October 1998

Liver Disease

A variety of disease states, vascular anomalies and metabolic disorders result in liver dysfunction. This newsletter reviews the more common causes of liver disease and discusses the associated hemostatic abnormalities.

Portosystemic Shunts

The most common hepatic vascular anomaly, portosystemic shunts are functional vascular channels from the portal to systemic circulation that bypass liver sinusoids. When these are of significant extent, they lead to hepatic encephalopathy and liver failure. The disorder is congenital in dogs and cats but is much more frequently seen in dogs. Most cases are diagnosed in animals less than 3 years old. Shunts are likely to be single and extrahepatic in breeds such as the Yorkshire and Cairn Terriers, Dachshund, and Miniature Poodle. In the Yorkshire Terrier they may be found incidentally, even in geriatric pets during routine laboratory screening as part of a wellness examination.

Breeders also screen affected families or breeds with bile acids testing, which may reveal the presence of asymptomatic shunts. Intrahepatic shunts are most often reported in the Doberman Pinscher, Golden and Labrador Retrievers, Irish Wolfhound and Samoyed. Diagnosis is usually based on finding high levels of fasting and post-prandial bile acids, increased blood ammonia levels, and variable changes in laboratory parameters such as increased ALT and SAP, decreased BUN, and mild anemia, hypoalbuminemia and hypoglycemia. Confirmatory tests include ultrasonography, portography or scinography. Some single or large multiple shunts can be corrected surgically, while others can only be managed medically. Prognosis varies but is generally guarded to poor.

Copper Toxicosis

Copper toxicosis is a metabolic disorder in which hepatic accumulation of dietary copper produces progressive hepatopathy with cirrhosis and liver failure. Breeds most often affected include the Bedlington, West Highland, Kerry Blue and Skye Terriers, Doberman Pinscher, Cocker Spaniel, Labrador Retriever, German Shepherd Dog, Miniature Schnauzer, Bulldog and Pekingese. The disease in Bedlington Terriers has autosomal inheritance and is a model for human Wilson's disease. The specific gene involved is linked to esterase D which is used as a marker enzyme for genetic screening. Clinically, the diagnosis is made by the presence of a bronzing skin color in an affected breed, increased ALT and SAP with reduced serum protein, and a small liver. Confirmation involves genetic marker testing in Bedlingtons and/or hepatic biopsy. Long-term prognosis is guarded to poor.

Hepatic Lipidosis

A severe accumulation of fat in the liver, termed hepatic lipidosis, occurs in cats and dogs and is idiopathic in the cat. Typically, affected cats are obese and anorexic, and the condition is often associated with a recent stress event. It may be secondary to diabetes mellitus, malnutrition or exposure to drugs or toxins. The Miniature Schnauzer is one of the more commonly affected dog breeds. Diagnosis is based on finding very high SAP (up to 20 times elevated) and ALT (up to 10 times elevated), and high bilirubin and fasting bile acids. Ultrasonography and hepatic biopsy are used for confirmation. Prognosis is guarded to poor.

Chronic Active Hepatitis

Chronic active hepatitis is a progressive inflammatory condition believed to have an autoimmune or infectious cause. It has been associated with infectious canine hepatitis, leptospirosis and copper toxicosis, and has a genetic predisposition in breeds such as the Shetland Sheepdog, Golden Retriever and Doberman Pinscher. The condition progresses to liver failure. It has not been reported in cats.

Drug-Induced Liver Disease

Drugs such as mebendazole occasionally can produce acute diffuse hepatic necrosis, and oxybendazole-diethylcarbamazine has been associated with nonspecific hepatitis especially in Doberman Pinschers, Samoyeds and Akitas. Increased APTT and PT with changes in liver biochemical profile occur in the acute or end-stage form of toxicity. In dogs, sustained topical or parenteral glucocorticoid use produces a characteristic steroid hepatopathy with hepatomegaly and accumulation of glycogen within hepatocytes. Clinically, signs are those of hyperadrenocorticism with laboratory findings of markedly increased SAP, increased ALT and GGT. Liver biopsy shows typical lesions of vacuolar hepatopathy and swelling of hepatocytes. Naturally occurring as opposed to iatrogenic hyperadrenocorticism produces a similar clinical and laboratory picture. While steroid hepatopathy is the most common cause of increased SAP in dogs, it seldom occurs in cats.

Anticonvulsants such as primidone, phenytoin and phenobarbital produce chronic hepatic disease after long-term use, which may progress to cirrhosis and hepatic failure after 2-3 years. Phenobarbital generally has a less toxic effect although these drugs cause increases in serum ALT and SAP.

Thiacetarsamide is used to treat dogs for heartworm

disease and can produce acute hepatic injury and liver failure. Increases in ALT and SAP are seen in about 20% of dogs treated with this drug. More recently, ivermectin or milbemycin has replaced arsenicals for treating heartworm disease.

In cats, acetaminophen toxicosis produces severe oxidative stress to hepatocytes as cats lack the ability to conjugate glucuronides for detoxification of the drug.

Cirrhosis

End-stage liver disease from a variety of causes produces cirrhosis (widespread hepatic fibrosis with abnormal hepatic architecture from nodular regeneration). In addition to the laboratory biochemical changes typical of liver dysfunction, excessive bleeding may be seen clinically from decreased platelet numbers and/or increased coagulation times.

Neoplasia

Various neoplasms can involve the liver. Primary neoplasms are usually hepatocellular (hepatoma, hepatic carcinoma), bile duct carcinoma, or multicentric lymphosarcoma. Metastic liver neoplasia usually arises from mammary gland adenocarcinoma, splenic hemangiosarcoma or pancreatic carcinoma.

Coagulation Abnormalities

Because the liver is the primary site of coagulation factor synthesis, significant hepatic disease produces prolongation of coagulation tests and may cause an overt bleeding tendency. Other factors contribute to the hemostatic abnormalities seen with liver disease including production of structurally abnormal clotting factors, increased consumption leading to local or disseminated intravascular coagulation (DIC), impaired hepatic clearance with sequestration of platelets and clotting factors in the hepatic microcirculation, and fibrinolytic abnormalities. Up to 85% of humans and 66% of dogs with liver disease are reported to have an elevated PT and APTT, although 93% of dogs, and 82% of cats studied recently, had at least 1 coagulation abnormality. In cats with hepatic lipidosis, 45% had an abnormal coagulation profile.

In the recent study of 22 cats, the PT was most commonly prolonged (16/22) and factor VII activity was low in 15 of them. This finding reflects the very short half-life of factor VII which has been used in humans and animals as a marker for hepatic dysfunction and for response to therapy (reversal of deficiency state). The underlying pathogenesis in this group of cats included vitamin K deficiency (11/22), reduced hepatic synthesis (13/22), indeterminate cause (3/22), and DIC (1/22). Importantly, cats with marked increases in SAP were those most likely to show coagulation abnormalities.

In acute generalized or chronic end-stage liver failure, the patient may exhibit DIC. Classical laboratory changes are moderate to severe thrombocytopenia, prolonged PT, APTT, and thrombin time, low antithrombin III and fibrinogen, presence of fragmented red blood cells (schizocytes), and elevated fibrin degration products or D-dimer.

References: Cornelius and Bjorling, In Morgan (ed.), Handbook Sm Anim Pract, 2nd ed, Churchill Livingstone, 1992, pp 437-458; Bateman et al, Vet Emerg Crit Care 1998; 8:29-45; Lisciandro et al, J Vet Int Med 1998; 12:71-75.

LAB TIPS

FIA/Blood Parasite Screening

Effective October 1st, Antech Diagnostics will perform a Blood Parasite screening on the blood smears of all feline CBCs with a PCV less than 25%. Any CBC with a PCV of less than 25% will automatically generate a Blood Parasite Screen. The corresponding blood smear will be reviewed microscopically, and either Positive or Negative will be entered for blood parasites. This automatic Blood Parasite Screen will be performed without additional charge. The screen will look for Hemobartonella, and any other blood parasite present.

If a clinician would like a Blood Parasite Screen performed regardless of PCV, please submit a fresh blood smear or EDTA specimen and order a Blood Parasite Screen [test code 5336 West Coast or 104 East Coast]. A blood parasite evaluation on felines with PCVs greater than 25% is seldom indicated.