Canine hepatopathies are a common problem encountered in primary care practice; however, the diagnosis of liver disease can be challenging because dogs often show non-specific clinical signs. Additionally, non-specific laboratory abnormalities can further complicate the diagnosis, which can result in delayed treatment or incorrect diagnoses.
History and clinical signs
The liver has a huge functional reserve and an impressive ability to regenerate following hepatic injury. As such, overt hepatic dysfunction does not develop until at least 70 to 80 percent of its functional capacity is lost. The majority of clinical signs are non-specific and include lethargy, anorexia, vomiting, diarrhoea and polyuria/polydipsia which could wax and wane.
More specific signs that could increase your index of suspicion for hepatic dysfunction include jaundice (Figure 1), ascites or neurological abnormalities consistent with hepatic encephalopathy. It is not uncommon for dogs with hepatic dysfunction to document hepatic encephalopathy shortly after a meal due to the sudden increase in serum ammonia, which highlights the importance of taking a thorough history from the owner.
Clinical signs of liver disease in dogs include:
- Weight loss
- Hepatic encephalopathy (eg seizures, ataxia, altered mentation)
Whilst routine haematology is an important tool to assess for underlying disease processes such as infectious/inflammatory diseases or anaemia, the results are usually non-specific in dogs with liver disease. A mild non-regenerative anaemia of chronic disease is not uncommon, and mild neutrophilia and monocytosis can be seen with inflammatory liver diseases.
Liver enzymes, including ALT, ALKP, GGT and AST, should be measured in all cases of suspected liver disease. The hepatocellular enzymes ALT and AST are released from damaged hepatocytes and are therefore markers of hepatocellular damage. The biliary enzymes ALKP and GGT are markers of cholestasis and will increase with any disease that impairs bile flow. Importantly, the degree of elevation does not necessarily correlate with the severity of disease.
Non-specific tests for liver disease
Albumin is synthesised exclusively by the liver. However, hypoalbuminaemia due to reduced hepatic function is only seen when the liver loses more than 75 percent of its function.
Hypoglycaemia is another uncommon and very non-specific sign of marked hepatic dysfunction. Hypoglycaemia occurs most commonly in acute hepatic failure, in small-breed dogs with portosystemic shunts and in end-stage chronic liver failure.
A low urea can occur in canine liver disease, reflecting a reduced ability to synthesise urea from ammonia in the hepatic urea cycle. However, it is influenced by many extrahepatic variables such as protein level of the diet and fluid therapy.
Cholesterol may be increased, decreased or normal in canine liver disease. Hypercholesterolaemia is associated with decreased biliary excretion and also with endocrine diseases which secondarily affect the liver (such as diabetes mellitus and hyperadrenocorticism). Hypocholesterolaemia occurs most commonly in dogs with portosystemic shunts.
Certain urine abnormalities may be present in animals with liver disease, including poorly concentrated urine (USG <1.025), bilirubinuria, ammonium biurate crystals and bacteriuria.
More specific tests of liver function
Hyperbilirubinaemia occurs when there is an abnormality of bilirubin processing, although it is not specific for hepatobiliary disease. Differentials for hyperbilirubinaemia can be categorised as pre-hepatic, hepatic and post-hepatic.
Bile acid stimulation test:
Measurement of bile acids should be considered the primary test to assess liver function in a non-jaundiced dog. Significantly elevated pre- or post-prandial serum bile acids can result from reduced hepatic reuptake following active absorption of bile acids from the intestinal lumen (enterohepatic circulation). If hepatic jaundice is present, then measurement of bile acids is not helpful because they are elevated in biliary stasis.
Failure of the liver to detoxify ammonia, or shunting of portal blood away from the liver, results in hyperammonaemia. This is an important cause of hepatic encephalopathy (HE), although not all animals with HE will have markedly abnormal blood ammonia levels, as other toxic substances are involved. Ammonia is very labile in blood samples and therefore its interpretation can be challenging. Bile acid measurement has a very similar sensitivity to ammonia for portosystemic shunting and suffers from far fewer sampling errors.
The liver synthesises all coagulation factors except for factor VIII. Several factors also require hepatic activation by a vitamin K-dependent carboxylation reaction. Vitamin K deficiency may develop during hepatobiliary disease, resulting in prolonged prothrombin time and activated partial thromboplastin time.
Abdominal radiography can be used to assess liver size, position and shape, and evaluate for the presence of other abdominal pathology. As a general rule, dogs with acute liver disease have normal to enlarged livers, and those with chronic disease have small livers. Reduced hepatic size is also a common finding in dogs with portosystemic shunts. Radiography in the presence of ascites is generally unhelpful because the fluid obscures serosal detail. Table 1 documents the most common differential diagnoses for hepatomegaly and microhepatica.
The liver may appear normal on routine radiographic evaluation despite severe disease, but rarely appears normal on ultrasound in these circumstances. In most cases ultrasonography is an extremely useful tool in the investigation of hepatobiliary disease and also allows the differentiation of focal from diffuse hepatic disease.
Ultrasonography is also an excellent tool for the examination of the biliary system. The presence of gravity-dependent echogenic material in the gallbladder, so-called “biliary sludge”, is a common finding and unlikely to be clinically significant. Abdominal ultrasonography is also very useful for the identification of both congenital and acquired portosystemic shunts. It must be stressed that ultrasound is not a histological diagnosis and no dog should be euthanised on the basis of ultrasonographic findings alone.
Other imaging modalities
Advanced imaging modalities such as CT are becoming more frequently performed in veterinary medicine for the investigation of liver disease, even in primary care practice. Contrast CT in particular can be hugely useful during investigations of congenital portosystemic shunts.
The gold standard for obtaining a definitive diagnosis of liver disease is to perform histopathology. The only exception is with portosystemic shunts that have been identified with imaging. Table 2 discusses the methods available for collection of liver tissue, and the technique used will depend on clinician preference, equipment availability, technical skill and patient stability.
Coagulation status should be checked prior to all biopsy techniques other than fine needle aspiration. If coagulation times are prolonged, vitamin K supplementation should be given parenterally for 24 to 48 hours before re-evaluating. All animals should be monitored carefully for signs of haemorrhage for at least 12 hours post-biopsy. Particular attention should be paid to mucous membrane colour, heart rate and blood pressure.
Treatment of acute liver disease is often supportive, while treatment of chronic liver disease should be tailored to liver biopsy findings whenever possible.
Several non-specific treatments are available that are beneficial in the majority of acute and chronic liver disease cases; however, more specific medications are particularly useful for individual diseases.
High-quality, easily digestible protein and carbohydrate diet:
Many animals with liver disease are fed diets with inappropriate protein restriction, which may restrict hepatic regeneration and result in malnutrition. Whilst prescription hepatic diets can be useful and contain additional benefits such as zinc and B-vitamin supplementation, the author generally prefers to use a soya-based hypoallergenic diet fed little and often.
These include vitamin E, zinc, silymarin, S-adenosylmethionine and silybin. There is no clear evidence to date of improved survival in dogs with liver disease given antioxidants; however, human research has documented significant benefits when given to people with toxic hepatopathies.
Cholerectics and bile acid modifiers:
Ursodeoxycholic acid (for example Destolit) is a bile acid modifier. It has been used safely in dogs but is not licensed for use in animals. Evidence does exist to support its use in liver disease cases, to promote bile flow and displacement of toxic hydrophobic bile acids. It should not be given to dogs with complete biliary obstruction.
Patients with acute hepatitis of an infectious origin should be treated with broad-spectrum antibiotics, for example intravenous amoxicillin-clavulanate. Ideally, the antibiotic choice should be based on culture and sensitivity; however, initiating treatment with an appropriate antibiotic is indicated while awaiting culture results. In severe cases, metronidazole can also be added to the antibiotic regime at a reduced dose (7.5mg/kg/BID) due to its hepatic metabolism.
Ensuring these patients maintain their calorie intake is important, and therefore nauseous patients should be treated appropriately with maropitant, metoclopramide or ondansetron.
Proton pump inhibitors:
If concerned about gastrointestinal ulceration, omeprazole 1mg/kg/BID intravenously is warranted, although it is not currently licensed. Cimetidine is contraindicated in liver disease due to cytochrome P450 inhibition.
In cases of hepatic encephalopathy, addition of oral or per rectum lactulose can be an important method to improve clinical signs. Once signs have been controlled, the dose can be slowly tapered.
This is indicated in cases of primary copper hepatopathy, or those with severe secondary copper accumulation. Copper chelators include zinc and penicillamine; however, neither are licensed for small animals in the UK. Penicillamine is the most readily available, but it must be noted that chelation can take weeks to months before an effect is seen.
Anti-inflammatory doses of prednisolone have been reported to have a benefit in cases of chronic hepatitis; however, the risk of gastrointestinal ulceration is significant, particularly if portal hypertension is documented. It is recommended that the case be discussed with a specialist if you are unsure if corticosteroids should be started.
Increasing evidence is supporting the theory of an immune-mediated aetiology in specific breeds with hepatitis – in particular, the Dobermann and English Springer Spaniel. The author has had success treating English Springer Spaniels with severe, chronic hepatitis with prednisolone 1 to 2mg/kg/SID, with complete resolution of their clinical signs. Cases responding to cyclosporine have also been reported. Speaking to a specialist prior to initiating immunosuppressives would be recommended in these cases.
Spironolactone +/- furosemide:
If a patient with portal hypertension develops marked ascites then spironolactone, and possibly also short-term furosemide, can help relieve the abdominal fluid efficiently to improve patient comfort.
Canine hepatopathies include a range of both reversible and irreversible disease processes, with many treatments remaining non-specific. However, as our understanding of specific breed-related hepatopathies improves, we are seeing our treatments concentrate on the underlying inciting cause and we hope that with further research we can continue to focus our treatment regimens for these patients.
Until that time, providing good supportive care with the medications discussed in this article is the optimal way of ensuring that your patient is receiving the highest quality of care.