Innovation

Mesenchymal Stem Cell Therapy for Labrador Retriever Chronic Hepatitis

Labrador retrievers develop a breed-specific chronic hepatitis (CH) that progresses to cirrhosis and hepatic failure. Vague clinical signs include decreased appetite, lethargy, PU/PD and vomiting.  Median age at diagnosis is between 6.4-9.3 years (range: 2-15 years).  A female predominance is noted in some, but not all reports. Dogs typically have increases in serum  ALT and AST with more modest and variable increases in ALP and GGT. Some dogs also have renal tubular disease manifested by the presence of normoglycemic glucosuria. Definitive diagnosis is by hepatic histopathology, which shows varying degrees of necrosis/apoptosis with centrolobular to periportal mononuclear inflammation (lymphocytes, plasma cells and histiocytes), regeneration and fibrosis (Fig 3). In some dogs cirrhosis is present at diagnosis. Median survival is 374 days (range:1-2,645 days).

Fig 3

Figure 3: Hepatic biospy from a 5-year-old spayed female Labrador that presented for anorexia, weight loss, and PU/PD. H and E stains (A, B) show marked portal inflammation consisting of lymphocytes, plasma cells and macrophages. Multifocal lipogranulomas are present. Siruis Red stains (C, D) highlight the abundant fibrosis with prominent bridging between portal areas. Low (A C, 100X)) and high (B, D 400X) power.

The etiologic factors in Labrador CH have not been fully characterized. Some dogs accumulate excess hepatic copper, but it is unknown if this copper accumulation is the primary cause for the inflammatory process or simply predisposes the liver to harm from other insults such as toxic or immune injury.  Without identification of a specific etiologic trigger, no standard treatment for Labrador CH exists. Copper chelation therapy, low copper diets and a variety of hepatoprotective agents (vitamin E, ursodeoxycholate and S-adenosylmethionine) are recommended, although these have not been shown to stop disease progression. Anecdotal evidence suggests that some dogs respond to immunosuppressive therapy with prednisone. However, prednisone therapy can be associated with serious side effects in dogs with compromised hepatic function, including worsening of ascites and hepatic encephalopathy, gastric ulceration, and increased susceptibility to portal vein thrombosis. Thus, alternative therapies to capture remission are necessary.

At Tufts Foster Hospital for Small Animals we are beginning an innovative pilot study to look at the therapeutic efficiency of mesenchymal stem cells in treating canine CH. Human clinical trials using MSCs to treat CH have demonstrated decreases in serum liver enzyme activity and/or improvements in clinical or hepatic histological scoring systems. Of particular interest is the fact that MSC therapy can ameliorate hepatic fibrosis. The effect of MSCs may be due to their ability to differentiate into hepatocytes in vivo and thus aid in hepatic regeneration, and/or to the presence of paracrine effects which suppress inflammation and collagen deposition.  Inclusion criteria for the Labrador study include the presence of moderate to severe activity on hepatic biopsy and a serum ALT and/or AST at least 3 times the upper limit of normal.  Contact Dr. Cynthia Webster (cynthia.leveille-webster@tufts.edu) or our clinical trials technician, Jessica Schavone (jessica.schavone @tufts.edu) if you have interested clients. Funds are available to off-set the cost of the medical work up (including laparoscopic hepatic biopsy) and all treatments are free.