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


tions in the brain may have direct effects on pH, membrane potential, and neurotransmission in ad- dition to cellular metabolism and cerebral water balance.243 Although undoubtedly the most impor- tant single neurotoxin involved in HE, ammonia should not be considered the sole cause. In fact, a moderate number of horses with HE do not have blood ammonia values above the reported normal range.20 Other neurotransmitters are frequently discussed as playing a role in HE but their associa- tion has not been well documented, these neu- rotransmitters include endogenous benzodiazepine- like compounds, mercaptans, monoamines, and aromatic amino acids.244 Increased blood brain barrier (BBB) permeability


for gut-derived neurotoxins may also play an inte- gral role in HE. The BBB is the physical and met- abolic barrier separating the peripheral circulation from the central nervous system and regulates ex- changes between the two.245 Changes in BBB per- meability may be due to both structural alterations in tight junctions and inflammatory vascular effects, as well as functional changes. Increases in blood ammonia, metalloproteinase activity, and endotoxin may increase permeability of the BBB in liver fail- ure, permitting transport of other neurotoxins to the brain.245 Systemic inflammation and sepsis from endotox-


emia or bacterial translocation are often part of the syndrome of HE. Breakdown products of injured hepatocytes as well as increases in systemic inflam- matory cytokine production, free radicals, and met- alloproteinases in liver failure have severe systemic effects in addition to increasing permeability of the BBB.246 The toxic effect of these events on the brain with HE is believed to result in both cytotoxic (intracellular swelling without increased permeabil- ity of BBB) and vasogenic (increased permeability of BBB allowing net gain of fluid) brain edema.238,241,242 The clinical signs of HE in horses may be mild with only depression, anorexia, and frequent yawning. In other cases the signs can be fulminant and include head pressing, blindness, cir- cling, and coma. Ataxia can be noticeable in some cases and absent in others. Rarely, ataxia may pre- cede HE signs or icterus in acute liver failure.247,248 Clinical examination may reveal decreased muscle tone of the lower lips, delayed or absent response to touching the inner nares, and cortical blindness of- ten accompanied by mydriasis. These signs are all a result of the cortical disease that occurs with HE. Laryngeal paralysis or dysphagia (presumably due to HE and functional disturbance in the nucleus ambiguous)122 and gastric impaction/rupture121 (presumably due to autonomic nerve dysfunction) are additional findings that may be associated with HE in horses. Laboratory findings that are directly associated


with HE include hyperammonemia, occasionally hy- poglycemia, and metabolic acidosis. Increased blood ammonia is common, but certainly not always


above the normal range in all horses with HE. The normal range of blood ammonia in the horse varies between laboratories but is generally less than 90 mol/L. Many cases of HE have concen- trations in the 100–200 mol/L range, a few cases are greater than 200mol/L, and the highest per- centage of cases seem to be in the upper-normal range, 70–90 mol/L. Horses with HE as a result of liver failure generally do not have ammonia levels as high as those seen with primary enteric hyper- ammonemia, portosystemic shunts, or Morgan foal hyperammonemia syndrome, which often have blood ammonia concentrations greater than 300 mol/L.168,198,199 Metabolic acidosis, mostly due to lactic acidosis, is common in horses with HE. The increase in L-lactic acid is likely a result of de- creased hepatic metabolism of lactate, poor perfu- sion and cellular hypoxia, and enhanced hepatic and extra-hepatic aerobic glycolytic activity and lactate production. Hypoglycemia is rather uncommon in adult horses with HE but common in young foals with HE.20,36 In one report of 50 horses with liver failure20 none had hypoglycemia, but we have occa- sionally examined a horse or pony with liver failure and hypoglycemia. Dr. Bud Tennant reminded me of a HE case that was hypoglycemic and comatose and following glucose treatment quickly stood up and eventually recovered. Pathologic findings in the central nervous system


of horses and other animals with HE or other hyper- ammonemia syndromes consist of reactive astrocy- tosis in gray matter, Alzheimer type II cells, and cerebral edema.249,250 Alzheimer type II cells (en- larged astrocytes with basophilic nucleoli that seem to be metabolically hyperactive) are closely associ- ated with increased blood and CSF ammonia; these cells are also routinely found in the brain of horses dying from primary intestinal hyperammonemia and we know from foal studies with acute hepatic failure that Alzheimer cells can be found in the brain within 2 days of the hepatic failure.13,251 Treatments for HE revolve around decreasing en- teric-derived neurotoxins (primarily ammonia), de- creasing cerebral edema, correcting glucose, electrolyte, and acid-base abnormalities, and main- taining perfusion and oxygenation to the brain and other vital organs.251 Providing specific treatment for the liver disease per se, such as hepatic lipidosis or bacterial cholangiohepatitis, is imperative but in many cases of liver failure there are no specific treatments for the hepatic disease and only support- ive care, as outlined below, can be provided. Addi- tional general supportive treatments that inhibit both systemic and neuronal inflammation, reduce oxidative stress, and prevent multiple organ dys- function are recommended. Correction of intravascular volume deficits should


be the initial focus for fluid therapy in most horses with liver failure (LF).252 Expansion of the vascu- lar volume can improve perfusion to the diseased liver and other organs that may be secondarily in-


AAEP PROCEEDINGS  Vol. 61  2015 93


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