Acute Hepatic Failure

Symposium on Liver Diseases

Acute Hepatic Failure Robert C. Sherding, D. V.M. *

Acute hepatic failure occurs whenever there is a sudden, severe disturbance of normal hepatic function. The clinical manifestations and laboratory features of acute liver failure are generally quite consistent and predictable; yet, they are nonspecific and reflect the general failure of liver function rather than an underlying diagnosis or etiology. The functions of the liver are essential to life and include synthesis of plasma proteins and clotting factors; metabolism of carbohydrate, lipid, and amino acids; detoxification and/or excretion of drugs and toxins; and formation and elimination of bile. The manifestations of acute hepatic failure reflect a catastrophic compromise in these vital processes. Injury or disease of the liver must be extensive, impairing 70 to 80 per cent of hepatocellular mass, before exceeding the liver's functional reserve capacity and causing overt hepatic failure . ETIOLOGY

The hepatocyte is susceptible to damage, injury, or degeneration caused by a wide variety of etiologic agents (Table 1). Acute hepatic failure may be produced by injurious hepatotoxins, drugs, infectious agents, or metabolic disturbances. In many cases, however, the specific inciting cause is not determined, so that the liver disease can only be categorized using descriptive histopathologic characteristics such as acute necrosis, acute hepatitis, steatosis, and so on . Acute, widespread hepatic necrosis is the lesion that most consistently produces acute hepatic failure. In addition, what may seem to be acute failure may not always actually be due to an acute disease of the liver. Because, in occult chronic liver disease, the signs are vague and rarely evident until the disease is advanced, the final phase of hepatic decompensation may seem to be fulminant hepatic failure of acute onset.

* Diplomate,

American College of Veterinary Internal Medicine; Associate Professor and Head of Small Animal Medicine, Department of Veterinary Clinical Sciences, Ohio State University College of Veterinary Medicine, Columbus, Ohio

VP.tp-rinam Clinics of North America: Small Animal Practice-Vol. 15, No.1 , January 1985

119

120

ROBERT

Table 1.

G.

SHERDING

Etiologies of Acute Hepatic Failure MISCELLANEOUS INFECTIOUS AND

EXTRAHEPATIC

HEPATOTOXINS

PARASITIC AGENTS

DISORDERS

Chemicals Arsenic Carbon tetrachloride Chlordane Chlorinated hydrocarbons, naphthalenes, biphenyls Chloroform Dieldrin Dimethylnitrosamine Metals-copper, iron, mercury Phosphorus Selenium Tannic acid

Viral Infectious canine hepatitis (adenovirus) Canine herpesvirus Feline infectious peritonitiS (coronavirus)

Acute pancreatitis Colitis (inflammatory bowel disease) Acute hemolytic anemia

Anesthetics Methoxyflurane Halothane

Bacterial Gram-negative septicemia! endotoxemia Salmonella sp. Clostridia sp. Leptospira (L. canicola, L. icterohemorrhagiae) Bacillus pili/ormis (Tyzzer's disease) Mycotic (histoplasmosis, coccidioidomycosis, blastomycosis, etc.)

Protozoal (toxoplasmosis) Drugs Acetaminophen (feline) Heartworm -associated Anticonvulsants (postcaval syndrome) (phenytoin, primidone) Aprindine Ketoconazole Mebendazole Methotrexate Phenazopyridine (feline) Tetracycline Thiacetarsamide Tolbutamide Trimethoprimsulfadiazine Biologic substances Aflatoxin Blue-green algae endotoxin Amanita mushroom toxin Bacterial endotoxin

Hepatotoxins

Chemical-induced injury of the liver may lead to hepatocellular necrosis or degeneration (fatty infiltration, for example) and cause acute hepatic failure. Many substances have the potential to induce hepatic damage (see Table 1), including hepatotoxic chemicals, drugs, and biologic substances (for example, aflatoxins, algae toxins, poisonous mushrooms, and bacterial endotoxins). When the damage is severe and widespread, death from fulminant hepatic failure usually occurs within 3 to 4 days after exposure; in other cases, however,

ACUTE HEPATIC FAILURE

121

long-term, low-level exposure to a hepatotoxin may lead insidiously to chronic liver disease and cirrhosis . The hepatotoxicity of compounds such as carbon tetrachloride and drugs such as thiacetarsamide sodium is predictable and well established, whereas the liver injury associated with many other substances is idiosyncratic. In contrast to the toxicity of chemicals and drugs that are intrinsically hepatotoxic, idiosyncratic reactions are not time- or dose-dependent and they are unpredictable, causing liver injury in a rare individual within an exposed population. 9 The cause and effect relationship between liver failure and drug or toxin exposure is generally difficult to establish, often making the diagnosis of hepatotoxicity a circumstantial one . Chemical-induced Liver Injury. Many industrial chemicals, organic solvents, pesticides, and metals have been associated with acute hepatotoxicity; these substances include arsenic, copper, iron, mercury, selenium, phosphorus, chloroform, chlordane, carbon tetrachloride, chlorinated hydrocarbons, chlorinated naphthalenes, chlorinated biphenyls, dimethylnitrosamine, dieldrin, and tannic acid. 9,26 Exposure to hepatotoxic chemicals may be rapidly fatal in some animals; in other animals, however, the hepatic injury resolves and recovery is complete. The outcome of exposure is influenced by individual susceptibility, nutritional status of the animal, preexisting health of the liver, type of toxin, and dose and duration of exposure . 9 Anesthetic-induced Liver Injury. Halogenated inhalation anesthetics are associated with hepatitis-like idiosyncratic reactions in humans. 5 In dogs, icterus and fatal hepatic failure due to fulminant hepatic necrosis have been attributed to methoxyflurane* in two case reports 17,29 and to halothane in another.8 However, the association between postoperative hepatic failure and an anesthetic must be considered speculative. Anesthetic-induced liver injury is essentially indistinguishable from other perioperative hepatopathies caused by hypoxic-ischemic injury, endotoxemia, infection, surgical trauma, other drugs, or the combined effects of several of these mechanisms . Drug-induced Liver Injury. Therapeutic agents are probably an under-recognized cause of liver failure in animals, although associations between drugs and liver damage are being established as awareness of this potential mechanism of liver injury increases . In humans, it has been estimated that 25 per cent of cases of acute hepatic failure are associated with drug reactions. 9 Drugs that have been associated with adverse drug reactions that primarily involve the liver and were reported to the Bureau of Veterinary Medicine Drug Surveillance Program are listed in Table 2.2 Icterus and serum liver enzyme elevations are well-known complications of thiacetarsamide sodium, t the arsenical used to treat heartworms. Acute hepatic failure, which is characterized by vomiting, icterus, anorexia, depression, biochemical evidence of liver

* Metofane. t Caparsolate. Abbott Laboratories, North Chicago, Illinois.

122

ROBERT

Table 2.

G.

SHERDING

Adverse Drug Reactions Involving the Liver*

DRUG

REPORTED ADVERSE REACTION

Aspirin Butamisole Diethylcarbamazine Glycobiarsol Ketamine Mebendazole Mibolerone Phenylbutazone Phenytoin Prednisolone Primidone Thiacetarsamide

Hepatitis Icterus Icterus Icterus Fatty liver Abnormal liver function tests Icterus, elevated liver enzymes Elevated liver enzymes Hepatotoxicity Elevated liver enzymes Icterus, liver failure Icterus, elevated liver enzymes

* Reported

to the Bureau of Veterinary Medicine Drug Surveillance Program. 2

damage, and hepatic necrosis, has been associated with the anthelmintic, mebendazole, * in numerous dogs. 9,22,27,31 Anticonvulsants, particularly primidone and phenytoin, cause elevated serum levels of hepatic enzymes in dogs. 13 Acute fatal hepatic necrosis with icterus, vomiting, and serum liver enzyme elevations was described in a dog shortly after the addition of phenytoin to a long-term primidone regimen. 16 This resembled the acute phenytoin-induced hepatic injury that sometimes occurs early in the course of therapy in humans and is thought to represent a hypersensitivity drug reaction. 15 Fatal subacute hepatic necrosis characterized by icterus, ascites, hepatic encephalopathy, and coagulopathy was reported after a 13-week course of methotrexate in a dog. 23 Nonfatal hepatocellular injury and icterus have been associated with the use of trimethoprim-sulfadiazine in two dogs. 1,30 Parenteral tetracycline has caused acute fatal hepatotoxicity characterized by fatty infiltration of the liver in the pregnant bitch, but not in the male or nonpregnant female. 7 Tolbutamide, an oral hypoglycemic agent for human diabetics, is hepatotoxic for dogs. 33 Aprindine Hel, an experimental antiarrhythmic drug used for control of ventricular arrhythmias, caused hepatotoxicity in a dog after 14 days of oral therapy that was characterized by markedly elevated serum liver enzymes that returned to normal 5 days after cessation of the drug. 14 Acetaminophent 25 and the urinary analgesic, phenazopyridine,lo are hepatotoxic for the cat. The au~hor has received several unconfirmed reports of icterus and serum hepatic enzyme elevations associated with ketoconazole,:j: which is an oral antifungal drug used to treat systemic mycoses. Aflatoxicosis. Mycotoxins are metabolites of ubiquitous, toxinproducing saprophytic fungi that can grow on animal feeds under

* Telmin.

Pitman-Moore, Inc., Washington Crossing, New Jersey.

t Tylenol. McNeil, Fort Washington, Pennsylvania. :j: Nizoral. Janssen pharmaceutica, Inc. , Piscataway, New Jersey.

ACUTE HEPATIC FAILURE

123

certain optimal conditions . 18,21 Various mycotoxins affect specific target organs. An aflatoxin produced by Aspergillus flavus has a special affinity for the liver and has reportedly been a contaminant of dog-food ingredients such as corn and peanut meal. The toxic hepatitis of acute aflatoxicosis is characterized by anorexia, icterus, polyuria and polydipsia, coagulopathy (melena), and death. 18,21 Toxin-producing Algae. Freshwater blue-green algae (especially Anabaena sp.) which are found on the surfaces of shallow ponds, lakes, and sewage lagoons can produce endotoxin-like substances that cause gastrointestinal and fatal hepatotoxicity. Algae poisoning occurs when animals ingest contaminated water, particularly in spring and summer when favorable conditions promote prolific growth of blue-green algae (algae "blooms").6,20 Mushroom Poisoning. Mushroom poisoning in small animals results mostly from the Amanita genus of fungi, which grows abundantly in pastures and wooded areas in warm, humid climates. Acute gastrointestinal signs of vomiting, diarrhea, and abdominal pain are followed by a severe toxic hepatitis, which may be fatal. 11,20 Bacterial Endotoxin-induced Liver Injury. Circulating bacterial endotoxins, originating endogenously from the intestinal lumen or major bacterial infection of any body system, may cause severe hepatic dysfunction as a result of hepatocellular injury (necrosis, steatosis) or may produce functional change, such as intrahepatic cholestasis. The liver itself is an essential organ for detoxification of endotoxin. Failure to detoxify endotoxin may initiate or perpetuate liver injury and may contribute to the extrahepatic manifestations of hepatic failure. 19 The diagnosis of endotoxin-induced liver injury is difficult to establish clinically but should be considered when hepatic dysfunction responds to (1) antibiotic control of bacterial sepsis or extrahepatic infection, (2) the use of nonabsorbable intestinal antibiotics, or (3) the use of intestinal endotoxin adsorbers such as cholestyramine.

Acute Hepatic Failure Due to Infectious Agents

Viral Hepatic Disease. The fulminating form of infectious canine hepatitis (ICH), which is due to canine adenovirus I, is characterized by acute hepatic necrosis, widespread vasculitis , and severe disseminated intravascular coagulation (DIC).32 In addition to clinical features of acute hepatic failure, common manifestations include fever, leukopenia, proteinuria, and generalized bleeding diathesis. The widespread use of modern immunizing agents has made fulminant ICH an uncommon cause of acute hepatic failure. Canine herpesvirus is the only other known viral hepatic disease of dogs. In the cat, liver failure may result from necrotizing pyogranulomatous hepatitis caused by the feline infectious peritonitis (FIP) coronavirus. Bacterial Hepatic Disease.' Generalized sepsis and severe nonhepatic infections with gram-negative bacteria may be complicated by icterus and hepatic necrosis. Hepatic dysfunction may be caused

124

ROBERT

C.

SHERDING

by direct invasion of liver parenchyma by organisms or by structural or functional changes induced by circulating bacterial endotoxins . 34 Salmonella sp. will occasionally invade the liver during septicemic episodes. Anaerobes, especially Clostridia sp., are normally present within the liver; however, they may proliferate to pathologically significant levels under hypoxic conditions of liver ischemia.9 Leptospira canicola and L. icterohemorrhagiae are important primary invaders of the liver. Canine leptospirosis is typically manifested clinically by acute hepatitis (icterus and elevated serum hepatic enzymes), renal failure, leukocytosis, and fever. Tyzzer's disease is a highly fatal infection in dogs and cats that is characterized by acute multifocal hepatic necrosis accompanied by severe necrotizing enterocolitis. 12,24 This rare condition is caused by Bacillus pilijormis, a gram-negative fusiform bacteria mostly carried by rodents. Mycotic Liver Disease. Liver failure may result from acute or chronic pyogranulomatous hepatitis caused by one of the systemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis). Liver involvement may be the most prominent manifestation of a systemic mycosis, or it may be overshadowed by extrahepatic manifestations (for example, pulmonary, intestinal, ocular, cutaneous, or central nervous system involvement). Toxoplasma Liver Disease. The rapidly multiplying tachyzoite stage of the protozoan parasite, Toxoplasma gondii, may cause acute liver failure that is due to hepatic invasion and acute pyogranulomatous hepatitis with multifocal necrosis. Toxoplasmosis occurs more often in the cat, and hepatic involvement is usually associated with simultaneous invasion of other tissues, such as the lung, eye, and central nervous system. Heartworm-associated Acute Liver Failure. Canine dirofilariasis occasionally leads to acute fatal hepatic failure accompanied by DIC and intravascular hemolysis-a condition called the postcaval syndrome. Occlusion of the postcava by adult heartworms and severe congestion of the liver are found at necropsy. Miscellaneous Extrahepatic Disorders Associated with Acute Hepatic Failure

Acute Pancreatitis. Acute pancreatitis in the dog is frequently associated with hepatocellular injury, icterus, and marked elevation of serum liver enzymes. 9,26 Mechanisms of secondary liver damage are (1) obstruction of the adjacent bile duct by peripancreatic inflammation, and (2) release of enzymes, endotoxin, vasoactive substances, and other toxic substances from the inflamed pancreas into the portal circulation and local lymph system. 26 Colitis. Acute hepatic necrosis has been associated with inflammatory large bowel disease in the dog. 26 The pathogenesis has been speculated to involve absorption of injurious substances-for example, bacteria, endotoxins, dietary substances, tissue toxins, and immune complexes-through the damaged colonic mucosa. 26 Hemolytic Anemia. Acute hemolytic anemia, especially au-

ACUTE HEPATIC FAILURE

125

toimmune hemolytic anemia, is frequently accompanied by secondary centrilobular hepatic necrosis with sinusoidal thrombosis . 28 Icterus and serum liver enzyme elevations may be seen. The postulated mechanism of hepatic injury is acute hypoxia.

CLINICAL RECOGNITION AND DIAGNOSIS The clinical findings in acute hepatic failure tend to be vague and nonspecific, reflecting general liver dysfunction rather than a specific diagnosis. It can be a challenge to even recognize that illness is due to liver failure until the results of laboratory evaluation (such as a serum chemistry profile) are available, because many of the clinical signs are 'not specific for liver disease and can be associated with many other disorders of other body systems. A clinically useful approach to follow in acute hepatic failure is a stepwise scheme. The first step is to determine if liver disease is present and if it is acute or chronic through the evaluation of history, physical examination, routine laboratory tests (for example, serum chemistries , complete blood count, urinalysis), and abdominal radiography (to assess liver size). The determination of chronicity has implications for therapy and prognosis. Because recovery is possible after acute liver injury, the prognosis may be better for acute hepatic failure; early intensive supportive therapy is indicated to sustain the animal long enough to allow recovery from the initial crisis. The second step is to categorize the disorder as primarily cholestatic or hepatocellular using various liver function tests. This categorization will help suggest potential etiologies and direct the clinician toward further diagnostic tests and procedures. As a general guide, liver disease that is predominantly cholestatic is characterized by a disproportionately large elevation of serum alkaline phosphatase that is accompanied by a lesser elevation of serum alanine aminotransferase (ALT, SGPT); acute massive hepatocellular injury, however, has a greater likelihood of marked increase in serum ALT. The clinician must bear in mind that this distinction is very imprecise. The third step is to determine a definitive etiologic or histopathologic diagnosis using specific diagnostic tests (for example, appropriate serologic titers for infectious disease) or liver biopsy. Liver biopsy is usually required to determine the cause and prognosis in most cases of acute hepatic failure. The final step in management of hepatic failure is treatment. In acute hepatic failure, however, supportive therapy and nonspecific treatment measures that are discussed later in this article are instituted initially as the first priority of management. This sustains the animal while definitive diagnosis is pursued in order to eventually determine if specific therapy is available. History and Clinical Signs The typical presenting history (Table 3) for acute hepatic failure is acute onset of anorexia, depression, vomiting, and diarrhea. Poly-

126

ROBERT

Table 3.

G.

SHERDING

Clinical Features of Acute Hepatic Failure

HISTORICAL FINDINGS (ACUTE ONSET)

FINDINGS OF PHYSICAL EXAM

Anorexia

Hepatomegaly

Depression

Hepatodynia

Vomiting

Icterus

Diarrhea

Pigmented urine

Polyuria and Polydipsia

Bleeding diathesis Petechiae and ecchymoses Hematemesis and melena Hematuria Pallor (anemia)

Jaundice (sclerae, skin, membranes) Pigmented urine Bleeding Tendency (gastrOintestinal, skin, urine) Encephalopathy Alteration of consciousness Personality changes Motor disturbances Seizures

Encephalopathy Depression and stupor Dementia and disorientation Pacing, circling, head-pressing Seizures

uria and polydipsia are also common. Signs of hepatic encephalopathy, which include alterations of consciousness, personality changes, motor abnormalities, seizures, and transient blindness, may be seen with severe hepatic failure . Because hyperbilirubinemia and bilirubinuria occur frequently in severe acute hepatic failure, the observant owner may notice pigmented urine (dark or orange-colored) or jaundiced sclerae, skin, and mucous membranes. In those occasional animals with abnormalities of hemostasis, the owner may observe bleeding tendencies, such as gastrointestinal bleeding (hematemesis, melena), hematuria, or cutaneous hemorrhages. In addition, key aspects of patient history for the animal that is suspected to be in acute liver failure are the following: 1. 2. 3. 4. 5.

Recent drug therapy (especially those drugs listed in Tables 1 and 2) Recent anesthetic procedures Exposure to toxins, particularly those categories listed in Table 1 Vaccination status (because of ICH and leptospirosis) Geographic location or potential for exposure to infectious diseases such as the systemic mycoses, toxoplasmosis, FIP, salmonellosis, Tyzzer's disease, and heartworms.

It is also important not to overlook signs of extrahepatic or systemic disease. These signs often provide important diagnostic clues in liver failure associated with septicemia and endotoxemia, pancreatitis, hemolytic disease, and many of the infectious diseases.

Physical Examination Findings of the physical examination of an animal in acute hepatic failure (see Table 3) are sometimes minimal; however, many animals manifest icterus, pigmented urine (bilirubinuria), bleeding diathesis (hematemesis, melena, hematuria, petechiae and ecchymoses, pallor due to blood loss anemia), and hepatic encephalopathy

ACUTE HEPATIC FAILURE

127

(depression, stupor, dementia, disorientation, ataxia, weakness, pacing, circling, head-pressing, intermittent blindness, seizures) . Liver palpation may sometimes elicit pain (hepatodynia) in acute disease of the liver, and hepatomegaly is a feature of infiltrative diseases (inflammation, steatosis, neoplasia), congestion, or cholestasis (bile engorgement). Clinical features that tend to be more suggestive of chronic, rather than acute, liver disease are a protracted clinical course, emaciation (malnutrition), ascites or edema (hypoalbuminemia), and microhepatica (liver atrophy or cirrhosis). Extrahepatic physical findings may be very helpful in the diagnosis. Some notable examples include the signs of renal failure that are seen with the concurrent renal involvement of leptospirosis; the uveitis that may be seen with certain systemic infectious diseases (FIP, toxoplasmosis, mycotic infections, for example); the pulmonary involvement that may be seen in some disorders (mycotic infections, toxoplasmosis, heartworms, for example); the extreme pallor of hemolytic anemia; and the various features of pancreatitis when associated with liver failure. In addition, liver failure secondary to sepsis or endotoxemia should be suspected whenever coexistent septicemia, major bacterial infection of any body tissue, or severe enteric disease (for example, parvoviral enteritis) are found. Laboratory Evaluation The potential abnormal laboratory parameters in acute hepatic failure and their clinical interpretations and correlations are presented in Table 4. A substantial elevation of serum alanine aminotransferase (ALT, SCPT), which is a cytoplasmic enzyme of the hepatocyte, is the most consistent finding in severe acute hepatocellular injury or necrosis. 26 In experimental canine studies, for example, fulminant ICH infection elevated serum ALT (SCPT) to greater than 1600 IU per L within 4 d ays 32, whereas serum ALT (SCPT) increased 20- to 50-fold within the first 24 hours after hepatotoxin-induced necrosis. 26 Increased serum ALT correlates somewhat with the morphologic findings in the initial period following hepatocellular injury; however, the serum enzyme elevation may subsequently persist or decline in the days that follow despite the persistence of extensive necrosis. 26 Several other enzymes that are similar, but less liverspecific, such as aspartate aminotransferase (AST, SCOT), tend to parallel the ALT (SCPT) in acute hepatic failure. Another enzyme, alkaline phosphatase (AP), is released from the liver at an increased rate during cholestasis; thus, serum AP concentration usually also is increased in acute hepatic injury. 9 Widespread hepatic necrosis often leads to cholestasis and icterus. Consequently, laboratory findings may include hyperbilirubinemia (typically a mixture of conjugated and unconjugated types) and increased urine bilirubin or the presence of bilirubin crystals in the urine. Abnormalities of hemostasis can occur in acute hepatic failure,

128

ROBERT

Table 4. LABORATORY PARAMETER

Red blood cells (RBC) RBC morphology RBC count

G.

SHERDING

Potential Abnormal Laboratory Parameters in Acute Hepatic Failure ABNORMALITY

CORRELATION

Target cells, acanthocytes Liver disease Anemia Blood loss (coagulopathy, gastrointestinal ulcer)

Serum chemistries Alanine aminotransferase Increased

Hepatocellular injury or necrosis

(ALT, SGPT)

Alkaline phosphatase Bilirubin Glucose

Increased Increased Decreased

Potassium Albumin

Decreased Decreased

Cholesterol

Decreased Increased

Cholestasis Cholestasis Hypoglycemia (severe liver disease) Hypokalemic alkalosis Hypoalbuminemia (suggests chronicity) Hepatocellular disease or failure Cholestasis

Acid-base status

pH, HC0 3 , PaC0 2

Metabolic and respiratory alkalosis

Ammonia challenge

Ammonia intolerance

Hepatic encephalopathy (severe liver failure)

BSP retention

Increased

Severe hepatic uptake/excretory failure

Dilute Increased Absent Bilirubin Ammonium biurate

Compatible with liver disease Cholestasis Extrahepatic cholestasis Cholestasis Hepatic encephalopathy (severe liver failure)

Hemostasis APTT

Prolonged

OSPT

Prolonged

Platelets FDP

Decreased Increased

Coagulopathy (factor deficiency, DIC, etc.) Coagulopathy (factor deficiency, DIC, etc.) DIC DIC

UrinalYSiS Specific gravity Bilirubin Urobilinogen Crystals

although only occasionally are they clinically significant. A variety of mechanisms are considered to be responsible, including DIe, failure of the liver to synthesize clotting factors, failure of the liver to remove activated clotting factors and fibrin degradation products, and liverinduced imbalance between activators and inhibitors of fibrinolysis . The abnormal coagulation tests-prothrombin time (OSPT) and activated partial thromboplastin time (APTT) and clotting factor abnormalities in dogs with liver disease have been described. 3,4 Laboratory features of hepatic encephalopathy are usually not apparent until liver failure is extremely severe. Resting hyperammonemia and intolerance to oral ammonia challenge may be found.

129

ACUTE HEPATIC FAILURE

Table 5.

Ancillary Diagnostic Evaluations Used to Diagnose Acute Hepatic Failure Due to Extrahepatic or Multisystemic Disease

DIAGNOSTIC EVALUATION

INTENDED DIAG N O SIS ("RULE- OUT")

Bacterial cultures Liver/bile Blood, feces, infected tissues

Bacterial invasion of the liver Sepsis , endotoxemia

Serology (antibody titers)

Mycoses (histoplasmosis, coccidioidomycosis, blastomycosis) Toxoplasmosis Leptospirosis Feline infectious peritonitis (FIP)

Urine darkfield exam (for spirocheturia)

Leptospirosis

Lymph node aspiration cytology

Mycoses Lymphoid neoplasia

Thoracic radiography

Mycoses Toxoplasmosis Heartworm disease

Microfilaria exam

Heartworm disease

Serum amylase and lipase

Acute pancreatitis

Abdominal ultrasound

Pancreatic disease Hepatic abscess or neoplasia Biliary or gall bladder disease

Coomb's Test

Autoimmune hemolytic anemia

Ammonium biurate crystals may rarely be seen in the urine . It has been found that plasma concentrations of most amino acids increase markedly during acute hepatic necrosis with hepatic failure, although branched-chain amino acids increase to a lesser degree and arginine decreases. 26 Other potential findings in severe hepatic failure include hypoglycemia, abnormal BSP retention, hypokalemia, respiratory and metabolic alkalosis, and decreased serum albumin and cholesterol, although both of these are more likely to decrease in chronic liver failure. The complete blood count may reveal blood loss anemia from coagulopathy or bleeding gastrointestinal ulcers. Circulating red blood cells in liver disease may develop morphologic abnormalities such as acanthocytosis and target cell formation . Another goal of the diagnostic evaluation of acute hepatic failure is to determine if the liver disease is associated with a multisystemic disorder or is secondary to an underlying extrahepatic disease. Ancillary diagnostic tests for this purpose are listed in Table 5. Liver Biopsy Liver biopsy can be very helpful for diagnosis and prognosis of acute liver failure . Four methods of biopsy procurement are percutaneous needle biopsy (Menghini, Tru-Cut), key-hole needle biopsy (Tru-Cut), laparoscopy, and laparotomy. The biopsy specimen should

130

ROBERT

C.

SHERDING

at least be examined by routine histopathology. Impression smears and cultures of the specimen can be taken for bacteria or fungi, special stains can be used to detect organisms or abnormal liver constituents, toxin analysis can be performed, and electron microscopy may be helpful under special circumstances. TREATMENT The objectives of therapy of acute hepatic failure are (1) to eliminate the inciting cause (if known) or predisposing factors, (2) to provide optimum conditions for hepatic regeneration, and (3) to prevent or control complications. Circumstances in which it is possible to direct specific therapy at the inciting cause are the exception. However, one obvious situation in which this is plausible is one in which drug-induced hepatic injury is suspected; in this situation, the treatment is withdrawal of the offending drug. Another notable situation is one in which a treatable infection is associated with hepatic failure; in this situation, an appropriate antibiotic or antifungal agent can be instituted. For example, penicillin and streptomycin are indicated for leptospirosis, and amphotericin Band ketoconazole are recommended for systemic mycoses. In many cases of acute hepatic failure, the inciting cause is unknown, or no definitive treatment is available once the cause is found . Therefore, therapy is first directed at general support of fluid balance and metabolism (Table 6). Rehydration is followed by administration of maintenance intravenous fluids (0.9 or 0.45 per cent sodium chloride) supplemented with dextrose (to yield a 2.5 to 5 per cent solution) and potassium chloride (10 to 15 mEq per 500 ml of maintenance fluids). In acute hepatic failure, fluid therapy supports hepatic microcirculation, aids in elimination of hepatotoxins, and helps to prevent complications such as shock, DIC, and renal failure. Dietary modification, which helps to promote liver regeneration and prevent hepatic encephalopathy, is based on protein and fat restriction, a source of protein with low encephalopathic potential (for example, cottage cheese, Prescription Diets kid or u/d*), high carbohydrate intake, and supplementation of B-complex and fat-soluble vitamins (A, D, E, K). In those cases with frequent vomiting, complete restriction of oral intake may be required initially. Rest and confinement also facilitate recovery. 9 The other major therapeutic goal that is generally applicable to any animal in acute hepatic failure is early recognition and prompt therapy of complications such as hepatic encephalopathy, hypoglycemia, acid-base and electrolyte disturbances, bleeding diathesis, gastric ulcer, and sepsis and endotoxemia (see Table 6). Intravenous

* Hills

Pet Products, Inc., Topeka, Kansas.

131

ACUTE HEPATIC FAILURE

Table 6.

General Therapy of Acute Hepatic Failure

THERAPEUTIC GOAL

THERAPEUTIC REGIMEN

Rest and confinement

Until liver regeneration is underway

Fluid therapy 1. Maintain hydration 2. Prevent hypokalemia 3. Prevent hypoglycemia Control hepatic encephalopathy 1. Avoid central nervous system depressants (e.g:, anticonvulsants, tranquilizers, sedatives, anesthetics) 2. Prevent formation and absorption of encephalopathic toxins

3. Dietary restriction (low-protein, low-fat, high-carbohydrate) 4. Control gastrointestinal hemorrhage

0.9 or 0.45% NaCI, intravenously Add 10 to 15 mEq KCl to each 500 ml of intravenous maintenance fluids Monitor serum potassium daily Add dextrose to intravenous maintenance fluids to make 2.5 to 5% solution Use phenobarital at reduced dose if an anticonvulsant is required Cleansing enemas every 6 hours Neomycin (10 to 20 mg per kg, orally every 6 hours) Lactulose (10 to 30 ml, orally, every 6 hours) Or, in coma use retention enemas: Neomycin (15 mg per kg) Lactulose diluted 1:2 in water (50 to 200 ml dose) Cottage cheese, kid or u/d No meats Correct coagulopathies Rx gastrointestinal parasites Rx gastric ulcers (cimetidine)

Control coagulopathy

Vitamin K[ (5 to 20 mg, intramuscularly, every 12 hours) Fresh plasma (or blood) transfusion For DIC: heparin (5 to 10 fJ,/kg, subcutaneously, every 8 to 12 hours)

Control gastric ulcers

Cimetidine (5 to 10 mg per kg, orally or intravenously, every 8 hours)

Control infection and endotoxemia

Systemic: antibiotics (penicillin, ampicillin, cephalosporins, gentamicin, kanamycin, etc.) Enteric: antibiotics (neomycin) and toxin binder (cholestyramine)

administration of maintenance electrolyte solution supplemented with dextrose and potassium chloride as has already been mentioned will stabilize fluid, electrolyte, and acid-base balance and prevent hypoglycemia. The details of therapy to control hepatic encephalopathy are discussed in other articles in this symposium. Central nervous system depressants (anticonvulsants, tranquilizers, sedatives, anesthetics) should be avoided, for they may potentiate hepatic coma. If an anticonvulsant is required to control seizures, a low dose of phenobarbital is suggested . The formation and absorption of enteric encephalopathic toxins (ammonia, for example) is reduced by lactulose (10 to 30 ml, four times a day) and neomycin (10 to 20 mg per kg,

132

ROBERT

G.

SHERDlNG

four times a day) given orally or by retention enema. Metronidazole has also been used. Protein in the diet should be restricted to reduce the nitrogenous substrate for encephalopathic toxins. Simple and effective diets have been based on cottage cheese or Prescription Diets (kid or u/d). Gastrointestinal bleeding, another source of nitrogenous substrate, should be prevented by correcting overt coagulopathies, eradicating gastrointestinal parasites, and controlling liver-associated gastric ulcers with cimetidine (Tagamet) at 5 to 10 mg per kg, three times a day. Overt bleeding due to coagulopathy is uncommon in liver failure. If it occurs, vitamin Kl (5 to 20 mg, intramuscularly, twice a day) and a fresh plasma or blood transfusion can be given to replenish clotting factors. If DIC is the cause of bleeding, low-dose heparin therapy can be used cautiously. Gastric ulcers are often found in animals with liver failure. The pathogenesis is incompletely understood. Bleeding gastric ulcers may contribute to vomiting and hematemesis and melena seen in liver failure. The treatment is cimetidine (Tagamet). Infection (sepsis) and endotoxemia may be associated with acute hepatic failure, as discussed previously. These manifestations should be controlled with appropriate antibiotics. Oral cholestyramine can be used to nonspecifically bind enterotoxin within the gut lumen. REFERENCES 1. Anderson, W. I., Campbell, K. L., Wilson, R. C., et al.: Hepatitis in a dog given sulfadiazine-trimethoprim and cyclophosphamide. Mod. Vet. Pract. 65:115, 1984. 2. Aronson, A. L., and Riviere, J. E.: Adverse drug reactions. In Kirk, R. W. (ed.): Current Veterinary Therapy VIII. Philadelphia, W. B. Saunders Co., 1983, p. 122. 3. Badylak, S. F., Dodds, w. J., and Van Vleet, J. F.: Plasma coagulation factor abnormalities in dogs with naturally occurring 'hepatic disease. Am. J. Vet. Res., 44:2336-2339, 1983. 4. Badylak, S. F., and Van Vleet, J. F.: Alterations of prothrombin time and activated partial thromboplastin time in dogs with hepatic disease. Am. J. Vet. Res., 42:2053-2056, 1981. 5. Cooperman, L. H ., Wollman, H., and Marsh, M. L.: Anesthesia and the liver. Surg. Clin. North Am., 57:421-428, 1977. 6. Coppock, R. W.: Garbage-, food-, and water-borne intoxication. In Kirk, R. W. (ed.): Current Veterinary Therapy VII. Philadelphia, W. B. Saunders Co., 1983, p . 163. 7. Davis, L. E.: Adverse effects of drugs on reproduction in dogs and cats. Mod. Vet. Pract., 64:969-974, 1983. 8. Gaunt, P. S., Meuten, D. J. , and Pecquet-Goad, M. E.: Hepatic necrosis associated with use of halothane in a dog. J. Am. Vet. Med. Assoc., 184:478-480, 1984. 9. Hardy, R. M.: Diseases of the liver. In Ettinger, S. J. (ed.): Textbook of Veterinary Internal Medicine. Philadelphia, W. B. Saunders Co., 1983, pp. 1372-1434. 10. Harvey, J. W., and Kornick, H. P.: Phenazopyridine toxicosis in the cat. J. Am. Vet . Med. Assoc., 169:327-331, 1976. 11. Kingsbury, J. M.: Poisonous Plants of the United States and Canada. Prentice-Hall, Englewood Cliffs, New Jersey, 1964. 12. Kovatch, R. M., and Zebarth, G.: Naturally occurring Tyzzer's disease in a cat. J. Am. Vet. Med. Assoc. , 162:136-138, 1973. 13. Meyer, D. J., and Noonan, N. E.: Liver tests in dogs receiving anticonvulsant drugs

ACUTE HEPATIC FAILURE

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

133

(diphenylhydantoin and primidone). J. Am. Anim. Hosp. Assoc., 17:261-264, 1981. Muir, W. W., and Bonagura, J. D. : Aprindine for treatment of ventricular arrhythmias in the dog. Am. J. Vet. Res ., 43:1815-1819, 1982. M ullick, F G., and Ishak, K. G.: Hepatic injury associated with diphenylhydantoin therapy. Am. J. Clin. Pathol., 74:442-452, 1980. Nash, A. S., Thompson, H . , and Bogan, J. A.: Phenytoin toxicity: A fatal case in a dog with hepatitis and jaundice. Vet. Rec., 100:280-281, 1977. Ndiritre, C. G. , and Weigel, J.: Hepatorenal injury in a dog associated with methoxyflurane . Vet. Med. Small Anim. Pract., 72:545-550, 1977. Nicholson, S. S.: Mycotoxicosis. In Kirk, R. W. (ed.): Current Veterinary Therapy VIII. Philadelphia, W. B. Saunders Co., 1983, p. 167. Nolan, J. P.: The role of endotoxin in liver injury. Gastroenterology, 69:1346-1356, 1975. Osweiler, G. D.: Common poisonings in small animal practice. In Kirk, R. W. (ed.): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977, p. 109. Pier, A. C., Richard, J. L., and Cysewski, S. J.: Implications of my cotox ins in animal disease. J. Am. Vet. Med. Assoc., 176:719-724, 1980. Polzin, D. J., Stowe, C. M., O 'Leary, T. P., et al.: Acute hepatic necrosis associated with the administration of mebendazole to dogs. J. Am. Vet. Med. Assoc., 179: 1013-1016, 1981. Pond, E. C., and Morrow, D.: Hepatotoxicity associated with methotrexate therapy in a dog. J. Small Anim. Pract., 23:659-666, 1982. Qureshi, S. R., Carlton, W. W., and Olander, H. J.: Tyzzer's disease in a dog. J. Am. Vet. Med. Assoc., 168:602-604, 1976. St. Omar, V. E., and McKnight, E. D.: Acetylcysteine for the treatment of acetaminophen toxicosis in the cat. J. Am. Vet. Med. Assoc., 176:911-913, 1980. Strombeck, D. R.: Small Animal Gastroenterology. Davis, California, Stonegate Publishing Co., 1979. Swanson, J. F, and Breider, M. A. : Hepatic failure following mebendazole administration to a dog. J. Am. Vet. Med. Assoc., 181 :72-73, 1982. Thornburg, L. P.: Liver disease in the dog and cat. Compend. Contino Ed., 4:538547, 1982. Thornburg, L. P., Rottinghaus, G. B., and Glassberg, R.: Drug-induced hepatic necrosis in a dog. J. Am. Vet. Med. Assoc., 183:327-328, 1983. Toth, D. M ., and Derwelis, S. K.: Drug-induced hepatitis in a dog: A case report. Vet. Med. Small Anim. Clin., 75:421-422, 1980. Van Cauteren, H., Marsboom, R., Vandenberghe, J., et al.: Safety studies evaluating the effect of mebendazole on liver function in dogs. J. Am. Vet. Med. Assoc., 183:93-98, 1983. Wigton, D. H., Kociba, G. J., and Hoover, E . A.: Infectious canine hepatitis: Animal model for viral-induced disseminated intravascular coagulation. Blood, 47:287296, 1976. Wilson, R. B., and Wilson, W. D.: Hepatotoxicity of tolbutamide in dogs. J. Am . Vet. Med. Assoc., 156:1557-1566, 1970. Zimmerman, H. J., Fang, M., Utili, R., et al.: Jaundice due to bacterial infection. Gastroenterology, 77:362-374, 1979.

Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus, Ohio 43210