Bacterial, Parasitic, and Fungal Infections of the Liver, Including Liver Abscesses

The liver serves as the initial site of filtration of absorbed intestinal luminal contents and is particularly susceptible to contact with microbial antigens of all varieties. In addition to infection by viruses (see Chapter 78, Chapter 79, Chapter 80, Chapter 81, Chapter 82, Chapter 83 ), the liver can be affected by (1) spread of bacterial or parasitic infection from outside the liver; (2) primary infection by spirochetal, protozoal, helminthic, or fungal organisms; or (3) systemic effects of bacterial or mycobacterial infections.

Bacterial Infections Involving or Affecting the Liver

Gram-Positive and Gram-Negative Bacteria

A number of extrahepatic infections can lead to derangements in hepatic function, ranging from mild abnormalities of liver biochemical test results to frank jaundice and, rarely, hepatic failure.

Toxic Shock Syndrome: Staphylococcus Aureus or Group A Streptococci

Toxic shock syndrome is a multisystem disease caused by toxic shock syndrome toxins, which are superantigens that cause T-cell activation and massive cytokine release. Originally described in association with serious infections caused by S. aureus , this syndrome is now more frequently a complication of group A streptococcal infections, particularly necrotizing fasciitis. Risk factors for S. aureus toxic shock syndrome include tampon use and surgical wound infection. Typical findings include a scarlatiniform rash, mucosal hyperemia, hypotension, vomiting, and diarrhea. Hepatic involvement is almost always present and can range from elevations of serum aminotransferase levels to jaundice and extensive hepatic necrosis. Histologic findings in the liver include microabscesses and granulomas. The diagnosis is confirmed by culture of toxigenic Streptococcus pyogenes or S. aureus from the wound, blood, or other body sites. For wound infections or necrotizing fasciitis, surgical intervention is critical. Clindamycin, in conjunction with another active agent, is recommended to interfere with bacterial toxin production. Antibiotics effective against S. aureus include nafcillin for methicillin-sensitive isolates and vancomycin or linezolid for methicillin-resistant isolates, whereas penicillin remains active against S. pyogenes . Treatment with IV immunoglobulin in the setting of toxic shock syndrome associated with S. pyogenes is controversial and not recommended at this time.

Clostridium perfringens

Clostridial myonecrosis involving C. perfringens usually is a mixed anaerobic infection that results in the rapid development of local wound pain, abdominal pain, and diarrhea. The skin lesions become discolored and even bullous, and gas gangrene spreads rapidly, leading to a high mortality rate. Jaundice may develop in up to 20% of patients with gas gangrene and is predominantly a consequence of massive intravascular hemolysis caused by an exotoxin elaborated by the bacterium. Evidence of liver involvement may include abscess formation and gas in the portal vein. Hepatic involvement does not appear to affect mortality. The presence of clostridial bacteria portends a poor prognosis in persons with cirrhosis. Surgical débridement with wide excision is essential; penicillin and clindamycin are effective antibiotics.

Actinomyces

Actinomycosis is caused most commonly by Actinomyces israelii , a Gram-positive anaerobic bacterium. Although cervicofacial infection is the most frequent manifestation of actinomycotic infection, GI involvement occurs in 13% to 60% of patients. ^, Hepatic involvement is present in 15% of cases of abdominal actinomycosis and is believed to result from metastatic spread from other abdominal sites. Common presenting manifestations of actinomycotic liver abscess include fever, abdominal pain, and anorexia with weight loss. ^, The course is more indolent than that seen with the usual causes of pyogenic hepatic abscess (see later) and thus may be mistaken for a tumor. Fistula formation and invasion of other surrounding tissues such as the pleural space can occur. Anemia, leukocytosis, an elevated erythrocyte sedimentation rate, and an elevated serum alkaline phosphatase level are nearly universal. Imaging findings are nonspecific; multiple abscesses may be seen in both lobes of the liver.

The diagnosis is based on aspiration of an abscess cavity and either visualization of characteristic sulfur granules or positive results on an anaerobic culture. Most abscesses resolve with a prolonged course of IV penicillin or oral tetracycline. Large abscesses can be drained percutaneously or resected surgically.

Listeria

Hepatic invasion in adult human Listeria monocytogenes infection is uncommon. One report described 34 cases of listeriosis involving the liver, ranging from solitary to multiple abscesses and acute and granulomatous hepatitis. Hepatic histologic features include multiple abscesses and granulomas. Predisposing conditions include immunosuppression, diabetes mellitus, and underlying liver disease, including cirrhosis, hemochromatosis, and chronic hepatitis. The diagnosis of disseminated listerial infection is based on a positive culture result from blood or from an aspirate in the case of a liver abscess. Cholecystitis with L. monocytogenes has also been described. Treatment is with ampicillin or penicillin, often with gentamicin for synergy.

Shigella and Salmonella

Several case reports have described cholestatic hepatitis attributable to enteric infection with Shigella spp. ^, Histologic findings in the liver have included portal and periportal infiltration with polymorphonuclear leukocytes (neutrophils), hepatocyte necrosis, and cholestasis. Severe hepatic dysfunction associated with Shigella spp. infection has been reported.

Typhoid fever, caused by Salmonella Typhi , is a systemic infection that frequently involves the liver. Elevation of serum aminotransferase levels is common, whereas the serum bilirubin level may rise in a minority of cases. Some patients may present with an acute hepatitis-like picture, characterized by fever and tender hepatomegaly. Cholecystitis and liver abscess may complicate hepatic involvement with S. Typhi infection.

Hepatic damage by S. Typhi appears to be mediated by bacterial endotoxin, although organisms can be visualized within the liver tissue. Endotoxin may produce focal necrosis, a periportal mononuclear infiltrate, and Kupffer cell hyperplasia in the liver. These changes resemble those seen in Gram-negative sepsis. Characteristic typhoid nodules scattered throughout the liver are the result of profound hypertrophy and proliferation of Kupffer cells. The clinical course can be severe, with a mortality rate approaching 20%, particularly with delayed treatment or in patients with other complications of Salmonella infection. Severe typhoid fever with jaundice and encephalopathy may be differentiated from ALF by the presence of an elevated serum alkaline phosphatase level, mild hypoprothrombinemia, thrombocytopenia, hepatomegaly, and an AST level greater than the ALT level. Ceftriaxone is the first-line agent for the treatment of typhoid fever, with ciprofloxacin as an alternative in areas where resistance is uncommon.

S. Paratyphi A and B ( Salmonella enterica serotypes paratyphi A and B) are the predominant causes of paratyphoid fever. As in typhoid fever, abnormalities in liver biochemical test results, particularly elevated serum aminotransferase levels, with or without hepatomegaly, are common. Liver abscess is a rare complication. Treatment is with a third-generation cephalosporin or, where prevalence of resistance is low, a fluoroquinolone.

Yersinia

Infection with Yersinia enterocolitica manifests as ileocolitis in children and as terminal ileitis or mesenteric adenitis in adults. Arthritis, cellulitis, erythema nodosum, and septicemia may complicate Yersinia infection. Most patients with complicated disease have an underlying comorbid condition, such as diabetes mellitus, cirrhosis, or hemochromatosis. Excess tissue iron, in particular, may be a predisposing factor because growth of the Yersinia bacterium is enhanced by iron.

The subacute septicemic form of the disease resembles typhoid fever or malaria. Multiple abscesses are distributed diffusely in the liver and spleen. In some cases, the occurrence of Y. enterocolitica liver abscesses may lead to the detection of underlying hemochromatosis. ^, The mortality rate is approximately 50%. Fluoroquinolones may be used for most cases; for septicemia, third-generation cephalosporins are preferred.

Gonococci

In approximately 50% of patients with disseminated gonococcal infection, serum alkaline phosphatase levels are elevated, and in 30% to 40% of patients, AST levels are elevated. Jaundice is uncommon.

The most common hepatic complication of gonococcal infection is the Fitz-Hugh–Curtis syndrome, a perihepatitis that is believed to result from direct spread of the infection from the pelvis (see later). Clinically, patients describe a sudden, sharp pain in the RUQ. The pain may be confused with that of acute cholecystitis or pleurisy. Most patients have a history of pelvic inflammatory disease. The syndrome is distinguished from gonococcal bacteremia by a characteristic friction rub over the liver and negative blood culture results. The diagnosis is made by vaginal culture for gonococci. The overall prognosis of gonococcal infection appears to be unaffected by the presence of perihepatitis. Although resistance to various antibiotics is of increasing concern, ceftriaxone remains the antibiotic of choice. Presumed coinfection with Chlamydia trachomatis should be treated empirically (see later) with azithromycin or doxycycline.

Legionella

Legionella pneumophila , a fastidious Gram-negative bacterium, is the cause of Legionnaires’ disease. Although pneumonia is the predominant clinical manifestation, abnormal liver biochemical test results are frequent, with elevations in serum aminotransferase levels in 50%, alkaline phosphatase levels in 45%, and bilirubin levels in 20% of cases (but usually without jaundice). Involvement of the liver does not influence clinical outcome. Liver histologic changes include microvesicular steatosis and focal necrosis; organisms can be seen occasionally. The diagnosis is confirmed by detection of a direct fluorescence antibody in the serum or sputum or of antigen in the urine. The antibiotic of choice is azithromycin or a fluoroquinolone.

Burkholderia pseudomallei (Melioidosis)

Burkholderia pseudomallei is a soil-borne and water-borne Gram-negative bacterium that is found predominantly in Southeast Asia. The clinical spectrum of melioidosis ranges from asymptomatic infection to fulminant septicemia with involvement of the lungs, GI tract, and liver. Histologic changes in the liver include inflammatory infiltrates, multiple microabscesses, and focal necrosis. Organisms can be visualized with a Giemsa stain of a liver biopsy specimen. With chronic disease, granulomas may be seen. Some liver abscesses may demonstrate a “honeycombing” appearance on CT. Abscesses may need to be drained or débrided, and ceftazidime or meropenem is the initial drug of choice, followed by a prolonged course of trimethoprim/sulfamethoxazole, with or without doxycycline.

Brucella

Brucellosis may be acquired from infected pigs, cattle, goats, and sheep ( Brucella suis , Brucella abortus , Brucella melitensis , and Brucella ovis , respectively) and typically manifests as an acute febrile illness. Hepatic abnormalities are seen in a majority of infected persons, and jaundice may be present in severe cases. Typically, multiple noncaseating hepatic granulomas are found in liver biopsy specimens; less often, focal mononuclear infiltration of the portal tracts or lobules is seen. Rarely, brucellosis also may produce hepatosplenic abscesses. ^, The diagnosis can be made by isolation of the organism from a cultured specimen of liver tissue and is confirmed by serologic testing in combination with a history of exposure to animals. Surgical drainage may be required for management of Brucella abscesses. The combination of streptomycin and doxycycline is the most effective antimicrobial therapy.

Coxiella burnetii (Q Fever)

Infection by C. burnetii , typically acquired by inhalation of animal dusts, causes the clinical syndrome of Q fever, which is characterized by relapsing fevers, headache, myalgias, malaise, pneumonitis, and culture-negative endocarditis. Liver involvement is common. The predominant abnormality is an elevated serum alkaline phosphatase level, with minimal elevations of AST or bilirubin levels. The histologic hallmark in the liver is the presence of characteristic fibrin ring granulomas. The diagnosis is confirmed by serologic testing for complement-fixing antibodies. Treatment with doxycycline is usually effective.

Bartonellosis (Oroya Fever, Cat-Scratch Fever, and Bacillary Angiomatosis)

Bartonella species are fastidious, Gram-negative bacilli that cause a range of illnesses. Bartonella bacilliformis is endemic to Colombia, Ecuador, and Peru. It is transmitted by a sand fly and causes an acute febrile illness known as Oroya fever accompanied by jaundice, hemolysis, hepatosplenomegaly, and lymphadenopathy. Centrilobular necrosis of the liver and splenic infarction may occur. As many as 40% of patients die of sepsis or hemolysis. Prompt treatment prevents fatal complications. First-line treatment is ciprofloxacin, in combination with ceftriaxone for severe cases.

Cat-scratch disease, caused by Bartonella henselae , usually affects children and young adults with typical cutaneous and lymph node manifestations but rarely can disseminate with visceral involvement, including necrotizing granuloma in the liver and spleen. Infection is frequently associated with exposure to cats or to their fleas. Mild cat-scratch disease is treated with azithromycin.

Bacillary angiomatosis is an infectious disorder that primarily affects persons with AIDS or other immunodeficiency states, in many cases caused by B. henselae but in some cases by Bartonella quintana . Bacillary angiomatosis is characterized most commonly by multiple blood-red papular skin lesions but disseminated infection with or without skin involvement has also been described. The causative bacilli can infect liver, lymph nodes, pleura, bronchi, bones, brain, bone marrow, and spleen. Additional manifestations include persistent fever, bacteremia, and sepsis. Hepatic infection should be suspected when serum aminotransferase levels are elevated in the absence of other explanations. Hepatic infection in persons with bacillary angiomatosis may manifest as peliosis hepatis, or blood-filled cysts (see Chapter 85 ). Histologically, peliosis in patients with AIDS is characterized by an inflammatory myxoid stroma containing clumps of bacilli and dilated capillaries surrounding the blood-filled peliotic cysts. Increasingly, the diagnosis of Bartonella infection is by PCR-based methods. Bacillary angiomatosis is treated with doxycycline with either rifampin or gentamicin added for severe manifestations. For visceral infection, prolonged treatment should be administered.

Bacterial Sepsis and Jaundice

Jaundice may complicate systemic sepsis caused by Gram-negative or Gram-positive organisms. Exotoxins and endotoxins liberated in overwhelming infection can directly or indirectly, through cytokines such as TNF-α, inhibit the transport of bile acids and other organic anions across the hepatic sinusoidal and bile canalicular membranes, thereby leading to intrahepatic cholestasis (see Chapter 21 ). Serum bilirubin levels can reach 15 mg/dL or higher. The magnitude of the jaundice does not correlate with mortality. Results of cultures of liver biopsy specimens are usually negative.

Chlamydia

Fitz-Hugh–Curtis Syndrome

Although perihepatitis was first associated with gonococcal salpingo-oophoritis (see earlier), it is now most frequently associated with C. trachomatis infection. The presentation is similar to perihepatitis caused by gonococcal infection, with RUQ pain accompanying a urogenital infection such as pelvic inflammatory disease. The diagnosis can be made by direct visualization at laparoscopy or laparotomy and supported by pathologic demonstration of endometritis, salpingitis, and microbiologic detection of C. trachomatis in the genital tract. Liver biochemical test results are generally normal. The treatment of choice should follow guidelines for treatment of C. trachomatis or pelvic inflammatory disease.

Rickettsiae

Rocky Mountain Spotted Fever

Mortality from Rocky Mountain spotted fever, a systemic tick-borne rickettsial illness, has decreased considerably as a result of prompt recognition of the classic maculopapular rash in association with fever and an exposure history. A small subset of patients, however, present with multiorgan manifestations and have a high mortality rate. A characteristic severe vasculitis develops in these patients and is believed to be the result of a microbe-induced coagulopathy. Hepatic involvement is frequent in multiorgan disease. In one postmortem study, rickettsiae were identified in the portal tracts of 8 of 9 fatal cases. Portal tract inflammation, portal vasculitis, and sinusoidal erythrophagocytosis were consistent findings, but hepatic necrosis was negligible. The predominant clinical manifestation was jaundice; elevations of serum aminotransferase and alkaline phosphatase levels varied. Jaundice probably results from a combination of inflammatory bile ductular obstruction and hemolysis and is associated with increased mortality. ^,

Ehrlichiae

Ehrlichiae are rickettsiae that parasitize leukocytes. In the USA, human monocytic ehrlichiosis is caused principally by Ehrlichia chaffeensis and, less often, by Ehrlichia canis . Human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis) is caused by Anaplasma phagocytophilum . ^, In contrast to Rocky Mountain spotted fever, a rash is often absent. Hepatic involvement is seen in more than 80% of cases, usually in the form of mild, transient serum aminotransferase elevations. More marked aminotransferase elevations may occur occasionally, in association with cholestasis, hepatosplenomegaly, and liver failure. Liver injury is attributable to proliferation of organisms within hepatocytes and provocation of an immune response. Focal necrosis, fibrin ring granulomas, and cholestatic hepatitis can be observed. A mixed portal tract infiltrate and lymphoid sinusoidal infiltrate are usually seen. The disease generally resolves with appropriate antibiotic therapy with doxycycline.

Spirochetes

Leptospirosis

Leptospirosis is one of the most common zoonoses in the world, and the causative organism has a wide range of domestic and wild animal reservoirs. Humans acquire the spirochete by contact with infected urine or contaminated soil or water. In humans, disease can occur as anicteric leptospirosis or as Weil’s syndrome.

Anicteric leptospirosis accounts for more than 90% of cases and is characterized by a biphasic illness. The first phase begins, often abruptly, with viral illness-like symptoms associated with fever, leptospiremia, and conjunctival suffusion, which serves as an important diagnostic clue. Following a brief period of improvement, the second phase in 95% of cases is characterized by myalgias, nausea, vomiting, abdominal tenderness, and, in some cases, aseptic meningitis. During this phase, a few patients have elevated serum aminotransferase and bilirubin levels with hepatomegaly.

Weil’s syndrome is a severe icteric form of leptospirosis and constitutes 5% to 10% of all cases. The first phase of this illness is often marked by jaundice, which may last for weeks. During the second phase, fever may be high, and hepatic and renal manifestations predominate. Jaundice may be marked, with serum bilirubin levels approaching 30 mg/dL (predominantly conjugated). Serum aminotransferase levels usually do not exceed 5 times the upper limit of normal. Acute tubular necrosis often develops and can lead to renal failure, which may be fatal. Hemorrhagic complications are frequent and are the result of capillary injury caused by immune complexes. Spirochetes are seen in renal tubules in a majority of autopsy specimens but rarely are found in the liver. Hepatic histologic findings are generally nonspecific and do not include necrosis. Altered mitochondria and disrupted membranes in hepatocytes on electron microscopy suggest the possibility of a toxin-mediated injury.

The diagnosis of leptospirosis is made on clinical grounds in conjunction with a positive result of a blood or urine culture specimen in the first and second phase, respectively. Serologic testing confirms the diagnosis when culture results are unrevealing. Doxycycline is effective if given within the first several days of illness. Most patients recover without residual organ impairment.

Syphilis

Secondary Syphilis

Liver involvement is characteristic of secondary syphilis. The frequency of hepatitis in secondary syphilis ranges from 1% to 50%. ^, Symptoms and signs are usually nonspecific, including anorexia, weight loss, fever, malaise, and sore throat. A characteristic pruritic maculopapular rash involves the palms and soles. Jaundice, hepatomegaly, and tenderness in the RUQ are less common. Almost all patients exhibit generalized lymphadenopathy. Biochemical testing generally reveals low-grade elevations of serum aminotransferase and bilirubin levels, with a disproportionate elevation of the serum alkaline phosphatase level; isolated elevation of the alkaline phosphatase is common. Proteinuria may be present.

Histologic examination of the liver in syphilitic hepatitis generally discloses focal necrosis in the periportal and centrilobular regions. The inflammatory infiltrate typically includes neutrophils, plasma cells, lymphocytes, eosinophils, and mast cells. ^, Kupffer cell hyperplasia may be seen, but bile ductule injury is rare. Granulomas may be seen. Spirochetes may be demonstrated by silver staining in as many as 50% of patients. Resolution of these findings without sequelae follows treatment with penicillin.

Tertiary (Late) Syphilis

Tertiary syphilis is now rare. Although hepatic lesions are common in late syphilis, most patients are asymptomatic. Some patients describe anorexia, weight loss, fatigue, fever, or abdominal pain. The characteristic hepatic lesion in tertiary syphilis is the gumma, which can be single or multiple. It is necrotic centrally, with surrounding granulation tissue consisting of a lymphoplasmacytic infiltrate and endarteritis; exuberant deposition of scar tissue may occur, giving the liver a lobulated appearance (hepar lobatum). If hepatic involvement is unrecognized, hepatocellular dysfunction and portal hypertension with jaundice, ascites, and gastroesophageal varices can ensue. Hepatic gummas may resolve after therapy with penicillin.

Lyme Disease

Lyme disease is a multisystem disease caused by the tick-borne spirochete Borrelia burgdorferi . Predominant manifestations are dermatologic, cardiac, neurologic, and musculoskeletal. Hepatic involvement has been described. Among 314 patients, abnormal liver biochemical test results with generally increased serum aminotransferase and lactate dehydrogenase levels were seen in 19%. Clinical findings include anorexia, nausea and vomiting, weight loss, RUQ pain, and hepatomegaly, usually within days to weeks of the onset of illness and often accompanied by the sentinel rash, erythema migrans. Coinfection with ehrlichiosis or anaplasmosis should be considered.

In early stages of the illness, the spirochetes are believed to disseminate hematogenously from the skin to other organs, including the liver. Histologic examination of the liver in Lyme hepatitis reveals hepatocyte ballooning, marked mitotic activity, microvesicular fat, Kupffer cell hyperplasia, a mixed sinusoidal infiltrate, and intraparenchymal and sinusoidal spirochetes.

The diagnosis of Lyme disease is confirmed with serologic studies in patients with a typical clinical history. Hepatic involvement tends to be more frequent in disseminated disease but does not appear to affect overall outcome, which is excellent in primary disease after institution of treatment with oral doxycycline, amoxicillin, clarithromycin, or azithromycin. Ceftriaxone is the drug of choice for late disease. ^,

Mycobacteria

Granulomas are found in liver biopsy specimens in approximately 25% of persons with pulmonary TB and 80% of those with extrapulmonary TB. Tuberculous granulomas can be distinguished from sarcoid granulomas by central caseation, acid-fast bacilli, and the presence of fewer granulomas, with a tendency to coalesce. Multiple granulomas in the liver also may be seen following vaccination with Bacille Calmette-Guérin, especially in persons with an impaired immune response. Patients with multiple granulomas caused by TB rarely have clinically significant liver disease. Occasionally, tender hepatomegaly is found. Jaundice with elevated serum alkaline phosphatase levels may occur in miliary infection. The treatment of tuberculous granulomatous disease of the liver is the same as that for active pulmonary TB—namely, 4-drug therapy. Hepatic involvement in Mycobacterium avium complex infection is discussed in Chapter 35 .

Parasites ( TABLES 84.1 AND 84.2 )

Protozoa (see also Chapter 113 )

Malaria

An estimated 300 to 500 million persons in more than 100 countries are infected with malaria each year. The liver is affected during 2 stages of the malarial life cycle: first in the pre-erythrocytic phase and then in the erythrocytic phase, which coincides with clinical illness.

TABLE 84.1

Classification of Parasitic Diseases of the Liver and Biliary Tract by Pathologic Process

Pathologic Process	Diseases
Liver
Granulomatous hepatitis	Capillariasis
	Fascioliasis
	Schistosomiasis
	Strongyloidiasis
	Toxocariasis
Portal fibrosis	Schistosomiasis
Hepatic abscess or necrosis	Amebiasis
Hepatic abscess or necrosis	Toxoplasmosis
Cystic liver disease	Echinococcosis
Peliosis hepatis	Bacillary angiomatosis
Reticuloendothelial Cells
Kupffer cell infection or hyperplasia	Babesiosis
Kupffer cell infection or hyperplasia	Malaria
	Toxoplasmosis
	Visceral leishmaniasis
Biliary Tract
Cholangitis	Clonorchiasis/opisthorchiasis
	Fascioliasis
Biliary hyperplasia	Ascariasis
	Clonorchiasis
	Cryptosporidiosis
	Fascioliasis
Cholangiocarcinoma	Clonorchiasis/opisthorchiasis

TABLE 84.2

Parasitic Diseases of the Liver and Biliary Tract

Disease (cause)	Endemic areas	Predisposing factors	Pathophysiology	Manifestations	Diagnosis	Treatment ∗
Protozoans
Amebiasis (Entamoeba histolytica) (see also Chapter 113 )	Worldwide, especially Africa, Asia, Mexico, South America	Poor sanitation, sexual exposure	Hematogenous spread and tissue invasion, abscess formation (see Fig. 84.10 )	Fever, RUQ pain, peritonitis, elevated right hemidiaphragm, rupture	Cysts in stool, serology (e.g., ELISA, CIE, IHA), hepatic imaging	Metronidazole 750 mg (oral or IV) 3 times daily × 7-10 days or tinidazole 2 g × 3 days, followed by iodoquinol 650 mg 3 times daily × 20 days or diloxanide furoate 500 mg 3 times daily × 10 days or aminosidine (paromomycin) 25-35 mg/kg/day in 3 divided doses × 7-10 days
Malaria (Plasmodium falciparum, P. malariae, P. vivax, P. ovale, P. knowlesi)	Africa, Asia, South America	Blood transfusion, IV drug use	Sporozoite clearance by hepatocytes; exoerythrocytic replication in the liver	Tender hepatomegaly, splenomegaly, rarely hepatic failure (P. falciparum)	Identification of the parasite on a blood smear	P. falciparum : chloroquine (chloroquine-sensitive), mefloquine, or quinine and either doxycycline or clindamycin; or pyrimethamine-sulfadoxine (Fansidar); or atovaquone/proguanil (chloroquine-resistant); or an artesiminin P. malariae : chloroquine P. vivax, P. ovale, P. knowlesi : chloroquine and primaquine (chloroquine-sensitive) or mefloquine and primaquine (chloroquine-resistant) ^†
Babesiosis ( Babesia spp.)	USA	Exposure to deer tick	Hemolysis with multiorgan involvement	Fever, anemia, hepatosplenomegaly, abnormal liver test results, hemoglobinuria	Identification of the parasite on a blood smear, PCR	Azithromycin 500 mg on day 1, then 250 mg daily and atovaquone 750 mg twice daily × daily days or clindamycin 300-600 mg IV every 6 hr or 600 mg orally every 8 hr and quinine 650 mg every 8 hr × 7-10 days
Visceral leishmaniasis (Leishmania donovani)	Eurasia, Central America, South America	Immunosuppression (AIDS, organ transplantation)	Infection of RE cells	Fever, weight loss, hepatosplenomegaly, secondary bacterial infection, skin hyperpigmentation (kala-azar)	Amastigotes seen in the spleen, liver, or bone marrow	Pentavalent antimonial (stibogluconate sodium and meglumine antimoniate) 20 mg/kg/day × 28 days; or liposomal amphotericin B (IV) 3 mg/kg/day on days 1-5, 14, and 21; or aminosidine (paromomycin) 16-20 mg/kg/day × 21 days; or pentamidine isethionate, 2-4 mg/kg/day for up to 15 days; or miltefosine 2.5 mg/kg/day × 28 days
Toxoplasmosis (Toxoplasma gondii)	Worldwide	Congenital infection, immunosuppression (AIDS, organ transplantation)	Replication in the liver leading to inflammation, necrosis	Fever, lymphadenopathy, occasionally hepatosplenomegaly, atypical lymphocytosis	Serology (IF, ELISA), isolation of the organism in the tissue	Pyrimethamine 100 mg loading dose followed by 25-50 mg/day, plus sulfadiazine 2-4 g/day in 4 divided doses; or clindamycin 300 mg 4 times daily, plus folinic acid 10-25 mg daily for 2-4 wk
Nematodes (see also Chapter 114 )
Toxocariasis (Toxocara canis, T. cati)	Worldwide	Exposure to dogs or cats, especially for children <5 yr	Migration of larvae to the liver (visceral larva migrans)	Granuloma formation with eosinophilia	Larvae in tissue, serology (ELISA)	Albendazole 10 mg/kg/day × 5 days or mebendazole 100-200 mg twice daily × 5 days
Hepatic capillariasis (Capillaria hepatica)	Worldwide	Exposure to rodents	Migration of larvae to the liver; inflammatory reaction to eggs	Acute, subacute hepatitis, tender hepatomegaly, occasionally splenomegaly, eosinophilia	Adult worms or eggs in a liver biopsy specimen (see Fig. 84.2 )	Supportive; possibly dithiazine iodide, sodium stibogluconate, albendazole, or thiabendazole
Ascariasis (Ascaris lumbricoides)	Tropical climates	Ingestion of raw vegetables	Migration of larvae to the liver; invasion of the bile ducts by adult worms	Abdominal pain, fever, jaundice, biliary obstruction, granulomas	Ova or adult in stool or contrast study	Albendazole 400 mg × 1 dose; or mebendazole 100 mg twice daily × 3 days; or pyrantel pamoate 11 mg/kg up to 1 g; or ivermectin 200 μg/kg × 1 dose
Strongyloidiasis (Strongyloides stercoralis)	Asia, Africa, South America, Southern Europe, USA	Immunosuppression (AIDS, chemotherapy, organ transplantation) predisposes to hyperinfection	Larval penetration from the intestine to the liver	Hepatomegaly, occasionally jaundice, larvae in the portal tract or lobule	Larvae in the stool or duodenal aspirate	Ivermectin 200 μg/kg/day × 2 days; or albendazole 400 mg/day × 3 days
Trichinosis (Trichinella spiralis)	Temperate climates	Ingestion of undercooked pork	Hematogenous dissemination to the liver	Occasionally jaundice, biliary obstruction, larvae in hepatic sinusoids	History, eosinophilia, fever, muscle biopsy	Glucocorticoids for allergic symptoms; albendazole 400 mg twice daily × 10-15 days; or mebendazole 200 mg/day × 10-15 days
Trematodes (see also Chapter 114 )
Schistosomiasis (Schistosoma mansoni, S. japonicum)	Asia, Africa, South America, Caribbean	Travelers exposed to bodies of fresh water	Fibrogenic host immune response to eggs in the portal vein	Acute: eosinophilic infiltrate Chronic: hepatosplenomegaly, presinusoidal portal hypertension, granulomas	Ova in the stool, rectal or liver biopsy	Praziquantel 40-60 mg/kg in 2-3 divided doses × 1 day; or oxamniquine for S. mansoni (not readily available) Acute toxemic schistosomiasis: praziquantel 40-60 mg/kg in 2-3 divided doses × 1 day + glucocorticoids
Fascioliasis (Fasciola hepatica)	Worldwide	Cattle or sheep raising; ingestion of contaminated watercress	Migration of larvae through the liver; penetration of the bile ducts or surgery	Acute: fever, abdominal pain, jaundice, hemobilia Chronic: hepatomegaly	Ova in the stool, flukes in the bile ducts at ERC	Triclabendazole 10 mg/kg × 1 dose
Clonorchiasis and opisthorchiasis (Clonorchis sinensis, Opisthorchis viverrini, O. felineus)	Southeast Asia, China, Japan, Korea, Eastern Europe	Ingestion of raw fresh-water fish	Migration through the ampulla; egg deposition in the bile ducts	Biliary hyperplasia, obstruction, sclerosing cholangitis, stone formation, cholangiocarcinoma	Ova in the stool, flukes in the bile ducts at ERC or surgery	Praziquantel 75 mg/kg in 3 divided doses × 1 day
Cestodes
Echinococcosis (Echinococcus granulosus, E. multilocularis)	Worldwide	Cattle or sheep raising (E. granulosus)	Migration of larvae to the liver; encystment (hydatid cyst)	Tender hepatomegaly, fever, eosinophilia, cyst rupture, biliary obstruction	Serology (ELISA, IHA), hepatic imaging	Surgical resection or percutaneous drainage. Perioperative albendazole 400 mg twice daily continuing × 8 wk

CIE , counterimmunoelectrophoresis; ELISA , enzyme-linked immunosorbent assay; ERC , endoscopic retrograde cholangiography; IF , immunofluorescence; IHA , indirect hemagglutination assay; RE , reticuloendothelial.

∗ All drugs are given orally unless otherwise specified.

† For dosing guidelines for malaria, please refer to https://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf .

The Plasmodium Life Cycle

The life cycle of the prototypical malarial parasite is illustrated in Figure 84.1 . Malarial sporozoites injected by an infected mosquito circulate to the liver and enter hepatocytes. Maturation to schizonts ensues. When the schizont ruptures, merozoites are released into the bloodstream, where they enter erythrocytes. The major species of Plasmodium responsible for malaria differ with respect to the number of merozoites released and the maturation times. Infection by Plasmodium falciparum and Plasmodium malariae is not associated with a residual liver stage after the release of merozoites, whereas infection by Plasmodium vivax and Plasmodium ovale is associated with a persistent exoerythrocytic stage, the hypnozoite, which persists in the liver and, when activated, can divide and mature into schizont forms. Plasmodium knowlesi has been identified as a fifth species capable of infecting humans and occasionally results in severe manifestations including jaundice, hepatic dysfunction, and acute kidney injury.

Fig. 84.1, The life cycle of Plasmodium species.

The extent of hepatic injury varies with the malarial species (most severe with P. falciparum ) and the severity of infection. Unconjugated hyperbilirubinemia is most commonly seen as a result of hemolysis, but hepatocellular dysfunction is also possible, leading to conjugated hyperbilirubinemia. Moderate elevations of serum aminotransferase and 5′-nucleotidase levels may be observed. Synthetic dysfunction (e.g., prolongation of the prothrombin time, hypoalbuminemia) may be seen, as well. In severe falciparum malaria, hypoglycemia and lactic acidosis are late and life-threatening complications. Reversible reductions in portal venous blood flow have been described during the acute phase of falciparum malaria, presumably as a consequence of micro-occlusion of portal venous branches by parasitized erythrocytes.

Histopathologic Features

In acute falciparum malaria in a previously unexposed person, hepatic macrophages hypertrophy, and large quantities of malarial pigment (the result of hemoglobin degradation by the parasite) accumulate in Kupffer cells, which phagocytose parasitized and unparasitized erythrocytes. Histopathologic features include Kupffer cell hyperplasia with pigment deposition and a mononuclear infiltrate. Hepatocyte swelling and centrizonal necrosis may be seen. All abnormalities are reversible with treatment.

Clinical Features

Only the erythrocytic stage of malaria is associated with clinical illness. Symptoms and signs of acute infection typically develop 30 to 60 days following exposure and include fever, which often is hectic, malaise, anorexia, nausea, vomiting, diarrhea, and myalgias. Jaundice caused by hemolysis is common in adults, especially in heavy infection with P. falciparum . In general, hepatic failure is seen only in association with concomitant viral hepatitis or with severe P. falciparum infection. ^, One series identified evidence of hepatic encephalopathy in 15 of 86 patients with falciparum malaria and jaundice; 4 cases were fatal. Tender hepatomegaly with splenomegaly is common. Cytopenias are common in acute infection. The differential diagnosis includes viral hepatitis, gastroenteritis, amebic liver abscess, yellow fever, typhoid, TB, and brucellosis.

Diagnosis

The diagnosis of acute malaria rests on the clinical history, physical examination, and identification of parasites on peripheral thin and thick blood smears. Because the number of parasites in the blood may be small, repeated smear examinations should be performed by an experienced examiner when the index of suspicion is high. P. knowlesi may resemble P. malariae in morphology, and PCR-based tests may help distinguish these 2 species. Rapid antigen detection assays are available but have yet to be implemented widely.

Treatment

The treatment of acute malaria depends on the species of parasite and, for falciparum infection, the pattern of chloroquine resistance. Chloroquine generally is effective in areas endemic for chloroquine-sensitive species. Resistant falciparum infections can be treated with mefloquine alone; quinine and either doxycycline or clindamycin; pyrimethamine-sulfadoxine (Fansidar); a combination of atovaquone and proguanil; or artemisinin derivatives, including artemisinin, artemether, and artesunate. For P. vivax and P. ovale infections, the addition of primaquine (in persons without glucose-6-phosphate dehydrogenase deficiency) to chloroquine or mefloquine is indicated to eliminate the exoerythrocytic hypnozoites in the liver.

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