Lymphocytic cholangitis in cats: a microbiological, histological and clinical approach

Abstract

In this thesis, a general overview is given of the healthy feline liver and feline diseases of the gall bladder and biliary tree. Lymphocytic cholangitis (LC) is one of the most common inflammatory hepatic diseases in cats. It is a chronic disease that affects the biliary tree and progresses slowly over months or years. Histopathology is considered the gold standard for diagnosing and the lesions are characterized by aggregates of inflammatory cells in portal tracts, and in and around bile ducts. Chronic inflammation in the bile ducts causes dilatations and strictures and may eventually lead to fibrosis and cirrhosis. Clinical signs include nausea and vomiting, changes in appetite, and gradual weight loss. Jaundice is often present later in the course of disease. Blood analysis sometimes reveals elevated hepatic enzymes and bile acids, but hypergammaglobulinaemia is the most consistent finding. Male cats are affected more frequently than female cats. The aetiology is still unknown. Past research has linked bacteria such as Helicobacter spp. to the aetiology of LC which is why bile samples were analysed with molecular methods based on the amplification of the 16S ribosomal RNA gene. A 16S rDNA gene based PCR and denaturing gradient gel electrophoresis (DGGE), followed by direct sequencing, were used for this purpose. Bacterial DNA was present in bile samples from LC patients, while none of the control samples showed any bacterial presence. Based on the variety of organisms found and the presence of Helicobacter spp. DNA in both patients and controls, bacteriobilia in LC patients seems not to be the cause but rather a consequence of the disease. Therefore, treatment with antibiotics is unlikely to be a successful strategy. Common treatments for LC include prednisolone or ursodeoxycholic acid (UDCA). Clinical evaluation of prednisolone and UDCA in cats with LC showed that prednisolone treatment resulted in a statistically significantly longer survival time than treatment with UDCA. Liver histology during treatment showed that prednisolone reduces hepatic inflammation more than UDCA. Additionally, regeneration of the injured liver in cats with LC is supported by the activation of hepatic progenitor cells and their niche. Immunohistochemical stainings for vimentin, laminin, Wnt/β-catenin, and Notch/NICD were developed and applied for cats based on earlier findings in other species. Vimentin expression has been shown in hepatic progenitor cells of rats, mice, human beings, and dogs and has been shown to indicate proliferative activity of cells and an undifferentiated state of HPCs. Remodelling of the extracellular matrix (ECM) and deposition of laminin have been shown to play an important role in HPC activation in hepatic injury in both rodents and human beings. It also promotes cholangiocyte differentiation of bipotent cells. The Wnt/β-catenin signalling pathway has a central role in hepatic and bile duct development and regeneration, promoting gene activation, inhibiting apoptosis and increasing cellular proliferation. It also guides cells to a biliary phenotype. Notch/NICD is involved in the proliferation, differentiation and apoptosis in all stages of organ development, including healthy and diseased livers. This might prove an exciting opportunity for future treatment options.