Epidemiology

2. Epidemiology

Causes

Non-infectious Inflammatory Liver Diseases

These represent one of the most common manifestations of liver disease in the dog (Table 3) (Center, 1996a; Watson, 2004). The liver has a very active reticuloendothelial system and plays an important role in blocking substances from the gastrointestinal tract that have been transported by the portal vein. The liver is also sensitive to endogenous and exogenous toxins, and drugs. Immune-mediated mechanisms may furthermore lead to the perpetuation of inflammation following hepatic damage caused by any agent (Center, 1999b). Primary autoimmune hepatitis, which is an important disease in humans, has however not been conclusively demonstrated to exist in dogs.

Infectious Inflammatory Liver Diseases

Viral causes are not important in dogs, in contrast to man. However, infections with "atypical" leptospires (i.e., those not covered in routine vaccinations) may be a more significant cause of chronic hepatitis than previously assumed (Adamus et al., 1997; Bishop et al., 1979).

Non-inflammatory Liver Diseases

Vacuolar hepatopathies are a vague term used to describe a non-inflammatory liver disease that occurs in conjunction with cytoplasmic vacuoles in hepatocytes (Cullen, 2001). Generally, vacuole formation is a nonspecific response to hepatic injury, with glucocorticoid excess (either endogenous or exogenous) the main cause in dogs.

Clinically more important are liver diseases related to vascular anomalies, such as congenital portosystemic shunts and portal hypoplasia (e.g., microvascular dysplasia and juvenile fibrosing liver disease). Neoplasia, commonly secondary, is less frequent.

Steroid hepatopathy. (©C. Rutgers).

Predisposition and Risk Factors

Chronic Hepatitis

The cause of chronic hepatitis in dogs is usually unknown. Some breeds are however more likely to suffer from chronic hepatitis than others (Table 4). A familial predisposition has been described in Bedlington Terriers, West Highland White Terriers, Skye Terriers, Doberman Pinschers, Cocker Spaniels and Labrador Retrievers (Johnson, 2000). The increased incidence of chronic hepatitis in certain breeds suggests a possible genetic basis.

Chronic hepatitis in Doberman Pinschers is associated with increased liver levels of copper and iron, which is a consequence of reduced biliary copper excretion that has a different genetic basis than the disease in Bedlington terriers (Spee et al., 2005). (©DA Elliott).

So far, the genetic defect has only been demonstrated in copper storage hepatopathy in the Bedlington (Johnson et al., 1980). In this breed, copper storage hepatopathy is autosomal recessive.

Copper accumulates in the liver due to an inherited metabolic defect in biliary copper excretion; the increased hepatic copper content then causes hepatocellular injury, chronic hepatitis and cirrhosis (Twedt et al., 1979). The genetic defect was initially demonstrated via a DNA microsatellite marker (Yusbasiyan-Gurkan et al., 1997; Holmes et al., 1998; Rothuizen et al., 1999), but recently the locus of the abnormal copper toxicosis gene has been identified (van De Sluijs et al., 2002). Biopsy and determination of hepatic copper content are still essential for the diagnosis, although a DNA microsatellite marker test is now available to detect both affected and carrier Bedlington Terriers. This test is not 100% accurate (due to recombination), but offers a simple procedure that can be used by breeders to reduce the incidence of this disease.

It is sometimes difficult to establish whether copper accumulation in the hepatocytes is a cause of hepatic disease or a consequence of reduced biliary excretion of copper (Rolfe & Twedt, 1995; Thornburg, 2000). Copper accumulation in association with liver disease has been especially demonstrated in Doberman Pinschers, Dalmatians, West Highland White Terriers and Skye Terriers (Rolfe & Twedt, 1995). The mode of inheritance in these breeds is as yet unknown (Rolfe & Twedt, 1995; Webb et al., 2002). Chronic hepatitis in Cocker Spaniels is often associated with copper accumulation (Johnson, 2000). The copper-storage hepatopathy that was described in young Dalmatians may share some similarities with the disease in Bedlington Terriers, but this needs further investigation (Webb et al., 2002).

Portovascular Anomalies

Congenital intrahepatic portosystemic shunts are more common in large breed dogs. They have been shown to be autosomal recessive inherited in Irish Wolfhounds (Rothuizen et al, 2001). In contrast, most congenital extrahepatic shunts occur in small dogs. They are inherited via a polygenic trait in Cairn Terriers (Rothuizen et al., 2001), and are likely to be inherited in Yorkshire Terriers (Tobias, 2003; Tobias & Rohrbach, 2003).

Portal vein hypoplasia (microvascular dysplasia) occurs more commonly in small breed dogs (Van den Ingh et al., 1995). Yorkshire and Cairn Terriers are both predisposed to congenital portosystemic shunts as well as microvascular dysplasia.

Drugs

Certain therapeutic agents may provide a risk factor for development of acute or chronic liver disease. Chronic hepatitis has been most commonly associated with anticonvulsant drugs (primidone, phenobarbital, phenytoin), and diethylcarbamazine oxibendazole. Acute toxic injury has been described with several drugs, including carprofen, mebendazole and potentiated sulfonamides (trimethoprim-sulfadiazine) (Hooser, 2000; Trepanier et al., 2003). In addition, excess glucocorticosteroids, either exogenous or endogenous as in hyperadrenocorticism, frequently cause a typical vacuolar hepatopathy (steroid hepatopathy).