FRANK J. MILNE STATE-OF-THE-ART LECTURE


giohepatitis. Studies have identified CH and CL as diseases of middle-age-to-older horses with no obvi- ous sex or breed predilection.30,40,43 Although the etiopathogenesis of CH and CL in horses is uncer- tain, retrograde bacterial infection from the small intestine is considered probable and this hypothesis is supported by the studies by Johnston et al,40 Reef et al,44 and Peek.30 The isolation of enteric, pre- dominantly Gram-negative organisms from clinical cases of cholangiohepatitis and cholelithiasis is con- sistent with this hypothesis.30,40,44,45 Plant mate- rial has occasionally been found inside the stones,44 further supporting retrograde invasion of bacteria and even ingesta from the duodenum as a predis- posing cause of the disease.a As bacteria gain en- trance to the biliary system from the duodenum (bile is normally sterile), it would be expected that an inflammatory response would occur with tissue swelling thus potentially increasing the pressure within the common bile duct and forcing infection into the biliary canaliculi. The ascending infection is thought to initiate a cholangitis, which may then extend into the periportal region of the liver causing cholangiohepatitis.40 The occurrence of enteritis or inflammatory bowel disease prior to the onset of CH in some cases may also support the ascending en- teric bacterial infection hypothesis,46,47 although most cases ofCHdo not have a clear history of either prior enteritis or inflammatory bowel disease.30 The most common organisms cultured from the af- fected horses are E. coli, Actinobacillus equuli, Streptococcal spp., Klebsiella sp., Enterococcus spp., Clostridium spp., and Bacteroides sp.29,30,46 CH may predispose to hepatolith or cholelith formation. Equine choleliths are predominantly composed of calcium bilirubinate and to a lesser extent calcium phosphate.30,44,48,49 Ascending enteric bacterial in- fection is thought to be critical in the development of brown pigment stones (calcium bilirubinate) in man.50,51 Deconjugation of bilirubin diglucuronide by bacterial beta glucuronidase such as Clostridium spp., Bacteroides spp., Escherichia coli, and Pepto- coccus spp. occurs with subsequent precipitation of calcium bilirubinate, and cementation by anionic glycoproteins is thought to result in the formation of these calculi.50 It is clinically important to realize that calcium bilirubinate crystals may form ini- tially, followed by sludge formation and then stone formation. If that hypothesis is true, then each stage of the process may signal further decreases in the efficacy of medical treatment. In the majority of clinical cases of equine cholelithiasis, stones are found in more than one area of the biliary tree and can include intrahepatic and extrahepatic chole- liths, as well as choledocholiths (stones of the com- mon bile duct).44 Multiple stones are common, with one extreme case reported as having 1,120 stones.52 Stones in the common bile duct would almost always be expected to produce signs charac- teristic of obstructive failure whereas stones in other areas of the biliary tree may be silent.


Clinical signs associated with these conditions in-


clude pyrexia, colic, icterus, and in chronic cases, significant weight loss.30,40,43,44,48,53–56 In a small percentage of cases, both neurologic signs caused by hepatic encephalopathy (HE) and photosensitization may be seen.40,57 Unless the disease is chronic and extensive fibrosis has occurred, hepatocellular func- tion is not severely compromised, thus accounting for the absence of HE in many cases. Although nonspecific, colic and marked icterus are the most common clinical findings in horses with obstructive CH and CL.30,40,43,48 Fever would be expected but is not always evident on a single exam. Some de- gree of depression may be present. Affected horses have markedly elevated serum concentrations of the hepatobiliary enzymes GGT and ALP and bilirubin. A proportionate increase in the conjugated bilirubin fraction to greater than 25% of the total bilirubin is common40,43,48,49 but in approximately one third of cases the percentage of conjugated/total bilirubin is lower than 25%.30 Affected horses almost always have an increase in hepatocellular enzymes SDH, GLDH, and AST (commonly 2–4 times normal), al- though the proportionate increase above normal val- ues is usually less than that seen with serum GGT elevations (commonly 7–20 times normal). Hyper- fibrinogenemia was common in nine of 10 horses diagnosed with CH in our initial retrospective study of CH at the University of Pennsylvania40 but that was not the case in our second study of nine horses at Cornell.30 Other notable serum biochemical ab- normalities with CH include increased serum bile acids and hyperglobulinemia.30,40 If one is trying to diagnose CH and discovers that globulins are not elevated then this could be a red flag for either a wrong diagnosis or some complicating factor; I learned that from a case that Dr. Sandy Tasse dis- cussed with me in 2012. That case had all of the classic clinical and laboratory findings associated with CH but the total protein was only 5.6 g/dL and albumin was normal. The horse did have liver fail- ure due to infectious CH but did not respond to routine and extended therapy for CH on the farm. After consulting with Dr. Julia Felippe at Cornell, it was found that the horse also had combined variable immunodeficiency necessitating euthanasia. I felt badly that I had not diagnosed it earlier. Clotting function tests (PT and PTT) were consis-


tently normal in our second study, despite biochem- ical evidence of advanced hepatobiliary disease30 but there are reports of severe CH and CL causing prolongation of both PT and PTT times.40,43 Transabdominal ultrasound examination of the


liver with a 5 megahertz (MHZ) sector scanner is required for diagnostic imaging purposes and for monitoring treatment of equine liver disease. The liver can almost always be visualized on the right in horses with cholelithiasis, even in older horses that commonly have atrophy of the right lobe, because hepatomegaly is present in all cases except for those with chronic and diffuse fibrosis. The ultrasono-


AAEP PROCEEDINGS  Vol. 61  2015 71


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