Liver function

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The liver has a tremendous capacity for regeneration and its functional mass in health greatly exceeds the body’s needs.In veterinary medicine, there are no standard definitions for the terms hepatic dysfunction and hepatic failure.

  • Dysfunction: One can consider dysfunction as being a laboratory definition, i.e. identifying defects in liver function by biochemical testing (as listed below) whether or not this dysfunction lead to clinical signs. Many animals with liver disease or injury can have some evidence of liver dysfunction on laboratory testing (e.g. low urea nitrogen, increased total bilirubin due to unconjugated bilirubin) and some related clinical signs (e.g. icterus) even though the animal has not lost >70-75% of functional hepatic mass and they are not in liver failure. For example, a low urea nitrogen is common in dogs with portosystemic shunts, as are high bile acids, but these animals are not in liver failure. They do have abnormal liver function secondary to atrophy (decreased functional mass) from loss of trophic substances supplied by the portal vein. In addition, in different diseases, some of the functions of the liver are maintained whereas others may be lost due to ill-defined reasons.
  • Failure: In contrast, liver failure implies a clinical syndrome, i.e. clinical signs related to liver dysfunction (hepatic encephalopathy, hemorrhagic diathesis, photosensitization) plus laboratory evidence of dysfunction due to a loss of greater than 70-75% of the liver’s functional mass. Similarly, there is no consensus in human medicine as to what defines acute liver failure (Wlodzimirow et al 2012), although some define acute liver failure as a clinical syndrome due to sudden loss of over 75% of functional hepatic mass with insufficient hepatic parenchyma remaining to maintain synthetic and excretory demands in the absence of pre-existing liver disease (Lee 2012). In contrast, chronic liver failure would be a clinical syndrome due to a progressive loss of >70-75% of the functional liver mass due to pre-existing liver disease (which in human beings, is mostly cirrhosis from viral or alcohol-induced disease). There is also a newly defined syndrome of acute on chronic liver failure in human beings (Sarin and Choudury 2016). Hepatic failure can be secondary to various conditions in animals, such as chronic active hepatitis and copper accumulation (Fuentealba and  Aburto 2003), drugs (e.g. xylitol, zonisamide [Miller et al 2011, DuHadway et al 2015]), toxins (e.g. blue-green algae, aflatoxins [Newman et al 2007, Dereszynsk et al 2008Sebbag et al 2013]), plant toxicity (e.g. cycad in dogs [Ferguson et al 2011], mushrooms in dogs and cats [Puschner and Wegenast 2012]) and infectious agents (e.g. Platynosomum infection in cats [Basu and Charles 2014], hepacivirus in horses [the suspected cause of Theiler’s disease, Chandriana et al 2013] and leptospirosis).


Hepatic dysfunction can manifest biochemically as:

  • Decreased uptake and excretion of bilirubin and bile acids:
    • Increased total bilirubin concentrations (mostly unconjugated or a mixture of conjugated and unconjugated bilirubin).
    • Increased bile acid concentrations. Of these, bile acids is used more than bilirubin as a marker of hepatic dysfunction (or portosystemic shunting).
  • Decreased uptake and conversion of ammonia to urea
    • High ammonia concentrations, with ammonium biurate crystal formation in urine (potentially)
    • Low urea nitrogen concentrations: Polyuria with secondary polydipsia can result due to defective urine concentrating ability (urea contributes substantially to medullary interstitial tonicity in the kidney). These are often early findings in hepatic disease.
  • Decreased synthetic capacity of the liver
    • Alterations in lipid metabolism
      • Typically low cholesterol. In one study of 20 dogs with hepatic failure, the cholesterol concentration was below 150 mg/dL in 70% of the dogs designated as being in hepatic failure (Toulza et al 2006).
      • RBC plasma membrane defects: Presence of poikilocytes, such as acanthocytes, target cells and many different shapes (cats, particularly those with lipidosis). This occurs in animals with or without synthetic liver failure.
    • Alterations in glucose homeostasis (hypoglycemia most common)
      • Decreased gluconeogenesis, decreased glycogen stores, delayed insulin clearance
    • Alterations in protein synthesis
      • Albumin, transferrin (TIBC): Note that cytokine-mediated downregulation of albumin, protein C and transferrin production (negative acute phase protein) may also be operative in hepatic or systemic inflammation.
      • Coagulation factors (of these factors, fibrinogen is frequently used as a marker of synthetic liver function, likely due to its easy measurement compared to specific factor coagulant activity): Deficient production of coagulation factors may result in prolonged times of screening coagulation assays (PT and APTT) and low fibrinogen (in 71% and 75%, respectively, of the 20 dogs with hepatic failure in the study by Toulza and colleagues). Note that some hepatic diseases causing dysfunction or failure can also result in DIC (secondary to hepatic injury or inflammatory cytokines liberating or inducing tissue factor, with phosphatidylserine exposure and extracellular vesicle release from dying or injured cells). Also, if cholestasis is concurrent, there may be defects in vitamin K absorption, affecting activity of the vitamin K-dependent coagulation factors (factors II, VII, IX, X and proteins C and S).
      • Coagulation inhibitors, such as protein C and antithrombin. These may also be low if there is concurrent sepsis or DIC. Inflammatory cytokines also decrease protein C activity (by downregulating thrombomodulin and the endothelial protein C receptor). Protein C synthesis may also be low due to abnormal portal blood flow.
  • Reduced immunologic function: Decreased Kupffer cell number and/or function can decrease clearance of toxins, ingested foreign antigens etc. resulting in systemic antigenic stimulation with increases in immunoglobulins (polyclonal gammopathy).

There is no concrete pattern or defined order in which the above functions of the liver are affected in any animal with liver disease or failure. Some tests are more sensitive than others for detection of hepatic dysfunction or failure. For instance, in one study of 20 dogs with hepatic failure, low protein C, antithrombin and cholesterol concentrations were found in more dogs than low urea, glucose or albumin concentrations (Toulza et al 2006). Each of these analytes, however, can also be affected by non-hepatic disorders, rendering them unreliable as primary indicators of hepatic function. Note that liver “leakage” enzymes (e.g. ALT, AST) can be normal in a failing liver if there is no active hepatocellular injury occurring. Also, bilirubin is more of a test of hemolytic anemia and cholestasis, than hepatic dysfunction or failure, although in the above study by Toulza and colleagues, all 20 dogs diagnosed with hepatic failure had high total bilirubin concentrations (the bilirubin split was not provided).

Hepatic function is assessed primarily by determination of ammonia and bile acids, especially the latter as it the most accessible test for the veterinary practitioner. The most readily accessible test of liver function is bile acid measurement, which is used most frequently in small animals, horses and camelids and less so in ruminants due to wide reference intervals. Ammonia is an excellent test of liver function but difficult to measure due to sample instability. More specialized tests can be performed that evaluate the ability of the liver to clear exogenously administered compounds, such as ammonia (ammonia tolerance test) (van Straten et al 2015), and dyes , e.g bromsulphalein (BSP) and indocyanine green (Center et al 1983, Engelking et al 1985, Flatland et al 2000). These “challenge” tests are not performed on a routine basis.

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