundice. Liver biopsy showed intense bile stasis and intense neutrophilic infiltration of bile ducts that suggested extrahepatic bile duct obstruction with cholangitis. A rickettsial immunofluorescent antibody panel confirmed the presence of ehrlichiosis, and the patient responded to a course of chloramphenicol (135). A tetracycline such as doxycycline also is reported to be effective.
In a review of eight cases of ehrlichiosis managed at an Arkansas medical center, seven patients had raised aminotransferase levels that suggested biochemical hepatitis, and three patients had jaundice with a peak bilirubin level of 13.8 mg/dL. All eight patients were treated with and responded to doxycycline, including one patient who had multiple-organ failure but eventually recovered. The authors concluded that in the appropriate clinical setting, ehrlichiosis should be considered a cause of elevated liver enzyme values (136).
Rocky Mountain Spotted Fever
Infection with the tick-borne Rickettsia rickettsii causes the multisystemic disease that is occasionally associated with an increased alkaline phosphatase level and jaundice (137). Zaidi and Singer recently reviewed the gastrointestinal and hepatic manifestation of Rocky Mountain Spotted Fever (118a).
Tick-Borne Diseases
The prevalence of tick-borne diseases has been increasing in the United States as a result of greater outdoor activity and migration of the population into rural areas (118a).

The eight most common tick-borne diseases include Lyme disease, ehrlichiosis, Rocky Mountain spotted fever, tularemia, Colorado tick fever, tick-borne relapsing fever, Q fever, and babesiosis; many of these entities have been considered separately in this chapter. Table 50.1 summarizes the gastrointestinal and hepatic manifestations of tick-borne diseases. With the exception of Colorado tick fever and babesiosis, most of these infections may cause a form of acute hepatitis and should be considered in areas of endemicity. Ehrlichiosis is most likely to cause cholestasis and jaundice, whereas Q fever, Lyme disease, ehrlichiosis and, to a lesser extent, tularemia, may cause granulomatous hepatitis.
Table 50.1. Laboratory and Clinical Manifestations of Tick-Borne Liver Infections
Manifestation Lyme disease Ehrlichiosis RMSF Tularemia Colorado tick fever TBRF Q fever Babesiosis
Anorexia + ++ + + + + + +
Nausea + ++ ++ ++ ++ +++ ++ +
Vomiting + ++ ++ ++ ++ +++ ++ +
Abdominal pain + ++ ++ to +++ ++ + ++ + +
Diarrhea + ++ ++ ++ to +++ + + to ++ ++ +
Hepatomegaly R + to ++ + + to ++ R + + +
Splenomegaly + + to ++ + + to ++ R R to + + +
Jaundice + +++ + + + + + + to ++
Elevated bilirubin level + +++ + to ++ + + + + to ++ ++ to +++
Elevated ALT level ++ ++++ ++ to +++ ++ + ++ ++a +
aElevated alkaline phosphatase level is the predominant abnormality.
ALT, alanine aminotransferase; R, rare; RMSF, rocky mountain spotted fever; TBRF, tickborne relapsing fever; +, uncommon; ++ common; +++, very common; ++++, almost always present.
Reprinted with permission from Zaidi SA, Singer C. Gastrointestinal and hepatic manifestations of tick-borne diseases in the United States. Clin Infect Dis 2002;34:1206–1212.
Fungal Infections
Histoplasmosis has a worldwide distribution, including the central and northeastern United States, Central and South America, India, and the Far East. It is the most common cause of fungal infection in the Ohio River Valley of the United States. It is usually transmitted after inhalation of the organism Histoplasma capsulatum, which is particularly associated with bird droppings, especially those of chickens. In most cases, exposure to the fungus is asymptomatic, and documentation of previous exposure is in the form of delayed-type cutaneous sensitization.
Although liver involvement is common in cases of disseminated histoplasmosis, in which case the infection may travel from the lungs to involve other organs, the disease may also present as an isolated liver mass or as an infiltrative liver disorder. A 39-year-old HIV-negative alcoholic man from New Delhi presented with a 3-month history of weakness associated with fever and jaundice. Laboratory studies showed anemia, leukocytosis, and marked alkaline phosphatase elevation. A pharyngeal culture was positive for H. capsulatum, and a liver biopsy showed granulomas consisting of macrophages and giant cells. Multiple periodic acid-Schiff (PAS) positive ovoid fungal bodies were seen causing a swelling of the Kupffer cells consistent with the diagnosis of hepatic histoplasmosis, and treatment with amphotericin B was started with clinical improvement. This case, with a negative chest x-ray, demonstrates the potential for isolated liver involvement in cases of histoplasmosis (138).
Hepatic involvement with histoplasmosis may manifest as fever of unknown origin and cause a considerable diagnostic dilemma (139). It may also manifest as unexplained biochemical cholestasis with fatigue and weight loss, which can mimic neoplasia or even cholangitis (140). The disease occurs among persons without HIV infection, but immunosuppression in the form of chronic glucocorticoid therapy may be present. Liver biochemical abnormalities in many cases may be nonspecific, and biopsy may be needed for the correct diagnosis. Thrombocytopenia may be present and necessitate a transjugular approach to biopsy. Hepatic lesions may include diffuse granulomas distributed throughout the liver or parenchymal infiltration with macrophages filled with the organism, seen with fungal staining. One report described a rare case that presented as a solitary right-sided liver lesion invading the diaphragm (141).
A review of the pathologic spectrum of cases of gastrointestinal histoplasmosis showed that 10% of 52 patients had histologic evidence of liver disease, most commonly portal lymphohistiocytic inflammation (Fig. 50.6). Discrete hepatic granulomas were found in fewer than 20% of livers that were involved (142).
▪ Figure 50.6 Elderly diabetic man who lived in an area endemic for histoplasmosis had fever and hepatomegaly. A: Confluent portal granulomas in a patient with hepatic histoplasmosis (hematoxylin and eosin). B: Special stain shows uniform, oval, yeast-like cells morphologically typical of Histoplasma capsulatum (hematoxylin and eosin, methenamine silver). (Courtesy of Laura Lamps, MD.)

Early diagnosis may be lifesaving, so this infection requires diagnostic consideration. Management is the same as that of other disseminated fungal infections and usually includes intravenous amphotericin B. The use of newer antifungal agents has not been described.
Another case of an unusual manifestation of hepatic histoplasmosis involved a 56-year-old “university lecturer” from Canada with a 10-year history of disabling fatigue, and a 6-month history of anorexia, weight loss and abnormal liver biochemistries, primarily alkaline phosphatase elevations. A liver biopsy showed non-caseating granulomas with multinucleated giant cells, and screening serologies were positive for H. capsulatum. His only risk factor was having lived in Indiana from his youth. Additional studies confirmed Addisonian crisis. After appropriate antifungal therapy, his fatigue and constitutional symptoms improved (143).
Caused by infection with the fungi of the genus Candida, the clinical spectrum of candidal liver disease is varied. The most common species causing human infection is Candida albicans, although other species also cause disease. Liver involvement in systemic candidiasis often goes unrecognized, and hepatic lesions may be found incidentally at autopsy. Therefore the entity of focal hepatic candidiasis may be part of the syndrome of hepatosplenic candidiasis or, more appropriately, chronic disseminated candidiasis (144), because other organ systems may be involved. Although systemic disease is presumed, results of blood cultures may be negative, and appropriate diagnosis requires a high degree of clinical suspicion.
The typical patient has leukemia and fever, jaundice, and biochemical cholestasis after induction chemotherapy–associated neutropenia. After the nadir of neutropenia, the serum alkaline phosphatase level begins to increase, suggesting the presence of an infiltrative or infectious process. The pathogenesis of the disease probably relates to mucosal damage of the colonic mucosa at the time of neutropenia. Local invasion and subsequent entry of the Candida organisms into the portal circulation result in liver infection (145). Results at CT and ultrasonography are often normal in the early stage of neutropenic fever, whereas as the neutrophil count returns to normal, imaging studies may show focal liver lesions with a bull’s-eye appearance (145,146,147,148) (Fig. 50.7). These lesions may be absent on images, however, even with jaundice. In such cases, diagnostic laparoscopy with local anesthesia may show discrete focal yellowish-white punctate lesions scattered throughout the liver surface (149) (Fig. 50.8). Direct-guided biopsy (Figs. 50.9, 50.10 and 50.11) may establish the diagnosis and allow for appropriate antifungal therapy.
Cholangitis with common bile duct stenosis secondary to Candida colonization of the biliary tract was recently described in a patient on long-time mechanical ventilation. Cholangiography revealed bead-like deformity consistent with sclerosing cholangitis. Microbiologic analysis of aspirated bile confirmed Candidiasis (150).
Although the diagnosis of hepatic candidiasis required histologic findings previously, confirmation by culture (not possible in formalin-fixed samples), or immunofluorescence, or PCR testing now allows for a sensitive and specific diagnosis, and further permits Candida species identification. Kirby et al. (151) described a typical case of hepatosplenic candidiasis in which PCR was positive for candida DNA in both the sera and liver biopsy. The authors noted the importance of identifying species, because candida shows species-specific antifungal resistance patterns, that is, some resistant to fluconazole and others to amphotericin.
▪ Figure 50.7 Computed tomography scan of an 8-year-old girl with leukemia undergoing chemotherapy who had a fever. Images before (top) and after (bottom) administration of contrast material reveal numerous areas of low attenuation throughout the liver and spleen. Rim enhancement of the lesions after injection of contrast material is caused by inflammation. Open biopsy of the hepatic lesion proved the diagnosis of hepatic candidiasis. (Courtesy of Ali Shirkhoda, MD.)

Optimal therapy for hepatic candidiasis has not been established, in part because of the rarity of the condition, the paucity of controlled trials, and the absence of established end points of treatment. A relapse of the infection may be related to either premature discontinuation of therapy or inadequate antifungal treatment of patients with chemotherapy-induced neutropenia (144). Furthermore, the hepatic lesions of chronic disseminated candidiasis may transiently disappear during neutropenia, and therefore antifungal therapy should not be discontinued on the basis of radiologic findings alone (152). The original therapy for this infection consisted of amphotericin B, yet prolonged treatment with amphotericin B may cause renal toxicity and often fails to eradicate infection. Some experts have advocated the addition of other antifungal agents or the addition of liposomal formulations (153,154), which may be better targeted to enter the liver. Pappas et al. recently reviewed the treatment of candidiasis (155). Both fluconazole and caspofungin are as effective as and less toxic than amphotericin B, and can

be given orally (153,156). As illustrated in the recent case report by Kirby et al. (151), identification of the specific candida species may guide appropriate therapy, such as an oral azole, therefore obviating the need for prolonged parenteral amphotericin treatment. The heightened awareness of the entity of hepatic candidiasis in the patient with neutropenic leukemia undergoing chemotherapy has highlighted the importance of factors that promote its development, including intravenous catheters and broad-spectrum antibiotics; furthermore, there has been the suggestion that prophylactic antifungal agents may prevent systemic fungal disease, but results are conflicting (157,158).
▪ Figure 50.8 A 60-year-old woman with leukemia had fever and jaundice after induction chemotherapy. Computed tomography scan shows no significant pathologic process. At laparoscopy, however, the liver was diffusely infiltrated with small discrete lesions of focal candidiasis.
▪ Figure 50.9 Focal hepatic candidiasis. Same patient as in Fig. 50.8 is shown here. Centrally necrotic granuloma is surrounded by a thick fibrous capsule (hematoxylin and eosin, 80×). (Courtesy of John Watts, MD.)
▪ Figure 50.10 Focal hepatic candidiasis. Gross wedge biopsy specimen of liver shows necrotic granuloma encapsulated by fibrous tissue with central cavitation. This cavitation results in the bull’s-eye lesion often seen on imaging studies. (Courtesy of John Watts, MD.)
Actinomycosis is a chronic, progressive, suppurative disease caused by actinomycetes of the genus Actinomyces, notably Actinomyces israelii, Actinomyces bovis, and Actinomyces naeslundii. Infection often occurs in the mouth (cervicofacial) area, thorax, abdomen, or uterus (pelvic). Early management of dental sepsis is believed to have prevented the cervicofacial form of the disease, which is thought to cause infection by local proliferation of organisms (159).
▪ Figure 50.11 Focal hepatic candidiasis. Grocott-stained section shows numerous yeast-like cells and mycelial elements of Candida in the center of a granuloma (80×). (Courtesy of John Watts, MD.)
The involvement of the liver is rare, but primary hepatic actinomycosis is an important differential diagnosis to hepatocellular carcinoma in endemic areas, and may present as a solid liver mass. In a recent review of 57 cases reported in the literature, the mean age of patients was 43 years (range, 4–65 years) with a male predominance. Most patients presented with fever, abdominal pain and weight loss, typically with a subacute presentation of up to 18 months. Leukocytosis was common, as was serum alkaline phosphatase elevations (160).
Hepatic actinomycosis had been reported to occur in 15% of abdominal cases (5% of all cases). In a review of 11 cases of actinomycosis of the liver from Japan (161), investigators found that in six cases (55%), partial hepatectomy had been performed because of involvement of liver tumors and that five patients had liver abscess. The authors concluded that hepatic actinomycosis should be considered in the differential diagnosis of pyogenic liver abscess and space-occupying lesions of the liver.
The hepatic disease probably is caused by spread through the portal vein caused by a mucosal injury due to ulcer, inflammatory bowel disease, or surgery. Local aggregates of Actinomyces organisms are often associated with other bacteria, such as coliforms, and these other bacteria may be involved in the pathogenesis of the infection. The hallmark of the infection is the formation of inflammatory masses containing granules (Fig. 50.12) (162,163).
The CT scan appearance may be a multiloculated low-attenuation lesion with low intensity on the T1-weighted sequence at magnetic resonance imaging (high intensity on the T2-weighted sequence) with surrounding edema. A peripherally thickened and irregular inner wall may suggest the presence of an abscess (164). Angiography may show a hypervascular hepatic mass mimicking hepatic neoplasm in the arterial phase (166,167). These radiographic features are nonspecific, however, and there is debate regarding how best to establish the diagnosis.
Establishment of the correct diagnosis may be prolonged, as noted in the preceding text, because cases may manifest as nonspecific subacute presentations including fever of unknown origin (162,165) or inflammatory pseudotumors (163), which have the gross appearance of malignant lesions. This manifestation emphasizes the need to search for bacteria in such lesions. Often such patients have underlying sepsis due to chronic abdominal abscesses. The histologic examination of tissue samples (168) is needed to establish the appropriate diagnosis. In one case (169) a positive blood culture established the correct diagnosis, but a recent review of hepatic actinomycosis (170) observes that percutaneous or surgical interventions for tissue samples were more likely to be diagnostic than

positive peripheral blood cultures for A. israelii. In rare instances, the lesion may infiltrate the diaphragm and right lung (162).
▪ Figure 50.12 A: Microcolony of Actinomyces organisms (sulfur granule) surrounded by acute suppurative inflammation (hematoxylin and eosin, 80×). B: High-power Brown-Brenn stained section of a sulfur granule, which is composed of gram-positive filamentous bacteria. The diagnosis of actinomycosis was confirmed with direct immunofluorescence (not shown) (780×). (Courtesy of John Watts, MD.)
Most patients respond to prolonged intravenous penicillin G, alone or in combination with clindamycin or ciprofloxin, often for several months (160). Lack of response to such therapy may necessitate surgical drainage. Alternative regimens include erythromycin and tetracycline. One recent report described a 53-year-old immunocompetent male with hepatic actinomycosis who failed to respond to intravenous antibiotic and underwent right posterior hepatic segmentectomy, with successful resolution of infection and without evidence of recurrence (171).
The disease known as San Joaquin Valley fever is caused by the dimorphic fungus Coccidioides immitis. It is endemic in the Southwest region of the United States, Central America, and Mexico and is characterized by a respiratory infection and fever after an incubation period of 7 to 28 days. The route of infection follows inhalation of the fungus, and the disease may then spread from the primary lung focus to involve the liver. Extrapulmonary disease is rare, but case reports clearly show that both liver and biliary involvements are manifestations of coccidioidomycosis.
A 26-year-old man from New Delhi had right upper quadrant pain, and ultrasonography revealed a solitary right lobe liver abscess. Aspiration of the abscess revealed pure growth of coccidioidomycosis, which was confirmed with culture (172). In the United States, 8 of 1,347 (0.59%) patients who underwent liver transplantation at a California medical center had coccidioidomycosis, showing that this organism can cause a serious and in some cases fatal infection after liver transplantation and that the incidence of this disease appears to be increasing (173).
The usual clinical features are those of nonspecific anicteric hepatitis, often with biochemical cholestasis, in a person who has recently traveled to Mexico or the American Southwest. It commonly presents as a hepatopulmonary syndrome with eosinophilia (174). Biopsy of the liver shows granulomatous hepatitis (174,175). In rare instances, obstructive jaundice may relate to granulomatous involvement of the bile duct epithelium. Ramirez et al. (176) reported the case of a 43-year-old man from Arizona who had fever and abdominal pain followed by jaundice and a cholestatic biochemical profile with no obvious lung involvement. The bilirubin level reached 7.4 mg/dL, and endoscopic cholangiography showed an irregular stricture involving the common bile duct and intrahepatic biliary tree necessitating placement of a biliary stent. Biopsy of the lymph node performed at laparotomy showed granuloma with spherules, and complement fixation antibody testing confirmed the presence of coccidioidomycosis. Endoscopic retrograde cholangiopancreatography after successful therapy (fluconazole and intravenous amphotericin B) showed resolution of the stricture.
Among 37 immunosuppressed patients who received liver transplants who later moved to Arizona, the incidence of new coccidioidal infection was 2.7%, suggesting that coccidioidomycosis was not frequent in this population (177). Nevertheless, among patients with end-stage liver disease listed for transplantation in this same region of Arizona, the incidence of new coccidioidal infection was 4.2%, compared with 0.04% in the same county in the general population. The authors suggested that treatment might alleviate some of the

symptoms of coccidioidomycosis originally attributed to disease of the liver (178).
Other Infections
Nonspecific aminotransferase abnormalities occur in disseminated gonococcal infection (179,180). Cervical and pelvic gonorrhea may be associated with violin-string adhesions between the liver capsule and the peritoneal wall, known as Fitz-Hugh-Curtis syndrome. However, such adhesions are not pathognomonic for Neisseria infection, and may occur after other infections, including hepatic candidiasis (Fig. 50.13) (149).
A similar syndrome of perihepatitis occurs with infection with Chlamydia trachomatis (181), which may also cause prolonged fever and liver granuloma (182).
Mild liver dysfunction as well as acute hepatitis–like biochemical values may occur after infection with Campylobacter organisms (183). The organism has been isolated from bile during episodes of cholecystitis in association with gallstones (184).
▪ Figure 50.13 Perihepatic adhesion (Fitz-Hugh-Curtis syndrome) may occur in conditions other than gonorrhea. After therapy for hepatic candidiasis, a follow-up laparoscopy showed violin-string adhesions from the focal lesions to the peritoneal wall. Such adhesions may result in marked right upper quadrant pain.
Anecdotal case reports include a case of cholestatic hepatitis following infection with Shigella sonnei (185) and anicteric hepatitis associated with Shigella flexneri infection (186).
Cases of granulomatous hepatitis and cholestasis have been reported in association with disseminated yersinia infections (187).
Catscratch Disease
Hepatosplenic catscratch disease often manifests as fever of unknown origin in children who have had contact with an immature cat. The disease occurs when Bartonella henselae causes necrotizing granuloma in the liver or spleen or both. Fleas have also been suggested as vectors for this organism, because catscratches may be absent in some cases. Abdominal pain is common and occasionally is severe. Abdominal ultrasonography shows microabscesses in the liver or spleen. Positive serologic results for B. henselae establish the diagnosis. Several antibiotic regimens have proved effective (188). Among HIV-infected patients, a syndrome of peliosis hepatis (bacillary angiomatosis) is caused by B. henselae infection. Serologic assays, indirect immunofluorescence, and PCR assays may assist in diagnosis (189); prolonged antibiotic regimens with erythromycin, doxycycline, or macrolides have proved effective in various series (190,191).
Annotated References
Alvarez SZ. Hepatobiliary tuberculosis. J Gastroenterol Hepatol 1998;13:833–839.
Succinct review of the current approach to the classification, clinical spectrum, modern diagnostic techniques, and options in the management of hepatobiliary tuberculosis.
El-Newihi HM, Alamy ME, Reynolds TB. Salmonella hepatitis: analysis of 27 cases and comparison with acute viral hepatitis. Hepatology 1996;24:516–519.
This landmark paper from a U.S. medical center summarizes the clinical manifestations and relevance of salmonella (typhoid) hepatitis.
Marrie TJ, Raoult D. Q fever: a review and issues for the next century. Int J Antimicrob Agents 1997;8:145–161.
This review article discusses all aspects of Q fever, including its historical background, thorough literature review, and clinical and diagnostic advances. The hepatic manifestations of this disease are summarized.
Moseley RH. Sepsis and cholestasis. Clin Liver Dis 2004;8(1): 83–94.
Comprehensive overview of recent advances in the understanding of the pathophysiology of intrahepatic cholestasis in sepsis.
Mullick CJ, Liappis AP, Benator DA, et al. Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature. Clin Infect Dis 2004;39(10):100–105.
Report that emphasizes the need to consider syphilis as a cause of treatable liver dysfunction in HIV-positive patients.

Zaidi SA, Singer C. Gastrointestinal and hepatic manifestations of tick borne diseases in the United States. Clin Infect Dis 2002;34:1206–1212.
A practical review of the hepatic manifestations of tick borne disorders including Lyme disease.
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