Hepatobiliary diseases in dogs and cats (Proceedings)

Recently, the Liver Disease Standardization group of the World Small Animal Veterinary Association (WSAVA, www.wsava.org) published WSAVA Standards for Histological and Clinical Diagnosis of Canine and Feline Liver Diseases.  A group of 9 specialists in hepatobiliary disease collaborated on this project with the goal of developing a world standard of guidelines for the diagnosis of liver diseases in dogs and cats using both histological and clinical criteria.  By providing a standardized scheme for terminology, diagnosis, and staging of canine and feline liver disorders, WSAVA is contributing to the improvement in the quality of care provided by veterinarians for dogs and cats with hepatobiliary disease.  I have chosen to describe what I consider to be the most common and/or most clinically significant hepatobiliary diseases of dogs and cats.

When considering hepatobiliary disease as a differential diagnosis in an ill patient, it is useful to follow a systematic approach, such as provided by the DAMNIT or MINIVADITTI scheme (Table 1).

Examples of systematic approach to hepatobiliary disease D = degenerative (cirrhosis) A = anomalous (congenital PSS) M = metabolic (hyperadrenocorticism) N = neoplasia (lymphosarcoma), nutritional (hepatic lipidosis in cats) I = inflammatory (lymphocytic cholangitis), immune-mediated, infectious (blastomycosis), idiopathic, iatrogenic (prescribed medications) T = toxic (many medications), traumatic (blunt force trauma) V = vascular (ischemic disease, thrombotic disease)

(Obstructive disease should be added!)

Degenerative

Fibrosis and cirrhosis may result from any severe or chronic hepatic insult:  toxicity, heavy metal accumulation, infection, etc. Damage that results in inflammation and or necrosis may lead to the development of collagen producing cells, leading to replacement of functional hepatic tissue with fibrosis.  Cirrhosis is diagnosed when the hepatic fibrosis is severe and bridges one portal area to another, leading to disruption of normal hepatic architecture.  This is usually associated with regenerative nodules.  Cirrhosis can also be associated with the development of acquired portal shunts.  At this point in time, cirrhosis represents end-stage liver disease as there currently are no clinically available therapies to reverse collagen production and restoration of normal hepatic tissue.

Dogs are much more likely to develop cirrhosis than cats.  Patients with liver disease may not be presented to a veterinarian until cirrhosis is present.  Although a liver biopsy is required for a definitive diagnosis, a clinically diagnosis is usually made based on a small liver size, chronicity of clinical signs and evidence of hepatic dysfunction on a routine serum biochemistry pattern.  Treatment is supportive and the prognosis is grave.

Anomalous

Congenital portosystemic shunts (PSS) are abnormal blood vessels present in a puppy or kitten, which send blood draining into the portal vein (from the GI tract, spleen, etc) into the systemic circulation. This blood is not detoxified by the liver, leading to an increase in toxins (including ammonia) and bacteria in the general circulation. In addition, trophic substances bypass the liver, leading to microhepatica.  The severity of clinical signs is related to the degree of blood that is shunted.  Clinical signs usually involve the CNS, GI and urinary system and may manifest as hepatic encephalopathy, hyporexia, vomiting, diarrhea and lower urinary tract signs, due to urate stones. Patients may also be small in stature, compared to litter mates or breed standard, and develop clotting disorders.  Extrahepatic shunts are more likely to occur in small breed dogs while intrahepatic shunts are more likely to occur in large breed dogs.

Portal vein hypoplasia, also known as microvascular dysplasia and noncirrhotic portal hypertension, is a congenital vascular abnormality, in which the intrahepatic vein +/- extrahepatic vein are abnormally small or absent.  It is more common in dogs than in cats.  Patients with this condition can develop portal hypertension, acquired shunts and ascites.  Patients can also be asymptomatic although most have small livers. 

Metabolic

Many metabolic diseases can lead to elevation in liver enzymes although they are not usually associated with significant liver dysfunction:  pancreatitis, hyperthyroidism, hyperadrenocorticism, etc.  In cats with unregulated diabetes mellitus, clinical hepatic lipidosis may occur.

The primary metabolic disarrangement associated hepatopathy, is feline hepatic lipidosis, which is discussed in the section on nutritional hepatobiliary diseases.

Nutritional

Hepatic lipidosis (HL) is one of the most common hepatobiliary diseases in cats.  It also has the potential to be fatal. Mild hepatic fat accumulation is common in systemically ill cats, but does not cause clinical illness or hepatic dysfunction.  When, however, rapid weight loss occurs or prolonged hyporexia or anorexia occur, massive hepatic fat accumulation can occur, leading to clinical HL. Clinical disease may develop as quickly as one week after onset of anorexia.

Unlike dogs, cats are predisposed to accumulating fat in their hepatocytes.  Increased body condition leads fat accumulation in the liver in healthy cats.  When marked hyporexia/anorexia occurs, there is stimulation of hormone-sensitive lipase.  Many hormones that are elevated during stressful conditions, glucagon, thyroid hormone, catecholamines, glucocorticoids, etc) stimulate horomone-sensitive lipase, resulting in the breakdown of peripheral fat.  Lipolysis leads to the formation of fatty acids that enter circulation and are taken up by the liver.  Once in the liver, the fatty acids can be used as an energy source.  Alternately, the fatty acids may be synthesized into triglycerides (TG).  TG then either accumulate in vacuoles within hepatocytes or are packaged into very low-density lipoproteins (VLDL) and secreted into circulation.  In cats with HL, the rate of TG accumulation surpasses excretion of TG in the form of VLDL. In cats with HL, the amount of hepatic fat may increase 2-3 fold in weight.. 

The exact pathogenesis of HL is unknown, although many hypotheses have been proposed:  L-carnitine deficiency, insulin-resistance (due to obesity), diminished ability of the liver to secrete VLDL, decreased delivery of VLDLs to peripheral tissue, etc.

Iatrogenic

The most common iatrogenic causes of liver disease is due to administration of potentially hepatotoxic medications.  Numerous medications are known to be associated with hepatotoxicity in people, fewer with our veterinary patients; however it is wise to always review a patient's medication history, including over-the-counter medications, nutraceuticals and herbal remedies, when assessing a patient with a new hepatopathy.  Additional potential iatrogenic causes include ischemia due to hypovolemia/hypotension and trauma.  See Table 2                                                        

Inflammatory/Immune-mediated (?)

Dogs

The primary inflammatory liver diseases in dogs are acute hepatitis (see Table 2), chronic hepatitis (CH), and copper-associated hepatitis. See Table 2 for causes of acute hepatitis include infectious disease.

Example of causes of acute hepatitis and/or hepatic necrosis Toxicants: lead, arsenic, iron, copper, zinc, selenium, chlorinated compounds, tannic acid, pine oil, xylitol Infectious agents: FIP, infectious canine hepatits, leptospirosis, salmonellosis, Tyzzer's diseae, Neospora, Toxoplasma, Histoplasma, trematodes, Dirofiliaria Acetaminophen: Amiodarone, Azathioprine, Carprofen, Diazepam, Griseofulvin Environmental agents: Aflatoxins (Amanita mushrooms, blue-green algae, sago palm nuts), Ischemia Halothane: Ketoconazole, Oxibendazole, Mebendazole, Methimazole, Methotrexate Shock (thromboembolic disease) Potentiated sulfas: Phenobarbital, Stanozolol, Tetracycline Alternative medicine (Pennyroyal oil, Germander), Kava (Jin Bu Huan, Chaparral 

*VCNA, May 2009; CVT XIV; Vet Int Med, 2010

Chronic hepatitis (CH) has also been called chronic active hepatitis, chronic lobar hepatitis, etc. Common histologic findings include variable inflammatory infiltrates, hepatocellular necrosis or apoptosis, regeneration and fibrosis. The cause is undetermined in most cases, and most likely anything that damages the liver can lead to chronic hepatitis:  infection, medications, toxicity, copper  accumulation, immune-disease. CH is overrepresented in several breeds:  Doberman, terriers, Cocker, Standard poodle, Labrador retriever, German shepherd, Springer spaniel and beagle.  Most affected dogs are 4-7 years.  Female Dobermans and male Cockers are predisposed.

Copper-associated hepatitis (CAH) has been associated with the previously mentioned breeds as well as in the Collie, Golden retriever, Pekingese, Keeshond, bulldog, Dalmatian, Samoyed and Old English Sheepdog. Primary, or inherited copper storage disease (as occurs in the Bedlington) leads to copper accumulation in the central lobules. The excess copper causes necrosis, chronic inflammation and eventually cirrhosis.  Bedlingtons have an inherited autosomal recessive defect that prevents normal copper excretion. Secondary copper accumulation, which can occur secondary to any cause of cholestasis, is found in the periportal parenchyma and is of lesser magnitude than with primary CAH.

Cats

Variable terminology has been used to describe inflammatory hepatobiliary disease in cats. Since the primary lesions are biliary, with secondary hepatic involvement cholangitis is the preferred term.   Cholangiohepatitis and cholangitis-cholangiohepatitis complex are terms that have been used previously.  

WSAVA has categorized cholangitis in cats into three basic categories:  neutrophilic, lymphocytic and chronic (associated with liver flukes).

Neutrophilic cholangitis, previously referred to as suppurative cholangiohepatitis, is divided into acute and chronic entities and may be the most common biliary disease in cats in this country.  Acute neutrophilic cholangitis (ANC) is characterized by a primary neutrophilic cellular infiltrate and is usually caused by Gram negative bacteria, probably as a result of an ascending infection from the gut.  There may be an association with ANC and inflammatory disease of the intestines and/or pancreas.  Although E. coli is the most commonly cultured from bile or the liver of affected cats, other bacteria have been associated with acute neutrophilic cholangitis:  Enterococcus, Bacteriodies, Clostridia, Staph. Strep, etc.  Helicobacter spp. may also play a role in neutrophilic cholangitis.  Most cats with ANC are young (~3-5 years of age) and male cats may be predisposed.  The onset of clinical signs is usually acute and fever is common.  Chronic neutrophilic cholangitis (CNC) is thought to be a progression of ANC. Mixed inflammation, including lymphocytes, plasma cells and neutrophils are present in portal areas, predominantly affecting bile ducts. Fibrosis and bile duct proliferation may also be present.  Middle-aged to older cats, usually > 10 years, are more likely to be affected with CNC and clinical signs are usually less severe, specific and intermittent.

Previous terms for lymphocytic cholangitis (LC) include lymphocytic portal hepatitis and non-suppurative cholangiohepatitis, and lymphocytic cholangiohepatitis.  Histological changes include moderate to lymphocytic inflammation in portal areas, biliary proliferation and variable fibrosis.  The etiology of LC is unknown; genetic factors, immune-mediated disease and an association with Helicobacter have been suggested.  Although any age cat can develop LC, > 50% of affected cats are < 4 years of age.  Persians are thought to predisposed.  LC may be more common in Europe than in North America. Clinical disease is typically slowly progressive over months or longer with minimal signs initially.  Progression to cirrhosis and portal hypertension have been described.

Lymphocytic portal hepatitis (LPH) is histologically described as mild lymphocytic inflammation of the hepatic parenchyma with minimal biliary involvement.  Its clinical significance is uncertain as in one study > 80% of cats > 10 years of age had LPH.  Only 10% of younger cats had LPH.  LPH may be an aging change in cats, reflect extrahepatic disease or represent a mild or subclinical syndrome.

Toxicity

The liver is at increased risk of xenobiotic (drugs, environmental chemicals) toxicity compared to other organs.  It receives ~75% of its circulation from splanchnic venous drainage, which is concentrated in xenobiotics absorbed from the GI tract.  Intrinsic hepatoxicity occurs due to direct action of a toxin or its metabolite on a hepatocyte   (i.e. acetaminophen).  The most common reaction is hepatic necrosis without inflammation, particularly affecting zone 3.  Most enzymes that metabolize drugs decrease their toxicity, but some actually increase toxicity.  Idiosyncratic drug reactions occur randomly and are not dose-related.  This type of drug reaction is most likely immune-mediated and initiated by specific cell surface receptors that signal apoptosis or necrosis.  Both genetic and environmental factors may predispose to idiosyncratic drug reactions.  Such hepatotoxicity usually occurs regionally or as a mixed zonal pattern. 

The clinical spectrum includes asymptomatic patients with increased liver enzyme activity to critically ill animals with icterus and liver failure.  Clinical signs can occur within hours to days of exposure and may resolve within days of discontinuation of toxin or progress to fatal liver failure and death within a week. 

Miscellaneous

Gallbladder mucoceles were rarely reported prior to 1990, but now are one of the more common biliary diseases diagnosed in dogs.  A biliary mucocele is an accumulation of mucoid bile within the gallbladder. The cause is unknown. Obstruction of the cystic or common bile duct, infection and inflammation are rarely diagnosed in dogs with mucoceles. Conditions associated with mucoceles include chronic pancreatitis, hyperadrenocorticism, exogenous steroids and concurrent hepatic disease. Cocker spaniels, Shetland sheepdogs, dachshunds and miniature schnauzers may be predisposed. The median age is 10 years, but mucoceles have been diagnosed in dogs 3-17 years of age.

Mucoceles are found often incidentally during an abdominal ultrasound and may never cause clinical problems. As they probably develop slowly some dogs present with progressive and nonspecific signs:  abdominal discomfort, hyporexia, lethargy, etc. In other cases gallbladder obstruction leads to rupture and bile peritonitis and an acute abdomen. Cholecystectomy is indicated in these cases.  In patients with minimal clinical signs, medical management with ursodiol, +/- antibiotics, +/- antioxidants have been used.  Successful resolution has rarely been reported.

References

Kirk's CVT XIV, eds. Bonagura, Twedt, 2009.

VCNA, eds. Armstrong, Rothuizen May 2009

Textbook of Veterinary Internal Medicine, eds Ettinger, Feldman, 2010