18 Jul 2016
Maria Siaz and David Walker discuss some of the most common hepatobiliary disorders in cats and dogs, focusing on identification and the various treatment options available.
Figure 1. Icterus in a cat with immune-mediated haemolytic anaemia.
This article will review the most common hepatobiliary disorders in cats and dogs and consider their diagnosis and management.
Clinical signs of liver disease can be very variable and include waxing and waning gastrointestinal or neurological signs. A number of animals are identified with a hepatopathy on “routine” blood work taken for other purposes. Unfortunately, given the liver’s large structural and functional reserve, specific clinical signs of liver disease, such as icterus, hypoglycaemia, coagulopathies, ascites or hepatic encephalopathy, are not typically seen until late in disease – when 70% to 80% of the functional liver mass is lost.
Additionally, due to the liver’s dual blood supply, its high blood flow and the connection to other organs drained by portal circulation, the liver is also prone to secondary injury (“reactive hepatopathies”).
Diagnosis can be achieved, in some cases, by a combination of compatible history, clinical signs, clinicopathological abnormalities and diagnostic imaging. However, definitive diagnosis, in most cases, ultimately relies on histological examination of liver tissue (liver biopsy).
Treatment of liver disease depends on the type of hepatobiliary disorder, but, in general, involves the following steps:
Liver diseases are frequently encountered in companion animals, but their diagnosis and management can be challenging.
Clinical signs of liver disease can be variable and are often initially subtle; they may include waxing and waning gastrointestinal or neurological signs. In addition, specific clinical signs of liver disease are not typically seen until late in the disease – when 70% to 80% of the functional liver mass is lost.
Diagnosis can be achieved, in some cases,with a combination of compatible history, clinical signs, clinicopathological abnormalities and diagnostic imaging. However, definitive diagnosis, in most cases, ultimately relies on histological examination of liver tissue (biopsy). Treatment and prognosis will depend on the underlying cause.
Liver diseases can be categorised into four broad groups: vascular liver disorders, biliary tract disorders, parenchymal disorders and neoplasia (Table 1)1,2.
Cats and dogs with liver disease can have variable clinical signs and, therefore, a thorough and accurate history is the first step in diagnosis. Questions about the previous use of potential hepatotoxic drugs/supplements, exposure to toxins, human medications, recent anaesthesia, travel history, vaccination and worming status should be asked.
The breed, age and onset of clinical signs can also increase the suspicion of certain types of liver disease, such as a puppy with a portosystemic shunt.
Patients can present with a wide range of non-specific clinical signs, including lethargy, inappetence/anorexia, vomiting, diarrhoea, weight loss, polyuria and polydipsia. Other clinical signs include obtundation, jaundice, abdominal pain, hepatomegaly, ascites, pyrexia and ptyalism (cats)1.
Specific clinical signs of liver disease, such as icterus, ascites, hepatic encephalopathy, hypoglycaemia and coagulopathy, are not evident until more than 70% to 80% of the hepatic function has been lost. Moreover, given the liver’s dual blood supply, its high blood flow and the connection and proximity to other organs drained by portal circulation, the liver is also prone to secondary injury, so called “reactive or secondary hepatopathies” (Figure 1).
Complete blood cell count from animals with liver disease may reveal anaemia that could be either regenerative (due to gastrointestinal bleeding or coagulopathy) or non-regenerative (anaemia of chronic disease), microcytosis (PSS), poikilocytosis and Heinz body formation may be seen on blood smear examination. In addition, there could be concurrent thrombocytopenia (due to consumption or decreased production)1.
Serum biochemistry often reveals liver enzyme activity elevation. Enzyme activities reflect either the integrity of the hepatocyte membrane – alanine aminotransferase (ALT) and aspartate aminotransferase (AST) – or the patency of the biliary system, gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP). The elevation of hepatic transaminases is usually proportional to the severity of hepatic damage; however, the degree of elevation does not reflect hepatic function or correlate with prognosis.
Moreover, elevated liver enzyme activities have a high sensitivity to detect liver disease, but at poor specificity, meaning, although elevation of liver enzymes is seen with many liver diseases, many other conditions could cause this. Mild elevations should be considered relevant in cats, given the shorter half-life compared to dogs.
On a routine biochemical profile, it is also important to look at the liver function parameters, which include albumin, glucose, urea and cholesterol, all of which decrease with significant hepatic dysfunction. In addition, prolonged clotting times (activated partial thromboplastin time/prothrombin time) is also seen with significant hepatic dysfunction.
More specific function tests would include the measurement of serum bile acid concentrations, plasma ammonia and bilirubin concentrations. It is important to remember hepatic function can be significantly abnormal despite normal serum activities of hepatic enzymes, such as PSS and end-stage cirrhosis2.
A bile acid stimulation test is not necessary if the patient is clinically jaundiced, as both results will be elevated due to cholestasis. Fasting bile acids greater than 25µmol/L should raise the suspicion of a hepatobiliary disorder and postprandial bile acids greater than 100µmol/L are suggestive of a PSS; a normal concentration does not exclude PSS.
Measurement of bile acid concentrations is, however, not specific for the type of liver disease and diseases that secondarily affect the liver, such as hyperadrenocorticism, pancreatitis and chronic enteropathies, can also increase bile acid concentrations3.
Maltese terriers may have falsely elevated bile acid concentrations due to the presence of a chemical that interferes with spectrophotometry assay2,4.
Any diet can be used for the bile acid stimulation test. If the patient is not eating, force-feeding a small amount of food is usually enough. In the case of discordant preprandial and postprandial concentrations, the higher of the two samples is always used as the diagnostic measurement.
Hyperbilirubinaemia appears when there is considerable hepatocellular disease or increased bilirubin load (haemolysis). Icteric plasma is detected when serum bilirubin concentration is between 10.26µmol/L and 17.1µmol/L (Figure 2). Icteric mucous membranes are detected with bilirubin concentrations more than 30µmol/L to 35µmol/L.
Hyposthenuria (urine specific gravity <1.008) due to secondary nephrogenic diabetes insipidus and ammonium biurate crystals may be identified with urinalysis in cats and dogs with hepatic dysfunction.
Ammonium biurate crystals and amorphous urates are fairly common in dogs and cats with congenital/acquired PSS, with or without concomitant ammonium urate uroliths; however, they can be seen in urine from normal Dalmatians and bulldogs, both of which are predisposed to urate urolithiasis.
In cats, any bilirubinuria is pathological and further investigation should be pursued2.
Interestingly, urine can be used as an alternative to plasma for bile acid stimulation tests. A study revealed good correlation between both techniques5.
Abdominal radiographs may be helpful in determining liver size and shape; nevertheless, abdominal ultrasonography is the preferred method to assess the liver parenchyma and vasculature (Figure 3). The main disadvantage of ultrasonography is it is highly operator and equipment dependent.
Other imaging techniques sometimes needed to diagnose certain diseases such as PSS may include intraoperative portography or percutaneous splenic portograms, nuclear scintigraphy and helical CT, many of which are available in referral centres.
A retrospective study reported CT angiography was 5.5 times more likely to correctly ascertain the presence or absence of PSS when compared to abdominal ultrasonography6.
Frequently, ultrasound-guided hepatic fine needle aspirates (FNAs) are collected for cytological assessment. Clotting times and platelet count should be checked prior to liver sampling, especially biopsy. Ultrasound guided FNAs are quick, straightforward and normally carry a low risk of haemorrhage.
Several studies have compared hepatic cytology with histopathology and the results are highly variable. In one study, the best correlation between hepatic cytology and biopsy was seen with hepatic lipidosis, lymphoma and carcinoma, whereas the worst was seen with inflammatory and fibrotic disorders7.
In addition to hepatic cytology, collection of a bile sample by cholecystocentesis for cytology and culture should be performed as a part of diagnostic workup of hepatobiliary disease in small animals.
A publication suggested cholecystocentesis was associated with little risk in experienced hands and cytological analysis of bile yielded clinically relevant results that culture alone would not provide, such as protozoal infections or the presence of inflammatory cells8.
A specific diagnosis, in many cases, of primary liver disease requires tissue sample collection9. Biopsies can be taken during exploratory surgery, laparoscopically or ultrasound-guided. Each technique has advantages and disadvantages and the decision of which procedure to use should be based on the individual patient.
The risks of collecting a liver biopsy include haemorrhage, peritonitis and needle tract spread of disease. The patient’s clotting times should be evaluated prior to the procedure.
A study correlated the clotting time results with bleeding complications after ultrasound-guided biopsies in 310 dogs and 124 cats. Overall, major complications were seen in 6% of patients and minor complications were seen in 22%. These complications were more likely if the patient had thrombocytopenia, in dogs with prolonged prothrombin times and in cats with prolonged activated partial thromboplastin times.
However, overall, in this study, no apparent correlation existed between coagulation parameters and major complications following liver biopsy10. Samples should be submitted for histopathology, and copper quantification, when necessary, with or without culture. A cholecystocentesis sample should be collected for bile culture7.
Treatment of liver disease depends on the diagnosis, but, in general, involves the following steps:
Anti-inflammatories/immunosuppressives generally indicated if was evidence of inflammatory cells on hepatic histopathology (immune-mediated chronic hepatitis) exists. A retrospective study found some dogs with chronic hepatitis treated with glucocorticoids have prolonged survival. However, most of these dogs had concurrent diseases and other therapies were used simultaneously12.
The most common suggested dose for prednisolone is 1mg/kg/d, with gradual reduction to a dose of 0.5mg/kg/d every other day. Patients treated with prednisolone will develop a steroid-induced hepatopathy with increased liver enzyme activity – particularly ALP, making determination of any improvement difficult.
In this scenario, improvement of the serum ALT and AST activities may be more reliable to monitor improvement than serum ALP, due to the corticosteroid isoenzyme component of the latter. The only accurate way to evaluate response to treatment is to re-biopsy the patient in the future (6 to 12 months) or perform serum biochemistry once corticosteroids have been discontinued. Given the difficulties in interpreting liver enzyme activity in the face of corticosteroids, other immune-suppressive medications have been suggested, such as azathioprine (only in dogs) or ciclosporin (dogs and cats).
Copper chelating agents are recommended when hepatic copper concentrations are greater than 1,000µcg/g dry weight liver. Chelators compete with binding sites for metals and produce a water soluble complex, which is then excreted in bile and urine.
Penicillamine is the most common copper chelator recommended for use in dogs. It also has anti-inflammatory, antifibrotic and immunosuppressive effects, and increases the synthesis of metallothionein, a copper-binding protein that stores copper as a non-toxic form in the liver. The recommended dose of penicillamine is 10mg/kg to 15mg/kg PO bid. Clinical improvement might take weeks to months and large inter-individual variations occur regarding the effectiveness.
Follow-up liver biopsies are generally required to determine the length of penicillamine therapy. Side effects have been reported in 20% dogs and include gastrointestinal signs. Trientine is another chelator designed for patients intolerant to penicillamine.
Oral zinc could also be given to reduce dietary copper absorption. Zinc induces the production of metallothionein in the enterocytes, which binds to copper. When the intestinal cell dies, the metallothionein-bound copper becomes excreted through the faeces. Zinc also has antifibrotic and hepatoprotective properties. The recommended dose is 5mg/kg to 10mg/kg PO of elemental zinc q12h for 3 months, then 50mg PO q12h for maintenance.
Ursodeoxycholic acid (ursodiol) is a synthetic hydrophilic bile acid that changes the bile acid pool to less toxic hydrophilic bile acids. Ursodiol also increases bile acid-dependent flow, reduces hepatocellular inflammatory changes and fibrosis, and possibly has some immunomodulating and antioxidant effects.
Ursodiol may be useful as adjunctive therapy for the medical management of the initial stages of a gallbladder mucocele and/or in patients with chronic liver disease, particularly where cholestasis plays an important role. The dose for ursodeoxycholic acid is 15mg/kg PO daily.
Side effects are rare. Controversy exists about its use in the presence of a bile duct obstruction for fear of biliary rupture; however, some argue its use is safe, as ursodiol is not a prokinetic drug2,11.
Antibiotics are indicated for primary hepatic infections. The antibiotic choice should be based on the results from culture and sensitivity; however, empirical treatment with potentiated amoxicillin, cephalosporin or metronidazole has been suggested, while the results are pending, particularly if bacteria have been detected on bile cytology.
Colchicine has been used in people with chronic hepatitis and other types of liver fibrosis. This drug interferes with the deposition of hepatic collagen and also stimulates collagenase activity to break down deposited fibrous tissue in the liver. However, a lack of convincing data exists for humans and dogs with liver disease to support the benefits of colchicine.
Half of dogs and cats with liver disease have reduced glutathione concentrations (main antioxidant)13. Antioxidants with scientific basis for benefit include d-alpha-tocopherol (vitamin E), S-adenosylmethionine (SAMe), silymarin and N-acetylcysteine.
SAMe is an endogenous molecule synthesised by cells throughout the body. It is formed from methionine and ATP, in conjunction with SAMe synthetase enzyme, and is involved in cell replication and protein synthesis. It has a modulating influence on inflammation and plays a role as a precursor of glutathione in the hepatocyte. The recommended dose is 20mg/kg/day, generally given on an empty stomach.
A study investigated the amount of SAMe present in different supplements for veterinary use available in UK. The results revealed more than a threefold variation in the percentage of measured SAMe compared to the stated amount on the packaging and, therefore, one could argue the lack of response could be due to deficient supplementation. A trial with a different SAMe product could be considered prior to assuming lack of response14.
The remainder of supportive therapy consists of treating secondary complications of liver disease, such as hepatic encephalopathy, gastrointestinal ulceration and ascites (Table 1).
Inappetence and anorexia are very common in patients with liver disease, particularly cats. If anorexia has been present for more than three days, placement of a feeding tube should be considered.
The diet chosen should not be protein-restricted, unless the patient has clinical signs of hepatic encephalopathy. In addition, a high carbohydrate and moderate fat content is important to supply caloric needs. There is evidence the addition of fibre (psyllium) may have beneficial effects in patients with liver disease, similar to lactulose15. Most formulated “liver diets” have lower copper concentrations and are often supplemented with additional zinc to decrease further absorption of copper in cases with a copper hepatopathy.
