INTRODUCTION

Liver failure, also referred to as fulminant hepatic failure(FHF), is the ultimate common pathway of severe hepatocyte injury, regardless of the cause.^1-3 This condition can manifest as an acute (acute liver failure [ALF]) or chronic (chronic liver failure [CLF]) process. The loss of hepatic function leads to a spectrum of metabolic derangements. FHF is commonly defined by the onset of hepatic encephalopathy (HE) and coagulopathy. Other complications associated with FHF include gastrointestinal (GI) ulceration, bacterial sepsis, cardiopulmonary dysfunction, and ascites. Before the development of hepatic transplantation, humans with FHF had a mortality rate greater than 90%.^1,2 The liver is capable of regenerating 75% of its functional capacity in only a few weeks if the disease process is interrupted and therapy and supportive care are provided.

Common causes of liver disease that can result in FHF in dogs and cats are listed in Table 127-1.^4-6

Table 127-1 Etiology of Fulminant Hepatic Failure^4–6

	Dog	Cat
Infectious agents	Canine adenovirus-1 Acidophil cell hepatitis virus Canine herpes virus Clostridiosis Bartonellosis Leptospirosis Liver abscess Tularemia Hepatozoonosis Rickettsia rickettsii Histoplasmosis Coccidiomycosis Blastomycosis Leishmaniasis Toxoplasmosis Dirofilaria immitis Ehrlichia canis	Feline infectious peritonitis Clostridiosis Liver abscesses Histoplasmosis Cryptococcosis Toxoplasmosis Liver flukes
Drugs	Acetaminophen Aspirin Phenobarbital Phenytoin Carprofen Tetracycline Macrolides Trimethoprim-sulfa Griseofulvin Thiacetarsamide Ketoconazole, itraconazole Halothane	Acetaminophen Aspirin Diazepam Halothane Griseofulvin Ketoconazole, itraconazole Methimazole Methotrexate Phenobarbital Phenytoin
Chemical agents and toxins	Industrial solvents Plants (sago palm) Envenomation Heavy metals (copper, iron) Mushrooms (Amanita phalloides) Aflatoxins Blue-green algae Cycad seeds Carbon tetrachloride Dimethylnitrosamine Zinc phosphide	Same as for dogs
Miscellaneous	Chronic hepatitis, cirrhosis Idiopathic Copper storage disease Leptospirosis induced Idiosyncratic drug reaction Lobular dissecting hepatitis Granulomatous hepatitis Hepatic amyloidosis (Chinese Shar Pei) Hepatic neoplasia (primary or metastatic disease) Portosystemic shunting Portal venous hypoplasia/microvascular dysplasia (Yorkshire Terrier and Cairn Terrier)	Feline hepatic lipidosis Inflammatory bowel disease Pancreatitis Cholangitis, cholangiohepatitis Septicemia, endotoxemia Hemolytic anemia Neoplasia (lymphoma, mastocytosis) Metastasis Amyloidosis (Abyssinian, Oriental, and Siamese cats)
Traumatic, thermal, hypoxic	Diaphragmatic hernia Shock Liver torsion Heat stroke Massive ischemia	Same as for dogs

PATHOPHYSIOLOGY

The histologic changes in the liver of patients with ALF or CLF are variable, depending on the underlying disease process. Acute causes of liver disease are likely to display hepatocellular necrosis as the main lesion. Fat accumulation or hepatocellular drop-out may also be noted. Although a chronically diseased liver may also demonstrate hepatocellular necrosis, fibrosis and hyperplasia of ductal structures are often present.

All patients with FHF display common physiologic features, regardless of the cause. These include hypotension, poor oxygen uptake by muscle and peripheral tissues with associated lactic acidosis, electrolyte alterations, HE, and coagulopathy. Over time, dysfunction of multiple organ systems can occur. In humans renal failure is a common sequela to liver failure (hepatorenal syndrome),⁷ although this has rarely been described in veterinary patients.⁵

Hepatic Encephalopathy

HE, the hallmark feature of FHF, is a neuropsychiatric syndrome involving a gamut of neurologic abnormalities. The pathogenesis of HE is incompletely understood in both veterinary and human medicine. HE occurs when more than 70% of hepatic function is lost.^2,4,8-11 Multiple aspects of central nervous system (CNS) metabolism have been implicated in the pathophysiology of HE, and over 20 different compounds can be found in increased concentrations in the circulation when liver function is impaired (Table 127-2).^4,8,9,11,12 ALF 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 FHF, and 33% of those patients develop fatal herniation.^3,8,9 It is theorized that combinations of synergistic events and complex metabolic derangements occur in animals or humans with hepatic insufficiency and are responsible for the variable neurologic signs seen. Contributing factors include systemic toxins (see Table 127-2), metabolic derangements (hypoglycemia, dehydration, azotemia, hypokalemia, hyponatremia alkalemia), ingestion of a high-protein diet, GI ulceration, stored red blood cell transfusions constipation, and drug therapy (sedatives, analgesics, benzodiazepines, antihistamines). These factors, in addition to altered permeability of the blood-brain barrier, will impair cerebral function in variable ways^4,8,9 (see Chapter 103, Hepatoencephalopathy).

Table 127-2 Toxins Implicated in Hepatic Encephalopathy^4,6,8-12

Toxins	Mechanisms Suggested in the Literature
Ammonia	Increases brain tryptophan and glutamine levels Brain edema Decreases ATP availability Increases excitability Increases glycolysis Decreases microsomal Na,K⁺-ATPase in brain
Decreased α-ketoglutaramate	Diversion from Krebs cycle for ammonia detoxification Decreases ATP availability
Glutamine	Alters blood-brain barrier amino acid transport
Aromatic amino acids	Decreases dopa neurotransmitter synthesis Alters neuroreceptors Increases production of false neurotransmitters
Short chain fatty acids	Decreases microsomal Na,K⁺-ATPase in brain Uncouple oxidative phosphorylation Impairs oxygen utilization Displaces tryptophan from albumin, increasing free tryptophan Increases free tryptophan
False Neurotransmitters
Tyrosine → octopamine	Impairs norepinephrine action
Phenylalanine → phenylethylamine	Impairs norepinephrine action
Methionine → mercaptans	Synergistic with ammonia and short chain fatty acids Decreases ammonia detoxification in brain urea cycle GIT derived (fetor hepaticus [breath odor in HE]) Decreases microsomal Na,K⁺-ATPase
Tryptophan	Directly neurotoxic Increases serotonin Neuroinhibition
Phenol (from phenylalanine and tyrosine)	Synergistic with other toxins Decreases cellular enzymes Neurotoxic and hepatotoxic
Bile acids	Membrane cytolytic effects alter cell membrane permeability Blood-brain barrier more permeable to other HE toxins Impairs cellular metabolism due to cytotoxicity
GABA	Neural inhibition: hyperpolarize neuronal membrane Increases blood-brain barrier permeability to GABA
Endogenous benzodiazepines	Neural inhibition: hyperpolarize neuronal membrane

ATP, Adenosine triphosphate; GABA, γ-aminobutyric acid; GIT, gastrointestinal tract; HE, hepatic encephalopathy; Na,K⁺-ATPase, sodium-potassium adenosine triphosphatase.