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Canine Liver Cancer

The majority of veterinary pharmacists encounter patients with hepatic (liver) disease. The liver is a vital organ responsible for energy digestion and metabolism, vitamin and mineral storage, and detoxification of waste. It is a complex, highly functional organ that performs over 1,000 unique biological tasks. The liver comprises multiple lobes, and each segment of the liver has the capability of performing exactly the same functions as any other lobe. Each segment of the liver is able to increase its output and efficiency when stressed, and it can also actually regenerate or recover when removed or severely damaged. The liver has thousands of miles of blood vessels that transport blood to hepatic cells. In fact, 20% of the blood pumped by every mammalian heartbeat goes through the liver. The liver is also responsible for recovery of most nutrients from the gastrointestinal tract, and every blood vessel that flows through the intestines and stomach goes directly to the liver. In order for the veterinary pharmacist to fully understand treatment of hepatic disease and monitor for the signs of iatrogenic hepatocellular toxicity, a thorough understanding of hepatic function, disease, and treatment is essential.

Signs and Symptoms of Hepatic Insufficiency

Many of the signs and symptoms of hepatic disease are insidious in onset. Animals may exhibit behavior changes (from encephalopathies) such as vomiting, diarrhea, grey-white feces, polydipsia/polyuria, reduced appetite, and weight loss. Other more profound clinical signs include seizures, jaundice, anesthesia or drug intolerance, and abdominal distention due to ascites or liver enlargement. During a physical examination of a patient, the veterinarian may also find that the animal has pale mucous membranes from anemia, hepatomegaly, and splenomegaly.

Abnormal Hepatic Enzyme Values

The normal hepatic enzyme values in dogs and cats are listed in Table 1. The hepatic enzyme alanine aminotransferase (ALT), previously referred to as serum glutamic-pyruvic transaminase (SGPT), is an enzyme that leaks from damaged hepatic cells. The blood levels of ALT are roughly proportional to the number of injured liver cells. This enzyme typically remains elevated for 3 weeks after hepatic injury. The magnitude of elevated ALT, however, does not correlate with the seriousness of the disease or the prognosis. Aspartate aminotransferase, previously referred to as serum glutamic-oxaloacetic transaminase (SGOT), is another enzyme found in the liver, as well as in red blood cells and muscle. Damage to any of these cells can result in increased aspartate aminotransferase, which indicates more severe damage to hepatic cells than is indicated by increases in ALT. Serum alkaline phosphatase (SAP), also known as alkaline phosphatase (ALP), is a hepatic enzyme that may become elevated in liver disease. SAP may also become elevated in certain forms of cancer and muscle disease. Moderate elevations of SAP in dogs are not always significant, but any increase in SAP in cats is significant. SAP is usually higher in pediatric patients and may be elevated by certain drugs. y-Glutamyl transpeptidase (GGT) is elevated in diseases associated with blocked bile ducts. As albumin is made exclusively in the liver, low albumin can indicate low production by a failing liver; or an excessive loss of albumin may be due to failing kidneys. When hemoglobin is spent, the liver converts hemoglobin to bilirubin to be secreted as bile. Several conditions can cause a buildup of bilirubin in the blood: an excessive number of red blood cells presenting for breakdown, a blocked bile duct, and other hepatocellular problems. Elevated bilirubin will cause the animal to appear icteric (jaundiced) but does not indicate what the hepatic problem is, nor does it indicate the severity of the hepatic problem. It is important for the veterinary pharmacist to know which drugs are commonly used in treating veterinary hepatic disease, as well as any precautions associated with the use of such drugs. These drugs and precautions are listed in Table 2. It is also important for the veterinary pharmacist to know which drugs can cause an iatrogenic increase in hepatic enzymes (Table 3).

Hepatic Diseases

Although disease of the liver is uncommon in dogs, there are many diseases that affect the performance of the liver. The most common factors that exert an adverse effect on the liver include infectious agents (ie, bacteria, viruses, fungi), drugs (especially antiepileptic drugs), congenital malformation of the hepatic vasculature, and copper storage disease. Other functional problems, such as a blocked bile duct, can cause buildup of bilirubin and bile, which can be toxic to liver cells. The most common manifestations of liver disease in dogs are described below.

Hepatic Encephalopathy

Hepatic encephalopathy is a metabolic disorder that is a result of liver damage. It is manifested through unusual central nervous system activity caused by the buildup of ammonia from inefficient hepatic processing of protein metabolism. Signs of encephalopathy are excessive drooling, behavior changes, visual deficits (including blindness), circling, pacing, anxiety, stupor, and seizures. Hepatic encephalopathy is the end result of hepatic injury, resulting from conditions such as canine infectious hepatitis or leptospirosis, portosystemic shunts (congenital malformation of hepatic blood vessels), and cirrhosis, itself a result of chronic scarring of the liver due to hepatic insult. Treatment of hepatic encephalopathy includes surgical repair of the malformed blood vessels, a low-protein diet to decrease the amount of toxic ammonia byproducts, and medications (ie, neomycin and lactulose) to control the amount of ammonia formed. Table 2 lists the mechanisms, proper dosages, and precautions of neomycin and lactulose for the treatment of hepatic encephalopathy in dogs and cats.

Acute Hepatic Failure

Acute hepatic failure occurs as a result of a rapid loss of liver function due to the death of a large number of liver cells. Acute hepatic failure in dogs is most commonly caused by drugs, ie, acetaminophen overdose, mushroom poisoning and carprofen toxicity (see Table 3); toxins (pesticides); infectious disease, eg, canine infectious hepatitis; and hypoxia to liver cells from poor perfusion or methemoglobinemia. The usual clinical signs of acute hepatic failure are acute and severe depression, vomiting, diarrhea, icterus, seizures, and hemorrhage. Treatment requires intravenous fluids, blood transfusions, antibiotic therapy, and vitamin and mineral support. If an active toxin has been identified, antioxidants such as glutathione precursors, ie, S-adenosylmethionine-SAMe, alpha-lipoic acid, and acetylcysteine, can be administered to bind hepatotoxins. SAMe is available as a veterinary product in tablet form (see Table 2 for precautions). Botanical antioxidants that contain silysibins and silymarins (milk thistle) have been used anecdotally in dogs that suffer from Amanita mushroom hepatotoxicity. It is not known whether chronic administration of milk thistle to dogs is safe, but short-term use should prove beneficial.

Chronic Active Hepatitis

Chronic active hepatitis is a result of an accumulation of inflammatory cells and scars in the liver. This disease, which is more common in dogs than in cats, can be due to a variety of causes, eg, infectious canine hepatitis, leptospirosis, immunemediated disease, or copper storage disease. Treatment usually consists of giving a high-calorie, low-protein diet, as well as supportive care with intravenous fluids, corticosteroids, broad-- spectrum antibiotics, vitamin B complex, and vitamin K. Diuretics such as furosemide may be given to reduce accumulation of ascites. Ursodiol (Actigal) may be given to a patient to increase bile flow from the liver. Ursodiol is well absorbed orally. It enters the liver directly from the portal system and is extracted and secreted into the bile. Table 2 lists important precautions on the use of ursodiol.

Copper Storage Disease

Copper storage disease is a result of improper copper elimination and is mostly seen in certain breeds of dogs such as Bedlington terriers, Skye terriers, and West Highland white terriers. Due to genetic metabolic deficiencies in some of these dogs, copper is not eliminated; and the presence of copper in the patient's metabolic system has a direct toxic effect on liver cells. Doberman pinschers are also at an increased risk for copper storage disease and are more likely to develop cirrhosis and hepatitis. Treatment includes the use of penicillamine to chelate and increase urinary excretion of copper. Zinc acetate helps to bind copper, which prevents its absorption. Extra vitamin E is supplied as an antioxidant therapy to help reduce damage to the liver. Vitamin C should be avoided in dogs with copper accumulation because it may increase the copper's damage to the liver. The use of copper-chelating agents in the Doberman pinscher is controversial, since the disease tends to progress even if copper levels are decreased to normal.

Summary

The liver performs over 1,000 vital functions; therefore, hepatic dysfunction can lead to multiple problems. Liver disease is always serious but does not always have to be fatal. The veterinary pharmacist can become a valuable part of the veterinary care team and assist animal patients to regain their proper hepatic health by becoming familiar with the causes, signs, and symptoms of liver disease in animals and providing clients with the proper programs of prevention, care, and treatment.

Suggested Reading

1. Ettinger SJ, Feldman EC. Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat. Vol 1. 5th ed. Philadelphia, Pennsylvania:WB Saunders Company; 2000.

2. Leveille-Webster CR, Center SA. Chronic hepatitis: Therapeutic considerations. In: Bonaguara JD, Kirk RW eds. Kirk's Current Veterinary Therapy XII Small Animal Practice. Philadelphia, Pennsylvania:WB Saunders Company; 1995.

3. Laflamme DP. Nutritional management of liver disease. In: Bonagura JD, ed. Kirk's Current Veterinary Therapy XIII. Philadelphia, Pennsylvania:WB Saunders Company, 2000.

4. Weiss DJ, Armstrong, PJ, Gagne JM. Feline cholangiohepatitis. Kirk's Current Veterinary Therapy XIII. Philadelphia, Pennsylvania:WB Saunders Company; 2000.

5 Schall WD. Use of zinc acetate for the treatment and prevention of canine copper hepatotoxicosis. Kirk's Current Veterinary Therapy XiI Small Animal Practice. Philadelphia, Pennsylvania:WB Saunders Company; 1995.

6. Center S. New approach to managing hepatic dysfunction. Veterinary Forum. 2000 (December). Roundtable on therapeutic use of S-adenosylmethionine. Veterinary Forum 2000;12:44-49.

7. Cornelius LN, Bartges JW, Miller CC. CVT update: Therapy for hepatic lipidosis. In: Bonagura, JD, ed. Current Veterinary Therapy XIII. Philadelphia, Pennsylvania:WB Saunders Company; 2000.

B. Day DG. Diseases of the liver. In: Sherding RG, ed. The Cat: Diseases and Clinical Management. Philadelphia, Pennsylvania:WB Saunders Company; 1994.

9. Dimski DS, Taboada J. Feline idiopathic hepatic lipidosis. In: Dimski DS, ed. The Veterinary Clinics of North America. Philadelphia, Pennsylvania:WB Saunders Company; 1995.

10. Johnson SE, Sherding RG. Disease of the liver and biliary tract. In: Birchard SJ, Sherding RG, eds. Saunders Manual of Small Animal Practice. 2nd ed. Philadelphia, Pennsylvania:WB Saunders Company; 1994.

fi. Twedt DC. Cirrhosis: A consequence of chronic liver disease. Vet Clin N America: Small An Pract 1985;15:151-176.

Gigi Davidson, BS, RPh, FSVHP, DICVP

North Carolina State University

College of Veterinary Medicine

Raleigh, North Carolina

Address correspondence to: Gigi Davidson, BS, RPb, FSVHP, DICVP, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina 27606. E-mail: gigi_davidson@ncsu.edu

Copyright International Journal of Pharmaceutical Compounding May/Jun 2003
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