615

CHAPTER 116 HEPATIC FAILURE

Allyson Berent, DVM, DACVIM (Internal Medicine)

KEY POINTS

• Hepaticfailuretypicallyholdsapoorprognosis;apromptdiagnosis,searchforanunderlyingcause,andrapidandappropriatetreatmentarecriticalforsurvival.

• Hepaticencephalopathyandcoagulopathyaretypicallythemainclinicalconsequencesofhepaticfailureandshouldbetreatedaccordingly.

• Therapyshouldbeaimedatminimizingsignsofencephalopathyandtreatingtheunderlyingpathology,therebyallowingthelivertoregenerate.

• Researcherscurrentlyareexploringadipose-derivedmesenchymalstemcelltherapyandliverreplacementtherapy.Thishaspotentialpromiseforveterinarymedicine.

Liver failure occurs as a result of severe hepatocyte injury or dysfunc-tion, regardless of the cause,1-3 manifesting as an acute or chronic process. The loss of hepatic function leads to a spectrum of metabolic derangements, which results in devastating clinical consequences and most commonly the clinical onset of hepatic encephalopathy and coagulopathy. Other complications associated with this state include gastrointestinal ulceration, bacterial sepsis, cardiopulmonary dys-function, and ascites. Before the development of hepatic transplanta-tion, liver failure had a mortality rate greater than 90% in people.1,2 Early detection, treatment, and aggressive supportive care is critical to embracing the regenerative capacity of the liver because it is capable of regenerating 75% of its functional capacity in only a few weeks. Common causes of liver disease that can result in failure in dogs and cats are listed in Table 116-1.4-6

PATHOPHYSIOLOGY

The histologic changes seen in the liver of patients with acute or chronic liver failure are variable and depend on the underlying cause. Acute liver diseases are likely to display hepatocellular necrosis as the prominent lesion. Fat accumulation or hepatocellular drop-out also may be noted. A chronically diseased liver also may demonstrate hepatocellular necrosis, but fibrosis, inflammation, and hyperplasia of ductular structures are often present as well.

Patients with hepatic failure display common physiologic clinical features, regardless of the cause. These include hypotension, lactic acidosis resulting from the poor oxygen uptake by muscles and peripheral tissues combined with decreased hepatic lactate metabo-lism, electrolyte alterations, hepatic encephalopathy, and coagulopa-thy. Over time, dysfunction of multiple organ systems can occur. In people, acute kidney injury is a common sequela to liver failure (hepatorenal syndrome),7 although this is described rarely in veteri-nary patients.5

Hepatic EncephalopathyHepatic encephalopathy (HE), the hallmark feature of hepatic failure, is a neuropsychiatric syndrome involving many neurologic abnor-

malities. The pathogenesis of HE is understood incompletely in vet-erinary and human medicine and typically occurs when more than 70% of hepatic function is lost.2,4,8-11 This results in the central nervous system (CNS) entering an encephalopathic state. More than 20 different compounds have been found in excess in the circulation when liver function is impaired, including ammonia, aromatic amino acids, endogenous benzodiazepines, γ-aminobutyric acid (GABA), glutamine, short-chain fatty acids, tryptophan, and others (Table 116-2).4,8,9,11,12 These substances may impede neuronal and astrocyte function, causing cell swelling, inhibition of membrane pumps or ion channels, an elevation in intracellular calcium concentrations, depression of electrical activity, and interference with oxidative metabolism.8-10

Ammonia often is considered the most important neurotoxic substance. Increased concentrations trigger a sequence of metabolic events that have been implicated in HE in rats, humans, and dogs.8,9,11,13,14 Ammonia is produced by the gastrointestinal flora and then converted in the normal liver to urea and glutamine via the urea cycle. Ammonia is excitotoxic and associated with an increased release of glutamate, the major excitatory neurotransmitter of the brain. Overactivation of the glutamate receptors, mainly N-methyl-D-aspartate (NMDA) receptors, has been implicated as one of the causes of HE-induced seizures. With chronicity, inhibitory factors such as GABA and endogenous benzodiazepines surpass the excit-atory stimulus, causing signs more suggestive of coma or CNS depression.8,9,13 Long-standing metabolic dysfunction, as seen in patients with chronic liver failure, also results in alterations in neu-ronal responsiveness and energy requirements.9,14

Acute liver failure may result in a form of HE that leads to cerebral edema, increased intracranial pressure, and possible herniation of the brain.8,9 Edema is described in up to 80% of humans with hepatic failure, and 33% can develop fatal herniation.3,8,9 Clinical signs associated with HE are variable, with most being suggestive of neu-roinhibition. Excitatory activity such as seizures, aggression, and hyperexcitability also occur. A combination of complex metabolic derangements that occur in patients with hepatic insufficiency (e.g., hypoglycemia, dehydration, hypokalemia, azotemia, alkalemia) and systemic toxins (see Table 116-2) are responsible for a variety of signs that can be exacerbated by exogenous substances such as nonsteroidal antiinflammatory drugs (NSAIDs), high-protein meals, gastrointestinal ulcerations, constipation, stored blood trans-fusions (because of ammonia levels), and drugs (sedatives, analgesics, benzodiazepines, antihistamines). Recently inflammation and ele-vated manganese levels also have been proven to be associated with HE in people and dogs.15,16 These factors, in addition to an altered permeability of the blood brain barrier, impair cerebral function in various ways.4,8,9,15,16

Treatments that decrease ammonia concentrations, which are measured easily in animals, seem to reduce the signs of HE. In humans, the degree of encephalopathy is not well correlated with the blood ammonia levels,17 suggesting that other suspected neuro-toxins are also important in pathophysiology of HE. Ammonia

616 PART XII • INTRAABDOMINAL DISORDERS

Table 116-1  Causes of Hepatic Failure4-6

Dog Cat

Infectious agents Canine adenovirus-1Acidophil cell hepatitis virusCanine herpes virusClostridiosisBartonellosisLeptospirosisLiver abscessTularemiaHepatozoonosisRickettsia rickettsiiHistoplasmosisCoccidiomycosis/blastomycosisLeishmaniasisToxoplasmosisDirofilaria immitisEhrlichia canis

Feline infectious peritonitisClostridiosisLiver abscessesHistoplasmosisCryptococcosisToxoplasmosis

Drugs AcetaminophenAspirinPhenobarbitalPhenytoinCarprofenTetracyclineMacrolidesTrimethoprim-sulfaGriseofulvinThiacetarsemideKetoconazole/itraconazoleHalothane

AcetaminophenAspirinDiazepamHalothaneGriseofulvinKetoconazole/itraconazoleMethimazoleMethotrexatePhenobarbitalPhenytoin

Chemical agents/toxins Industrial solventsPlants: sago palmEnvenomationHeavy metals (Cu, Fe, P)Mushrooms (Amanita phalloides)AflatoxinsBlue-green algaeCycad seedsCarbon tetrachlorideDimethylnitrosamineZinc phosphideXylitol (dogs only)

Same as for dogs

Miscellaneous Chronic hepatitis/cirrhosis-idiopathic, copper storage disease, leptospirosis induced,idiosyncratic drug reaction, lobular dissecting hepatitis

Granulomatous hepatitisHepatic amyloidosis (Chinese Shar-Pei)Hepatic neoplasia (primary or metastatic disease)Portosystemic shuntingPortal venous hypoplasia/microvascular dysplasia

(Yorkshire and Cairn Terrier)

Feline hepatic lipidosisInflammatory bowel diseasePancreatitisCholangitis/cholangiohepatitisSepticemia/endotoxemiaHemolytic anemiaNeoplasia: lymphoma, mastocytosisMetastasisAmyloidosis (Abyssinian, Oriental, and

Siamese cats)

Traumatic/thermal/hypoxic Diaphragmatic herniaShockLiver torsionHeat strokeMassive ischemia

concentrations do not correlate always with signs of HE in veterinary patients either, and on rare occasions, dogs with normal ammonia concentrations have obvious HE signs. In addition, many dogs with high ammonia levels appear neurologically normal.

Coagulation DisordersCoagulation abnormalities that develop in patients with liver failure are multifactorial, depending on the interactions of the coagulation, anticoagulation, and fibrinolytic systems. Spontaneous hemorrhage

is uncommon. Hemorrhagic complications usually are induced with associated factors such as gastrointestinal ulceration, invasive proce-dures (aspiration, biopsy, surgery), or other concurrent medical problems. Suggested causes of coagulopathy in liver failure patients include decreased factor synthesis, increased factor utilization, decreased factor turnover, increased fibrinolysis and tissue thrombo-plastin release, synthesis of abnormal coagulants (dysfibrinogen-emia), decreased platelet function and numbers, vitamin K deficiency (particularly in patients with bile duct obstruction), and increased production of anticoagulants.4,18

CHAPTER 116 • HEPATIC FAILURE 617

agents (leptospirosis, feline infectious peritonitis) also cause acute and chronic kidney injury.

Portal hypertension, typically secondary to cirrhosis, is a common sequela of chronic liver failure. It has been seen in some acute patients and typically holds a poor prognosis. Massive sinusoidal collapse can block intrahepatic flow, causing portal pressure elevations. In addi-tion, portal vein thrombosis can be seen.19 This may lead to severe congestion of the splanchnic vasculature, exacerbating gastrointesti-nal bleeding and diarrhea.3-5

CLINICAL SIGNS

Most of the clinical signs seen in dogs and cats with hepatic failure are nonspecific and include anorexia, vomiting, diarrhea, weight loss, and dehydration. Icteric mucous membranes, sclera, hard palate, and skin, are seen commonly in patients with liver failure associated with intrahepatic cholestasis. If icterus is documented, prehepatic (hemo-lysis), hepatic (intrinsic hepatic injury/failure), and/or posthepatic (functional or mechanical bile duct obstruction) causes should be discerned. Dogs and cats with liver failure secondary to congenital portosystemic shunting should not be icteric. Polyuria and polydipsia are common findings, which may be due to failure of the liver to produce urea, resulting in defective renal medullary concentrating ability, and a decreased release and/or responsiveness of the renal collecting ducts to antidiuretic hormone (ADH). Primary polydipsia, resulting from the central effects of hepatotoxins, also has been hypothesized. Other theories include increased renal blood flow and increased adrenocorticotropic hormone (ACTH) secretion with associated hypercortisolism.20,21

Clinical signs associated with HE include behavioral changes, ataxia, blindness, circling, head pressing, panting, pacing, seizures,

OtherIn addition to altered mentation and coagulation disorders, hepatic failure has been associated with an increased susceptibility to infec-tion, systemic hypotension, pulmonary abnormalities, acid-base dis-turbances, renal dysfunction, and portal hypertension. Bacterial infection occurs in 80% of human patients, and this may be due to various mechanisms.1,3,4,18 Inhibition of the metabolic activity of granulocytic cells, cell adhesion, and chemotaxis, as well as decreased hepatic synthesis of plasma complement, has been described.1,3,4,18 Kupffer cells also have shown reduced phagocytic ability, allowing pathogens to translocate from the portal circulation into the systemic circulation. Hypotension is seen in most people with hepatic failure and may be due to systemic vasodilation. This is likely a centrally mediated phenomenon and may be linked to systemic infection, inflammation, cytokine release, cerebral edema, or circulating toxins. Approximately 33% of humans with hepatic failure develop pulmo-nary edema. Altered permeability of pulmonary capillaries leading to vascular leak, as well as decreased albumin/colloid osmotic pres-sure and vasodilation, has been implicated in the development of edema. This may be associated with endotoxemia as well.1,3

Tissue oxygen extraction decreases in patients with hepatic failure, resulting in tissue hypoxia and the development of lactic acidosis. Hypoxemia (which can occur with pulmonary edema) further exac-erbates cerebral dysfunction in patients with HE, accelerating cere-bral hypotension and additional cerebral edema. Ventilatory support may be needed if respiratory distress or arrest occurs. This may be of central origin or secondary to muscle weakness.1,18 The develop-ment of acute kidney injury has been well described in humans and rarely suggested in dogs.5 Hypovolemia and hypotension, secondary to vasodilation, can diminish renal blood flow and glomerular filtra-tion rate.1-3 Some hepatotoxins (nonsteroidal drugs) and infectious

Table 116-2  Toxins Implicated in Hepatic Encephalopathy4,6,8-12,15,16

Toxins Mechanisms Suggested in the Literature

Ammonia Increased brain tryptophan and glutamine; decreased ATP availability; increased excitability; increased glycolysis; brain edema; decreased microsomal Na+/K+-ATPase in brain

Aromatic amino acids Decreased DOPA (dihydroxyphenylalanine) neurotransmitter synthesis; altered neuroreceptors; increased production of false neurotransmitters

Bile acids Membranocytolytic effects alter cell/membrane permeability; blood-brain barrier more permeable to other HE toxins; impaired cellular metabolism because of cytotoxicity

Decreased alpha-ketoglutaramate Diversion from Krebs cycle for ammonia detoxification; decreased ATP availability

Endogenous benzodiazepines Neural inhibition: hyperpolarize neuronal membrane

False NeurotransmittersTyrosine→ OctapaminePhenylalanine → PhenylethylamineMethionine → Mercaptans

Impairs norepinephrine actionImpairs norepinephrine actionSynergistic with ammonia and SCFADecreases ammonia detoxification in brain urea cycle; GIT derived (fetor hepaticus-breath

odor in HE); decreased microsomal Na+/K+-ATPase

GABA Neural inhibition: hyperpolarize neuronal membrane; increase blood-brain barrier permeability to GABA

Glutamine Alters blood-brain barrier amino acid transport

Manganese Elevated manganese levels seen with hepatic failure and HE and results in neurotoxicity. Its toxicity is associated with disruption of the glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle (GGC) between astrocytes and neurons, thus leading to changes in Glu-ergic and/or GABAergic transmission and Gln metabolism

Phenol (from phenylalanine and tyrosine)

Synergistic with other toxins; decreases cellular enzymes; neurotoxic and hepatotoxic

Short chain fatty acids (SCFA) Decreased microsomal Na+/K+-ATPase in brain; uncouple oxidative phosphorylation, impairs oxygen use, displaces tryptophan from albumin, increasing free tryptophan

Tryptophan Directly neurotoxic; increases serotonin: neuroinhibition

ATP,AdenosinetriphosphateDOPA,dihydroxyphenylalanine,GABA,γ-aminobutyricacid.

618 PART XII • INTRAABDOMINAL DISORDERS

protein-losing enteropathy (PLE), and third-spacing protein loss). Cholesterol is synthesized in many tissues, although up to 50% of its synthesis occurs in the liver. In patients with hepatic failure, hypo-cholesterolemia is observed commonly. With extrahepatic bile duct obstruction or pancreatitis, cholesterol elimination is altered and hypercholesterolemia can develop. Because the liver helps to main-tain glucose homeostasis via gluconeogenesis and glycogenolysis, hypoglycemia may develop when less than 30% of normal hepatic function is present.4,6

Urine sediment examination may show ammonium biurate or urate crystals, particularly in animals with portal-systemic vascular anomalies. Dogs have the ability to produce and conjugate bilirubin in their renal tubules, accounting for a small amount of bilirubinuria in a healthy state (males more than females). Cats, on the other hand, do not have this ability and have a higher threshold (9 times higher) than dogs to reabsorb bilirubin rather than eliminate it in the urine.4,22 Therefore bilirubinuria in the cat is always inappropriate and indicative of abnormal bilirubin metabolism.

Additional testing may be performed to assess hepatic function. Coagulopathies are seen classically in animals with hepatic failure. Prolongation of the activated partial thromboplastin time (aPTT), prothrombin time (PT), activated clotting time (ACT), and buccal mucosal bleeding time (BMBT) may be observed. Increased fasting and postprandial serum bile acids are indicative of hepatic dysfunc-tion and classically seen in animals with hepatic failure. They also may play a role in inciting inflammatory liver disease.4,6 Plasma fasting ammonia, 6-hour postprandial ammonia, or ammonia toler-ance testing are sensitive tests of liver function. The ammonia toler-ance test is contraindicated in animals with encephalopathy and may precipitate seizure activity.4-6,22

Electrolyte abnormalities also may be seen in patients with hepatic failure. Hypokalemia may develop because of inadequate intake, vomiting, or the use of potassium-wasting diuretics for treatment of ascites. Centrally induced hyperventilation and respiratory alkalosis may encourage renal potassium excretion, worsening the hypokale-mia, and a decrease in potassium levels may exacerbate HE. In addi-tion, hypocapnia results in a shift of intracellular carbon dioxide into the extracellular space, raising intracellular pH and accelerating the use of phosphate to phosphorylate glucose. This may result in hypophosphatemia, which ultimately can cause hemolysis of red blood cells.

Diagnostic imaging is often useful to determine the underlying cause of hepatic failure. Abdominal radiographs are useful for deter-mining liver size and contour, identifying mass lesions and evaluating abdominal detail, which may be decreased in the presence of ascites. Abdominal ultrasonography is valuable for the evaluation of hepatic parenchymal architecture, the biliary tract, and vascular structures. It also can help to guide diagnostic sampling procedures, when indi-cated. Computed tomography with angiography is a great tool to diagnose portosystemic shunting but requires general anesthesia, which carries considerable risk in patients with clinical HE.

Ultimately cytologic or histologic evaluation is necessary to deter-mine the underlying cause of hepatic failure if a congenital PSS is not found. Fine-needle aspiration cytology is useful for diagnosing infiltrative neoplasia such as lymphoma but gives little information about the hepatic parenchymal changes needed for a definitive diag-nosis of the inflammatory/infectious, necrotic, fibrosing, and micro-vascular diseases. Aspiration has been proven insensitive in making a definitive diagnosis.24 Histopathologic evaluation of liver tissue is more useful and should be obtained whenever possible. Liver biop-sies can be performed with ultrasound guidance, laparoscopy, or surgery. In humans, a transjugular approach, under fluoroscopic guidance, is used commonly, particularly in coagulopathic patients, to avoid penetrating the hepatic capsule and cause third space

coma, and ptyalism (especially cats). The clinical manifestations of HE range from minimal behavior and motor activity changes, to overt deterioration of mental function, decreased consciousness, coma, and/or seizure activity. Bleeding diathesis, melena (resulting from gastroduodenal ulceration), and ascites (resulting from portal hypertension and/or hypoalbuminemia) are also common findings.

DIAGNOSIS

Fulminant hepatic failure is diagnosed when a patient shows signs of HE, changes in the liver function parameters on blood chemistry, possible evidence of coagulopathy, and associated historical and physical examination findings. Hematologic abnormalities may include the presence of target cells, acanthocytes, and anisocytosis. A nonregenerative anemia may be noted in association with chronic disease, chronic GI bleeding, or portosystemic/microvascular shunt-ing. A regenerative anemia may be noted in association with blood loss from gastroduodenal ulceration. A leukocytosis or leukopenia may be seen with infectious causes or bacterial translocation, depend-ing on the agent and severity of infection. A consumptive thrombo-cytopenia may occur in animals that develop disseminated intravascular coagulation and an immune-mediated thrombocyto-penia can be associated with infectious or immune causes of liver failure.

Serum biochemical analysis reveals elevated activities of hepatic enzymes in most cases. Alanine aminotransferase (ALT) and aspar-tate aminotransferase (AST) are found in the cytosol of hepatocytes and leak from the cell after disruption of the cell membrane. ALT is the more liver specific of these enzymes and has a short half-life (24 to 60 hours).4,6,22,23 AST is present in many tissues (liver, muscle, red blood cells) and has a shorter half-life than ALT. Alkaline phosphatase (ALP) has many clinically significant isoenzymes (bone, liver, and steroid induced [in the dog only]). The hepatic isoenzyme is located on the membranes of hepatocyte canalicular cells and biliary epithe-lial cells. Its activity increases in association with cholestatic disease. ALP has a short half-life in cats, making any elevation suggestive of active liver disease. γ-Glutamyltransferase (GGT) also is found in many tissues, although most of the biochemically measured enzyme is located on membranes of hepatocyte canalicular cells and biliary epithelial cells. GGT is useful in the diagnosis of cholestatic disease and is more specific and less sensitive than ALP (particularly in feline patients). The presence of normal or only mildly elevated liver enzyme activity does not eliminate hepatic failure as a possible diag-nosis because animals with end-stage hepatic failure or portal-systemic vascular anomalies may have normal, or near normal, enzyme activities.

Serum biochemical analysis also may reveal hyperbilirubinemia in animals with hepatic failure. Bilirubin is one of the breakdown metabolites of hemoglobin, myoglobin, and cytochromes. With sig-nificant cholestasis, bile duct obstruction, or canalicular membrane disruption, bilirubin escapes into the systemic circulation, resulting in hyperbilirubinemia and the typical icteric appearance to the skin, mucous membranes, and organs (visible when values are at least 2.3 to 3.3 mg/dl).6,22,23

The liver functional parameters that are noted classically when hepatic failure is present include hypoalbuminemia with normal to increased globulins, hypocholesterolemia, hypoglycemia, and decreased blood urea nitrogen (BUN). Albumin is produced only in the liver, representing approximately 25% of all proteins synthesized by the liver. Altered albumin synthesis is not detected until more than 66% to 80% of liver function is lost.23 Because of its long half-life (8 days in dogs and cats) hypoalbuminemia is a hallmark of chronic liver dysfunction (although concomitant disease processes also may contribute to its loss, including protein-losing nephropathy (PLN),

CHAPTER 116 • HEPATIC FAILURE 619

Table 116-3  Therapies for Hepatic Failure

Symptom Therapy

Bacterial translocation Cleansing enemas with warm water or 30% lactulose solution at 5-10 ml/kg (see Chapter 88 for further details)

Antibiotics:Metronidazole: 7.5 mg/kg IV or PO q12hAmpicillin: 22 mg/kg IV q8hNeomycin: 22 mg/kg PO q12h (avoid if any evidence of intestinal bleeding, ulcerations, or renal failure)

Gastrointestinal ulceration

Antacid20:Famotidine: 0.5-1.0 mg/kg/day IV or PO q12-24hOmeprazole: 0.5-1.0 mg/kg/day q12h POEsomeprazole: 0.5-1 mg/kg IV q24hMisoprostol: 2-5 mcg/kg PO q6-12hProtectant:Sucralfate: 0.25-1 g PO q6-12hCorrect coagulopathy

Coagulopathy Fresh frozen plasma (10-15 ml/kg over 2-3 hours)Vitamin K1: 1.0-2.0 mg/kg SC q12h for three doses, then once daily

Control seizures Avoid benzodiazepines: consider propofol 0.5-1 mg/kg IV bolus + IV CRI at 0.05-0.4 mg/kg/minORIV phenobarbital (16 mg/kg IV, divided into 4 doses over 12-24 hours), or potassium bromide/sodium

bromide loading (see Chapter 166) ORIV levetiracetam: 30-60 mg/kg once, then 20 mg/kg q8h

Decrease cerebral edema Mannitol (0.5-1.0 g/kg IV over 20-30 min)

Hepatoprotective therapy SAMe (Denosyl): 17-22 mg/kg PO q24hUrsodeoxycholic acid (Actigall): 10-15 mg/kg/dayVitamin E: 15 IU/kg/dayMilk thistle: 8-20 mg/kg divided q8hL-Carnitine: 250-500 mg/cat q24hVitamin B complex: 1 ml/L of IV fluids

Antifibrotic therapy D-Penicillamine: 10-15 mg/kg PO q12hColchicine: 0.03 mg/kg/dayPrednis(ol)one: 1 mg/kg/day

Nutritional support Moderate protein restriction: 18% to 22% dogs and 30% to 35% cats; dairy or vegetable proteins; vitamin B supplementation; multivitamin supplementation

bleeding.1 This currently is not recommended in veterinary patients. A blood type and coagulation profile should be obtained before liver biopsy in all animals. A small amount of liver tissue should be stored so that further testing can be performed, if indicated, after histopa-thology is complete, such as aerobic and anaerobic culture, copper analysis (dogs), or PCR testing for certain infectious agents.

THERAPY

Successful management of patients with hepatic failure requires treatment of the underlying liver disease, therapy aimed at the com-plications of hepatic failure (HE and coagulopathy), and routine supportive care. Fortunately, hepatocytes have an immense ability to regenerate if given appropriate support and time. Treatment of the primary disease process, if possible, is critical. However, a discussion of the treatment recommendations for each specific liver disease is beyond the scope of this chapter. Supportive care is required to maintain the normal physiologic functions of the patient while the liver recovers from the insult (Table 116-3).

Animals that are presented with, or develop, focal or generalized seizure activity require immediate anticonvulsant therapy (see Table 116-3 and Chapters 82, 88, and 166). Propofol (0.5 to 1 mg/kg IV bolus, then 0.05 to 0.1 mg/kg/min constant rate infusion) generally is recommended for rapid control of seizures resulting from

hepatoencephalopathy. More recently the use of levetiracetam has been shown to prevent postanesthetic seizures in dogs with porto-systemic shunts, so prophylactic loading and maintenance therapy now is performed commonly.25 Endotracheal intubation should be performed in patients that are hypoventilating because hypercap-nia further increases intracranial pressure. Animals that lose their gag reflex also should be intubated to protect the airway from aspira-tion. Mannitol therapy also may prove beneficial if cerebral edema is present (0.5 to 1 g/kg IV over 20 to 30 minutes), especially because cerebral edema is associated with herniation in people (see Chapter 84).1-3

The use of diazepam for the treatment of HE-associated seizures in animals is controversial. GABA and its receptors are implicated in the pathogenesis of HE, and the use of a benzodiazepine antagonist, such as flumazenil, has been proven beneficial in humans with HE-induced comas.8,9 Flumazenil therapy for HE has not been evalu-ated yet in veterinary patients, however.

Symptomatic therapy for patients with HE may include withhold-ing food, cleansing enemas with warm water and/or lactulose, oral lactulose therapy, and antimicrobial therapy.4-6,10 Antimicrobials such as metronidazole, neomycin, or ampicillin decrease GI bacterial numbers, thus reducing ammonia production. Metronidazole and ampicillin also help decrease the risk of bacterial translocation and systemic bacterial infections. However, neurotoxicity from

620 PART XII • INTRAABDOMINAL DISORDERS

static liver disease. It has antiinflammatory, immunomodulatory, and antifibrotic properties, as well as promoting choleresis and decreasing the toxic effects of hydrophobic bile acids on hepatocytes. This medi-cation is contraindicated in patients with biliary duct outflow obstruction until after the obstruction is relieved.

Zinc is an essential trace mineral involved in many metabolic and enzymatic functions of the body and is an important intermediary involved in enhanced ureagenesis, glutathione metabolism, copper chelation, and immune function. Zinc appears to have antifibrotic activities as well. Zinc deficiency occurs in many humans with liver disease, and this decrease seems to correlate with hepatic encepha-lopathy, demonstrating its importance in ureagenesis. Please refer to Chapter 88 and other sources for further explanation.26-29

PROGNOSIS

The prognosis for animals with hepatic failure is generally poor. Few published guidelines are established to predict outcome. Some factors suggested to be poor prognostic indicators include PT of greater than 100 seconds, very young or very old animals, viral or idiosyncratic drug reaction as the underlying cause, and a markedly increased bili-rubin.4 When a known hepatotoxin is involved, the use of an appro-priate antidote can improve survival markedly, although most do not have an antidote. Better survival rates likely are attained in a hospital where aggressive and intensive supportive therapy is available. The prognosis for hepatic failure associated with congenital portosys-temic shunting is considered good if the patient is medically managed appropriately and the shunt ultimately can be occluded.

FUTURE THERAPIES

People with severe HE are placed immediately on a liver transplant list, which may be an option for veterinary patients in the future. Substitution of hepatocytes with various forms of artificial liver support has been promoted over the past 10 years in human medi-cine. A multicenter randomized trial using a bio-artificial liver showed no benefit over traditional therapy while awaiting transplan-tation in overall outcome, although more advanced equipment is showing great promise. More recently research has shown the benefit of this modality, especially in acute-on-chronic liver failure.* This may be something for the future in veterinary medicine.

Over the past 5 years great advances have been made in the area of stem cell therapy for the treatment of liver failure in various animal models. Mesenchymal stem cells (MSC) have been used in veterinary medicine for osteoarthritis and kidney disease,31-33 with the goal of autogenous multipotent stem cells acting in a paracrine manner to improve the regenerative environment of an organ under-going inflammation, fibrosis, and necrosis. More recently the use of MSC for chronic and acute inflammatory liver disease in dogs is being investigated. Studies in mice have shown that undifferentiated MSC have the ability to improve hepatic function in mice with acute liver injury.34 In a rabbit model35 of acute-on-chronic liver failure, those who received adipose-derived MSC had improved biochemical parameters, histomorphologic scoring, and survival rates when com-pared with those that did not. This holds great promise for the future of veterinary medicine.

Overall, hepatic failure is a severe life-threatening disease that holds a poor prognosis. With aggressive intensive care, avid supportive therapy, and early diagnosis, the regenerative capacity will improve, as will the outcome.

metronidazole therapy may occur more commonly in animals with hepatic disease.

Symptomatic therapy is necessary for bleeding patients. Those with gastric ulceration should be treated with acid receptor blockade (H2 blocker, proton pump inhibitor, prostaglandin analog) and sucralfate (see Chapter 161). Recent evidence suggests that ranitidine may not be as effective as famotidine in reducing gastric acid in dogs.26 Coagulopathic patients with signs of active bleeding should be treated with fresh frozen plasma or fresh whole blood and subcu-taneous vitamin K1 (especially if the coagulopathy is thought to be due to cholestasis and fat malabsorption).4-6 Patients that are signifi-cantly anemic benefit from packed red blood cell or whole blood transfusions. If HE is evident, fresh whole blood is preferred because stored blood has increased levels of ammonia (see Chapter 61).

Ascites and hepatic fibrosis may be seen in patients with chronic, severe liver disease. If ascites is due to low oncotic pressure, then synthetic colloidal therapy should be considered (see Chapters 58 and 59). If the ascites is due to portal hypertension, the use of diuret-ics and a low-sodium diet should be considered. Spironolactone is the initial diuretic of choice for its aldosterone antagonism and sub-sequent potassium-sparing effects. Furosemide may be necessary as well but should be used with caution because it may potentiate hypo-kalemia. A number of drugs theoretically decrease connective tissue formation and may be helpful in patients with hepatic fibrosis (i.e., prednisone, D-penicillamine, and colchicines; see Table 116-3).4-6,23

Fluid therapy and nutritional support are the cornerstones of supportive therapy. Fluid therapy is indicated to maintain hydration and provide cardiovascular (and occasionally oncotic) support. Lac-tated Ringer’s solution often is avoided because of the need for hepatic conversion of lactate to bicarbonate. Supplementation with potassium and glucose often are required. Nutritional management is important in patients with acute and chronic liver failure, particu-larly cats with hepatic lipidosis. The diet should be readily digestible, contain a protein source of high biologic value (enough to meet the animal’s need, but not worsen HE), supply enough essential fatty acids, maintain palatability, and meet the minimum requirements for vitamins and minerals. Low-protein diets should be avoided unless HE is noted. Milk and vegetable proteins are lower in aromatic amino acids and higher in branched chain amino acids (valine, leucine, isoleucine) than animal proteins and are considered less likely to potentiate HE.4,6,23 In the patient with hepatic failure, total parenteral or partial parenteral nutrition should be considered if enteral intake cannot be tolerated (see Chapter 130). If the animal is not vomiting or regurgitating and temperature and systemic blood pressure are stable but the patient will not eat voluntarily, a feeding tube should be considered to allow for localized enterocyte nutrition (see Chapter 129).

Supportive nutraceutical therapy has been recommended for a variety of liver diseases. Drugs in this class include S-adenosylmethionine (SAMe), vitamin E, and milk thistle.26 SAMe has hepatoprotective, antioxidant, and antiinflammatory properties. It also serves as a precursor to the production of glutathione, which plays a critical role in detoxification of the hepatocyte. Vitamin E is another antioxidant and should be considered to prevent and mini-mize lipid peroxidation within the hepatocytes. Silymarin is the active extract in milk thistle. An abundance of in vivo animal and in vitro experimental data show the antioxidant and free radical scav-enging properties of silymarin.27 Specifically, it inhibits lipid peroxi-dation of hepatocyte and microsomal membranes. Silymarin increases hepatic glutathione content and appears to retard hepatic collagen formation.26

Ursodeoxycholic acid, another hepatoprotective medication, is recommended for most types of inflammatory, oxidative, and chole- *References 1-3, 8, 9, 28, 30.

CHAPTER 116 • HEPATIC FAILURE 621

19. Respess M, O’Toole TE, Taeymans O, et al: Portal vein thrombosis in 33 dogs: 1998-2011, J Vet Intern Med 26(2):230-237, 2012.

20. Center SA: Serum bile acids in companion animal medicine, Vet Clin North Am Small Anim Pract 23:625, 1993.

21. Berent A, Weisse C: Hepatic vascular Anomalies. In Ettinger SJ, Feldman ED, editor: Textbook of veterinary internal medicine: diseases of the dog and cats, ed 7, St Louis, 2010, Elsevier Saunders.

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