November 2024

D-V27

Signalment (JPC# 2424206): A golden lion tamarin (Leontopithecus rosalia)

HISTORY: This animal was found on the floor of a large indoor jungle exhibit in a depressed state. It did not respond to supportive therapy and died 30 minutes later. Its mate had died a few days earlier.

HISTOPATHOLOGIC DESCRIPTION: Liver: Affecting 30% of the hepatic parenchyma, there are multifocal, random areas of hepatocellular necrosis characterized by loss of hepatic cord architecture and individualization of hepatocytes surrounded by small amounts of necrotic debris, as well as individual shrunken, hypereosinophilic hepatocytes often within sinusoids that exhibit karyorrhexis, karyolysis, or pyknosis (single cell death, acidophilic bodies). Hepatocytes adjacent to areas of necrosis are often degenerate, characterized by pale, swollen microvacuolated cytoplasm. Multiple random foci of hepatocytes contain a single, discrete, round cytoplasmic vacuole that often displaces the nucleus (macrovesicular vacuolar degeneration, lipid type). Rarely hepatocytes contain intracytoplasmic 3-5µm eosinophilic inclusions. Occasionally within Kupffer cells there are phagocytized, round, 5-8 um diameter acidophilic bodies (apoptotic hepatocytes, acidophilic bodies). Within affected areas there are few mitotic figures. Multifocally within portal areas, there are low numbers of lymphocytes, fewer neutrophils, and rare plasma cells. Diffusely hepatocytes are mildly swollen, multifocally compressing sinusoids, and contain abundant brown to black granular to globular pigment (hemosiderin, normal in this species).

MORPHOLOGIC DIAGNOSIS: Liver: Hepatocellular degeneration and necrosis, acute, random, multifocal, moderate, with acidophilic bodies and intracytoplasmic inclusions, golden lion tamarin (Leontopithecus rosalia), non-human primate.

ETIOLOGIC DIAGNOSIS: Arenaviral hepatitis

CAUSE: Lymphocytic choriomeningitis virus (arenavirus)

CONDITION: Callitrichid hepatitis (CH)

GENERAL DISCUSSION:

Rapidly progressive, fatal, viral hepatitis of captive marmosets and tamarins, including the endangered golden lion tamarin (New world monkeys); macaques have been experimentally infected
Lymphocytic choriomeningitis virus (LCMV) is a pleomorphic, enveloped, ssRNA arenavirus of the Arenaviridae family and measures 85-105 nm in diameter
Sporadic outbreaks in zoos and animal parks; affects a wide range of mammalian species.
Endemic in mice worldwide (Mus musculus, N-V18), natural reservoir host with life-long asymptomatic infection, persistent viremia, and urine shedding (immune tolerance)

Dam can pass infection to fetus; few mice develop immunodeficiency.
A source of contamination concern in laboratory animal facilities that create biological products derived from mice
LCMV is a frequent contamination of transplantable tumors

Zoonotic, may cause subclinical disease in humans or meningitis in severe cases
Moderate iron storage in normal captive tamarins is routinely observed as pigment in hepatic tissue and may be related to captive diet.

PATHOGENESIS:

In mice, vertical and horizontal (oronasal, skin abrasion) transmission; virus is shed in saliva and urine
Non-human primates become infected through contact with or ingestion of infected mice
Virus introduced to animal colonies by either wild mice or the intentional feeding of neonatal laboratory mice (“pinkies”)
1-2 week incubation period
Virus genome has S segment that encodes glycoprotein precursor and nucleoprotein; the L segment encodes the viral polymerase and small zinc-binding protein.

TYPICAL CLINICAL FINDINGS:

Acute onset; rapid course; usually death within 24-48 hours
Signs include dyspnea, anorexia, weakness, and lethargy, often followed by prostration and death; or sudden death without clinical signs
In animals with a longer clinical course: jaundice and coagulopathies with elevations of aspartate aminotransferase (AST), serum bilirubin, and alkaline phosphatase; +/- coagulopathy
Serologic evidence of infection of captive marmosets without recognized clinical signs has been demonstrated.

TYPICAL GROSS FINDINGS:

Hepatosplenomegaly, pleural and pericardial effusions, jaundice, and subcutaneous and intramuscular hemorrhage
Yellow-tan, mottled liver

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Multifocal hepatic necrosis with lipid degeneration and periportal lymphocytic, histiocytic, and neutrophilic infiltrate
Round acidophilic bodies, representing apoptotic hepatocytes, are prominent and present in hepatic sinusoids or within Kupffer cells (similar to Councilman bodies in Yellow Fever virus)
Rare intracytoplasmic 3-5µm eosinophilic inclusions
Necrosis in abdominal lymph nodes, adrenal cortex, spleen, and gastrointestinal tract
Lymphocytic meningitis and cerebral perivasculitis

ULTRASTRUCTURAL FINDINGS:

Pleomorphic, 85-105 nm, enveloped virions within hepatocellular intracytoplasmic vesicles

DIFFERENTIAL DIAGNOSIS:

Hepatocellular necrosis in nonhuman primates:

Dubin-Johnson-like syndrome in golden lion tamarins: Histologically similar, with centrilobular and midzonal non-iron pigment deposition; no acidophilic bodies; dark brown-black liver grossly
Yellow fever (flavivirus, D-V23): Similar histologically with midzonal hepatocellular necrosis and Councilman bodies; primarily a disease of wild non-human primates
Herpesvirus saimiri type 1 (Herpes tamarinus, D-V14) and human herpesvirus type 1: Necrosis of the skin, oral mucosa, and parenchymal organs; multifocal, random, acute hepatocellular necrosis and numerous intranuclear inclusion bodies.
Francisella tularensis: Multifocal hepatocellular caseous necrosis; grossly, multiple small, white foci scattered throughout the liver and spleen, fibrinous peritonitis, and marked mesenteric lymphadenopathy

COMPARATIVE PATHOLOGY:

LCMV in other species:

Mice (N-V18): Signs range from asymptomatic (more common) to acute fatal choriomeningoencephalitis (less common); will kill adults but not neonates when inoculated intracerebrally; target cell is the dendritic cell and causes immune exhaustion in adult mice

Persistently infected mice may have vasculitis, glomerulonephritis, and lymphocytic infiltration brain, liver, adrenal, kidney, liver

Hamsters: Primary source of human infections; clinical disease rare; choriomeningoencephalitis, vasculitis, glomerulonephritis, lymphocytic infiltrates of visceral organs
Pygmy marmosets: Intense lymphocytic portal hepatitis with extension into portal vessels; lymphocytic gastritis/pancreatitis; interstitial pneumonia
Baboons: Abortions in early infections and anomalies in later infections.
Guinea pigs, rats, rabbits, dogs, and swine can be infected experimentally
Humans: Subclinical infections to influenza-like symptoms; rarely meningitis or encephalomyelitis; teratogenic resulting in fetal loss or development defects

Other selected Arenaviruses:

Snakes: Boid inclusion body disease (D-V30)
Humans: several causative agents of viral hemorrhagic fevers, including:
- Lassa virus: Cause of viral hemorrhagic fever in West Africa (must be differentiated from Ebola)
- Machupo virus: Causative agent of Bolivian hemorrhagic fever

REFERENCES:

Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents & Rabbits. 4th ed. Ames, IA: John Wiley & Sons, Inc.; 2016:23-25, 178, 220.
Brady AG, Carville AL. Digestive System Diseases of Nonhuman Primates. In: Abee, ed. Nonhuman Primates in Biomedical Research: Diseases. Volume 2. San Diego, CA: Elsevier Inc; 2012:612.
Cline, JM, Brignolo, L, Ford, EW. Urogenital system. In: Abee, ed. Nonhuman Primates in Biomedical Research: Diseases. Volume 2. San Diego, CA: Elsevier Inc; 2012:54-56.
Matz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:355-356.
Wachtman L, Mansfield K. Viral Diseases of Nonhuman Primates. In: Abee, ed. Nonhuman Primates in Biomedical Research: Diseases. Volume 2. San Diego, CA: Elsevier Inc; 2012:54-56.