Infectious Diseases of the Liver in Small Animals
Viral diseases associated with liver dysfunction include infectious canine hepatitis, canine herpesvirus, inadvertent parenteral injection of an intranasal Bordetella bronchiseptica vaccine in dogs, feline infectious peritonitis, and virulent systemic calicivirus infection in cats. Rarely, canine parvovirus can lead to hepatic injury as a result of portal systemic sepsis.
Infectious canine hepatitis is caused by canine adenovirus 1. In addition to acute hepatic necrosis, chronic hepatitis and hepatic fibrosis can be sequelae if neutralizing antibody is inadequate to eliminate the infection during the active phase. See Infectious Canine Hepatitis for clinical findings, diagnosis, treatment, and control.
Canine herpesvirus affects neonatal puppies, causing hepatic necrosis as well as other systemic changes. It is usually fatal in puppies.
Accidental parenteral injection of intranasal B bronchiseptica vaccine in dogs can cause both a local inflammatory reaction at the injection site and acute, nonseptic hepatocellular degeneration and necrosis that evolves into chronic hepatitis. There is no known treatment other than symptomatic therapy for chronic inflammatory liver disease.
Feline infectious peritonitis virus is a coronavirus that causes diffuse pyogranulomatous inflammation and vasculitis. Icterus, abdominal effusion, vomiting, diarrhea, and fever are common clinical signs. See Feline Infectious Peritonitis for clinical findings, diagnosis, treatment, and control.
Virulent systemic calicivirus, a recently emerged variant of feline calicivirus, can have mortality rates of 33%–60% in adult cats. Primarily identified in shelter or cattery populations, this virus causes profound fever, anorexia, marked subcutaneous edema (limbs and face especially), jaundice, alopecia, and crusting and ulceration of the nose, lips, ears, and feet. Adult cats are most severely affected. Individual hepatocyte necrosis ranging to centrilobular or more extensive necrosis is associated with neutrophilic inflammatory foci and intrasinusoidal fibrin deposits.
Infections with Leptospira interrogans serovars Icterohemorrhagiae and Pomona and chronic infections with Grippotyphosa have been associated with liver disease in dogs. Other serotypes may also involve the liver. No specific histologic lesions are pathognomonic. Markedly increased liver enzyme activity and hyperbilirubinemia indicate hepatic involvement. However, these parameters may reflect hepatic response to a sepsis syndrome rather than specific organ invasion in acutely ill dogs. Clinical and clinicopathologic features of liver involvement may worsen initially with treatment (fever, liver enzymes, hyperbilirubinemia), a Jarisch-Herxheimer reaction. Diagnosis depends on demonstrating a rise in convalescent titer or PCR detection of leptospiral DNA in blood or urine. Identification of organisms in stained liver specimens is difficult. Treatment includes supportive care and specific antimicrobial therapy. Penicillins are used initially for the acute phase, (eg, ampicillin [22 mg/kg, IV, qid] or amoxicillin [22 mg/kg, PO, bid]). Aminoglycosides (dose depends on drug used; streptomycin was historically used to clear leptospirosis) or doxycycline (5 mg/kg, PO, bid for 4 wk) are recommended to treat the carrier phase. Aminoglycosides are currently not recommended for treatment of leptospirosis owing to the high risk of causing nephrotoxicity. Special precautions are recommended when handling animals suspected of having leptospirosis (and their urine specimens) because of the zoonotic potential. (See also Leptospirosis.)
Tyzzer disease (see Tyzzer Disease) is a rare but fatal condition caused by Clostridium piliforme. Infections in dogs or cats most commonly occur in immunocompromised hosts, either neonatal animals or adults affected with other conditions. Because C piliforme is a commensal organism in the intestines of laboratory rodents, infection is acquired by contact with or ingestion of rodent feces transporting bacterial spores. Clinical signs (lethargy, anorexia, abdominal discomfort) are acute in onset, and illness rapidly progresses to death within 24–48 hr. Marked increase in ALT activity immediately precedes death. Special stains are needed to identify organisms in liver tissue because organisms do not grow in routine bacterial culture media. Although there is no effective treatment, a vaccine has been developed for research colony animals.
Hepatic infection with disseminated M avium has been described in young Abyssinian and Somali cats that had an apparent innate immunodeficiency (unknown cause). The clinical course included vague illness characterized by a several month history of weight loss in the face of polyphagia. Marked diffuse interstitial pulmonary infiltrates developed in cats with and without respiratory signs. Hepatomegaly and increased ALT and AST activities were notable. Liver samples revealed granulomatous inflammation. Treatment with clarithromycin (62.4 mg/cat, PO) combined with either clofazimine (25 mg/cat/day, PO, or 50 mg/cat, PO, every other day) or rifampicin (5–10 mg/kg, bid, PO) and a fluoroquinolone or doxycycline (5–10 mg/kg, bid, PO) achieved remission in affected cats. Relapse should be expected because of the immunocompromised status of these cats.
Systemic infections, including granulomatous hepatitis due to Mycobacterium spp has been reported by several investigators in Basset Hounds, Miniature Schnauzers, and additional dogs. Affected dogs are suspected to have some form of cell-mediated immunodeficiency (Basset Hounds) or unique exposure to another infected animal or person. Susceptibility to various Mycobacterium spp vary among mammals. M tuberculosis can induce progressive disease in people, nonhuman primates, dogs, and swine. Clinical signs in animals infected with M tuberculosis depend on the route of exposure and degree of localization of the infection or its systemic dissemination. Early infection is subclinical, leading to cachexia, weakness, anorexia, dyspnea, and a low-grade, fluctuating fever. Hepatic involvement caused increased transaminase activity, reflecting pyogranulomatous hepatitis. Many animals infected with Mycobacterium spp are euthanized because of the severity of organ involvement at the time of diagnosis and because of zoonotic concerns. Diagnosis of M tuberculosis in an animal should be reported to local health officials. At least 6–9 mo of treatment using a multidrug regimen is advised; single-agent treatment is not advised owing to concern for emergence of resistant strains. Treatment recommendations include combined administration of isoniazid, ethambutol, and rifampin, with pyrazinamide sometimes substituted for ethambutol. However, experience in longterm treatment of dogs is lacking.
Diagnosis of Mycobacterium can be difficult because many of these organisms are slow growing (requires >1 mo), acid-fast organisms may not be found in tissue sections, and PCR from formalin-fixed tissue may be falsely negative. However, Mycobacterium sp have also been detected by both histologic staining and by PCR from formalin-fixed liver specimens from dogs with pyograulomatous hepatitis.
Extrahepatic infection and sepsis can cause cholestasis and hyperbilirubinemia. Increases in serum bilirubin may range from moderate to marked, while increases in liver enzyme activity remain modest. This type of jaundice has been seen in dogs with leptospirosis and in dogs and cats with ill-defined sepsis syndromes. Appropriate treatment targets the underlying organism causing infection. Increased liver enzyme activity in septicemia/sepsis also can reflect bacterial invasion of the liver or hepatocellular damage by associated cytokine release or hypoxia.
Animals with acute hepatic failure, chronic hepatobiliary disease, and cholestatic disorders are predisposed to systemic bacterial infection and endotoxemia due to diminished function of hepatic reticuloendothelial cells (hepatic Kupffer cells comprise the largest fixed macrophage population in the body) and reduced biliary elimination of bacteria derived from the enterohepatic circulation in bile. In acute fulminant hepatic failure, sepsis or septicemia may be masked by fever, hypoglycemia, and leukocytosis that might also represent clinical manifestations of hepatic injury.
Animals with chronic disorders causing stasis of bile flow or with chronic hepatic neoplasia are more likely to develop intrahepatic infections. Risk factors associated with biliary tract infection include advanced age, recent episodes of cholangitis, acute cholecystitis, choledocholithiasis, and obstructive jaundice.
Treatments that reduce susceptibility to infection and liver injury during fulminant hepatic failure and extrahepatic bile duct occlusion include administration of N-acetylcysteine, α-tocopherol, glutamine, oral bile acids, and enteric and systemic antibiotics. These strategies increase microvascular perfusion, reduce enteric bacterial translocation, augment innate immunity, and protect against oxidant injury. While awaiting results of culture and sensitivity (tissue, abdominal effusion, bile), antibiotics against enteric opportunists should be administered empirically, avoiding drugs extensively metabolized in the liver. Combination of a β-lactamase–resistant penicillin, metronidazole (7.5 mg/kg, PO, bid), and enrofloxacin (2.5–5 mg/kg, PO, IM, or IV, bid), may be beneficial during initial treatment when the underlying infectious cause remains unclear.
The most common mycotic infections associated with liver dysfunction are coccidioidomycosis (see Coccidioidomycosis) and histoplasmosis (see Histoplasmosis). In severely affected animals, clinical signs include ascites, jaundice, and hepatomegaly, in addition to signs associated with other involved organ systems. Antifungal treatment is variable, determined by the severity of infection, organ involvement, and individual clinical response. Because liver involvement in histoplasmosis is seen with disseminated disease, aggressive chemotherapy (including combinations of either itraconazole or ketoconazole and amphotericin B) are recommended. Debilitated animals have a poor prognosis. Coccidioidomycosis can be treated successfully with several antifungal medications (itraconazole and fluconazole are preferred to ketoconazole). Chronic treatment (6–12 mo) is required, and relapses may occur. Treatment efficacy is determined based on resolution of clinical signs and radiographic lesions and reduction in serologic titers. Termination of treatment should not be based on serologic titers alone, because these stabilize and persist in many dogs after clinical recovery. Owners must be informed that discontinuing medication may result in relapse. Animals recovering from CNS infection should receive lifelong treatment. Similarly, animals with disseminated disease suffering infection relapse after treatment discontinuation should continue on longterm or lifetime treatment with an azole antifungal. For chronic treatment, drug doses that effectively maintain remission may be lower than those needed to induce remission.
Toxoplasmosis (see Toxoplasmosis) can cause acute hepatic failure associated with hepatic necrosis. Toxoplasma gondii is more commonly seen in cats positive for feline immunodeficiency virus and feline leukemia virus. Icterus, abdominal effusion, fever, lethargy, vomiting, and diarrhea are seen in addition to clinical signs consistent with CNS, ocular, or pulmonary involvement. Liver disease in dogs is rare but when seen is either in an immunocompromised host or in young dogs and also involves systemic infection. Young dogs may be concurrently infected with canine distemper virus; in these, illness is acute in onset and rapidly fatal. Diagnosis of toxoplasmosis can be difficult; while a positive IgM titer indicates active clinical disease, IgG titers may be found in chronic infections and in animals lacking clinical disease. Clindamycin (12.5 mg/kg, PO or IM, bid for 4 wk) is the drug of choice. Because clindamycin is metabolized in the liver, dosage reduction may be necessary in severe hepatic insufficiency. Oral clindamycin should be followed by a bolus of water or food to prevent esophageal irritation. In some cases, initial treatment is combined with anti-inflammatory glucocorticoids to protect against tissue injury caused by inflammatory responses initiated by protozoal death. Prognosis depends on the degree of debilitation and stage of disease at initial diagnosis and the associated disorder causing immunosuppression. Despite improvement with treatment, animals should be considered chronically infected and thus must undergo surveillance for recrudescent disease.
Canine leishmaniosis (see Leishmaniosis) is a multisystemic disease caused by protozoan parasites of the genus Leishmania, most commonly encountered in animals that have lived in Mediterranean countries, Portugal, the Middle East, and some parts of Africa, India, and Central and South America. It also is occasionally encountered in dogs in the USA (especially Foxhounds). A serosurvey of >12,000 dogs (Foxhounds, other breeds, wild canids) and 185 people in 35 states and 4 Canadian provinces was done to assess geographic distribution prevalence, host range, and modes of transmission within North America and to assess possible infection in people. Findings identified Leishmania spp–infected Foxhounds in 18 states and 2 Canadian provinces but no evidence of human infection. North America leishmaniosis appears widespread in Foxhounds and is limited to dog-to-dog transmission. However, if the organism becomes adapted for vector transmission by indigenous phlebotomines, the probability of human exposure may greatly increase.
Clinical features in dogs with naturally occurring leishmaniosis include nonregenerative anemia, increased enzyme (ALP, ALT, and AST) activity, hypoalbuminemia, and variable bilirubinemia. Histologic response is characterized by a multifocal pyogranulomatous hepatitis associated with hepatocyte vacuolar degeneration with phagocytized organisms seen within macrophages. Severity of liver lesions represents sequential stages of hepatic infection in chronic visceral leishmaniosis. However, no correlation has been shown between histologic features and breed, sex, age, clinical features, or hepatic parasite load.
Treatment is rarely curative, and prognosis for debilitated animals is poor. Owing to the zoonotic potential of the organism, owners must be informed that their pet will never be completely free of the disease and that relapses may require repeated treatment. This is particularly important if an owner is immunocompromised. In the absence of renal insufficiency, a high-protein diet is recommended. The most common specific treatment recommended in the USA is allopurinol (7–20 mg/kg, PO, once to three times daily) given for 3–24 mo or indefinitely lifelong; other first-line treatments include meglumine antimony (100 mg/kg/day, IV or SC), sodium stibogluconate (30–50 mg/kg/day, IV or SC), or liposomal amphotericin B (0.25–0.5 mg/kg, IV, every other day until a total dose of 5–10 mg/kg is achieved). Numerous other second-line drugs have also helped control infections.