Welcome to the all-new Vetlearn

  • Vetlearn is becoming part of NAVC VetFolio.
    Starting in January 2015, Compendium and
    Veterinary Technician articles will be available on
    NAVC VetFolio. VetFolio subscribers will have
    access to not only the journals, but also:
  • Over 500 hours of CE
  • Community forums to discuss tough cases
    and networking with your peers
  • Three years of select NAVC Conference
  • Free webinars for the entire healthcare team

To access Vetlearn, you must first sign in or register.


  Sign up now for:
Become a Member

Compendium June 2013 (Vol 35, No 6)

Hepatic Encephalopathy: Etiology, Pathogenesis, and Clinical Signs

by Melissa Salgado, DVM, Yonaira Cortes, DVM, DACVECC


    Hepatic encephalopathy (HE) is a manifestation of clinical signs that may result from a variety of liver diseases. In small animals, HE is most commonly a result of portosystemic shunting. The pathogenesis is not completely understood, although it is likely multifactorial. Theories of pathogenesis include altered ammonia metabolism and glutamine and glutamate transmission, an increase in γ-aminobutyric acid agonists and benzodiazepine-like substances, alterations of the serotonergic system and amino acid metabolism, elevated taurine levels, contributions from inflammatory mediators, and toxic effects of manganese. An understanding of the underlying mechanisms that result in HE may lead to new treatments in the future.

    Hepatic encephalopathy (HE) is defined as an abnormal mental state with augmented neuronal inhibition in the central nervous system (CNS) resulting from liver dysfunction. It is caused by the accumulation of toxic byproducts that have not been adequately metabolized by the liver.1,2 The causes of HE can be further classified by the type of liver disease present and the nature of the associated clinical signs.

    Clinical Signs

    The clinical signs of HE are usually divided into four stages.1,3–5 Stage I occurs when gut-derived toxins are beginning to affect the CNS. Typical clinical signs include mild confusion, inappetence, dull demeanor, and mild irritability. The owner may be the only one to notice these subtle, nonspecific signs, and the patient may appear normal to the veterinarian. Stage II is characterized by lethargy, ataxia, markedly dull behavior, occasional aggressive behavior, head pressing, blindness, and salivation. The patient may seem disoriented. A patient with stage III HE is uncoordinated, confused in its surroundings, stuporous, and completely inactive but can be aroused. Severe ptyalism can be present, particularly in cats, and seizures may occur.1,3,6,7 Cats with a portosystemic shunt (PSS) are more likely to have a seizure than dogs. Seizures alone, in the absence of other clinical signs of HE, are never due to HE.3,7 Cats may also present with golden or copper-colored irises secondary to decreased hepatic metabolism.6,7 Stage IV HE is characterized by recumbency, unarousable somnolence, and coma leading to death1,3,4 (TABLE 1). It is characteristic for patients to fluctuate between stages I through IV in an episodic manner.3

    In all stages of the clinical syndrome, animals may show nonneurologic signs related to the underlying disease, such as vomiting, diarrhea, and weight loss. Animals with portal hypertension and moderateto severe hypoalbuminemia (<2.0 g/dL) secondary to liver dysfunction may develop ascites.3 Polyuria and polydipsia are common manifestations of HE in dogs with a PSS as a result of hypercortisolism and inhibition of arginine vasopressin release.8–10 Insufficient growth and dysuria due to ammonium biurate crystals may be seen if a congenital PSS or chronic hyperammonemia is present.3,6,11 PSSs are vascular abnormalities that permit the portal blood to bypass the liver and enter systemic circulation directly.11 Most cases of HE in cats and dogs are due to a single congenital PSS7,11–13

    Table 2. Congenital Portosystemic Shunts6,11–13,a–c

    Intrahepatic Shunt

    Extrahepatic Shunt

    • Ductus venosus remains patent
    • Abnormal communications between the fetal cardinal or vitelline venosus systems
    • Occurs in large-breed dogs (e.g., Irish wolfhounds, Labrador retrievers)
    • Most common type
    • Occurs in cats and small- or toy-breed dogs (e.g., Yorkshire terriers, miniature schnauzers, Maltese, Havanese, pugs)
    • Onset of clinical signs usually <1 year of age
    • Onset of clinical signs usually >1 year of age

    aGB. Effect of breed on anatomy of portosystemic shunts resulting from congenital diseases in dogs and cats: a review of 242 cases. Aust Vet J 2004;82(12):746-749.

    bJohnson CA, Armstrong PJ, Hauptman JG. Congenital portosystemic shunts in dogs: 46 cases (1979-1986). J Am Vet Med Assoc 1987;191(11):1478-1483.

    cTobias KM, Rohrbach BW. Association of breed with the diagnosis of congenital portosystemic shunts in dogs: 2400 cases (1980-2002). J Am Vet Med Assoc 2003;223(11):1636-1639.

    The onset of clinical signs is usually within the first year of life if a congenital PSS is present.11 Although congenital PSSs are typically identified in dogs younger than 2 years, they cannot be ruled out in older animals presenting with encephalopathic signs.14 Unlike dogs with a macroscopic congenital PSS, most dogs with portal vein hypoplasia do not develop clinical signs of HE.15 Animals with acquired hepatic disorders typically develop clinical signs as adults (older than 1 year).11 In acute HE (BOX 1), clinical signs are indicative of elevated intracranial pressure and include hypertension, bradycardia, irregular respirations, decerebrate posture, and pupillary abnormalities. They progress rapidly in a sequence of agitation, delirium, convulsions, and coma. Death may result from brain herniation.16,17 Clinical signs of chronic HE typically present gradually and episodically and are usually precipitated by an underlying risk factor.3,6

    Box 1. Causes of Acute Liver Disease3,16,a


    • Acetaminophen
    • Potentiated sulfonamides
    • Aflatoxins
    • Amanita mushrooms
    • Xylitol
    • Cycad seeds
    • Blue-green algae


    • Canine hepatitis
    • Feline infectious peritonitis
    • Toxoplasma spp
    • Neospora spp
    • Leptospirosis
    • Histoplasma spp
    • Caval syndrome due to dirofilariasis

    Ischemic insults

    • Severe hypotension
    • Hemolytic anemia
    • Arterial or venous occlusion
    • Neoplasia
    • Lymphoma
    • Malignant histiocytosis

    Metabolic disease

    • Hepatic lipidosis in cats (due to arginine depletion)
    • Copper storage disease (Bedlington terriers, West Highland white terriers, Dalmatians)

    aMorris JG, Rogers QR. Ammonia intoxication in the near-adult cat as a result of a dietary deficiency of arginine. Science 1978;199(27):431-432.


    In human medicine, HE has been categorized into three types based on the nature of liver dysfunction present, and these categories have been adopted for veterinary use. Type A is associated with acute liver failure.18,19 Type B is associated with portal-systemic bypass without intrinsic liver disease.18,19 Type C is associated with severe hepatic parenchymal disease and portal hypertension and is often complicated by the presence of multiple acquired PSSs.18,19

    Type A encephalopathy occurs in cases of acute, severe liver disease (BOX 1) and manifests with a sudden onset of clinical signs, which can be rapidly progressive. Encephalopathy develops due to exposure of the brain to products released by the necrotic liver and can be complicated by systemic inflammatory response syndrome (SIRS) and hypoglycemia.20,21 This type of HE frequently results in acute cerebral edema and intracranial hypertension, which are responsible for the neurologic abnormalities seen.2,22 Histopathology of the brain in humans and animals with acute encephalopathy reveals astrocytic swelling,23 contributing to cerebral edema. Type A HE is one of the factors that defines acute hepatic failure, and its presence is a poor prognostic indicator.17

    Key Points

    • Treatment of hepatic encephalopathy (HE) should include reducing risk factors that may precipitate clinical signs, such as gastrointestinal hemorrhage and metabolic derangements.
    • There is no definitive diagnostic test for HE.
    • Acute HE is commonly associated with intracranial hypertension and cerebral edema. Transfer to a tertiary care facility with an intensive care unit is recommended in these cases.
    • Ultrasonography is a noninvasive method for imaging the portal vasculature, liver, and other organs in an unsedated dog or cat, and it is a valuable tool in the diagnosis of the underlying cause of HE.
    • The mainstay of treatment for HE due to a portosystemic shunt includes lactulose and oral antibiotics.

    Type B encephalopathy is the type most commonly seen in small animal patients with intrahepatic and extrahepatic PSSs.6,11 Cairn terriers are predisposed to portal vein hypoplasia without portal hypertension (formerly known as hepatic microvascular dysplasia), a congenital disorder in which multiple shunting vessels within the liver bypass the hepatic sinusoidal system, rather than one grossly visible abnormal vessel.11 In cats and dogs, rare congenital deficiencies of one of the enzymes involved in ammonia metabolism can result in severe hyperammonemia and HE in the absence of a PSS or intrinsic liver pathology.24–36

    Type C encephalopathy is the most common type in humans.19 In dogs and cats with long-standing liver disease, type C HE can occur with acquired PSSs from chronic portal hypertension.11,27 Underlying liver disorders can be inflammatory, congenital, or vascular and include congenital arterioportal fistulas, hepatic cirrhosis, chronic hepatitis, and portal vein hypoplasia.28 Acquired PSSs can develop in dogs of any breed or age.28

    In animals, chronic HE associated with type B or C encephalopathy is characterized by episodic clinical signs that develop gradually. The patient may appear neurologically normal between episodes.3 Histopathology of brain tissue from human and animal patients with chronic liver dysfunction reveals Alzheimer type II astrocytosis, which is characterized by swollen astrocytes, enlarged nuclei, and displacement of the chromatin to the perimeter of the cell.1,11,23


    The pathogenesis of HE is complex and is likely a culmination of multiple factors. No single abnormality of hepatic or neurologic metabolism adequately explains all of the clinical, biochemical, and physiologic findings of HE, although hyperammonemia has been found to be play a key role in the development of HE23 (BOX 2). The following theories on the pathogenesis of HE shape the current treatment recommendations.

    Box 2. Brain Neurotoxins and Neuroinhibitors Implicated in the Pathogenesis of Hepatic Encephalopathy

    • Ammonia
    • Glutamine
    • γ-Aminobutyric acid
    • Benzodiazepine-like substances
    • Tryptophan/serotonin
    • Aromatic amino acids
    • Manganese
    • Opioids

    Altered Ammonia Metabolism

    Ammonia is generated in the body by four mechanisms: (1) degradation of intestinal protein and urea in the colon by urease-producing microorganisms, (2) intrahepatic metabolism of amino acids obtained from the diet, (3) enterocyte metabolism of glutamine, and (4) peripheral tissue (muscle) catabolism.1,23,29 More than 50% of blood ammonia is derived from the intestinal breakdown of protein and urea.23,29 During normal metabolism, ammonia reaches the liver from the portal circulation. Most of the ammonia then enters the urea cycle, resulting in the ultimate formation of urea, which is subsequently excreted by the kidneys (FIGURE 1).29 The rest of the ammonia is used in the conversion of glutamate into glutamine by glutamine synthetase within various tissues within the body, such as the muscle, brain, and liver. The end product, glutamine, enters the circulation and is metabolized in the intestinal mucosa and kidneys to liberate the ammonia again.3

    The ammonia hypothesis is central to the pathogenesis of acute and chronic HE. This hypothesis states that the major mechanism of HE is excessive accumulation of ammonia.23 Liver dysfunction reduces the capabilities of ammonia detoxification, while portosystemic shunting detours ammonia-rich blood away from the liver into the systemic circulation, resulting in hyperammonemia.

    The brain is devoid of a urea cycle. It relies instead on glutamine formation in astrocytes for effective removal of ammonia.30 Nerve stimulation releases glutamate, an excitatory neurotransmitter, from presynaptic neurons. Astrocytes take up excess glutamate from the synaptic cleft. This glutamate, in conjunction with blood-derived ammonia, is metabolized to glutamine by glutamine synthetase. Glutamine is then actively extruded from astrocytic cells and taken up by presynaptic nerve terminals for conversion back to glutamate and subsequent utilization in neurotransmission.23 Thus, astrocytes function to protect the brain from excessive neurotransmission.

    In states of hyperammonemia, ammonia favors glutamine formation but impairs glutamine release from astrocytes. This results in accumulation of glutamine within astrocytic cells. The osmotically active glutamine causes cellular swelling, leading to neuronal edema23 (FIGURE 2). Cellular edema is exacerbated by further ammonia metabolism within the astrocyte, a concept known as the “Trojan horse” hypothesis.31 This hypothesis states that once ammonia interacts with glutamate in astrocytes to form glutamine, the glutamine enters the mitochondria. There, it is cleaved by glutaminase back to ammonia and glutamate. The resulting elevation in mitochondrial ammonia causes the production of reactive nitrogen and oxygen species21,32 and failure of astrocytes to adequately regulate their intracellular volume.31,33–37 This leads to further cytotoxic cerebral edema31 (FIGURE 3). Ammonia accumulation also results in reduction of cerebral glucose and oxygen metabolism,34,38,39 redistribution of blood flow from the cerebral cortex to the subcortical regions of the brain,34,38,40 and increased permeability of the blood-brain barrier to ammonia.40

    Astrocyte swelling is a critical component of acute HE. When brain edema occurs in type A HE, it can lead to increased intracranial pressure, brain herniation, and death.35 Low-grade cerebral edema is believed to occur in patients with types B and C HE.41,42 Despite the many effects of hyperammonemia on the brain, blood ammonia levels do not correlate with the severity of clinical signs of HE,3 which suggests that ammonia may not be the only player in the development of HE.      


    Infections and SIRS are common in patients with liver impairment. In humans, neurologic status deteriorates after induction of hyperammonemia in the inflammatory state, but not after resolution of the inflammation, suggesting that the inflammation and its mediators may be important in modulating the cerebral effect of ammonia in chronic and acute liver disease.20,21,43,44 Lipopolysaccharide, a compound found on bacterial cell walls that is commonly implicated in sepsis and infections, enhances ammonia-induced changes in cerebral blood flow.45,46 Additionally, neutrophils and inflammatory cytokines such as tumor necrosis factor aand interleukin 6 are known to induce cerebral swelling through production of reactive oxygen species.43,44 Possible theories explaining how inflammation contributes to HE include cytokine-mediated changes in blood-brain barrier permeability, altered glutamate uptake by astrocytes, and altered expression of γ-aminobutyric acid (GABA) receptors.43,44,47 Recent studies using ibuprofen have demonstrated improvement of mild encephalopathy in rats with chronic liver failure due to portocaval shunts,48 and treatment with minocycline, a potent inhibitor of inflammatory cytokine production, attenuates the encephalopathy stageand prevents brain edema in experimental acute liver failure.49 Hence, antiinflammatory agents may be a target for future treatment of acute and chronic HE.20

    Alterations in Glutamate Transmission

    The CNS glutamatergic neurotransmitter system is altered in animals with acute and chronic HE. As described above, astrocytes protect the brain from excessive neurotransmission by inactivating glutamate released from presynaptic nerve terminals. Hyperammonemia decreases glutamate uptake by astrocytes, which may result in elevated extracellular glutamate levels.50 Downregulation of the glutamate transporter GLT-1, an essential transporter in the inactivation of glutamate at the synapse, has been shown in hyperammonemic rats, in rats with portocaval anastomosis, and in rats with experimentally induced liver failure.51,52 High ammonia concentrations seen in stage IV HE inactivate neuronal chloride extrusion pumps, suppress inhibitory postsynaptic potential formation, depolarize neurons, and, therefore, promote increased neuronal excitation and a preconvulsive state.53 Therefore, overstimulation by increased glutamate concentrations at synapses can result in seizures in animals with types A, B and, less commonly, C HE.53,54

    Increase in γ-Aminobutyric Acid Agonists

    The GABA hypothesis states that an excess of, or an increased sensitivity to, GABA (an inhibitory CNS neurotransmitter) is responsible for HE.55 In a rabbit model of acute liver failure that progressed to coma, visual-evoked potentials measured were identical to those of a coma induced by drugs that activate the GABA receptor complex, such as benzodiazepines, barbiturates, and GABA agonists.55 Further support for this hypothesis comes from human and animal studies showing the reversal of behavioral and electrophysiologic manifestations of HE by GABA receptor antagonists, such as flumazenil.4,56–58

    GABA originates from the intestinal tract. Plasma levels of GABA increase with liver dysfunction due to decreased hepatic extraction. In acute liver failure or type A HE, the blood-brain barrier is more permeable55; as a result, increased GABA enters the brain and activates GABA receptor complexes, inducing the opening of chloride channels. As a result, the neuronal membrane becomes hyperpolarized and inhibits neurotransmission.55 There is no evidence of increased blood-brain barrier permeability in dogs with a PSS or cirrhosis, and this mechanism does not appear to be a factor in the pathogenesis of types B and C HE.59

    The GABA receptor complex binds many substances in addition to GABA, including benzodiazepines and barbiturates.55 The binding of benzodiazepines to the benzodiazepine receptor induces a conformational change in the GABA receptor complex, enhancing its ability to bind GABA55 (FIGURE 4). The increased GABAergic tone present in HE enhances the sedative and anesthetic effects of these drugs, which should be avoided in patients with HE.3

    Increase in Benzodiazepine-like Substances

    The GABA hypothesis predicts that benzodiazepines increase the severity of clinical signsof HE.55 Laboratory rats, human patients, and dogs with acute and chronic HE have been found to have increased plasma levels of endogenous benzodiazepine-like substances due to decreased liver filtration.60–62 Benzodiazepine-like substances originate from intestinal flora, vegetables in the diet, and psychiatric medication.45,47,56,62,63

    Peripheral-type benzodiazepine receptors located on the outer mitochondrial membrane of astrocytes are increased in acute and chronic HE.64–67 These receptors play a role in the synthesis of the neurosteroids tetrahydroprogesterone and tetrahydrodeoxycorticosterone, which are potent agonists of the GABA receptor.53,54,68

    The GABA-ergic neurotransmission hypothesis and the ammonia hypothesis are not mutually exclusive. In studies using radioligand binding assays, ammonia was found to directly enhance inhibitory GABA neurotransmission and synergistically augment the potency of endogenous benzodiazepine agonists.53

    Altered Serotonergic System

    Alterations in the serotonergic system have been described in human and animal models of HE. CNS levels of serotonin, serotonin receptors, and monoamine oxidases have been found to be increased in human patients with HE.69 However, the exact role of the inhibitory neurotransmitter serotonin in HE is undefined.

    The level of tryptophan, an amino acid precursor of serotonin, is increased in the plasma of human patients with acute liver failure as a result of ammonia detoxification in astrocytes.12,70 However, a human study examining the relationship between plasma and brain levels of quinolinic acid, a derivative of tryptophan, and the severity of HE did not suggest a major role for this pathway in the pathogenesis of HE.71

    Altered Amino Acid Metabolism

    During liver failure or portosystemic bypass, there is an increase in levels of aromatic amino acids (AAAs), such as phenylalanine, tyrosine, and tryptophan, and a decrease in levels of plasma branched-chain amino acids (BCAAs), such as leucine, valine, and isoleucine1,3,72,73 (FIGURE 5). Normally, the liver removes AAAs efficiently from the portal circulation to keep levels within the systemic circulation low. The brain requires low levels of AAAs, which are the precursors of the excitatory catecholamine neurotransmitters dopamine and norepinephrine. The capacity of normal AAA metabolism in the brain is the rate-limiting step in the formation of excitatory neurotransmitters. High concentrations of AAAs in the brain during HE overwhelm normal AAA metabolism, causing the AAAs to be metabolized via alternative pathways, giving rise to alternative products such as octopamine and phenylethanolamine. These products act as false neurotransmitters, binding to catecholamine receptors but with decreased intrinsic activity, thereby blocking normal catecholamine activation.3,73 In addition, the conversion of tyrosine to dopamine is depressed in HE, further decreasing catecholamine activation.3,73

    The BCAAs have a passive role in this pathophysiologic mechanism. BCAAs are decreased in chronic liver disease because they are used as alternative energy sources in muscle and other tissues. BCAAs and AAAs share the same carrier system to enter the brain. A decrease in BCAAs decreases competition for the carrier, thereby allowing more AAAs to enter the CNS.3,72

    The net effect of an increased level of AAAs in the CNS includes (1) blockage of dopamine and norepinephrine-induced neurotransmission due to a decrease in dopamine and an increase in false neurotransmitters and (2) enhanced production of inhibitory neurotransmitters. The end result is CNS depression. Clinical trials in humans and dogs aimed at correcting imbalances of AAAs and BCAAs have shown conflicting results.72,74,75

    Manganese Toxicity

    The liver is responsible for manganese excretion; therefore, liver disease is associated with elevated blood manganese levels and manganese accumulation within the brain.30 Dogs with a congenital PSS have significantly increased blood manganese levels compared with healthy dogs and dogs with nonhepatic illnesses.76 Patients with chronic liver disease have been shown to have manganese deposition in the brain.77 In the CNS, manganese toxicosis causes Alzheimer type II astrocytosis, reduction in astrocyte glutamate uptake, alteration of glutamatergic and dopaminergic neurotransmission, and impairment of cerebral energy metabolism.35,45

    Alterations in Miscellaneous Neurotransmitters

    Taurine is an inhibitory neurotransmitter that is increased in the brain and cerebrospinal fluid of rodents with experimentally induced acute HE. Plasma levels of taurine have been correlated with the severity of encephalopathy.78

    Other neurotransmitters that have been implicated in the pathogenesis of HE include opioids,79 melatonin,23 methanethiols or mercaptans, and short-chain fatty acids,12,23,47,70 all of which are derived from bacterial products of gut flora. While many studies support the role of bacterial gut flora in the pathogenesis of HE based on formation of various neurotransmitters, other studies have negated the putative role of these factors, making it difficult to determine their true involvement.12


    The pathogenesis of HE is best explained as the interaction of many different factors contributing in an interrelated and synergistic manner. A thorough understanding of the various factors contributing to the clinical manifestation of HE is required in order to understand the treatment options recommended for this disease. Type A HE is associated with acute hepatic failure and cerebral edema, which carries a poor prognosis. Practitioners should be prepared to offer their clients referral to a specialty intensive care setting. In human medicine, acute liver failure complicated by HE dictates the need to transfer patients to a liver transplant center. In contrast, types B and C HE may respond dramatically to medical management. Future research may further elucidate the most significant aspects of the pathogenesis of HE, as well as introduce further theories that may contribute to the understanding of the clinical syndrome seen in veterinary patients.

    Downloadable PDF


    1. Gallardo M, Chaffin MK. Hepatic encephalopathy. Compend Equine 2006;1(3):159-170.

    2. Kelly JH, Koussayer T, He D, et al. An improved model of acetaminophen-induced fulminant hepatic failure in dogs. Hepatology 1992;15(2):329-335.

    3. Rothuizen J. Important clinical syndromes associated with liver disease. Vet Clin North Am Small Anim Pract 2009;39:419-437.

    4. Meyer HP, Legemate DA, van den Brom W, Rothuizen J. Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil. Metab Brain Dis 1998; 13(3): 241- 251.

    5. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812.

    6. Center SA, Magne ML. Historical, physical examination, and clinicopathologic features of portosystemic vascular anomalies in the dog and cat. Semin Vet Med Surg (Small Anim) 1990;5:83-93.

    7. Scavelli TD, Hornbuckle WE, Roth L, et al. Portosystemic shunts in cats: seven cases (1976-1984). J Am Vet Med Assoc 1986;189(3):317-325.

    8. Meyer HP, Rothuizen J. Increased free cortisol in plasma of dogs with portosystemic encephalopathy (PSE). Domest Anim Endocrinol 1994;11(4):317-322.

    9. Rothuizen J, Biewenga WJ, Mol JA. Chronic glucocorticoid excess and impaired osmoregulation of vasopressin release in dogs with hepatic encephalopathy. Domest Anim Endocrinol 1995;12:13-24.

    10. Sterczer A, Meyer HP, Van Sluijs FJ, Rothuizen J. Fast resolution of hypercortisolism in dogs with portosystemic encephalopathy after surgical shunt closure. Res Vet Sci 1998;66:63-67.

    11. Dewey CW. A Practical Guide to Canine & Feline Neurology. 2nd ed. Ames, IA: Wiley-Blackwell; 2008:143-147.

    12. Maddison JE. Hepatic encephalopathy: current concepts of the pathogenesis. J Vet Intern Med 1992;6:341-353.

    13. Rothuizen J, van den Ingh TSGAM, Voorhout G, et al. Congenital porto-systemic shunts in sixteen dogs and three cats. J Small Anim Pract 1982;23:67-81.

    14. Windsor RC, Olby NJ. Congenital portosystemic shunts in five mature dogs with neurological signs. J Am Anim Hosp Assoc 2007;43:322-331.

    15. Schermerhorn T, Center SA, Dykes NL, et al. Characterization of hepatoportal microvascular dysplasia in a kindred of cairn terriers. J Vet Intern Med 1996;10:219-230.

    16. Cooper J, Webster CRL. Acute liver failure. Compend Contin Educ Vet 2006;28(7):498-515.

    17. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41(5):1179-1197.

    18. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35(3):716-721.

    19. Mullen KD. Review of the final report of the 1998 working party on definition, nomenclature, and diagnosis of hepatic encephalopathy. Aliment Pharmacol Ther 2006;25(Suppl 1):11-16.

    20. Butterworth RF. Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology 2011;53:1372-1376.

    21. Seyan AS, Hughes RD, Shawcross DL. Changing face of hepatic encephalopathy: role of inflammation and oxidative stress. World J Gastroenterol 2010;16(27):3347-3357.

    22. Dempsey RJ, Kindt GW. Experimental acute hepatic encephalopathy: relationship of pathological cerebral vasodilation to increased intracranial pressure. Neurosurgery 1982;10(6):737-740.

    23. Martinez-Camacho A, Fortune BE, Everson GT. Hepatic encephalopathy. In: Vincent J, Abraham E, Moore FA, et al, eds. Textbook of Critical Care. 6th ed. Philadelphia, PA: Elsevier Saunders; 2011:760-770.

    24. Zandvliet MM, Rothuizen J. Transient hyperammonemia due to urea cycle enzyme deficiency in Irish wolfhounds. J Vet Intern Med 2007;21(2):215-218.

    25. Strombeck DR, Meyer DJ, Freedland RA. Hyperammonemia due to a urea cycle deficiency in two dogs. J Am Vet Med Assoc 1975;166:1109-1111.

    26. Vaden SL, Wood PA, Ledley FP, et al. Cobalamin deficiency associated with ethylmalonic academia in a cat. J Am Vet Med Assoc 1992;200:1101-1103.

    27. Agg EJ. Acquired extrahepatic portosystemic shunts in a young dog. Can Vet J 2006;47(7):697-699.

    28. Szatmari V, Rothuizen J, van den Ingh TSFAM, et al. Ultrasonographic finding in dogs with hyperammonemia: 90 cases (2000-2002). J Am Vet Med Assoc 2004;224(5):717-727.

    29. Dimski DS. Ammonia metabolism and the urea cycle: function and clinical implications. J Vet Intern Med 1994;8(2):73-78.

    30. Harris MK, Elliott D, Schwendimann RN, et al. Neurologic presentations of hepatic disease. Neurol Clin 2010;28:89-105.

    31. Albrecht J, Norenberg MD. Glutamine: a trojan horse in ammonia neurotoxicity. Hepatology 2006;44(4):788-794.

    32. Jayakumar AR, Panickar KS, Murthy ChRK, Norenberg MD. Oxidative stress and MAPK phosphorylation mediate ammonia-induced cell swelling and glutamate uptake inhibition in cultured astrocytes. J Neurosci 2006;26:525-531.

    33. Bai G, Rama Rao KV, Murthy CRK, et al. Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res 2001;66:981-991.

    34. Rama Rao KV, Norenberg MD. Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 2001;16(1/2):67-78.

    35. Rama Rao KV, Norenberg MD. Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis 2007;22:265-275.

    36. Margulies JE, Thompson RC, Demetriou AA. Aquaporin-4 channel is up-regulated in the brain in fulminant hepatic failure. Hepatology 1999;30:395a.

    37. Yang JH, Song ZJ, Liao CD, et al. The relationship of the expression of aquaporin-4 and brain edema in rats with acute liver failure. Zhonghua Gan Zang Bing Za Zhi 2006;14:215-216.

    38. Weissenborn K, Bokemeyer M, Ahl B, et al. Functional imaging of the brain in patients with liver cirrhosis. Metab Brain Dis 2004;19(3/4):269-280.

    39. Iversen P, Sorenson M, Bak L, et al. Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology 2009;136:863-871.

    40. Jalan R, Olde Damink SWM, Lui HF, et al. Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Metab Brain Dis 2003;18(1):37-49.

    41. Haussinger D, Laubenberger J, Vom Dahl S, et al. Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 1994;107:1475-1480.

    42. Moats RA, Lien YHH, Filippi D, Ross BD. Decrease in cerebral inositols in rats and humans. Biochem J 1993;295:15-18.

    43. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.

    44. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010;51:1062-1069.

    45. Sundaram V, Shaikh OS. Hepatic encephalopathy: pathophysiology and emerging therapies. Med Clin North Am 2009;93:819-836.

    46. Pederson HR, Ring-Larsen H, Olsen NV, et al. Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetized with pentobarbital. J Hepatol 2007;47:245-252.

    47. Williams R. Review article: bacterial flora and pathogenesis in hepatic encephalopathy. Aliment Pharmacol Ther 2006;25(Suppl 1):17-22.

    48. Cauli O, Rodrigo R, Piedrafita B, et al. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portocaval shunts. Hepatology 2007;46:514-519.

    49. Jiang W, Desjardins P, Butterworth RF. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 2009;109:485-493.

    50. de Knegt RJ, Schalm SW, van der Rijt CC, et al. Extracellular brain glutamate during acute liver failure and during acute hyperammonemia stimulatory acute liver failure: an experimental study based on in vivo brain dialysis. J Hepatol 1994;2019-26.

    51. Knecht K, Michalak A, Rose C, et al. Decreased glutamate transporters (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 1997;229:201-203.

    52. Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A. The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 1997;21:124-133.

    53. Basile AS, Jones EA. Ammonia and GABA-ergic neurotransmission: interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology 1997;25:1303-1305.

    54. Butterworth RF. Neurotransmitter dysfunction in hepatic encephalopathy: new approaches and new findings. Metab Brain Dis 2001;16(1/2):55-65.

    55. Jones EA, Schafer DF, Ferenci P, Pappas SC. The GABA hypothesis of the pathogenesis of hepatic encephalopathy: current status. Yale J Biol Med 1984;57:301-316.

    56. Als-Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy (review). Cochrane Database Syst Rev 2004;(2):CD002798.

    57. Ferenci P, Grimm G, Meryn S, Gangl A. Successsful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil. Gastroenterology 1989;96:240-243.

    58. Laccetti M, Manes G, Uomo G, et al. Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study. Digest Liver Dis 2000;32:335-338.

    59. Roy S, Pomier-Layrargues G, Butterworth RF, Huet PM. Hepatic encephalopathy in cirrhotic and portocaval shunted dogs: lack of changes in brain GABA uptake, brain GABA levels, brain glutamic acid decarboxylase activity and brain postsynaptic GABA receptors. Hepatology 1988;8(4):845-849.

    60. Lighthouse J, Naito Y, Helmy A, et al. Endotoxemia and benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation. Hepatol Res 2004;28:155-160.

    61. Zeneroli ML, Venturini I, Corsi L, et al. Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic failure. Scand J Gastroenterol 1998;33:310-313.

    62. Aronson LR, Gacad RC, Kaminsky-Russ K, et al. Endogenous benzodiazepine activity in the peripheral and portal blood of dogs with congenital portosystemic shunts. Vet Surg 1997;26:189-194.

    63. Basile AS, Pannell L, Jaouni T, et al. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Neurobiology 1990;87:5263-5267.

    64. Lavoie J, Layrargues GP, Butterworth RF. Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 1990;11:874-878.

    65. Giguère JF, Hamel E, Butterworth RF. Increased densities of binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand 3H-PK11195 in rat brain following portacaval anastomosis. Brain Res 1992;585:295-298.

    66. Rao VL, Qureshi IA, Butterworth RF. Increased densities of binding sites for the peripheral-type benzodiazepine ligand 3H-PK11195 in congenital ornithine transcarbamylase deficient sparse-fur mouse. Pediatr Res 1993;34:777-780.

    67. Itzhak Y, Norenberg MD. Ammonia-induced upregulation of peripheral-type benzodiazepine receptors in cultured astrocytes labeled with 3H-PK11195. Neurosci Lett 1994;177:35-38.

    68. Akwa Y, Sananes N, Gouezou M, et al. Astrocytes and neurosteroids: metabolism of pregnenolone and dehydroepiandrosterone. Regulation by cell density. J Cell Biol 1993;12:135-143.

    69. Lozeva-Thomas V. Serotonin brain circuits with a focus on hepatic encephalopathy. Metab Brain Dis 2004;19(3-4):413-420.

    70. Vaquero J, Chung C, Cahill ME, et al. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis 2003;23(3):259-269.

    71. Basile AS, Saito K, al-Mardini H, et al. The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy. Gastroenterology 1995;108:818-823.

    72. Meyer HP, Chamuleau RAFM, Legemate DA, et al. Effects of a branched-chain amino acid-enriched diet on chronic hepatic encephalopathy in dogs. Metab Brain Dis 1999;14(2):103-115.

    73. Neumann S, Welling H, Thuere S. Evaluation of serum L-phenylalanine concentration as indicator of liver disease in dogs: a pilot study. J Am Anim Hosp Assoc 2007;43:193-200.

    74. Chalasani N, Gitlin N. Severe recurrent hepatic encephalopathy that responded to oral branched chain amino acids. Am J Gastroenterol 1996;91:1266-1268.

    75. Marchesini G, Dioguardi FS, Bianchi GP, et al. Long term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized, double-blind, casein controlled study. J Hepatol 1990;11:92-101.

    76. Gow AG, Marques AIC, Yool DA, et al. Whole blood manganese concentrations in dogs with congenital portosystemic shunts. J Vet Intern Med 2010;24:90-96.

    77. Butterworth RF, Spahr L, Fontaine S, Layrargues GP. Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy. Metab Brain Dis 1995;10(4):259-267.

    78. Swain MS, Bergeron M, Andet R, et al. Monitoring of neurotransmitter amino acids by means of an indwelling cisterna magna catheter: a comparison of two rodent models of fulminant liver failure. Hepatology 1992; 16(4): 1028-1035.

    79. Yurdaydin C. The central opioid system in liver disease and its complications. Metab Brain Dis 2001;16(1/2):79-83.

    References »

    NEXT: Clinical Snapshot: Equine Lymphoma


    Did you know... Ethanol toxicosis can cause severe central nervous system (CNS) depression, coma, and acidosis in dogs.Read More

    These Care Guides are written to help your clients understand common conditions. They are formatted to print and give to your clients for their information.

    Stay on top of all our latest content — sign up for the Vetlearn newsletters.
    • More