David C. Twedt, DVM, DACVIM
The term "triaditis" is used to describe concurrent inflammation of the pancreas, liver and small intestines and is based on histological conformation. However, the specific conditions that constitute the diagnosis of triaditis include any inflammatory process within these organs but is most often associated with a combination of pancreatitis, cholangitis and inflammatory bowel disease (IBD). Triaditis has been reported in 50–56% of cats diagnosed with pancreatitis and 32–50% of those with cholangitis or inflammatory liver disease.
Although there appears to be a direct association between the three organ involvement, the etiology and pathophysiology of this syndrome is yet unknown. Likely causes of inflammation include bacterial infection, immune-mediated or idiopathic mechanisms. When all three organs (liver, pancreas and intestine) become inflamed, it becomes triaditis. Because the etiology of this syndrome is unknown, it is difficult to know how to best treat it. Since it is likely several etiologies are responsible, the specific therapies are also variable and will be different from case to case.
One theory for triaditis is that both acute and chronic pancreatitis could be the result of an extension of ductular inflammation from the biliary system. This is because the common bile duct and pancreatic duct both merge into a common channel before entering into the intestine. It is possible bile and enteric bacteria from the common channel enter both the pancreatic duct and common bile duct and are responsible for both inflammatory liver and pancreatic changes. With the theory of ascending bacteria from the intestine, bacteria may be responsible for both cholangitis and pancreatitis. It is known that cats also have on the order of 100 times higher concentrations of bacteria in the proximal duodenum than do dogs or humans (dogs 103 cfu/g vs, cats 105 to 108 cfu/g). High enteric bacterial concentrations coupled with inflammatory changes in the intestine would be a likely source of bacterial seeding either via the common channel or through intestinal translocation with hematogenous seeding. In either case, IBD would likely potentiate bacterial movement.
Fluorescence in situ hybridization [FISH] analysis, using a 16S rDNA probe that recognizes a specific class of enteric bacteria, is a non-culture method staining technique for bacteria. In a published study we found through FISH analysis that enteric bacteria were present in liver tissues of 69% of the cats having a chronic or acute inflammatory liver disease. The most common bacteria identified in the livers with cholangitis are E. coli and Enterococcus. In another, but yet unpublished study, we used FISH to examine the pancreas of cats with either acute or chronic pancreatitis and found a relatively high frequency of bacteria in that organ (35% or 11/31 cases). Infection was most prevalent in cats with moderate-to-severe acute or chronic pancreatitis. The localization and type of intrapancreatic bacteria suggests translocation of enteric bacteria. The most common organisms identified were E. coli, Streptococcus spp. and Enterococcus spp. Further, an experimental pancreatitis study in cats clearly demonstrated that E. coli translocated from the intestines into experimentally induced acutely inflamed pancreas, as well as into the liver and gallbladder supporting the intestinal translocation theory. These findings have substantial implications for the diagnosis and management of cats with pancreatitis.
Cats having chronic lymphocytic pancreatitis or lymphocytic cholangitis invasive bacteria are less commonly visualized. With the combination of lymphocytic (chronic) pancreatitis, lymphocytic or mixed lymphocytic and neutrophilic cholangitis and lymphocytic plasmacytic enteritis may all be a consequence of an immune-mediated process rather than active bacterial infection. In people and experimental animals, autoimmune pancreatitis and cholangitis are recognized as extraintestinal complications of IBD, with immune attack frequently directed against bile and pancreatic ducts. Immune-mediated damage may either be a consequence of immune responses against bacteria (that may or may not have established an active infection) that cross-react with host tissues with resultant innocent bystander immune responses in the intestines, liver and pancreas, or immune attack directed against host antigens unmasked by tissue damage. In further support for an immune etiology are human studies demonstrating that a variety of autoantigens have been implicated again suggesting that immune responses to translocated bacteria, perhaps facilitated by a leaky gut, may promote an immune inflammation in susceptible individuals. We also know feline IBD, when not dietary or antibiotic responsive, often improves with immunosuppressive therapy supporting again a possible immune theory. At this point there are no reliable clinical tests to detect an immune response.
The definitive diagnosis involves histopathology from each organ. It is important, whenever doing an exploratory surgery for a biopsy of intestine, pancreas, or liver, that all three organs should be carefully inspected and biopsied even if they appear normal because triaditis is so common. Evidence of liver disease is based on identification of elevations in liver enzymes and/or total bilirubin. Liver ultrasound findings in cats are quite variable and many affected livers can appear normal. Abnormal ultrasound changes in cholangitis include prominent portal areas, duct distention and thickened gallbladder wall. In some cases, bile duct obstruction can occur from duct inflammation, cholelithiasis, or thick bile sludge. Surgical flushing or even temporary stent placement may be required in these cases. I will also always culture the liver biopsy and bile that has been obtained from a gallbladder aspirate. A presumptive diagnosis of pancreatitis includes an elevated serum pancreatic lipase immunoreactivity test (fPLI) and abdominal ultrasound showing abnormal pancreatic changes. In one study, the fPLI sensitivity is reported to be 67% and the specificity of the fPLI to be 91%. Ultrasound will detect anywhere from 35 to 67% of cats with pancreatitis. Pancreatic biopsies are safe and easy to perform either at surgery or via laparoscopy. I also now culture most of my pancreatic biopsies as well. Intestinal disease is often diagnosed based on signs of GI disease (vomiting or diarrhea) and ultrasound changes in the bowel with mucosal thickening or loss of layering. Some cats may also have decreased folate of cobalamin (B12) serum concentrations with triaditis. Intestinal biopsies confirm inflammatory intestinal disease and are obtained via endoscopy or surgery. It is ideal to biopsy each segment of the small intestine because the IBD can be regional. Further, the most common area for GI T-cell lymphoma is the ileum that must be reached endoscopically via colonoscopy.
Since the etiology of feline triaditis is unknown, it is almost impossible to make absolute treatment recommendations. The first step in the therapy should be directed to the organ that is thought to be primarily responsible for the clinical signs. Because we believe that both bacterial and immune-mediated theories are possible, one should use all the clinical information available to help direct the course of therapy.
Inflammatory Bowel Disease (IBD)
The etiology of IBD is unknown. Possibly dietary constituents, bacterial causes, or an abnormal immune response are all thought to be likely etiologies. Lymphocytic-plasmacytic enteritis frequently responds to dietary modification with an antigen-restricted (novel protein) or a hydrolyzed diet. Refractory patients typically escalate to diet plus antimicrobial therapy using enteric antibiotics such as tylosin (15 mg/kg BID), metronidazole (7–10 mg/kg BID), or amoxicillin. If the patient fails to respond to more conservative therapy, then I will institute anti-inflammatory therapy using prednisolone (1–2 mg/kg q 24 h with gradual dose reduction based on response). Often B12 supplementation is required (250 µg SQ weekly). Concurrent low-grade small T-cell intestinal lymphoma can respond well to therapy with chlorambucil (2 mg PO given 3 times a week), prednisolone, and supplementation of B12.
Acute pancreatitis is less common than chronic pancreatitis, but acute can often progress to chronic pancreatitis or even exocrine pancreatic insufficiency. Acute (suppurative) pancreatitis carries a particularly poor prognosis. Complicating factors that can modify the situation are bacterial translocation and biliary obstruction. Fluid therapy, analgesics, antiemetics, and assisted alimentation are the basis of therapy. Antimicrobial therapy is warranted in moderate-to-severe cases and is supported by the finding of positive FISH staining in over 1/3 of the cases investigated. Escherichia coli, Streptococcus spp. and Enterococcus spp. are the most common organisms identified. Amoxicillin-clavulanic acid, cephalosporins, fluoroquinolones, or metronidazole are reasonable considerations. In cats with suspected disease, exploratory laparotomy with biopsy of the pancreas, liver, and intestine with appropriate cultures of pancreas and liver is frequently required to optimize therapy. Persistent biliary obstruction from pancreatitis is another indication for surgery and may be amenable to stenting or cholecystojejunostomy. It should be noted that corticosteroids are not typically employed in the treatment of feline acute pancreatitis.
Chronic pancreatitis is more common than acute pancreatitis in the cat. Lymphocytic or lymphocytic-plasmacytic pancreatitis with fibrosis is the characteristic finding. In some cases the pancreatic damage can be so severe resulting in exocrine pancreatic insufficiency requiring pancreatic enzyme supplementation. Bacteria can also be a component of chronic pancreatitis, so I generally begin with antibiotic (same listed above) and antioxidant therapy (i.e., SAMe, milk thistle, vitamin E). If there is a failure to respond to antibiotics or with evidence of IBD and/or lymphocytic cholangitis, then corticosteroid therapy would be indicated. Many cats will also require vitamin B12 supplementation.
The management of cholangitis is based in part on culture results and histopathology. The acute neutrophilic (suppurative) cholangitis or chronic neutrophilic (lymphocytic plasmacytic neutrophilic) cholangitis are often associated with bacteria. The specific antibiotic therapy to use is best determined based on culture and sensitivity of the liver biopsy or bile aspirate. Short of a positive culture, antibiotic therapy should be directed at enteric coliforms as suggested in the pancreatitis section. Other adjunct therapy may include ursodiol (ursodeoxycholic acid 10–15 mg/kg q 24 h or divided BID), SAMe, milk thistle products, or other antioxidants. The acute form usually responds quickly, while the chronic form is less predictable. Generally, a 4-week course of antibiotic therapy is indicated. If the patient fails to improve after several weeks of antibiotics, I will begin prednisolone therapy. The lymphocytic cholangitis is thought to be likely immune mediated and rarely has a bacterial component. But because pancreatitis is common with cholangitis and bacteria could play a role in both, I will usually also institute a course of antibiotic therapy. Cats having lymphocytic cholangitis will however generally require prednisolone therapy and sometimes even immunosuppressive therapy such as chlorambucil or others. A recent study found ursodiol was inferior to steroids based on follow-up biopsies after a course of therapy. I use ursodiol as an additional adjunct therapy in these cases. General supportive therapy, antioxidants, and vitamin B12 are generally used in these cases.
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