Hepatic encephalopathy is a metabolic neurologic disorder that develops secondary to liver disease.
Hepatic encephalopathy (HE) is a neurobehavioral syndrome affiliated with either critical liver failure (ie, fulminant hepatic failure or cirrhosis) or portosystemic shunting (ie, congenital or acquired portosystemic shunting with decreased functional hepatic mass and intrahepatic shunting of blood around regenerative nodules).
Failure to recognize and effectively manage HE contributes to decreased quality of life, euthanasia, or death.
Clinical signs are variable, involving disturbed sensorium ranging from mild dullness, anxiety, and inability to respond to basic commands to overt abnormalities, including propulsive circling, head pressing, aimless wandering, weakness, ataxia, rare myelopathy (chronic HE), rare signs suggestive of polyarthropathy, amaurosis (unexplained blindness), ptyalism, rare fine tremors (with chronic recurrent HE), behavior change (eg, aggression), hallucinations or dementia, collapse, seizures, and coma preceding death. Early HE recognition requires serial neurological evaluations by an experienced clinician. Some owners fail to recognize features of HE until they witness improvement with medical interventions.
Hepatic encephalopathy is first characterized as acute or chronic. Acute HE is encountered in animals with fulminant hepatic failure (FHF). HE in this scenario is closely integrated with biochemical and metabolic evidence of acute and massive loss of hepatic function and is often severe and unremitting. Chronic HE is more common and reflects delayed access of portal blood to hepatocytes (portosystemic shunting, either congenital or acquired) and is not inextricably linked with critical loss of functional hepatic mass.
Notably, animals with congenital portosystemic shunts are not in liver failure, and many animals with chronic liver disease associated with acquired portosystemic shunting also are not in liver failure. The latter animals have anatomically compromised sinusoidal perfusion (see portal hypertension).
User-friendly clinical classification schemes subdivide HE into three categories: type A, reflecting acute liver failure or FHF; type B, predominantly reflecting portosystemic shunting; and type C, reflecting cirrhosis where portosytemic shunting and decreased hepatic mass contribute. Clinical signs of types B and C are similar, whereas type A is usually severe and may be associated with increased intracranial pressure, brainstem compression, and risk of cerebral herniation. According to the time course, HE is also described as episodic or recurrent (bouts of HE every 6 months or less) or persistent (denoting persistent behavioral alterations interspersed with relapses of overt HE).
Otherwise, complicated grading schemes used to classify HE in human medicine consider psychometric assessment of cognitive functions. Generally, this scheme arbitrarily subdivides the continuum of HE for clinical and research purposes into four severity grades. This scheme is complicated by the wide variability in cognitive, behavioral, and motor signs and lack of coordinated progression. A subtle form of "minimal HE" described in humans is not classifiable in animals because classification requires psychometric evaluations (ie, calculating or organizing numbers, assessment of short- and longterm recall, writing, copying, understanding words, and carrying out a three-part command).
Using the four-part classification scheme noted previously:
Grade 1 HE is associated with mild vacillating lethargy and decreased mental alertness (ie, confusion or disorientation).
Grade 2 HE is associated with accentuation of grade 1 clinical signs, with increasing lethargy, drowsiness, personality change, mild ataxia, disorientation, and inappropriate behaviors (house soiling, loss of appropriate social interactions).
Grade 3 HE is typified by worsening incoordination or ataxia, mental confusion, ptyalism, head pressing, aimless wandering, circling, amaurotic blindness, marked personality change (sometimes to aggression), and increasing somnolence with slow arousal.
Grade 4 HE is severe and is characterized by unresponsive recumbency or obtundation, seizures, and coma, and is associated with a risk for impending death.
A final subcategorization of HE informs presence of precipitating factors: class 1, nonprecipitated HE and class 2, precipitated HE episodes. Precipitating factors must be investigated, specified, and controlled; these are usually identifiable in type C HE.
Pathophysiologic mechanisms underpinning HE are complex and yet to be completely understood. Synergistic effects between failure of the liver to detoxify ammonia and accumulation of other endogenous substances is well documented. The integrated concept of HE explains episodic variability and heterogeneous precipitating factors that correlate with diverse clinical scenarios.
Mechanisms interactive with ammonia toxicosis include increased accumulation of systemic or intracerebral inflammatory cytokines, neurosteroids, and manganese (Mn); altered brain microcirculation; development of neuronal edema; hypoxia; neuroglycopenia; mitochondrial dysfunction (adaptive anaerobic metabolism leading to lactate accumulation); and oxidative injury. Increased production of reactive oxygen and nitrogen oxide species are thought to trigger protein and RNA modifications deleterious to normal brain function.
Ammonia, a key player in the pathogenesis of HE, is thought to sensitize neurons to other encephalogenic factors. Ammonia can influence multiple brain neurotransmitter systems directly (chemical influence) and indirectly (alter substrate availability for transmitter formation). Nevertheless, blood and cerebral ammonia concentrations are often discordant, disqualifying blood ammonia as a simplistic reliable measure of HE. A weak nonlinear and nonexponential correlation exists between serum ammonia levels and severity of chronic HE. A more direct correlation exists in acute HE.
Most ammonia is derived in the gastrointestinal tract from enterocyte conversion of glutamine to glutamate (energy metabolism). Smaller ammonia contributions derive from urease-producing bacteria, mucosal ureases, and bacterial protein degradation. In healthy animals, most enteric ammonia circulates directly to the liver in the portal vein whereupon it is promptly removed by hepatocytes and used for amino acid interconversions or detoxified in the urea cycle or in formation of glutamine. Approximately 25% of systemically circulated urea accesses the alimentary canal (in saliva, bile, or via enteric diffusion), whereupon it is digested to ammonia by bacterial and mucosal ureases.
Ammonia also is eliminated by renal tubular secretion and via use for glutamine synthesis in skeletal muscles (temporary ammonia detoxification). The latter pathway underscores the importance of maintaining lean body mass (muscle) in hepatic insufficiency where this process transiently buffers hyperammonemia. In animals with portosystemic shunting or liver failure, blood ammonia concentrations escalate predominantly because of hepatofugal portal circulation or secondarily because of insufficient hepatocyte detoxification. Portal regions (zone 1 hepatocytes) conduct high rates of ammonia detoxification via the urea cycle whereas centrilobular regions (zone 3 hepatocytes) detoxify ammonia by synthesis of glutamine from glutamate.
Overall, the efficacy of hepatic ammonia detoxification is high with a large potential reserve capacity. Portosystemic shunting plays a dominant causal role in hyperammonemia associated with HE. In chronic liver disease or chronic portosystemic shunting, HE is potentially reversible and manageable. Comparatively, acute (fulminant) HE affiliates with abrupt-onset hyperammonemia and progression to brain edema and lethal structural brain-stem injury. Ammonia and other endogenous products such as lactate, inflammatory cytokines, and hyponatremia contribute to astrocyte swelling in acute HE, leading most often to brain edema and herniation.
Astrocytes contribute ~25%–50% of the brain's cellular volume and are prominently involved with HE. At high concentrations, ammonia crosses the blood-brain barrier, and astrocytes are the primary site of ammonia detoxification (glutamine from glutamate). Thereafter, glutamine reconverts (via neuronal glutaminase) to glutamate and is released into the synaptic cleft, initiating neuroexcitation. However, glutamine accumulation is fostered by hyperammonemia and leads to neuroinhibition. This contributes to the somnolence and cognitive dysfunction characteristic of HE.
Glutamine catabolism in astrocyte mitochondria further increases regional ammonia, contributing to oxidative stress and mitochondrial dysfunction (increased anaerobic metabolism with lactate accumulation). Because glutamine and lactate each impart osmotic effects, their pathological accumulation promotes cell swelling, contributing to brain edema, disturbed cerebral microcirculation, and increased intracranial pressure. These changes may lead to irreversible brain herniation, brainstem compression, and death.
While altered astrocyte metabolism and swelling are critical pathological changes contributing to acute HE, this is less relevant to chronic intermittent HE in which more important factors involve proinflammatory and inflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukins IL-1-beta, IL-6), gamma-aminobutyric acid (GABA), and manganese (Mn) accumulation. Inflammatory cytokines increase permeability of the blood-brain barrier to ammonia and other inflammatory mediators, leading to neuroinflammation. Additionally, the impact of hyperammonemia impairing neutrophil phagocytosis and enhancing spontaneous oxidative burst activity increases risk for systemic infection and inflammation.
Neurotransmitter dysregulation is a major pathomechanism of chronic episodic HE. In addition to the glutamate-glutamine imbalance, increased levels of GABA (GABAergic tone) contribute to neuroinhibition. Neurosteroid GABA ligands (allopregnanolone and tetrahydrodeoxycorticosterone) are synthesized in response to upregulated translocator protein in astrocyte mitochondria (formerly termed peripheral-type benzodiazepine receptors). This process is stimulated by hyperammonemia and Mn accumulation.
Manganese is considered proencephalogenic in chronic HE. Efficiently absorbed after ingestion, in health Mn is removed by the liver and eliminated in bile. Portosystemic shunting allows Mn direct access to the systemic circulation where it achieves widespread distribution. Astrocytes display high affinity for Mn uptake and may accumulate concentrations > 50-fold surrounding tissues. Manganese accumulation can be estimated with MRI (showing tissue hyperintensity) and has been demonstrated in dogs and cats with congenital portosystemic shunts.
Mechanistically, Mn accumulation provokes oxidative injury, mitochondrial dysfunction, and ammonia-associated Alzheimer type II astrocyte polymicrocavitation (enlarged, pale astrocytes with decreased chromatin staining). This histologic feature has been documented in dogs and cats with congenital portosystemic shunts with chronic hyperammonemic HE.
Increased plasma concentrations of aromatic amino acids (AAAs) and glutamine and concurrent low concentrations of branched-chain amino acids (BCAAs) commonly are associated with chronic HE. These metabolic shifts reflect glutamine synthesis (ammonia detoxification), preferential metabolism of BCAA in skeletal muscle, and decreased hepatic utilization of AAA. However, like ammonia, amino acid concentrations do not directly correlate with severity of chronic liver disease or chronic HE. Decreased plasma concentrations of cystathionine, cysteine, taurine, and glutathione, often associated with chronic liver disease, reflect impaired conversion of methionine to SAMe due to downregulation of the SAMe synthase as well as nutritional deficiencies (anorexia).
A number of clinical conditions can escalate blood ammonia concentrations or precipitate HE:
dehydration (prerenal/renal azotemia)
alkalemia and hypokalemia (increase renal ammonia production and CNS ammonia translocation)
hypoglycemia
catabolism (increase amino acid and ammonia turnover)
infection (catabolism, sepsis)
PU/PD (risk for dehydration and electrolyte loss)
anorexia
constipation (increased absorption of colonic ammonia and other HE toxins)
widespread heme loading (ie, hemolysis, blood transfusion, GI hemorrhage, rhabdomyolysis)
high dietary protein intake (especially red meat, fish, and in some animals, eggs)
various drugs (eg, benzodiazepines, tetracyclines, antihistamines, methionine, barbiturates, organophosphates, phenothiazines, diuretics [overdosage], metronidazole [overdosage], and certain anesthetics)
The most encephalogenic protein recognized is heme (hemoglobin/myoglobin), with causal syndromes having consequences similar to consumption of raw red meat meal.
Treatment of Hepatic Encephalopathy in Small Animals
Treatment of acute HE involves stabilizing vital signs, providing supportive care, curtailing HE-related neurotoxin formation, ameliorating the pathological impact of these toxins, and ensuring that metabolic complications masquerading as HE are recognized and correctly managed (ie, thiamine deficiency, severe hypophosphatemia or hyponatremia, drug-induced neurologic complications, and nonhepatic encephalopathies such as necrotizing or granulomatous meningoencephalitis common to small-breed dogs).
Animals obtunded with severe HE have risk for cerebral edema and brain herniation that should be addressed with mannitol (0.5–1.0 g/kg, IV, over 20 minutes). Such patients should be reclined on a slant board in head up position (25°–35° angle) to decrease gravity-related worsening of cerebral edema.
In the event of seizure activity, IV levetiracetam is recommended. Benzodiazepines (interact with GABA receptors) should be avoided. Alfaxalone, a neurosteroid anesthetic interacting with GABA receptors, should also be avoided. Use of any sedatives should be cautiously considered, deferring to gas anesthesia if painful procedures requiring anesthesia/analgesia are undertaken.
In animals with FHF due to toxic hepatopathy, there is potential for mitochondrial dysfunction. In these, propofol infusions should be avoided because this drug may critically suppress mitochondrial beta-oxidation. Esophageal or gastric feeding should be withheld in obtunded patients until neurologic status improves and enteric motility (gastric and intestinal) is confirmed. Parenteral alimentation is usually not undertaken in animals with acute severe HE.
In human and veterinary medicine, there is no consensus on the propriety of acute amino acid infusion for correcting altered BCAA:AAA ratio. Intravenous saline (0.9% NaCl) solution is initially used to correct hydration and to provide daily fluid requirements in animals without splanchnic hypertension and ascites. Otherwise, fluid support is provided using other balanced crystalloids containing less sodium.
Fluids should be judiciously supplemented with dextrose (2.5%–5.0% dextrose) to avoid neuroglycopenia, potassium chloride (sliding scale), and vitamin B complex including thiamine. Thiamine should be given before starting glucose infusions. Electrolyte and acid-base imbalances should be sequentially monitored until stabilized.
While monitoring plasma osmolality might help avoid plasma hypo-osmolality, this is seldom done. Lactated Ringer's solution and acetated buffered crystalloids should be avoided only in animals with acute HE associated with FHF; these have risk for impaired lactate and acetate metabolism.
Direct modification of enteric bacteria and toxins can be achieved with cleansing enemas, followed by retention enemas. Cleansing enemas of warm soapy water or warmed crystalloid solutions are followed by retention enemas containing lactulose (3 parts lactulose to 7 parts water at 20 mL/kg). Alternative retention enemas include 10% povidone-iodine solution (20 mL/kg, but rinsed well after 10–15 minutes dwell time), 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 hours until neurologic response is perceived. Retention enemas should be maintained for 15–20 minutes by use of a rectally positioned inflated Foley catheter.
Lactulose, metronidazole, neomycin, and povidone-iodine solutions may directly alter colonic bacterial flora, decreasing populations of ammonia-producing organisms. Fermentation of lactulose can further restrict ammonia absorption and urease activity (transforming urea to ammonia in the colon) by local acidification. Care is warranted in using neomycin because systemic uptake can occur, imposing risk for renal and otic (cochlear) toxicity. Metronidazole must be restricted to ≤ 7.5 mg/kg every 8–12 hours (if also using oral metronidazole, total dose administration should not exceed 7.5 mg/kg); higher dosages confer risk of neurotoxicity (vestibular clinical signs initially, ataxia, recumbency, seizures).
Oral administration or rectal instillation of probiotics or synbiotics (probiotic with fermentable fiber) with live Lactobacillus and Bifidobacterium organisms (live yogurt cultures, various probiotic products) also may assist in reducing enteric ammonia-producing microbes. However, there is limited information regarding the efficacy of this intervention.
Systemic circulatory dysfunction in patients with HE is an extremely unstable condition (see section on portal hypertension and ascites) with episodic bursts of circulating cytokines in the absence of an identifiable precipitating event or cause. In humans with decompensated cirrhosis, treatment with weekly high-dose albumin infusions (1–1.5 g/kg) substantially improves HE and other features contributing to this syndrome. Albumin infusions are shown to improve heart function (left ventricle dysfunction associated with decompensated cirrhosis) contributing to HE-associated systemic circulatory dysfunction, delay ascites re-formation, and impart an immunomodulatory effect declining release of inflammatory cytokines that contribute to HE. There are no species-specific albumin products available for similar intervention in dogs and cats with severe cyclic HE.
Nutritional Support
Historically, nutritional support included dogmatic recommendations on protein restriction for humans and animals with hepatic insufficiency and HE. Numerous studies in humans and clinical observations in dogs and cats have now debunked this supposition. Protein intake should be individualized to the patient's tolerance. The best strategy is to first stabilize the patient with treatments targeting prevention of HE recurrence.
Initially, a protein-modified diet is recommended (ie, restricted in red meat or fish; allowing dairy, vegetable, or white meat chicken protein). In dogs, a minimum of 2.5 g protein/kg is a safe starting point. Optimization of protein intake is thereafter achieved by cautious upward titration of protein allowances, while monitoring patient tolerance.
Progressive protein titration in 0.25–0.5 g/kg increments over 3–5 day intervals is done to achieve an additional 1–1.5 g protein/kg daily intake. During the optimization process, monitoring neurologic status and appearance or dissolution of ammonium biurate crystalluria is essential. Worsening neurologic status or emergence of ammonium biurate crystalluria evidences protein level intolerance.
However, it is important to also investigate for other HE-provocative conditions. Because of the instability of ammonia analyses, sequential ammonia measurement is not a reliable monitoring strategy. In fact, there are no clinicopathologic features aside from disappearance or appearance of ammonium biurate crystalluria that document substantial change in HE status.
In dogs, oral probiotic yogurt as supplemental protein can provide benefits similar to lactulose administration. Because cats are pure carnivores, feeding a feline balanced diet is essential. Initially a diet formulated for mild renal insufficiency is advised. Gradual supplementation with white meat chicken can be attempted to increase protein intake by an additional 1 g/kg.
Animals with HE should be supplemented with a cysteine donor; this is the rate-limiting amino acid for glutathione (GSH) synthesis. Enteric-coated S-adenosylmethionine (SAMe) is often used (20 mg/kg, PO on an empty stomach, every 24 hours). Tablet forms of GSH may supply cysteine; however, transport of GSH across cellular membranes does not occur. Rather, GSH is synthesized within the cell where it is recycled in the GSH redox cycle.
Thiamine supplementation is also highly recommended, especially in cats with HE (100 mg, PO, every 12 hours for 2 days, then 50 mg, PO, every 24 hours thereafter). Thiamine deficiency can cause neurologic signs mistaken for HE and will rapidly resolve with appropriate supplementation (within 48 hours) if corrected during the acute stages. In animals needing glucose supplementation to sustain euglycemia, thiamine supplements must be started before or concurrent with glucose infusions. Injectable thiamine is not recommended because it occasionally causes vasovagal collapse in dogs and cats and critical (sometimes lethal) neuromuscular weakness.
Modification of Enteric pH, Bacterial Population, Ammonia Absorption
Acidification of enteric luminal pH, decreased enteric ammonia generation and uptake, increased bacterial ammonia utilization, modification of the gut microbiome (increasing commensal and declining pathogenic bacteria), and induction of a laxative effect (assists elimination of colonic toxins) can be achieved with oral administration of lactulose. Lactulose is regarded as a critical intervention in animals and humans with HE and hyperammonemia and is considered the gold standard to which other interventional measures are compared. An initial low dose (0.25–0.5 mL/kg, PO, every 8–12 hours) is titrated upward to achieve several soft puddinglike stools per day.
Overdosing with lactulose can lead to painful cramping due to gas generation and severe liquid projectile diarrhea, persuading the client to refuse this highly effective intervention. Lactulose is a synthetic disaccharide indigestible by mammalian enzymes. Fermentation by enteric bacteria generates organic acids that acidify the luminal pH that traps ammonia as the ammonium ion, limiting mucosal permeability. The fermentation process generates an osmolar-catharsis (organic acids, other solutes) and growth of bacteria that "bulk" the stool resulting in passage of frequent soft puddinglike stools. Catharsis directly removes ammonia and other colonic toxins.
Colonic acidification decreases activity of mucosal and bacterial ureases (largely anaerobic colonic organisms), further declining ammonia generation. It also inhibits enteric glutaminase activity, reducing intestinal uptake of glutamine and thus, its subsequent metabolism to ammonia. Fermentation of lactulose also increases incorporation of ammonia nitrogen into bacterial protein synthesis (protein fixation). Lactitol, a synthetic disaccharide similar to lactulose, is less sweet and less objectionable to some humans. However, it is not as readily available as lactulose.
Feeding milk products also may achieve a lactulose-like effect in animals that cannot sufficiently digest lactose. Meta-analysis of efficacy of lactulose in humans with HE and with cirrhosis demonstrated a noteworthy beneficial treatment effect on HE (minimal and over), overall liver-related morbidity, and all-cause mortality rate. Lactulose also provides effective prophylaxis against HE development. Findings recommend lactulose as a first-line treatment for HE inpatients with cirrhosis and for its prevention.
In humans, cirrhosis is associated with dysbiosis and changes in the colonic microbiome with additional changes noted in the microbiome of patients with HE. It is assumed that comparable changes occur in animals. Concentrates of probiotic organisms combined with fermentable carbohydrate substrates (eg, fructo-oligosaccarides) appear to beneficially modify the enteric microbiome in these patients. Benefits reflects substrate competition, pH-related (acid) growth inhibition, and mechanical cleansing (catharsis, induced by the fermentable carbohydrates and proliferation of commensal organisms). Collective effects diminish uptake of ammonia, inflammatory and oxidative mediators, lipopolysaccharide (endotoxin), and other toxic enteric products contributing to HE.
Enteric antimicrobials are also often combined with fermentable carbohydrates to decrease enteric toxin formation.
Low-dose metronidazole is preferred (7.5 mg/kg, PO, every 12 hours) in dogs and cats, while amoxicillin (13–15 mg/kg, PO, every 12 hours) appears clinically effective in some cats. The dose of metronidazole must be restricted or cerebellar neurotoxicity, sensorimotor neurotoxicity, sensorineural ototoxicity, or seizures may emerge. This is not seen with chronic use of metronidazole at the restricted dose in dogs or cats with HE due to portosystemic shunting.
Use of neomycin is not recommended. Chronic absorption of small amounts of neomycin, an aminoglycoside, in liver patients imposes risk for ototoxicity and renal injury; this has been documented in both canine and feline patients with congenital portosystemic shunt–related HE.
Rifaximin (approved for treatment of HE in humans in 2010) has few adverse effects and has demonstrated benefit in HE in humans. To date, there is limited use in animals. This semisynthetic, gut-selective, nonabsorbable oral antimicrobial is derived from rifamycin and is a structural analogue of rifampin. Acting locally in the enteric lumen, rifaximin inhibits a variety of aerobic and anaerobic gram-positive and gram-negative bacteria, as well as protozoal agents.
Rifaximin has been administered (2.5–5 mg/kg, PO, every 12–24 hours) in a small number of dogs and cats with recalcitrant HE with apparent positive response. Optimal dosing has not been determined and there are rare anecdotal reports of hepatotoxicity. A high cost to benefit ratio in humans has declined its use for HE management.
Concurrent use of an antimicrobial with lactulose may impair the needed fermentation in some patients; this is associated with failure to acidify stool pH (can test with litmus paper), and failed catharsis implies loss of its other benefits. If this scenario occurs, the antimicrobial should be discontinued if it is not specifically targeting an infectious organism.
Alternative or Salvage Interventions for Recalcitrant Hyperammonemic HE
L-ornithine-L-aspartate (LOLA) Oral Granules
In chronic liver disease associated with HE, decreased hepatocyte ammonia detoxification reflects parenchymal loss, hepatic remodeling thwarting hepatocyte perfusion, and extrahepatic portosystemic shunting. In chronic hyperammonemic HE recalcitrant to conventional interventions, LOLA has been used as a salvage therapy. LOLA is a stable salt of the amino acids L-ornithine and L-aspartate. In humans it has been used to stimulate disrupted urea and glutamine synthesis associated with hyperammonemia.
LOLA is proposed to optimize ammonia detoxification to urea by correcting low concentrations of L-ornithine, a limiting urea cycle substrate. Furthermore, each amino acid in LOLA is a substrate for transamination reactions that increase glutamate availability for ammonia detoxification by glutamine formation (centrilobular hepatocytes, muscle, and brain). In humans, a dose of 9–18 g per day, divided every 8 hours, has attenuated hyperammonemia but has had no notable effect on mortality rate. One clinical trial in dogs with mild to severe HE treated with LOLA (0.154–1.2 g/kg, IV, every 24 hours (1); 0.03 g/kg/h constant-rate infusion in dogs with severe HE) did not reveal toxic effects but was not more effective than a lactulose control group.
Use of LOLA as an intervention requires recognition that ammonia is not a standalone toxin driving HE but only one pathogenic factor. Additional benefits ascribed to LOLA administration include protection against ammonia-driven sarcopenia (ammonia upregulation of myostatin) and an ill-defined hepatoprotectant and antioxidative effect.
Zinc Supplementation
Zinc, an essential micronutrient, plays fundamental roles in a broad spectrum of biological processes and physiologic processes, being affiliated with > 300 zinc-dependent enzymes/proteins. Zinc provides essential functions in cell metabolism; signal transduction; proliferation and differentiation; and the initiation/regulation of gene expression, immune responses, drug metabolism, and detoxification It also imparts antioxidant and anti-inflammatory properties.
As an abundant intracellular trace element, zinc is found in all tissues. However, the liver is the main site of zinc metabolism and plays a crucial role in its systemic homeostasis. In humans and rodent models of cirrhotic liver injury, zinc deficiency limits hepatic and muscle ammonia detoxification. Zinc deficiency or altered zinc metabolism in liver disease is associated with subnormal plasma zinc concentrations; this has been linked with inadequate intake, altered protein and amino acid metabolism, decreased hepatic zinc extraction, and urinary losses.
Both inadequate zinc intake and excessive urinary losses complicate portosystemic shunting. Additionally, zinc concentrations are suppressed by proinflammatory cytokines (mainly IL-6) and endotoxins.
Sarcopenia associated with catabolism in liver disease and diuretic use to manage ascites (polyuria) also contribute to urinary zinc losses. Hepatic zinc insufficiency is deleterious to ammonia detoxification because zinc is an essential cofactor for ornithine transcarbamylase (essential urea cycle enzyme) and glutamine synthetase (ammonia detoxification to glutamine in centrilobular hepatocytes, skeletal muscle, and astrocytes). Insufficient zinc availability can compromise ammonia detoxification and has been shown to worsen hyperammonemic HE. Low-dose zinc supplementation in some humans with hyperammonemic HE improves clinical status by reducing hyperammonemia.
There is no standard form of zinc used, and the dose is not well established for elemental zinc; supplemental elemental zinc for animals with suspected low liver zinc concentrations ranges from 0.25 to 2 mg/kg, PO, every 24 hours.
Elemental Zn calculations reflect the zinc contribution to the molecular weight of the form administered. Elemental zinc composition of commonly used forms of Zn include: zinc acetate = 30%, zinc gluconate = 14%, zinc sulfate: = 23%. Zn acetate may be the best tolerated of these.
An initial low dose is given in 2 divided doses, 30 minutes before feeding. Because there is no direct linear relationship between tissue and plasma Zn concentrations, plasma zinc measurement cannot ensure that tissue zinc repletion has been achieved. Plasma Zn measurements are recorded at baseline and then 1–2 weeks after starting supplementation to demonstrate an increased plasma Zn concentration but not to toxic values (> 800 mcg/dL [8 ppm] causes hemolysis). Too high a zinc dose can lead to gastric irritation, vomiting, and inappetence. Some dogs are exceedingly intolerant of zinc supplementation, developing nausea or gastric irritation with even small doses.
There are some reports in humans using polaprezinc a well-tolerated zinc supplement containing 225 mg tablets delivering 51 mg of a zinc chelate and 174 mg of L-carnosine. Healthy Beagles given polaprezinc at a dose of 8–20 mg/kg, PO, every 24 hours did not increase hepatic zinc concentrations whereas 50 mg/kg, PO, every 24 hours did increase hepatic zinc concentrations but also caused enteric distress. Use of polaprezinc in dogs with liver disease is unexplored.
N-acetyl-L-carnitine
L-carnitine (L-CN) is a conditionally essential micronutrient that orchestrates transfer of long-chain fatty acids (FA) from the cell cytoplasm to the inner mitochondrial membrane. Once translocated, FA are released and bound to coenzyme A (CoA) and escorted toward beta-oxidation. Acetyl-L-CN (ACL-Cn) is an ester of L-CN synthesized in brain, liver, and kidney from lysine and methionine.
In patients with compromised SAMe formation, carnitine synthesis can be insufficient. Because N-acetyl-L-carnitine can cross the blood-brain barrier, it can provision acetyl groups for neuronal energy. It also has been shown to enhance acetylcholine production, support membrane phospholipid synthesis (essential for cell repair and viability), and impart an antioxidant influence.
Use of ACL-Cn in HE is predicated on observations made in rodent models of liver injury where centrally mediated neuronal protection was demonstrated at the level of brain glutamate receptors and/or mitochondrial metabolism. Neuroprotection is proposed to involve attenuated ammonia toxicosis via activation of hepatic urea cycle (enzymes), interference with brain glutamate receptors, or decrease of oxidative free radicals. Importantly, ACL-Cn is thought to reactivate CoA, essential for modulating the acetyl-CoA/CoA-sulfhydryl ester (CoASH) ratio that regulates mitochondrial oxidation of pyruvate, alpha-ketoglutarate (intimately linked with glutamate/glutamine cycling in astrocytes), and FAs. Placebo-controlled clinical trials in humans and experimental work in rodent models of liver failure demonstrate improved HE metrics as well as plasma ammonia concentrations.
ACL-Cn is relatively nontoxic and has been administered without adverse effect to humans in hepatic coma at a dose of 2 g/person, PO, every 12 hours (~25–30 mg/kg, PO, every 12 hours). There is scant experience with this treatment in dogs and cats, where it presently is considered a salvage intervention for severe HE. This is not a standalone treatment for HE modulation. In several studies of aged healthy Beagles, 27.5 mg/kg ACL-Cn administered for 4 months had no adverse effects; this is considered a safe starting dose for this intervention. Cats with hepatic lipidosis treated with 250 mg of L-carnitine have no adverse effects, so it is expected that ACL-Cn can be used similarly.
Flumazenil
This GABA receptor antagonist is not recommended as a treatment of HE although occasional patients may show transient improvement after its administration. Initially this drug was proposed to block endogenous GABA receptors considered to provoke HE. This is now known to reflect neurosteroid binding to peripheral benzodiazepine receptors in the brain.
Occasionally, flumazenil (0.01 mg/kg, IV) transiently improves cognitive function in dogs or cats with overt HE. However, as in humans, such transient improvement does not translate to improved recovery or survival. This salvage therapy is only considered in severe HE with failure to respond to standard interventions in patients with declining status.
When benzodiazepines have been administered to a patient with HE, flumazenil can be used to reverse excessive sedation. Because the half-life of flumazenil is shorter than benzodiazepine effects, flumazenil may require repeated dosing.
Elimination or Control of Factors Precipitating Hepatic Encephalopathy
Clinical HE can be provoked or exacerbated by numerous factors:
excessive protein intake
severe anemia or other causes of hypoxia
gastrointestinal bleeding
bacterial infection or systemic sepsis syndrome
glucocorticoid use (enhanced catabolism of tissue protein) or endogenous hyperadrenocorticism
hypoglycemia
disseminated neoplasia
fever
azotemia or dehydration (increased BUN increases enteric ammonia production)
fluid restriction because of ascites
constipation (increases generation and absorption of colonic toxins including endotoxins)
fluid restriction because of ascites
constipation (increases generation and absorption of colonic toxins including endotoxins)
metabolic alkalosis (favoring renal production of ammonia and uptake of ammonia across the blood-brain barrier)
hyponatremia
use of diazepam, neurosteroid analgesics, or barbiturates (synergetic neuroinhibitors)
Proton pump inhibitors, sucralfate, control of fever and infection, proper hydration, maintaining euglycemia, and restriction of most sedatives and many anticonvulsant medications can help alleviate HE complications. For additional considerations, see Fulminant Hepatic Failure in Small Animals.)
Reference
Ahn JO, Li Q, Lee YH, et al. Hyperammonemic hepatic encephalopathy management through L-ornithin-L-aspartate administration in dogs. J Vet Sci. 2016 Sep 30;17(3):431–433. doi: 10.4142/jvs.2016.17.3.431. PMID: 26726023; PMCID: PMC5037314.
