Abnormal Liver Parameters - What Do They Tell Us?
World Small Animal Veterinary Association World Congress Proceedings, 2013
Reto Neiger, Dr.med.vet., PhD, DACVIM, DECVIM-CA
Small animal Clinic, University Giessen, Germany

Symptoms of liver disease are commonly nonspecific and can be gastrointestinal (vomiting, diarrhoea, anorexia), urinary (PU/PD, problems due to urate urolithiasis), haematological (pallor, icterus), and/or neurological (behaviour change, ataxia, seizure). Physical examination findings differ widely and may include hepatomegaly, ascites, abdominal pain, weight loss, fever and abnormal neurological test results. Hepatobiliary and vascular disorders can originate primarily from the liver, but can also be secondary to multiple extrahepatic disorders, such as gastrointestinal, haematological and circulatory diseases, endocrinopathies, neoplasia and systemic infections (including sepsis). Drugs and toxins can also cause primary and secondary liver problems.

Many biochemical tests are available to evaluate the liver's anabolic and/or catabolic function and hepatic circulation. These include measurement of serum bile acid concentrations, plasma ammonia concentration and bile pigment (bilirubin) concentration. Other tests of hepatic function include measurement of serum albumin, glucose, urea nitrogen, cholesterol and clotting factor analysis. Hepatic function can be markedly abnormal despite maintenance of the hepatocellular membrane (and therefore normal serum activities of hepatic enzymes). Examples include portosystemic vascular anomalies (PSVA), terminal cirrhosis, and metastatic hepatic neoplasia. Likewise, the liver can continue normal anabolic or catabolic function despite severe hepatocyte leakage of intracellular enzymes, because of its marked reserve capacity. This can occur, for example, in certain cases of hepatocellular necrosis or primary hepatic neoplasia.

The detection of abnormal liver biochemical tests in the asymptomatic, as well as the symptomatic patient, is a common finding on the routine blood screen. The identification of liver biochemical abnormalities should suggest certain diagnostic possibilities and should guide a protocol for further investigation. Liver biochemical abnormalities are mostly nonspecific. The measured enzymes can be isoenzymes from another tissue or the same enzyme from a different tissue source.

Laboratory results from screening tests influence decisions about the need for liver function testing and invasive diagnostic or therapeutic procedures, such as liver biopsy, abdominal surgery or more invasive imaging studies (contrast CT, splenoportography, etc.).

Serum Hepatic Enzyme Activities

Serum hepatic enzyme activities do not reflect hepatic anabolic/catabolic function. Enzyme activities reflect either the integrity of the hepatocyte membrane or the patency of the biliary system. The level of increase does not allow conclusions about the functional capacity of the liver nor on the prognosis of liver damage. Of all the hepatic enzymes, the two that are the most useful for evaluating hepatobiliary disease are ALT and ALP. Increased ALT is usually associated with hepatocellular damage or regeneration, while increased ALP activity is classically associated with cholestasis. Necrosis of cells or increased membrane permeability is responsible for increases in ALT, AST, and arginase. It is important to note that ALT is liver specific in both dogs and cats, so careful thought must be given to potential reasons for increased ALT in both species. Unlike in dogs, where bone growth in young dogs or bone disease must be considered as a cause of increased ALP, increased ALP in cats is almost always an indicator of cholestasis, and is the classic enzyme increase seen in hepatic lipidosis. Some drugs that cause increases in serum activity of ALP in dogs (notably corticosteroids) do not cause this change in cats, as there is no corticosteroid-induced isoenzyme of ALP in cats. Additionally, the serum half-life of ALP is very short in cats (few hours) compared to dogs (about 3 days). This means that increased ALP in cats is more of a concern than in dogs.

Serum Bilirubin

The breakdown of senescent red blood cells, other hemoproteins and other enzymes, such as the cytochromes, by the reticulendothelial system results in the non-water-soluble form of bilirubin (termed unconjugated or indirect bilirubin). In the hepatocyte, this will be conjugated to glucuronic acid for final excretion of its water-soluble form into the bile. Prehepatic, hepatic and posthepatic disturbance in the processing of bilirubin can lead to hyperbilirubinaemia, bilirubinuria and icterus. Prehepatic icterus due to haemolytic anaemia can be quickly differentiated by identifying a marked anaemia, whereas hepatobiliary diseases result in only a mild decrease in the haematocrit. Intrahepatic icterus occurs mostly due to hepatic disorders or in sepsis with gram-negative bacteria (the site of infection is distant to the liver) that leads to abnormal bilirubin processing by the liver (i.e., a "functional" cholestasis). Posthepatic icterus is due to biliary tract obstructions anywhere from the biliary canaliculi to the major papilla where the bile duct ends. To differentiate intrahepatic from posthepatic icterus, abdominal ultrasonography is commonly used to examine the liver parenchyma, hepatobiliary system and pancreas. Notably, patients with PSVA and steroid hepatopathy are rarely hyperbilirubinaemic.

Serum Cholesterol

Serum cholesterol can be decreased in parenchymal and vascular liver diseases. Hypocholesterolaemia is reported in dogs with late-stage chronic liver disease and PSVA. Monitoring cholesterol concentration is more important for assessing the severity of liver disease rather than making a diagnosis.

Glucose

Blood glucose homeostasis is maintained by the liver. Decreased glucose concentrations might point towards a hepatopathy, e.g., it can be seen in fulminant acute hepatic failure, PSVA in small dogs, and paraneoplastic syndrome due to hepatic neoplasia. Since other causes of hypoglycaemia are just as common, it is not diagnostic for liver diseases, but an indicator of disease severity and the need for further diagnostic work-up.

Urea

Urea is synthesized as part of the urea cycle, either from the oxidation of amino acids or from ammonia. Urea production occurs in the liver and is regulated by N-acetylglutamate. Amino acids from ingested food that are not used for the synthesis of proteins and other biological substances are oxidized by the body, yielding urea and carbon dioxide, as an alternative source of energy. In animals with hepatopathy, most notably PSVA, decreased urea is a common finding pointing to the need for further work-up.

Plasma Proteins

Hypoalbuminaemia can indicate reduced liver function associated with cirrhosis or PSVA. As there are quite a wide variety of causes of decreased serum albumin concentration, it is not diagnostic for a liver disease, but is important for assessing disease severity and prognosis. Almost all coagulation factors (except factor VIII) are synthesised by the liver. Altered coagulation test results might indicate reduced hepatic function. Furthermore, altered haemostasis, such as disseminated intravascular coagulation in dogs with hepatopathies, can complicate invasive diagnostic procedures, such as liver biopsy or exploratory surgery. Therefore, coagulation tests, such as prothrombin time, activated partial thromboplastin time, fibrinogen and D-dimers, are indicated in dogs with suspected liver disease.

Ammonia

Ammonia originates from the gastrointestinal tract, where it is produced by bacterial degradation of amino acids (via bacterial urease) and catabolism of glutamine. It is detoxified in the liver by conversion to urea or re-synthesis of glutamine. In dogs, ammonia is increased in hepatic failure, PSVA, urea-cycle enzyme deficiency and decreased availability of urea-cycle substrates, such as argininosuccinate synthetase or vitamin B12. Hyperammonaemia is one major factor in the development of hepatoencephalopathy. It is, therefore, important to determine its concentration in patients with suspected parenchymal or vascular liver disease and neurological signs. Ammonia needs to be measured from EDTA plasma within 1 hour after sampling.

Bile Acids

Bile acids are synthesized only in the liver as a result of cholesterol metabolism and are secreted into bile. Following feeding, bile acids enter the intestine and undergo an efficient enterohepatic circulation following active absorption from the ileum. Once absorbed, they are removed from the portal circulation by the liver and re-excreted into bile. Only small amounts of bile acids are lost in the faeces. Normally, the liver synthesizes enough bile acids to compensate for faecal losses. Although bile acid formation depends on hepatic synthesis, the liver reserve capacity for this is never exceeded because of the small amounts needed for physiologic purposes. Therefore, bile acid measurement is a reliable test even in end-stage liver disease. Abnormal hepatic function, biliary excretion, or portal circulation can interrupt the normal enterohepatic circulation and lead to an increase in serum bile acid concentration. The indications for obtaining serum bile acid concentrations include the need to identify occult hepatic disease when enzyme determinations are normal (as can occur with PSVA, cirrhosis, and metastatic hepatic neoplasia), to evaluate for the possibility of a PSVA in animals with suggestive symptomatology, to monitor hepatobiliary function, to assess progression of hepatic disease, and to identify abnormal hepatic function in animals for whom enzyme elevations may be due to extrahepatic causes.

While lipaemia may artifactually increase, haemolysis may artifactually decrease the serum bile acid value. If there is hyperbilirubinaemia (icterus), measurement of serum bile acids is not needed.

In dogs, fasting serum bile acid concentrations are significantly increased with PSVA, glucocorticoid-induced hepatopathy, hepatic neoplasia, hepatitis, cholestasis, hepatic necrosis, and cirrhosis. Although serum bile acid concentrations are a sensitive indicator of hepatic function, they do not distinguish the cause of the disease process. The magnitude of elevation in serum bile acid concentrations is weakly correlated with histologic severity. Furthermore, dogs with intestinal disease and normal hepatic function may have mildly abnormal serum bile acid concentrations. The determination of a 2-hour postprandial bile acid concentration further increases the sensitivity for most diseases. It is not necessary to use standardized diets to obtain a postprandial sample. Any diet should result in cholecystokinin release following feeding and, therefore, result in gallbladder contraction.

  

Speaker Information
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Reto Neiger, Dr.med.vet., PhD, DACVIM, DECVIM-CA
Small Animal Clinic
University Giessen
Germany


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