Definition

• Hepatic encephalopathy (HE) defines a broad spectrum of neurobehavioral signs.
• Associated with: (1) acute liver failure, (2) portosystemic bypass without intrinsic liver disease (portosystemic vascular anomaly [PSVA] shunt), (3) hepatic fibrosis/cirrhosis associated with portal hypertension and acquired portosystemic shunts (APSS).
• Direct metabolic/physiologic dysregulations responsible for HE are potentially reversible.

Pathophysiology

• Multifactorial origin.
• Ammonia best studied toxin; ammonia and glutamate function as neurotoxins adversely affecting astrocytes (site of ammonia detoxification to glutamine). Hyperammonemia causes astrocyte swelling and oxidative stress.
• Complex pathophysiology-energy failure (neuroglycopenia), altered cerebral pH, calcium ion flux, abnormalities of glutamatergic, GABAergic and catecholaminergic neurotransmission; perturbed aromatic amino acid metabolism (preferential systemic utilization of branched chain gluconeogenic amino acids), increased cerebral levels of endogenous benzodiazepine-like substances; inflammatory cytokines, oxidative injury; each factor contributes to electrophysiologic derangements. An altered blood-brain barrier likely contributes to pathophysiologic changes.
• Neurobehavioral abnormalities predominate with most signs attributed to gut-derived substances (bacterial and protein metabolism), particularly ammonia.

Systems Affected

• Nervous-abnormal cerebral function predominates; decreased awareness and function progresses to somnolence, coma, or agitation progressing to seizures; aggression and seizures more likely in cats with PSVA.
• GI-vomiting, diarrhea, and anorexia.
• Renal/urologic-ammonium biurate urolithiasis; renal pelvic and cystic calculi.

Genetics

• PSVA-polygenic inheritance of extrahepatic PSVA in small breed dogs (see Portosystemic Vascular Anomaly, Congenital).
• Certain chronic hepatopathies have increased prevalence in some breeds (see Chronic Hepatitis; Copper Associated Hepatopathy).

Incidence/Prevalence

Uncommon disorder

Signalment

Signs

Causes

• PSVA-congenital malformations.
• APSS-secondary to splanchnic portal hypertension (cirrhosis, sinusoidal fibrosis; intrahepatic AV malformation, intolerant to PSVA shunt attenuation); see Hypertension, Portal; Portosystemic Shunting, Acquired.
• Acute hepatic failure-induced by drugs, toxins, or infection (see Hepatic Failure, Acute; Hepatotoxins).

Risk Factors

• Alkalosis, hypokalemia, hypoglycemia.
• Certain anesthetics and sedatives.
• Certain drugs: e.g., methionine, tetracycline, antihistamines.
• Enteric bleeding-most common acute precipitating cause of HE.
• Transfusion-stored blood products may contain high concentrations of ammonia; incompatible blood transfusions; heme potently provokes HE.
• Infections.
• Constipation.
• Catabolism-disorders causing muscle wasting; large amounts of ammonia are transiently detoxified by storage in muscle.

Differential Diagnosis

• Lead toxicosis
• Urinary tract infection-other urolithiasis
• Intestinal parasitism
• Primary gastrointestinal disease
• Hypoglycemia: many causes
• Toxoplasmosis
• Congenital CNS disease or malformation-hydrocephalus; storage diseases
• CNS neoplasia
• Acute ethylene glycol or xylitol toxicosis
• Infectious diseases-rabies; canine distemper
• Thiamin deficiency-Wernicke's encephalopathy (especially cats)
• Drug intoxications; recreational human drugs

CBC/Biochemistry/Urinalysis

Other Laboratory Tests

• Blood ammonia-sensitive but inconsistent indicator of HE; fasting hyperammonemia unreliable; blood ammonia values less reliable than TSBA owing to analytic/methodologic issues and because samples cannot be mailed for analysis; ammonia tolerance testing-most reliable method for detecting ammonia intolerance (administer NH₄Cl; caution: may induce HE).
• TSBA-confirms hepatic insufficiency or shunting associated with HE.
• Coagulation tests-PSVA: abnormalities usually not associated with bleeding; APSS: increased PT, APTT, PIVKA, and low fibrinogen reflect severity of liver dysfunction, synthetic failure, DIC, and vitamin K adequacy.
• Protein C: low activity in dogs with substantial shunting, liver failure, PLE, DIC.
• Abdominal effusion-acquired liver disease; hepatic AV malformation; pure or modified transudate.
• Liver zinc values-often low (<120 µg/g dry weight liver tissue).

Imaging

See Portosystemic Vascular Anomaly, Congenital; Portosystemic Shunting, Acquired

Diagnostic Procedures

• Hepatic aspiration-cannot differentiate disorders causing portosystemic shunting.
• Liver biopsy-open surgical wedge biopsy or laparoscopic sampling (cup biopsy forceps) to collect tissue from several liver lobes.
• Tru-Cut needle biopsy: may inadequately sample tissue.

Pathologic Findings

• Gross-liver changes reflect underlying disorder; rare brain herniation in acute HE.
• Microscopic-liver lesions: define causal hepatic disorders and identify portal hypoperfusion associated with portosystemic shunting; CNS lesions: polymicrocavitation and Alzheimer type II astrocyte changes-inconsistent in dog.

Appropriate Health Care

• Depends on underlying condition.
• PSVA-surgical correction preferred; chronic medical treatment possible for some.

Nursing Care

• Depends on underlying condition; eliminate factors promoting HE.
• Improve dietary protein tolerance by concurrent oral or rectal (enema) treatments (see “Medications”) and altered protein intake (type, quantity).
• If hepatic coma-discontinue oral medications.
• Avoid risk factors.
• Fluids-balanced crystalloids but avoid lactate if fulminant hepatic failure, if hypoglycemic supplement fluids with 2.5–5.0% dextrose; provide 20–30 mEq/L potassium chloride (not to exceed 0.5 mEq/kg/h) titrated according to needs; sodium-restricted fluids with acquired liver disease associated with ascites, and/or marked hypoalbuminemia.
• B-soluble vitamins (2 mL/L fluids).

Activity

Keep patient warm, inactive, and hydrated.

Diet

• Adequate calories-avoid catabolism and maintain muscle mass (site for temporary ammonia detoxification/storage).
• Dietary protein restriction-cornerstone of medical management; use commercially formulated diets for liver disease or moderate renal insufficiency; dogs: dairy and soy protein best sources; 2.5 g protein /kg bodyweight; cats: pure carnivores must have meat-derived protein; 3.5 g protein/kg bodyweight.

• Good-quality vitamin supplements-vitamin metabolism perturbed with liver disease and losses in urine. S-adenosylmethionine preferred to methionine supplementation: 20 mg/kg PO/d.

• Ensure thiamin repletion-avoids Wernicke's encephalopathy; 50–100 mg daily for 3 days in cats, then in water-soluble vitamins in fluids; caution: anaphylactoid reactions may occur with injectable thiamin.
• Partial parenteral nutrition-if short-term inappetence; may reduce muscle catabolism.
• Total parenteral nutrition if >5 days inappetence and enteral route unavailable; use of branched-chain amino acid solutions remains controversial.

Client Education

• HE-often episodic; relapse if underlying disorder cannot be eliminated.
• Train owner to administer enemas and to judiciously adjust medications PRN.
• PSVA-surgical ligation may be curative but also may cause adverse complications (see Portosystemic Vascular Anomaly, Congenital); postoperative clinical signs may persist requiring chronic nutritional and medical management.
• APSS-depends on underlying cause.

Surgical Considerations

• See Portosystemic Vascular Anomaly, Congenital
• APSS-do not ligate

Drug(s)

• Medications increasing dietary protein tolerance alter enteric flora or condition, reduce production/availability of substances provoking HE.
• Antibiotics-spectrum altering intestinal flora (aerobic and anaerobic) or their products; first choice antimicrobial selections: systemic metronidazole (7.5 mg/kg q12h) or amoxicillin (esp. cats, 12.5–25 mg/kg PO q8–12h); combined with lactulose; caution if using neomycin (10–22 mg/kg PO q12h) as chronic administration may result in renal and otic toxicity (approximately 3% absorbed systemically).
• Local antimicrobials used in enemas: same dosages as oral but do not administer by both oral and rectal routes.
• In humans, rifaximin (semisynthetic rifamycin derivative) is as effective as lactulose and neomycin in treatment of HE and has a favorable safety and tolerability profile, but is expensive. There is no data accumulated for its utility for HE in animals. Suggested dose in dogs 5 mg/kg PO q24h or q12h.
• Nonabsorbable-fermented carbohydrates-lactulose, lactitol, or lactose (milk products, if lactase deficient); decrease production/absorption of ammonia; promote a cathartic effect; trap nitrogen in bacteria; lactulose most commonly used (start at 0.5–1.0 mL/kg q8–12h and titrate up to therapeutic goal of passage of 2 or 3 soft stools/day); may also administer as enema for acute hepatic encephalopathy and coma after cleansing enemas remove debris.
• Probiotics with nonabsorbable-fermented carbohydrates may be advantageous for altering gut flora to diminish HE toxin production (remains controversial).
• Enemas-cleansing enemas (warmed polyionic fluids) mechanically clean colon (10–15 mL/kg, until clear return); retention enemas deliver fermentable substrates or directly alter colonic pH and organisms: diluted lactulose, lactitol, or lactose (1:2 in water); neomycin in water (do not exceed PO dose, do not dose PO and rectally); diluted Betadine (1:10 in water, rinse well in 15 min); diluted vinegar (1:10 in water).
• Zinc supplementation-two urea cycle enzymes require zinc; measure baseline plasma zinc, (dose 1–3 mg/kg elemental zinc PO using zinc acetate); titrate dose using sequential plasma zinc measurements: avoid >800 µg/dL.
• Cerebral edema-complicates acute HE; head-up posture (15–20° incline); mannitol (1 g/kg diluted in saline, over 30 min); nasal oxygen; N-acetylcysteine (140 mg/kg IV diluted 1:2 in saline given through non-pyrogenic filter; then 70 mg/kg q8h); glucocorticoids controversial, may promote enteric bleeding.
• Salvage therapy for intractable HE (experimental)-L-ornithine-L-aspartate (humans, rats: 180–300 mg/kg/day divided into three doses); L-carnitine (100 mg/kg PO or IV), may attenuate hepatic encephalopathy-associated hyperammonemia.
• If epileptic seizure activity-Keppra (levetiracetam) is the preferred anticonvulsant as it is minimally metabolized in liver and largely excreted in urine; secondary anticonvulsants include: zonisamide (caution: sulfa drug, rare idiopathic hepatotoxicity) and lastly, KBr (complicated by fluid therapy) as preferred anticonvulsants to phenobarbital.

Contraindications

Avoid drugs metabolized by the liver.

Precautions

• Use anesthetics, sedatives, tranquilizers, potassium-wasting diuretics, analgesics, and highly protein-bound drugs cautiously.
• If possible, avoid drugs reliant on hepatic metabolism, biotransformation, or excretion.
• Consider altered pharmacokinetics; reduced first-pass extraction due to portosystemic shunting; low albumin reduces protein binding increasing free drug-receptor interaction.

Possible Interactions

Drugs that affect or depend on hepatic metabolism-e.g., cimetidine, chloramphenicol, barbiturates, ketoconazole.

Patient Monitoring

• Re-evaluate patient's at-home behavior, demeanor, body condition and weight.
• Monitor albumin and glucose-in patients with non-correctable disorders; adjust nutrition.
• Monitor electrolytes-especially potassium; avoid hypokalemia as it aggravates hyperammonemia.

Prevention/Avoidance

Avoid dehydration, azotemia, hemolysis, constipation, enteric bleeding, endoparasitism, infusion of stored blood, ammonium challenge, urinary tract infections (especially with urease-producing organisms, e.g., Staphylococcus), hypokalemia, hypomagnesemia, and alkalemia.

Possible Complications

Permanent neurologic damage (rare)

Expected Course and Prognosis

• Depends on underlying disorder.
• Acute or chronic hepatic failure-may be fully or partially reversible, or patient may die.

Age-Related Factors

PSVA-surgical outcome may be good in young and old patients; medically treat HE before anesthesia/surgery.

Synonyms

• Hepatic coma
• Portosystemic encephalopathy

See Also

• Arteriovenous Malformations of the Liver
• Hepatic Failure, Acute
• Portosystemic Shunting, Acquired
• Portosystemic Vascular Anomaly, Congenital

Abbreviations

• APSS = acquired portosystemic shunt
• APTT = activated partial thromboplastin time
• AV = arteriovenous
• CNS = central nervous system
• DIC = disseminated intravascular coagulation
• GABA = γ-aminobutyric acid
• GFR = glomerular filtration rate
• HE = hepatic encephalopathy
• PIVKA = proteins invoked by vitamin K absence or antagonism
• PLE = protein-losing enteropathy
• PT = prothrombin time
• PSVA = portosystemic vascular anomaly
• TSBA = total serum bile acids

Client Education Handout Available Online