JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-M07

 

SIGNALMENT (JPC #2372961):  Cat

 

HISTORY:  Found dead without any clinical signs with the exception of weight loss.

 

HISTOPATHOLOGIC DESCRIPTION:  Liver:  Diffusely and markedly expanding and bridging between portal areas is a dense inflammatory infiltrate composed of high numbers of lymphocytes, fewer plasma cells, and rare neutrophils and macrophages.  This inflammatory infiltrate separates and surrounds bile ducts and occasionally breaches the limiting plate and into adjacent sinusoids, where it separates and surrounds individual hepatocytes that are shrunken with bright eosinophilic cytoplasm and a pyknotic nucleus (piecemeal necrosis).  There are varying degrees of fibrosis within portal areas that occasionally forms a thick band separating portal areas from the limiting plate.  Adjacent hepatocytes are often pale, swollen, and vacuolated (degenerate).  Bile duct epithelium is often pale with vacuolated cytoplasm and/or shrunken (degeneration), and within areas of inflammation there is often distortion of bile ductule shape.  Diffusely, there are increased numbers small bile ducts (biliary ductular reaction).  There are often moderate amounts of granular to globular, yellow-brown, cytoplasmic pigment within centrilobular hepatocytes (lipofuscin) and Kupffer cells (hemosiderin or bile). The margin of the liver is undulant, rounded, and lobular.  The capsule is diffusely and markedly expanded by moderate amounts of clear space (edema) and few previously described inflammatory cells.  Portal lymphatics are occasionally dilated.

 

MORPHOLOGIC DIAGNOSIS:  Liver:  Hepatitis, portal and bridging, lymphocytic, chronic, diffuse, severe, with biliary hyperplasia and portal fibrosis, breed unspecified, feline.

 

CONDITION:  Lymphocytic portal hepatitis

 

SYNONYMS:  Lymphocytic cholangitis; nonsuppurative cholangitis / cholangiohepatitis

 

GENERAL DISCUSSION:

• Inflammatory liver diseases are the second most common type of liver disease in cats (after hepatic lipidosis)
• Distinct feline condition; slowly progressive
• Two histologically distinct feline inflammatory liver diseases:
  • Lymphocytic portal hepatitis (this condition) – Characterized by lymphocytic infiltration in the portal area, variable degree of bile duct and oval cell proliferation, peribiliary and portal-to-bridging fibrosis
  • Neutrophilic cholangitis: See discussion in Differential Diagnosis section
• Mild lymphocytic portal hepatitis is common in older cats (>10 years) and may be an aging change or a subclinical form of this slowly progressive disease

 

PATHOGENESIS:

• Unknown: Immune mediated etiology is suspected because of intense CD3+ lymphocytic inflammation

 

TYPICAL CLINICAL FINDINGS:

• Chronic weight loss, depression, lethargy, anorexia, vomiting
• Clinical pathology: consistent with chronic inflammatory liver disease
  • Increased serum bile acids, hyperbilirubinemia, bilirubinuria
  • Increased liver enzymes
    • Alanine transferase (ALT; leakage enzyme)
    • Serum alkaline phosphatase (SAP, ALP; inducible enzyme)
    • Gamma-glutamyl transpeptidase (GGT; inducible enzyme)
  • Hemogram: Usually normal; possibly mild nonregenerative anemia
  • Advanced disease: Hypoalbuminemia, decreased BUN

 

TYPICAL GROSS FINDINGS:

• Hepatomegaly, with exaggerated lobular pattern
• Chronic cases: Portal fibrosis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Subacute:
  • Portal tracts expanded by lymphocytes (T cells predominate with lower numbers of B cells) with few macrophages and neutrophils
  • Bile duct and oval cell proliferation variable; may be remarkable
  • Degenerative changes in biliary epithelium, ductopenia from destructive cholangitis, and portal lipogranulomas
• Chronic:
  • Portal to bridging fibrosis with bile duct proliferation
  • Minimal extension into the periportal hepatic parenchyma

 

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry to characterize lymphocytic infiltrate is an adjunct to distinguish lymphocytic hepatitis/cholangitis from lymphoma

 

DIFFERENTIAL DIAGNOSES:

• Neutrophilic (acute) cholangitis (suppurative cholangitis):
  • Neutrophils within walls or lumina of bile ducts; biliary epithelial degeneration; may progress to cholangiohepatitis with periportal hepatocyte necrosis
  • Acute, subacute, and chronic forms
    • Chronic stage may show concentric periportal fibrosis (see below)
    • Subacute cases may have disruption of limiting plate; extension of mixed inflammation into parenchyma; periportal hepatocellular necrosis; bile duct proliferation, +/- portal fibrosis
    • May be secondary to an ascending biliary infection ( Coli most commonly) resulting in inflammation in the biliary tree
    • Associated with extrahepatic biliary obstruction, pancreatitis, or inflammatory bowel disease
    • Hemogram: Usually neutrophilia with left shift
• Chronic cholangiohepatitis (lymphoplasmacytic/nonsuppurative cholangitis or cholangiohepatitis):
  • Majority are predominantly T-cell
  • 5 histologic features to differentiate from feline hepatic lymphoma:
  • Bile duct targeting
  • Ductopenia
  • Peribiliary, bridging fibrosis
  • Portal B- cell aggregates
  • Portal lipogranulomas
• More common in young cats (<4 years) and Persians
• Generally thought to be advanced stage of acute (neutrophilic) cholangiitis (see above)
• Primarily lymphocytes and plasma cells in portal areas and in bile ducts, with bile duct degeneration
• Marked bile duct proliferation
• Periportal hepatocellular necrosis
• Bridging fibrosis, leading to pseudolobule formation and cirrhosis
  • Hepatomegaly, pronounced nodularity of capsule, lobular fibrosis, and nodular hyperplasia
• Severe form called “sclerosing cholangitis”; small bile ducts are replaced by periductal “onion skin” concentric fibrosis
• Hyperglobulinemia
• Commonly associated with pancreatitis and inflammatory bowel disease
• Lymphoma:
  • No polymorphonuclear infiltrate (though may contain eosinophils); concentric layers of cells and collagen around the bile ducts; less intense biliary hyperplasia; often bridges limiting plate; primarily T-cell clonality; ductopenia, degeneration of bile duct epithelium, and portal lipogranulomas are NOT expected with lymphoma

 

COMPARATIVE PATHOLOGY:

• Dogs and humans: Chronic active hepatitis has similar hepatocellular piecemeal necrosis and destruction of the limiting plate as in chronic cholangiohepatitis; this is caused by Hepatitis B virus in humans
• Dogs: Destructive cholangitis has been associated with some chemicals including trimethoprim sulfa but may also have other causes (idiosyncratic drug reaction and distemper virus also implicated); histologic lesions are similar to cholangiohepatitis with ductopenia and inflammation in the portal areas including neutrophils, eosinophils and pigment laden macrophages
• Humans: Primary biliary cirrhosis is similar to chronic cholangiohepatitis in cats
• Amur tiger: single case report (Crook, J Zoo Wildl Med, 2014)
• Cats: Experimental infection with Bartonella henselae is reported to cause mild lymphocytic cholangitis/pericholangitis and lymphocytic hepatitis

 

REFERENCES:

1. Brown DL, Van Wettere AJ, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:462.
2. Crook EK, Carpenter NA. Acute lymphocytic cholangitis and liver failure in an Amur tiger (Panthera tigris altaica). J Zoo Wildl Med. 2014; 45(1):143-147.
3. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier; 2016:308, 318.
4. Forman MA. Feline inflammatory/Infectious Hepatic Disease. In: Ettinger SJ, Feldman EC, Côté E eds. Textbook of Veterinary Internal Medicine Diseases. Vol 2. 8th ed. Philadelphia, PA: Saunders; 2017:1633-1638.
5. Rothuizen J, Bunch SE, Charles JA, et. al. Morphological classification of billiary disorders of the canine and feline liver. In: WSAVA Liver Standardization Group, eds. WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Diseases. Philadelphia, PA: Saunders; 2006:68-69.
6. Warren A, Center S, McDonough S, et al. Hybridization in Cats With Lymphocytic Cholangitis/Cholangiohepatitis Histopathologic Features, Immunophenotyping, Clonality, and Eubacterial Fluorescence In Situ. Vet Pathol. 2011;48:627.

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