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Liver Tests

James Neuberger

Queen Elizabeth Hospital, Birmingham, UK

KEY POINTS

• The standard liver tests do not measure liver function and none of the analytes measured are specific for the liver.
• The normal range of analytes may vary according to age, sex, ethnicity.
• Normal liver tests do not exclude liver disease.
• Unexpected or unexplained liver tests indicate the need for further investigation.
• Investigation of unexpected abnormal liver tests usually require a full history (including use of drugs and alcohol), examination and usually further serology and imaging.

Introduction

The term "liver function test" (LFT) has become established in health care, but the term is misleading as the blood analytes measured may not accurately reflect the extent or nature of liver disease (Box 1.1). Although a more appropriate term is "liver blood tests," this term is not used in this chapter, as the old term of LFTs has become enshrined in medical use. In addition, other commonly measured analytes give useful guidance on the presence and extent of liver disease (such as full blood count, prothrombin count).

The Reference Range

The term "normal range" has also become established, although it is preferable to use the term "reference range." This range should ideally be determined for each laboratory and each piece of equipment. Factors that may affect the reference range include the selection of healthy people for determination of the reference range and the patient population; other factors that may affect the reference range include sex, age, and ethnic factors, time of day or season when samples are collected, variation in venipuncture technique, preparation, storage, and analysis of samples. The reference range should be established by testing at least 120 samples (although many regulatory bodies suggest a higher number) and clear outliers are usually excluded. The reference range may be determined by one of two approaches:

Box 1.1 Characteristics of Liver Blood Tests

• Not liver specific
• Do not measure function
• Not tests
• May be within normal limits when there is severe liver disease
• May be abnormal when the liver is structurally or functionally normal
• Normal ranges will vary:
  • between laboratories
  • with age
  • with sex
  • with ethnicity
  • with normal physiology (such as pregnancy).
• Not diagnostic for any specific liver disease
• Results in the high normal range may be associated with an increased risk of death

1. The parametric approach can be used only when the distribution of values falls within a normal distribution; the reference range lies within the 95% confidence interval.
2. The non-parametric approach defines the reference range as lying between the 2.5 and 97.5 percentiles of the population.

Whichever approach is adopted, the implication is that, for healthy individuals, around 5% samples will have values lying outside the reference range. In some cases, such as blood sugar or triglycerides, the reference range is determined more by consensus than the process outlined above.

When abnormal tests are reported, further investigations should be undertaken, the nature and extent will depend on the clinical situation. A guide to further management of abnormal liver tests is given in Box 1.2. This will help to define the presence (if any) of liver disease, the extent of liver damage, and the cause of the abnormal liver tests and, where appropriate, the response to treatment. A clinician needs to understand the several tests available to assess liver function and causes of liver disease and the limitation of these tests.

The Standard Liver Function Tests

Analytes measured in the battery of LFTs include:

• albumin
• aspartate amino transferase (AST)
• alanine amino transferase (ALT)
• alkaline phosphatase (AP)
• gamma-glutamyl transferase (GGT).

  Box 1.2 Guidelines for Management of Abnormal Liver Tests

  
  
  • Initial investigation for potential liver disease should include full blood count, bilirubin, albumin, alanine amino transferase, alkaline phosphatase and gamma-glutamyl transferase.
  • Abnormal liver blood test results should be interpreted after review of the previous results, past medical history and current medical condition, review of alcohol and drug history and clinical state.
  • The extent of liver blood test abnormality is not necessarily a guide to clinical significance. The clinical significance is determined by the specific analyte which is outside the reference range and the clinical context.
  • Patients with abnormal liver blood tests should be considered for investigation with a liver etiology screen, irrespective of level and duration of abnormality.
  • In adults, a standard liver etiology screen may include, as clinically appropriate:
    • abdominal ultrasound
    • testing for virus:
      • hepatitis B
      • hepatitis C
      • hepatitis E in those who are immunosuppressed
    • Autoantibodies, including
      • anti-mitochondrial antibody
      • anti-smooth muscle antibody
      • antinuclear antibody
      • anti-liver/kidney microsomal
      • celiac antibodies
    • Serum immunoglobulins
    • Serum ferritin and transferrin saturation
    • Serum caeruloplasmin if under 45-years of age

  Source: Adapted from Newsome et al. [1].

Interpretation of liver tests must always be made in the clinical context, and the extent, pattern of liver abnormality, and time course must be considered. For example, a falling high value for ALT may indicate improvement in the extent of hepatitis, but in the case of severe hepatitis, a return to normal values may indicate a failing liver (ALT predominantly coming from hepatocytes). Conversely, a serum ALT in the normal range may be misleading: cirrhosis may be present in the presence of an established cirrhosis and serum ALT in the upper part of the normal range is associated with an increased risk of death.

Albumin

Decreased circulating concentrations of albumin may be the result of either decreased production or increased loss. Levels are normally lower in the second and third trimesters of pregnancy because of increased plasma volume.

Decreased Production of Albumin

Liver disease: the liver synthetizes about 12-15?g albumin daily. Its long half-life (around 21?days) means that low levels from liver disease is not a robust marker of acute liver disease. In advanced liver disease from any cause, low albumin is a consequence of both decreased synthesis and increased catabolism. In those with ascites, loss of albumin to the ascites may contribute to the low serum albumin.

Nutritional deficiency: the synthesis of albumin is dependent on the availability of amino acids (especially tryptophane), iron, and zinc, so nutritional causes may be associated with low serum albumin.

Renal loss: normal loss of albumin through the kidney is normally very low but may increase with fever or exercise. Glomerular disease will lead to increased loss of albumin and may result in nephrotic syndrome.

Gut loss: Protein-losing enteropathy is characterized by loss of proteins including albumin via the gastrointestinal tract that exceeds synthesis. Protein loss through the gut may be due to mucosal disease without erosion (such as celiac disease), gut disease with mucosal erosions (such as Crohn's disease) or increased lymphatic pressure (such as lymphangiectasis).

Extravascular loss: albumin may leak from the vascular to extravascular compartments. For example, in burns, there is increased vascular permeability which, combined with an acute phase response, leads to inhibition of protein synthesis, with a resulting low serum albumin. Similar mechanisms account for low albumin levels in sepsis which is also associated with increased catabolism of albumin.

Multifactorial causes of low albumin: low serum albumin may be seen in a variety of conditions which are associated with a combination of decreased albumin synthesis (which may be induced by inflammatory cytokines switching protein production from albumin to acute phase proteins), leakage from the vascular compartment, and increased catabolism. This may be seen in critical illnesses, for example. In advanced cardiac failure low serum albumin is also due to combinations of poor intake, poor adsorption, decreased synthesis, leakage form vascular compartments, and increased catabolism.

Analbuminemia (with concentration of <?1?g/l) is a very rare cause of low albumin levels.

Increased Loss of Albumin

High levels of albumin are uncommon and are not related to liver disease. Causes include some respiratory disorders such as tuberculosis, dehydration, vitamin A deficiency, excess corticosteroids, and some leukemias. Samples not processed immediately can also...