Canine cholangitis/cholangiohepatitis syndrome (CCHS) is less common than copper-associated liver injury or a diagnosis of idiopathic hepatitis in dogs, but it is not an uncommon diagnosis. CCHS usually is associated with suppurative inflammation, implicating a disease causing bile flow stasis with potential for bacterial involvement. Depending on the interpreting pathologist, diagnosis of CCHS can be made in any dog with extrahepatic bile duct obstruction (EHBDO) because one of the first histologic changes in that process is development of a periductal neutrophilic infiltrate, periductal edema, and bile duct distortion (usually distention and tortuosity).
Because gallbladder mucocele (GBM) is a fairly common diagnosis in dogs culminating in cholecystectomy and liver biopsy, histologic description of CCHS has concurrently increased over the last decade. Lymphocytic cholangitis in dogs is comparably uncommon. In most cases, suppurative CCHS is associated with a diseased gallbladder or some extenuating circumstance associated with enteric translocation of bacteria to the portal circulation (ie, consumption of a raw meat diet, scavenging garbage or carcass remains, enteric neoplasia, or severe gastritis inflammatory bowel disease). The other chronic condition plagued by chronic suppurative and mixed neutrophilic/lymphocytic cholangitis is ductal plate malformation.
Clinical Signs of Canine Cholangiohepatitis in Small Animals
Considering the common association between canine cholangitis/cholangiohepatitis syndrome (CCHS), gallbladder, and enteric disease, there is considerable overlap in clinical signs among these disorders. In decreasing frequency of occurrence, clinical signs include lethargy and vomiting (> 70%), hyporexia (~65%), and diarrhea (~30%). Physical examination findings include pyrexia (~30%), jaundice (~25%), lethargy (26%), palpable hepatomegaly (10%), and occasional polyuria/polydipsia (PU/PD) and ascites.
Hematologic features of canine cholangiohepatitis may include a neutrophilic leukocytosis with a left shift and toxic neutrophils or a degenerative left shift, or hematology may be within normal limits. Most dogs display increased liver enzyme activities and total bilirubin with a subset demonstrating hypercholesterolemia at initial presentation.
Estimated frequencies of these abnormalities include increases in alkaline phosphatase (ALP) in 98%, ALT in 88%, AST in 79%, gamma-glutamyl transferase (GGT) in 42%, total bilirubin in ~64%, and cholesterol in ~56%. Expected median fold increases (ranges) include ALP ~10× (1–52×), ALT ~5× (1–36×), AST ~2–3× (1–17×), GGT ~2× (1–16×), total bilirubin ~5× (1–162×), and cholesterol ~1.3× (1–4.4×); values within reference ranges indicated as 1×. Rare abdominal effusion typically is not ascitic but rather reflects altered vascular integrity associated with sepsis, iatrogenic fluid overload, or bile peritonitis.
Imaging of Canine Cholangiohepatitis in Small Animals
Radiographic features of canine cholangiohepatitis may disclose a normal to slightly large liver size and rarely, evidence of abdominal effusion in canine cholangiohepatitis. Ultrasound image findings may disclose variable hepatic parenchymal echogenicity (normal, hyperechoic, or mixed echogenicity), subjective hepatomegaly, gallbladder distention ± distention of the extrahepatic biliary tree ± intrahepatic bile duct distention indicating isolated gallbladder disease or acute versus more chronic EHBDO, respectively.
There may be gallbladder changes consistent with a GBM (volume > 1.2 mL/kg with organized stellate nongravitational intraluminal debris), cholecystitis, or evidence of cholelithiasis. Relevant changes in nonhepatic viscera may include pancreatic or enteric architectural changes suggestive of pancreatitis, gastritis, or enteritis, and observation of enteric hypomotility (ileus). Discovery of abdominal effusion is rare. Cholecystic marginating shallow effusion develops with cholecystitis without discrete gallbladder rupture.
Histologic Features of Canine Cholangiohepatitis in Small Animals
Cholangitis is classified into suppurative and nonsuppurative categories; while this grouping does not designate specific etiology, finding a suppurative inflammatory process implicates involvement of bacteria.
Suppurative Cholangitis
Suppurative cholangitis is characterized by periductal accumulations of neutrophils and macrophages that are variably scattered within edematous periductal adventitia (loosely interwoven periductal mesenchyme). Neutrophils and macrophages migrate from the peribiliary vascular plexus into the portal tract, where they localize adjacent to ductal elements. This process is facilitated by vascular expression of chemokine-induced adhesion molecules. Injury initially derives from release of neutrophil granules (myeloperoxidase, superoxides) and macrophage chemokines and cytokines causing regional oxidative injury. Inflammatory cells often penetrate ductal epithelium and occasionally form intraluminal purulent plugs (cellular and mucinous biliary debris).
In some cases, direct neutrophilic invasion of ductal elements is not obvious although a distinct ductal tropism is evident. Mixed inflammatory infiltrates (neutrophils admixed with macrophages, lymphocytes, and occasional plasma cells) may emerge with chronicity. A light to moderate quantity of plasma cells, lymphocytes, and fewer neutrophils and macrophages often accumulates in centrilobular regions with a septic process (perivenular distribution).
Cholangitis may involve ducts of any size. While bacteria are often involved with a neutrophilic process, they are rarely observed in histologic sections (even with Gram staining). Bile duct hyperplasia and periportal ductular reactions are observed within and extending from portal tracts. When inflammatory cells penetrate the limiting plate (the designated portal tract margin) and extend into adjacent hepatic parenchyma, the process qualifies as cholangiohepatitis.
Suppurative cholangitis and cholangiohepatitis occasionally display periductal foci of leaked bile. Escape of cytotoxic bile acids contributes to bile duct epithelial and hepatocyte injury. Canalicular cholestasis is inconsistent. When present, this appears in centrilobular regions as golden globular casts filling canalicular profiles. This finding often implicates a septic process. Severe persistent and progressive portal inflammation and fibrosis with chronic CCHS terminates in bridging portal fibrosis and eventual biliary cirrhosis.
Destructive Cholangitis
In some cases of CCHS, bile duct epithelium is overtly damaged (epithelial vacuolation, degeneration, apoptotic or necrotic cell dropout), evolving asymmetric ductal profiles. Inflammatory infiltrates and ductal injury may then obscure bile duct silhouettes. Severe epithelial injury or loss of the peribiliary arterial plexus (ischemic injury) may result in bile duct involution or collapse. With chronicity, this process may progress to generalized ductopenia (bile duct:arterial ratio < 0.5) that may not be recoverable.
Bacterial Cultures
Numerous gram-positive and gram-negative bacterial organisms have been cultured from dogs with CCHS; most common isolates are aerobic with Enterococcus spp and Escherichia coli frequently involved. Polymicrobial infections are observed in ~30% of cases. The type of sample submitted profoundly influences culture findings. Combined inocula of multiple sample types is most profitable. Combined cultures should include, as a single submission, bile sediment (centrifuged from a large-volume bile sample), biliary debris (scraped from the wall of an excised gallbladder), a section of gallbladder wall, crushed cholelith, and liver biopsy.
It makes no sense to separate bile from liver inocula when considering cost and treatment strategies derived from this information. The only exception is that it is essential to know whether there is infection involving the gallbladder if on gross inspection it appears normal. Retaining an infected gallbladder should be avoided because it can serve as a sump of chronic bileborne infection. This can be clarified at the time of surgery to strategize cholecystectomy, by cytologic inspection of biliary debris. Finding bacteria in gallbladder biliary debris recommends cholecystectomy.
Treatment of Canine Cholangiohepatitis in Small Animals
Optimal management of CCHS in dogs requires identification and treatment of the underlying cause. This first includes recognition and amelioration of mechanical cholestasis by careful inspection of extrahepatic biliary structures and gallbladder (ie, for EHBDO, GBM, cholelithiasis, patency of the sphincter of Oddi). In cases with gallbladder disease involving a septic process, a cholecystectomy is indicated.
During surgery this is adjudicated by inspection of a large-volume bile aspirate (goal is to empty the gallbladder of bile) such that sediment from a centrifuged bile sample can be inspected for bacteria (routine commercial Romanowsky stain variant). The bacterial biofilm in the gallbladder adheres to mucinous precipitates and the villous mucosal surface; a few drops of liquid bile are not sufficient for this assessment. If bacteria are observed in biliary debris, Gram staining should be done. Most animals will have received presurgical prophylactic antimicrobials. If submitted cultures fail to grow organisms are observed cytologically, a Gram stain will at least provide morphology helpful in selecting antimicrobial coverage.
The other important consideration is to meticulously examine nonhepatic enteric viscera for localized pathologies that might explain bacterial translocation. If no specific lesion is identified, full thickness biopsies should be collected from the stomach, duodenum, jejunum, and ileum to investigate for inflammatory bowel disease or lymphoma. It is responsible to acknowledge that these observational assessments cannot be orchestrated during a laparoscopic procedure. Rather, this requires hands-on laparotomy exposure that will permit discrete (visual and palpation) inspection of structures and determination of patency of the extrahepatic biliary tree and gallbladder.
Similarly, diagnosis of neutrophilic cholangitis in a dog by ultrasound-guided gallbladder aspiration and needle biopsy of liver imposes critical diagnostic and therapeutic shortcomings. Based on survival analysis of clinical patients with a neutrophilic cholangitis or CCHS associated with bacterial infection or gallbladder disease, cholecystectomy has a strong positive survival advantage.
Rare lymphocytic cholangitis or CCHS in dogs may represent an immune-mediated process and requires immunomodulation if infection has been diligently ruled out. Treatment involves use of choleretics, antioxidants, and immunomodulation, as described in the section on chronic hepatitis.
Antibiotics
If a neutrophilic inflammatory response dominates CCHS or integrates within a mixed inflammatory response, antibiotic coverage is indicated, whether or not cultures retrieved bacteria. Responsible antimicrobial recommendations are best customized on the basis of culture findings. Before culture results are available and usually before biopsy collection, a triple antibiotic protocol is used. This cocktail combines metronidazole (7.5 mg/kg, every 12 hours, PO or IV); a fluoroquinolone; and a broad-spectrum penicillin (ie, ampicillin with a beta-lactamase inhibitor such as ticarcillin or a combination of ampicillin sodium and sulbactam sodium).
The cause of bacterial infection advises duration of antibiotic administration. If the lesion is associated with any of the following, antimicrobial treatment for 2–4 weeks is indicated:
dietary indiscretion
consumption of a raw meat diet or carcass remains
an infected gallbladder that was removed
resolved cholelithiasis
resection of a focal enteric lesion
This recommendation is tailored based on clinical health status and resolution of clinicopathologic abnormalities. If the causal process is one requiring chronic management with risk for repeated translocation or persistent infection, ie, chronic inflammatory bowel disease, enteric lymphoma, or ductal plate malformations (DPMs) that are predisposed to chronic infection, then longterm antimicrobial treatment is required, perhaps for months.
Sequential at-home assessments (for fever, lethargy, inappetence, and weight loss) and clinicopathologic assessments, including CBC (looking for neutrophilic leukocytosis, left shift, toxic neutrophils), liver enzymes, total bilirubin, and cholesterol help strategize antimicrobial recommendations.
Choleretics
Choleretics assist with mechanical cleansing of cellular debris and inflammatory mediators by increasing bile flux. They should not be used until EHBDO is decompressed. Ursodeoxycholic acid (UDCA, or ursodiol) is administered at a dosage of 10–15 mg/kg, divided every 12 hours, given with food to increase bioavailability. UDCA increases bile acid–dependent bile flow. High-dose bioavailable S-adenosylmethionine (SAMe; administered at a dosage of 40 mg/kg, every 24 hours, PO, on an empty stomach for best bioavailability) is used to increase non-bile acid–dependent bile flow (via increased GSH flux).
Antioxidants
Bioavailable SAMe, dosage as above, is used to improve circulating and hepatic GSH redox status and should be continued until clinicopathologic abnormalities resolve.
Low-dose vitamin E, 10 U/kg, every 24 hours, is similarly used for its membranoprotective antioxidant effect.
No oral product delivering milk thistle or silibinin is recognized to deliver therapeutic concentrations of this nutraceutical, according to numerous in vivo studies in humans with liver disease (meta-analysis of clinical trial outcomes) or in animal models of liver disease. Only IV forms of silibinin are recognized as therapeutic.
