LFTs – Liver Function Tests

Introduction

Almost every patient admitted to hospital will have their liver function tested, along with a full blood count, urea and electrolytes and glucose. Liver function tests (LFTs) are also one of the most commonly requested tests in primary care.

Interpreting liver function tests can be a tricky concept to understand. For starters, the term “liver function tests” is actually somewhat of a misnomer, and several authorities now recommend the term “liver blood tests” as an alternative. This is because only some of the tests included in a normal set of liver blood tests are actually tests of liver function. They are mainly indicators of liver damage or liver fibrosis. Tests that indicate the true synthetic function of the liver are not typically included in a standard set of “LFTs”.

A typical set of LFTs will include:

• Bilirubin – can show pre-hepatic, intra-hepatic and post-hepatic causes of jaundice. A patient won’t necessarily be visibly jaundiced if bilirubin is raised, especially if the bilirubin is not grossly elevated.
• ALP – can be raised by liver, bone and placental pathologies. When raised in liver disease it indicates biliary obstruction and hepatic metastasis
• ALT
• AST – is raised in liver and skeletal muscle pathologies
• Albumin – low albumin indicates capilliary leak
• GGT – is most useful to assess if raised ALP is due to liver, or other pathology.
• INR – is also usually measured in suspected liver disease. This is essentially a measure of the liver’s synthetic function, as it measures the liver’s ability to produce clotting factors. In hepatitis and other liver pathologies, a raised INR indicates significant liver damage

We can consider liver blood tests as being subdivided into three categories

• Indicators of liver damage e.g. in hepatitis, paracetamol overdose – hepatobiliary enzymes
  • ALT
  • AST
  • ALP
  • GGT – useful to discern if raised ALP is due to liver or bone (or rarely another) pathology
• Indicators of liver synthetic function (the true liver function tests) – indicators of severe advanced liver disease – e.g. alcohol liver disease
  • Bilirubin
  • Albumin
  • INR and other clotting function – particularly PT – prothrombin time
  • Platelets – synthesis of platelets requires production of thrombopoetin from the liver
• Indicators of liver fibrosis
  • Platelets – often considered along with albumin and INR as an indicator of liver function

When LFT’s are routinely measured (e.g. in primary care as a screening tool), an abnormality is found in 3.5% of people. 0.3% of patients have ALT levels 2x that of normal. Abnormal LFTs are unlikely to resolve spontaneously – and as such there is little benefit to simply repeating tests that are raised, without other investigation or management.
The majority of patients with abnormal test results have significant liver disease.
The two most common liver diseases are alcoholic liver disease, and non alcoholic fatty liver disease (NAFLD).
Normal LFT’s do not necessarily exclude the possibility of chronic liver disease.

In the case of raised liver blood tests, a liver screen is often performed to help identify the cause. Usually this includes:

• Autoantibodies and immunoglobulin – to look for autoimmune hepatitis
• Viral hepatitis serology (usually hepatitis B and hepatitis C)
• Ferritin – to look for haemochromatosis
• USS of the liver

ALT

• Can be raised up to 50x normal. When they are this high it suggests viral or drug induced hepatitis, or extensive hepatitis with necrosis of another source.
• Normal levels in infants are 2x that of adults
• This is an enzyme that catalyses a reaction between an amino acid and a keto-acid. Ultimately, they are important in producing various amino acids.
• Found mainly in the liver, but also smaller amounts in the kidneys, cardiac and skeletal muscle. It, however, is fairly specific for liver damage.
• During liver damage, ALT is released into serum causing raised levels that may remain high for weeks or months. Levels will be raised before jaundice appears.
• Levels of ALT fluctuate slightly throughout the day, and are particularly raised after exercise.
• It is generally raised in liver problems, and less so in problems with the bile duct. It may also be raised in heart problems.
• More specific for liver damage than AST.
• Levels of ALT and AST both raised above 2x normal then this is significant.
• If the transferases are very high (greater than 1000 U/L then the diagnosis is almost certainly hepatitis
• Alcoholic liver disease is unlikely cause an AST of >1000 u/L

AST

• Levels can go as high as 20x normal. This would normally indicate something like viral hepatitis, sever skeletal muscle trauma, extensive surgery, drug induced hepatic trauma,
• Levels from 10-20x normal may suggest MI, and alcoholic cirrhosis.
• 5-10x normal may suggest chronic cirrhosis
• Mildly raised levels are often found it fatty liver (steatosis), liver metastasis and PE.
• These type of enzymes have a similar function to ALT enzymes. These enzymes are found in the liver, RBC’s, cardiac and skeletal muscle, kidney and brain tissue. As a result, damage to any of these areas can result in an increased level on test result.
• It used to be used as a marker for MI, but is not specific enough, and has been superseded by tests for troponins.
• Remember, high levels are likely to be liver OR heart problems OR muscle damage (use other tests, namely ALT to help you decide)
• Levels of AST tend to fluctuate depending on the amount of current acute damage. So levels will be highly raised with a lot of current necrosis, and may only be very slightly raised if there is no current necrosis (even though there may be very severe disease present). Therefore, AST can be used as a monitoring mechanism.

ALP

• These enzymes work best in an alkaline environment are involved in hydrolysis reactions – i.e. they remove a phosphate group from a molecule.
• It is found in large concentrations in cells lining the bile duct and in bone. So when levels are raised in the plasma, it normally means damage to one of these areas. Levels can be physiologically elevated in times of high bone turnover, such as adolescence and in the third trimester of pregnancy.
• ALP is likely to be largely elevated in bile duct blockage, and slightly raised in liver disease (e.g. hepatitis or liver cancer)

Gamma-GT 

• Commonly raised in increased alcohol intake
• Also, very commonly a “false positive”
• Raised levels are common in obstruction of the bile ducts.
• GGT is often used to confirm that ALP readings are due to liver damage and not another cause.
  • If ↑ALP but normal GGT – likely bone – consider checking calcium
  • If ↑ALP and ↑GGT – likely liver cause
• GGT is used to particualrly monitor cirrhosis caused by alcoholism.
• In patients with known liver disease GGT is a strong predictor of mortality

Bilirubin

1-20 µmol/l
Most commonly used to asses for obstructive jaundice. Levels also likely to be raised in liver damage and in cases of severe RBC damage. Test for urobilinogen can be useful in determining whether it is due to RBC’s or a problem with the liver / bile system.

Albumin

33-49g/l
This is the major protein constituent of plasma, and accounts for over 50% of all plasma proteins. It is manufactured in the liver from ingested amno-acids. It helps to regulate osmotic pressure as well as transport nutrients and waste products.
It may often be reduced as a result of;

• Diarrhoea
• Liver disease
• Poor diet
• Iron deficiency
• Infection

Patterns of L​FT results

There are four main patterns of liver function test results, and these help identify what the cause of the abnormal results are. In reality, often there is a mixed picture, making interpretation much more difficult!

1. Obstructive aka Cholestatic Pattern – due to bile duct obstruction. Remember this could be any part of the ducts, even the tiny ones, within the liver itself, it doesn’t necessarily mean the common bile duct. This pattern will give:
   1. High bilirubin
   2. High ALP
   3. Normal ALT (or only slightly raised in comparison to ALP)
2. Hepatitic Pattern – this is a sign of acute liver inflammation. The pattern will give:
   1. Very high ALT – between 200- 2000 U/L
   2. Varying bilirubin – the higher the level, the greater the degree of damage
   3. Slightly raised ALP – should be no higher than 2x normal.
   4. Increased prothrombin time – usually will be slightly raised. In cases of severe liver failure it may exceed 25 seconds
3. Synthetic failure – an emergency presentation requiring urgent referral for ultrasound +/- urgent admission to hospital
   1. Jaundice (high bilirubin)
   2. Increased INR
   3. Low platelets
   4. Low Albumin
4. Isolated raised Bilirubin
   1. Usually the result of Gilbert’s Syndrome
   2. Check unconjugated and conjugated bilirubin to exclude hamolysis

Note that previous recommendations made a distinction between ALT or AST results <x2 normal and >x2 normal. The latest guidelines from the Royal Society of Gastroenterology no longer makes this distinction – as evidence suggests that the degree of elevation, and the duration of elevation does not correlate to the degree of liver disease. Therefore, any rise in these tests should be considered for further investigation. Liver disease is often “silent” until advanced.

Summary

Test Result	Initial Action	Management Plan
↑ Bilirubin only	Check conjugated / unconjugated ratio to exclude haemolysis	Reassure – likely to be Gilbert’s Syndrome
↑ gamma-GT only	From history: Alcohol? Enzyme inducing drugs? Obese?	Reduce alcohol intake Lose weight May require no action – consider repeating tests in 1-3 months
SYNTHETIC FAILURE ↑ INR ↓Albumin ↓ Platelets	Urgent Referral to hospital	In hospital – likely will have full “liver screen” of autoantibodies, ferritin, hepatitis serology
CHOLESTATIC PATTERN ↑ bilirubin ↑ ALP ↑ GGT	USS liver Hepatitis virus serology (Hep B and C) Autoimmune tests (autoantibodies and immunoglobulin)	Likely requires referral (non-urgent) to gastroenterology for further assessment – based on results of secondary investigations May require urgent referral if systemically unwell or signs of malignancy (e.g. weight loss) If all secondary tests are normal, can consider repeating initial LFTs – if resolved – no further management required
HEPATITIC PATTERN↑ ALP ↑ ALT ↑ AST	Further Tests: Hepatitis virus serology (Hep B and C) Autoimmune tests (autoantibodies and immunoglobulin) Ferritin USS liver	Dilated bile ducts on USS: Refer for cholangiography, ERCP Normal bile ducts: Treat underlying disorder – e.g. viral hepatitis, autoimmune liver disease, haemochromatosis, NAFLD, Alcoholic fatty liver disease If viral serology, autoimmune and ferritin tests are normal – likely AFLD or NAFLD – depending on risk factors Reduce alcohol intake Stop hepatotoxic drugs Advise weight loss Weight (BMI>25) Consider Fibroscan or ELF blood test Consider referral for further evaluation

Adapted from a table in – Davidson’s Principles and Practice of Medicine. 20^th ed. Churchill Livingstone, (2006), Boon, NA., Colledge, NR., Walker, BR. and updated with reference to Guidelines on the Management of abnormal liver blood tests by the Royal College of Gastroenterology, 2016. 

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Guidelines on the management of abnormal liver blood tests

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