Chronic liver disease in small animals (Proceedings)

The liver is an important organ, responsible for breakdown of nutrients and for the synthesis of many molecules such as albumin, coagulation factors, cholesterol, glucose, and many others. The liver has an enormous regenerative capacity. For example, in humans half of a liver can be transplanted from a living donor to a recipient and within 6 weeks both the transplanted liver and the remaining liver of the donor will reach a hepatic volume. Despite its regenerative capacity liver disease can lead to death as the body cannot survive without the liver and exogenous support of hepatic function in dogs and cats is currently not possible, even in the short-term. Liver disease is common in both dogs and cats. Acute liver disease can be caused by infectious diseases or intoxications. Chronic liver disease occurs much more commonly than acute liver disease. The most common chronic hepatic diseases are chronic hepatitis or cholangitis, copper-associated hepatopathies, iatrogenic liver disease, and hepatic vascular disorders, which, with the exception of hepatic vascular disorders, will be discussed in more detail in the following.

Chronic Hepatitis and Cholangitis

Chronic hepatitis is a heterogeneous group of chronic liver diseases in the dog that are associated with an inflammatory infiltration of the liver. Similarly, cholangitis is a heterogeneous group of diseases of the liver and biliary tract in cats that all lead to inflammatory infiltration of the liver and the biliary tract. There are many different etiologies of chronic hepatitis/cholangitis, including infectious (e.g. infectious canine hepatitis or leptospirosis), drug-induced (e.g. anticonvulsants), familial-predisposition (e.g. in the Doberman pincher, Bedlington terrier, Cocker Spaniel, West Highland White terrier, and others). However, most cases of chronic hepatitis/cholangitis are idiopathic.

Clinical presentation

Clinical signs in dogs and cats with chronic hepatitis/cholangitis are often non-specific. Lethargy, anorexia, weight loss, and vomiting are most common. Cats with cholangitis may also show fever and abdominal pain. Other signs such as diarrhea, polydipsia, polyuria, icterus, ascites, and bleeding diathesis may also be seen when the liver is failing.

The most common findings in dogs and cats with chronic hepatitis/cholangitis are an increase in liver enzymes, such as ALT and SAP. In more severe cases hypoalbuminemia, hyperbilirubinemia, hypocholesterolemia, and a decrease in BUN may also be observed. Approximately half of all cats with cholangitis have hyperglobulinemia but this is not a common feature in dogs with chronic hepatitis. Fasting and post-prandial bile acid concentrations may be increased depending on the severity of the disease process. In patients with hepatic failure coagulation parameters may be abnormal either due to lack of synthesis of coagulation factors or due to disseminated intravascular coagulation.

Abdominal radiographs are usually within normal limits. However, in patients with end-stage cirrhosis the liver may appear small. Abdominal ultrasound often reveals changes in hepatic echogenicity and irregular hepatic margins. In more severe cases ascites and acquired intrahepatic shunts may be visualized.

Diagnosis

A diagnosis of chronic hepatitis/cholangitis is based on histopathology. Cytological evaluation of a fine needle aspirate is not sufficient for diagnosis of chronic hepatitis/cholangitis. Biopsy samples for histopathology can be collected by true-cut biopsy, laparoscopy, or exploratory laparotomy. True-cut biopsy is least invasive but only allows for collection of small biopsy samples. In contrast laparoscopy allows for collection of much bigger samples and allows for visual inspection of the liver surface and also for direct control of bleeding. One study has suggested that biopsy by laparoscopy is superior to true-cut biopsy. However, more studies are needed in order to make a conclusive assessment. Regardless of the way the biopsy is collected one biopsy sample should always be submitted for bacteriologic culture.

Therapy

Therapy of chronic hepatitis/cholangitis can be directed at the underlying cause, the hepatic inflammation, or can be supportive or symptomatic in nature in patients with liver failure.

Therapeutic measures directed at the underlying cause may consist of antibiotic therapy in dogs with leptospirosis or cats with suppurative cholangitis. In other cases it may involve switching anticonvulsant agents in dogs with chronic hepatitis due to anticonvulsant therapy.

In patients, in which an infectious etiology has been excluded antiinflammatory therapy may be instituted. There are no controlled studies that evaluate the benefit of corticosteroid therapy in dogs with chronic hepatitis. However, a large retrospective study suggested a beneficial effect of corticosteroids in dogs with chronic hepatitis. The author prefers to use corticosteroids when the bacterial culture of the hepatic biopsy is negative and the patient has not responded to an empiric antibiotic trial. If corticosteroids are being used, the patient should be started on a high dose of prednisone or prednisolone of 2 mg/kg twice a day for 5 days, then 1 mg/kg twice a day for 6 weeks, after which the dose should be slowly tapered. If corticosteroid side effects become unbearable other antiinflammatory agents such as azathioprine could also be considered. Patients treated with antiinflammatory agents should be carefully monitored as some patients may not benefit from corticosteroids and may instead deteriorate.

Supportive therapy can include the use of ursodeoxycholic acid, SAME, or other antioxidants. While there are no controlled studies in dogs or cats, trials in human patients would suggest a beneficial effect of ursodeoxycholic acid in patients with chronic hepatitis. Recently, an antioxidant, s-adenosyl-l-methionine, has been (SAME) suggested for ancillary therapy of dogs and cats with chronic hepatitis/cholangitis. Initial studies did show that SAME replenishes glutathione, but few data in clinical patients are available. Other agents, such as vitamin E, silymarin or milk thistle have been suggested by some, but there is little evidence for their efficacy. Several agents are thought to have antifibrotic properties, including colchicine, prednisolone, azathioprine, and others. Unfortunately, none of these agents have been shown to be efficacious in either dogs or cats with chronic hepatitis/cholangitis.

In patients with hepatic failure a low protein diet should be fed. In addition oral lactulose and neomycin can be used to treat hepatic encephalopathy.

Copper-Associated Hepatopathies

Copper toxicosis (CT) is characterized by excessive copper accumulation in hepatocytes and is a hereditary liver disease that is mainly seen in the Bedlington terrier but also in the West Highland White terrier, Sky terrier, Doberman pinscher, and recently the Labrador Retriever. A similar disease has been rarely described in Siamese cats.

Hereditary background

In the Bedlington terrier CT has been shown to follow an autosomal recessive pattern. Linkage studies have identified linkage of CT with the marker CO4107. A genetic test for copper toxicosis is now available for the Bedlington terrier (www.vetgen.com). This test can be used to identify dogs that are affected and will benefit from anti-copper therapy in order to prevent development of clinical disease. The test also serves as a scientific tool to assist dog breeders with their breeding strategy.

Pathophysiology

Copper toxicosis in the Bedlington terrier is similar to Wilson's disease in humans. Copper is normally stored in hepatocytes. In dogs with CT, hepatic copper content increases until a critical threshold is reached. Tissue injury occurs depending on hepatic copper content and ranges from acute hepatic necrosis to hepatic cirrhosis. Dogs with CT can also undergo a severe hemolytic crisis after a stressful event such as whelping. Excess copper, stored in the liver, can get released into the circulation resulting in hemolytic anemia, acute renal failure, and DIC.

Clinical Signs

Anorexia, vomiting, and diarrhea are common clinical signs. Chronically affected dogs can also develop jaundice, ascites, and hepatic encephalopathy. A stress related acute hemolytic crisis can develop in any dog with CT.

Diagnosis

Diagnosis requires evaluation of hepatic biopsy specimens with a special copper stain. Measurement of hepatic copper concentration is preferable and a copper content exceeding 850 µg/g dry weight is considered indicative for copper storage disease.

Treatment

In dogs with CT the homeostasis of copper storage and release is disturbed. Therefore, the main therapeutic approach is to prevent excessive copper storage. In order to maintain a low copper intake protein sources such as shellfish, liver, kidney, and heart should be excluded from the diet. Many commercial dog foods also have a high copper content and thus should be carefully evaluated before being fed on a long-term basis.

Zinc has the ability to block enteric copper absorption and can thus be used as a supplement (100 mg zinc PO BID for 3 months followed by 50 mg PO BID) in a low copper diet. Early dietary management in dogs that carry the genetic defect for CT can prevent or delay the onset of clinical signs.

However, if copper storage disease has already developed copper chelating agents such as D-penicillamine (10-15mg/kg PO BID) should be administered to attempt to lower hepatic copper content.

Iatrogenic Liver Disease

Anticonvulsants

Anticonvulsants are probably the most common cause of iatrogenic liver disease in dogs, but rarely in cats as cats are placed on anticonvulsant therapy much less frequently than dogs. Phenobarbital, primidone, or phenytoin all can cause chronic liver disease.

Clinical signs of dogs with anticonvulsant-induced liver disease are similar to those seen in dogs with other chronic liver diseases, such as anorexia, lethargy, weight loss, jaundice, ascites, and bleeding diathesis. In addition, dogs may show ataxia, sedation, and a decreased seizure frequency.

Diagnosis of anticonvulsant-induced hepatic disease can be suspected in patients with a history of anticonvulsant administration and clinical signs of liver disease and/or increased serum activities of hepatic enzymes. It should be noted that anticonvulsant therapy with phenobarbital, primidone, and phenytoin all induce hepatic enzyme activities and not all increases in serum hepatic enzyme activities indicate hepatic injury. However, severe increases of hepatic enzyme activities, clinical signs of liver disease, and markers of hepatic disease, such as serum bile acid concentrations or serum albumin concentration may be useful for arriving at the diagnosis. Also, abdominal ultrasound is useful in revealing changes of the hepatic parenchyma.

Treatment of anticonvulsant-induced hepatic disease includes switching the patient to another anticonvulsant such as potassium bromide and potentially supportive and symptomatic therapy as described above.

Diazepam

Diazepam has been used as an appetite stimulant in cats. However, several cats have developed fatal hepatic necrosis. If cats treated with diazepam show any clinical or biochemical evidence of liver disease treatment should be discontinued immediately and supportive and symptomatic therapy applied as needed.

Carprofen

Carprofen is a nonsteroidal anti-inflammatory agent used to treat chronic arthritis in dogs. Carprofen has been associated with idiosyncratic hepatic injury in dogs. Labrador Retrievers have been reported to be at increased risk. Treatment includes the discontinuation of carprofen and supportive and symptomatic therapy as needed.

Many other drugs can be associated with hepatic injury. However, most are considered idiosyncratic reactions, occur acutely, and cannot reasonably be predicted.