Chronic progressive hepatitis, or "chronic active hepatitis," is any progressive fibrosing process within the liver, secondary to multiple etiologies. It is a histopathologic diagnosis in which there is evidence of sustained, aggressive, chronic liver disease with varying degrees of fibrosis and inflammatory changes that often involve the periportal areas. As with other hepatic disease, anorexia, weight loss and depression are the predominant clinical signs; intermittent fever and icterus may also be present. Treatment and prognosis depend on biopsy results.
Etiology of Chronic Progressive Hepatitis in Large Animals
The exact etiology of chronic progressive hepatitis is not known. Infectious, immune-mediated, or toxic processes are proposed. The early stages are associated with inflammation of the bile ducts and portal areas of the liver. Extension of ascending bacterial infection through the bile duct or portal venous drainage may be responsible for the lesions in animals with suppurative cholangiohepatitis. When lymphocytes and plasma cells predominate in the cellular infiltrate, an immune-mediated process is more likely. Many different causes of acute hepatic failure can progress to chronic progressive hepatitis.
Clinical Findings of Chronic Progressive Hepatitis in Large Animals
The predominant clinical signs of chronic progressive hepatitis are weight loss, anorexia, depression, intermittent fever, and lethargy. Icterus, behavioral changes, diarrhea, photosensitization, and hemorrhage are variably present. The duration of clinical signs varies, extending over days to months. Neurologic signs may seem to appear abruptly, even though there is histologic evidence of chronic disease (ie, acute exacerbation of chronic disease).
Sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), and aspartate aminotransferase (AST) activities are increased, indicative of hepatocellular injury, as are alkaline phosphatase (AP) and gamma-glutamyl transferase (GGT) activities; elevations in AST and GGT activity levels may predominate, given the short half-lives of SDH and GLDH. In chronic cases with marked hepatic fibrosis, enzyme activity may be normal (especially when not in an acute exacerbation), and BUN and albumin concentrations may be decreased. Plasma TP can be increased (dehydration or inflammatory response), normal, or decreased (lack of protein, especially albumin, production by a chronically ill liver). Globulins are usually increased. The total serum bile acid concentration is increased. Cholestasis may cause hyperbilirubinemia, with direct bilirubin making up > 25% of the bilirubin total. With diminishing hepatic function, serum glucose and coagulation factors can decrease, and prothrombin time (PT) and partial thromboplastin time (PTT) become prolonged. Blood ammonia concentrations may be increased. There may be neutrophilia or neutropenia with a left shift if endotoxemia develops. Anorexia can lead to hypokalemia.
Ultrasonography generally reveals increased echogenicity in the liver, indicative of hepatic fibrosis. The liver may be smaller than normal, possibly making it difficult to identify on ultrasonography, particularly on the right side in older horses.
Lesions
Grossly, the liver affected by chronic progressive hepatitis is firm, pale brown to green in color, and often small. Irregular markings may be present on the cut surface. Histologic lesions are predominantly in the periportal areas. Inflammatory cell infiltration may consist primarily of mononuclear cells, neutrophils with bacteria (often coliforms), or lymphocytes and plasma cells. The character of the infiltrate may indicate the nature of the primary disease process. Biliary hyperplasia may be marked if there is cholangiohepatitis. Variable degrees of necrosis and fibrosis are present.
Diagnosis of Chronic Progressive Hepatitis in Large Animals
History of prior liver insult, known hepatic dysfunction, or persistent/recurrent clinical signs
Increased plasma hepatobiliary enzymes and bile acids; decreased BUN
Smaller liver on ultrasonography, and chronic histopathologic changes on biopsy
Histologic examination of a liver biopsy is needed for a definitive diagnosis of chronic progressive hepatitis. The tissue should also be cultured, although in most cases important isolates are not identified.
Treatment of Chronic Progressive Hepatitis in Large Animals
Antimicrobials based on biopsy culture and sensitivity results
Corticosteroids, if biopsy shows evidence of plasma cells and/or lymphocytes
Supportive care: IV fluids with glucose, reduced protein intake (grass hay)
Many horses manifesting acute exacerbations of chronic liver disease may respond to antimicrobial treatment, particularly if the choice of antimicrobial can be based on biopsy culture results. Without a positive culture, antimicrobials may still be indicated in a horse with neutrophilic infiltration in the biopsy sample. Conversely, corticosteroid treatment has been used successfully in horses with a lymphocytic-plasmacytic infiltrate on liver biopsy. Reportedly, steroids act to enhance appetite, stabilize cell membranes, and decrease inflammation and connective tissue formation. Different treatment regimens using prednisolone or dexamethasone have been recommended. Clients should be warned about the potential detrimental effects of corticosteroids, such as laminitis or abortion.
In animals with progressive fibrotic changes, administration of colchicine (0.03 mg/kg per day, PO) has been recommended for its anti-inflammatory and antifibrotic effects. Colchicine may exacerbate pyrrolizidine alkaloid toxicosis. Other drugs recommended for arresting or slowing fibrosis include pentoxifylline (7.5 mg/kg, PO, every 12 hours) and S-adenosylmethionine (SAMe; 5 g every 24 hours, PO);however, the efficacy of SAMe in horses is unproved.
Supportive care should include fluid treatment with potassium chloride, glucose, and vitamin supplementation; dietary management (a diet low in protein and high in branched-chain amino acids and carbohydrates); and avoidance of exposure to the sun, if photodermatitis is present.
Prognosis
The prognosis for chronic progressive hepatitis varies and is best determined by the severity of fibrosis present on liver biopsy and by the response to treatment. The prognosis is fair to good in animals with less severe lesions, especially those with a lymphocytic-plasmacytic cellular infiltrate that responds well to corticosteroid treatment; however, it is poor in horses with hepatic failure, widespread fibrosis (or severe bridging fibrosis), and disruption of normal hepatic parenchyma.
Key Points
Chronic progressive hepatitis is often difficult to arrest, despite treatment.
The extent of fibrosis on biopsy is the main determinant of prognosis.
Treatment can be tailored to biopsy results: antimicrobials are indicated for positive culture or neutrophilic infiltrates; corticosteroids are indicated for lymphocytic-plasmacytic infiltrates.
