Liver Failure

Introduction

Liver failure results from inadequate liver function. It occurs even though the liver has a large functional reserve and a high regenerative capacity. Due to the multiple functions of the liver, the animal may present with a variety of clinical signs and although some syndromes such as photosensitisation and jaundice are very suggestive of hepatic disease, often ancillary tests are necessary to diagnose liver failure.

Causes

Primary Causes

Hereditory Liver Disease

Portosystemic vascular abnormalities such as portosystemic shunt (PSS) and storage diseases.

Impaired Function of One Specific/Many of its Diverse Functions

The liver's many functions include detoxification and inactivation of drugs and hormones; carbohydrate metabolism; lipid metabolism and storage; biotransformation and excretion; immunological function; vitamin storage, activation and elimination; and the storage of minerals. Failure of one or more of these functions can result in disease.

Direct Damage & Subsequent Repair

A direct insult to the liver, either by acute exposure to hepatoxic substances or trauma causes damage and may result in liver failure. Remodelling of the vascular and connective components after damage can lead to inadequate nutritional supply to the hepatocytes, thus reducing their function.

Low Liver Mass

A low liver mass depletes the functional reserve. This occurs secondary to chronic liver disease, where irreparible damage has caused fibrosis and cirrhosis of the liver. This is commonly seen in horses following ingestion of hepatotoxic plants such as ragwort.

NB: Liver enzyme levels in blood may not be markedly raised in chronic ongoing liver damage because there may be few liver cells remaining to leak enzymes.

Secondary Causes

Secondary causes of liver disease include endocrinopathies such as hyperadrenocorticism, diabetes mellitus, and hypothyroidism, right-sided congestive heart failure, metastatic neoplasia, hypoxia, toxaemia and sepsis, gastrointestinal disease, pancreatitis, and certain drug therapies. Primary causes should be ruled out before considering extra-hepatic causes of disease.

Signalment

Several breed predispositions exist. These include hereditary abnormalities such as PSS and storage diseases, amyloidosis and idiopathic chronic inflammatory hepatobiliary disease. Otherwise there may be a history of exposure to hepatotoxic substances, which may raises suspicion of disease.

Clinical Signs

The animal may present with non specific signs such as weight loss, anorexia, vomiting, diarrhoea, lethargy and PU/PD. As these signs may occur in many disease processes, clinical pathology may be necessary to confirm liver disease. The animal may also present with syndromes specifically related to primary or secondary liver disease such as:

• Icterus
• Photosensitisation - this is most commonly seen in large animals
• Hepatic Encephalopathy — this may be seen in the horse following chronic ragwort ingestion
• Bleeding Tendencies or coagulopathy
• Hypoalbuminaemia and ascites
• Hepatomegaly or fibrosis of the liver
• Drug intolerance

These specific signs are more likely to occur further into the disease course as the liver has an extremely large functional reserve.

Diagnosis

Laboratory Tests

Haematology, biochemistry, urinalysis

Haematology may show a hypoalbuminaemia as the liver is the site of albumin production, and either hyperglobulinaemia (in response to chronic inflammatory liver disease) or hypoglobulinaemia (as many globulins, such as α- and β-globulins are produced in the liver). Non regenerative normocytic and normochromic anaemia is also commonly seen.

Biochemistry may show an elevation in liver enzymes such as ALT, ALP, AST and GGT. However endocrinopathies, neoplasia, hypoxia, hypotension, muscle injury, corticosteroid and anti-convulsant administration, systemic infection and bone disorders can also increase serum levels of liver enzymes, therefore liver disease cannot be diagnosed on these results alone.

Urinalysis often reveals ammonium biurate crystalluria, particularly in PSS cases. Bilirubinaemia is always considered abnormal in the cat and indicative of either hepatobiliary or haemolytic disease.

Serum bile acid test

This is a first line test for assessing liver function in non-icteric companion animals. Samples should be taken both pre- and post-prandially (after twelve hours fasting and again two hours after feeding). Hepatobiliary disease can be confirmed if the pre-pranial values of bile acids are markedly elevated.

Coagulation profile

The liver is essential for the production, activation, clearance and catabolism of coagulation factors. Therefore a coagulation profile measuring the PT, APTT, fibrinogen levels and FDP levels can be performed to help diagnose liver disease and prior to performing any more invasive diagnostics such as biopsy.

Plasma ammonia

Plasma ammonia levels should be measured in any case suspicious of hepatic encephalopathy. Elevated blood ammonia levels can confirm the condition but a normal blood ammonia reading cannot rule out HE. High ammonia is most commonly seen associated with PSS and more advanced liver disease. Samples are difficult to handle, and to improve the diagnostic value of the results it is useful to perform a concurrent ammonia tolerance test.

Abdominocentesis

A transudate may be present secondary to hypoabluminaemia (causing ascites). A modified transudate may be produced secondary to hepatic congestion, and the presence of bile suggests rupture of the biliary tree.

Blood glucose and cholesterol levels can also be measured. Hypoglycaemia, and either hyper- or hypocholesterolaemia can be seen in animals with liver disease.

Imaging

Radiography can be used to assess the size and shape of the liver. Diffuse hepatomegaly is suggestive of infiltrative disease (such as neoplasia or amyloidosis), inflammation, and congestion. Focal hepatomegaly is more suggestive of a single neoplastic mass, cyst, abscess, regenerative nodule or granuloma. Hepatomegaly or a small liver may be suggestive of acute or chronic disease. Reduced liver size suggests fibrosis and atrophy. The use of radiographic contrast studies can be used to identify vascular abnormalities such as PSS.

Ultrasonography is a useful tool for assessing the liver for signs of disease. It can be used to evaluate the parenchyma, vascular system and biliary system for pathology but is not the most reliable tool for assessing liver size. Diffuse disease can be identified and further classified as hypoechoic or hyperechoic. Hypoechoic pathology includes hepatic lymphoma, congestion and suppurative disease. Causes of hyperechoic liver parenchyma include fibrosis (accompanied by regenerative nodules, ascites and a small size), neoplasia, lipidosis and corticosteroid hepatopathy. With localised disease a focal lesion should be identifed and ultrasonograhic appearance may allow the differentiation of cysts, regenerative nodules, abscesses, neoplasia, granulomas and haematomas, however this is not always possible due to their sometimes variable appearance. If disease is diffuse or a localised mass is amenable to biopsy then ultrasound can be used to guide sampling. It is also extremely useful for the diagnosis of vascular abnormalities and biliary stasis.

Biopsy

Livers with either diffuse disease or a focal lesion that is amenable to biopsy should be biopsied and the sample sent for histopathology if diagnosis has not yet been achieved.

Either a surgical biopsy or ultrasound guided needle biopsy should be performed to confirm diagnosis. However coagulation tests (including PT, APTT and a platelet count) should be performed before any biopsies are taken as the liver is a very vascular organ and animals with liver disease are often deficient in clotting factors (which results in a coagulopathy). Animals may be treated with vitamin K or fresh frozen plasma, but if the coagulopathy is severe the procedure should not be performed. Clearly due to the associated risks, risk-benefit should be considered before performing a biopsy.

Many inflammatory disease processes produce the same signs histologically, as the liver responds in the same way to a variety of chronic insults (eg infection and toxins). Therefore it is also important to note the extent of the damage to gauge both the severity of the disease and the prognosis.

Treatment

The aim of treatment are to:

• Remove the causative agent
• Stop inflammation
• Minimise fibrosis
• Promote regeneration
• Treat secondary complications such a ascites, secondary bacterial infection and hepatic encephalopathy.

There are numerous drugs that can be used to treat liver disease including glucocorticoids, immunosuppressive agents, bile acids (ursodeoxyycholic acid (UDCA)), antioxidants such as S-Adenosyl-L-methionine (SAMe), vitamin C and E and milk thistle (silymarin), and antifibrotic drugs. Treatment of liver-specific syndromes such as photosensitisation and hepatic encephalopathy are covered in their associated sections.

Prognosis

Prognosis depends on the success of treatment. As mentioned, the liver has a large functional reserve and a high regenerative capacity - but once fibrosis and cirrhosis of the liver has occured it is irreversible and functionality of the damaged portion is lost forever. If this is widespread, this is classed as end-stage liver disease and the prognosis is poor.

Liver Failure Learning Resources
Flashcards Test your knowledge using flashcard type questions	Equine Internal Medicine Q&A 03

References

Axiom Veterinary Laboratories Ltd (2007) Laboratory Guide Axiom

Bexfield, N & Watson, P (2006) Diagnosis of canine liver disease In Practice 2006 28: 444-45

Dunn, J (1992) Assessment of liver damage and function In Practice 1992 14: 193-200

Ettinger, SJ & Feldman, EC (2005) The Textbook of Veterinary Internal Medicine - Disease of the Dog and Cat Saunders, Elsevier, pp1422-1441, Volume 2, 6th Edition

Horace Hays, M (1995) Veterinary Notes for Horse Owners Revised Edition (17th) Stanley Paul

Mair, TS & Divers, TJ (1997) Self-Assessment Colour Review Equine Internal Medicine Manson Publishing Ltd

Rutgers, C (1996) Liver disease in dogs In Practice 1996 18: 433-44

Rutgers, C (1996) Feline liver disease In Practice 1998 20: 16-2