Hepatic Encephalopathy in Small Animals
Hepatic encephalopathy (HE) develops in liver disorders associated with portosystemic shunting, fulminant hepatic failure, or cirrhosis (acquired portosystemic shunts, reduced functional hepatic mass, intrahepatic shunting of blood around regenerative nodules). Clinical signs vary but involve disturbed sensorium ranging from mild dullness and an inability to respond to basic commands to overt abnormalities, including propulsive circling, head pressing, aimless wandering, weakness, ataxia, amaurosis (unexplained blindness), ptyalism, dementia, behavior change (eg, aggression), collapse, seizures, and coma. Although the pathophysiologic mechanisms of HE are not completely known, synergistic effects between the failure of the liver to detoxify ammonia and other endogenous substances, increased cerebral inflammatory cytokines, impaired brain perfusion, development of neuronal edema, hypoxia, mitochondrial dysfunction, neuroglycopenia, and oxidative injury are important interdependent mechanisms. Increased production of reactive oxygen and nitrogen oxide species are thought to trigger protein and RNA modifications that deleteriously influence brain function. The integrated concept of HE explains episodic variability and heterogeneous precipitating factors that correlate with diverse clinical scenarios.
Ammonia plays a key role in HE and is thought to sensitize the brain to numerous other precipitating factors/mediators. However, blood and cerebral ammonia concentrations are often discordant, disqualifying blood ammonia as a simplistic measure of HE. In healthy animals, most ammonia is removed by hepatocytes, converted into amino acids or urea, and excreted via kidneys in urine. In liver failure or portosystemic shunting, blood ammonia concentrations increase because of inadequate hepatic detoxification. In the circulation, ammonia can also be excreted by the kidneys (tubular secretion) and used for glutamine synthesis in skeletal muscle (temporary ammonia detoxification). This latter mechanism is why maintenance of lean body mass (muscle) is essential in animals with hepatic insufficiency that are susceptible to hyperammonemia and HE. A number of clinical scenarios and mechanisms can augment blood ammonia concentrations and precipitate HE, including dehydration (prerenal/renal azotemia), alkalemia, hypokalemia, hypoglycemia, catabolism, infection, PU/PD, anorexia, constipation, hemolysis, blood transfusion, GI hemorrhage, high dietary protein, and various drugs (eg, benzodiazepines, tetracyclines, antihistamines, methionine, barbiturates, organophosphates, phenothiazines, diuretics [overdosage], metronidazole (overdosage), and certain anesthetics).
Ammonia can influence multiple neurotransmitter systems directly (chemical influence) and indirectly (altered substrate availability for transmitters). There is substantial evidence that astrocytes play an important role in the pathogenesis of HE. Ammonia and other endogenous products, inflammatory cytokines, and hyponatremia (associated with portal hypertension) induce astrocyte swelling that can lead to brain edema and herniation most common in acute liver failure and acute severe HE.
Treatment of acute HE is aimed at providing supportive care and rapidly reducing neurotoxins produced in the GI tract. Severely encephalopathic animals may be semicomatose or comatose. Benzodiazepines and other sedatives should not be administered. Food should be withheld until neurologic status improves. Fluids (2.5% dextrose and 0.45% saline with potassium chloride and vitamin B complex added) should be administered to correct dehydration, electrolyte, and acid-base imbalances, but monitoring of plasma osmolality is essential to avoid hypoosmolality. Lactated Ringer’s solution should be avoided, because hepatic failure may thwart lactose metabolism and cause lactic acidosis. Cleansing enemas of warm soapy water are followed by retention enemas of either lactulose or lactitol (3 parts lactulose or lactitol to 7 parts water at 20 mL/kg), 10% povidone-iodine solution (20 mL/kg, rinsed well after 10–15 min dwell), neomycin (22 mg/kg mixed with water), or diluted metronidazole (7.5 mg/kg suspended in water at 10–20 mL/kg) given every 8 hr until the animal is neurologically responsive. Retention enemas should be maintained for 15–20 min by use of a Foley catheter. Administration (oral or rectal) of live Lactobacillus and Bifidobacillus organisms (live yogurt cultures or probiotic products) also can assist in displacing ammonia-producing microbes but remains a controversial intervention. Metronidazole, neomycin, and povidone-iodine solutions can directly alter colonic bacterial flora, decreasing populations of ammonia-producing organisms. However, care is warranted in using neomycin with concurrent inflammatory bowel disease because increased systemic uptake can increase potential for renal and otic (cochlear) toxicity. Metronidazole must be restricted to ≤7.5 mg/kg every 8 hr (combined oral and rectal dosing); higher dosages confer risk of iatrogenic neurotoxicity (vestibular signs initially).
Once the animal is stabilized, treatment is aimed at preventing recurrence. Protein-modified restricted diets should be fed (see Nutrition in Hepatic Disease in Small Animals). Oral probiotic yogurt and lactulose (0.1–0.5 mL/kg, PO, bid-tid, initial dose) can be used, with initial dose titrated to achieve several soft, pudding-like stools per day. Feeding milk may achieve a similar effect in some animals. The goal of administration of nondigestible carbohydrate is to promote fermentation in the gut. Concentrated probiotic organisms can prevent other bacteria from growing and replicating through substrate competition and pH-related (acid) growth inhibition or mechanical cleansing (catharsis) induced by fermentation products. These effects diminish uptake of ammonia, inflammatory and oxidative substrates, lipopolysaccharide, and other toxic enteric products contributing to HE. Unfortunately, the efficacy of probiotics remains unestablished for this purpose.
In recalcitrant HE, antibiotic therapy, preferably metronidazole (7.5 mg/kg, PO, bid) or amoxicillin (13–15 mg/kg, PO, bid) rather than neomycin, is recommended. Antibiotic therapy works synergistically to reduce enteric toxins along with indigestible carbohydrates. Rifaximin (approved for treatment of HE in people in 2010 because of its few adverse effects and pharmacologic benefits) is a semisynthetic, gut-selective, nonabsorbable oral antibiotic derived from rifamycin and a structural analogue of rifampin. It acts locally in the GI tract, with systemic adverse effects similar to those of placebo in people. It is active against a variety of aerobic and anaerobic gram-positive and gram-negative organisms, as well as protozoal infections. In vitro data indicate that the susceptibility of gram-positive organisms to rifaximin is greater than that of gram-negative organisms. Dosing at 5 mg/kg, once to twice daily, has been used in a small number of dogs and cats with recalcitrant HE with apparent positive response. Optimal dosing has not been determined.
Clinical signs of HE can be exacerbated by GI bleeding, infection, glucocorticoid use (enhanced catabolism of tissue protein), hypoglycemia, neoplasia, fever, azotemia or dehydration (increased BUN increases enteric ammonia production), constipation (increased generation and absorption of colonic neurotoxins), metabolic alkalosis (favoring both production of ammonia by the kidneys and uptake of ammonia across the blood-brain barrier), and use of diazepam and barbiturates (synergetic neuroinhibitors). Use of H2-receptor antagonists and sucralfate, control of fever and infection, proper hydration, and minimal (if any) use of anticonvulsant medications can help alleviate HE complications. For additional considerations, see Fulminant Hepatic Failure in Small Animals.)