Liver function tests (LFTs) are among the most commonly ordered blood tests in both primary and secondary care. The ability to interpret LFTs is, therefore, an important skill to develop. This guide provides a structured approach to the interpretation of LFTs which you should be able to apply in most circumstances.
Why check LFTs?
LFTs are ordered for two primary reasons:
- To confirm clinical suspicion of potential liver injury or disease
- To distinguish between hepatocellular injury (hepatic jaundice) and cholestasis (post-hepatic or obstructive jaundice)
What blood tests are used to assess liver function?
- Alanine transaminase (ALT)
- Aspartate aminotransferase (AST)
- Alkaline phosphatase (ALP)
- Gamma-Glutamyltransferase (GGT)
- Prothrombin time (PT)
Hint: ALT, AST, ALP and GGT are used to distinguish between hepatocellular damage and cholestasis. Bilirubin, albumin and PT are used to assess the liver’s synthetic function.
|PT||10-14 s/ 1|
*Reference ranges may vary between laboratories
Step 1 – Assess ALT and ALP
Is ALT and/or ALP raised?
- If the ALT is raised, decide if this is a more than a 10-fold rise (↑↑) or a less than a 10-fold rise (↑)
- If the ALP is raised, decide if this is a more than a 3-fold rise (↑↑) or a less than a 3-fold rise (↑)
Step 2 – Compare ALT and ALP levels
Key facts about ALT and ALP
ALT is found in high concentrations within hepatocytes and enters the blood following hepatocellular injury. It is, therefore, a useful marker of hepatocellular injury.
ALP is particularly concentrated in the liver, bile duct and bone tissues. ALP is often raised in liver pathology due to increased synthesis in response to cholestasis. As a result, ALP is a useful indirect marker of cholestasis.
How do we compare the rise in ALT and ALP?
- A greater than 10-fold increase in ALT and a less than 3-fold increase in ALP suggests a predominantly hepatocellular injury
- A less than 10-fold increase in ALT and a more than 3-fold increase in ALP suggests cholestasis
- It is possible to have a mixed picture involving hepatocellular injury and cholestasis (e.g. ALT < 10-fold increase and ALP > 3-fold increase)
What about Gamma-glutamyl transferase?
If there is a rise in ALP, it important to review the level of gamma-glutamyl transferase (GGT). A raised GGT can be suggestive of biliary epithelial damage and bile flow obstruction. It can also be raised in response to alcohol and drugs such as phenytoin. A markedly raised ALP with a raised GGT is highly suggestive of cholestasis.
A raised ALP in the absence of a raised GGT should raise your suspicion of non-hepatobiliary pathology. Alkaline phosphatase is also present in bone and therefore anything that leads to increased bone breakdown can elevate ALP.
Causes of an isolated rise in ALP include:
- Bony metastases / primary bone tumours (e.g. sarcoma)
- Vitamin D deficiency
- Recent bone fractures
- Renal osteodystrophy
Hint: Compare to what degree the ALT and ALP are raised. If ALT is raised markedly compared to the ALP, this is primarily a hepatocellular pattern of injury. If ALP is raised markedly compared to ALT, this is primarily a cholestatic pattern of injury.
What if the patient is jaundiced but ALT and ALP levels are normal?
An isolated rise in bilirubin is suggestive of a pre-hepatic cause of jaundice.
Causes of isolated jaundice include:
- Gilbert’s syndrome (most common cause)
- Haemolysis (check blood film, full blood count, reticulocyte count, haptoglobin and LDH levels to confirm)
Step 3- Assess hepatic function
The liver’s main synthetic functions include:
- Conjugation and elimination of bilirubin
- Synthesis of albumin
- Synthesis of clotting factors
Investigations that can be used to assess synthetic liver function include:
- Serum bilirubin
- Serum albumin
- Prothrombin time (PT)
- Serum blood glucose
Bilirubin is a breakdown product of haemoglobin. Unconjugated bilirubin is taken up by the liver and then conjugated. Hyperbilirubinaemia may not always cause clinically-apparent jaundice (usually visible >60 umol/l). The patient’s symptoms and clinical signs can help differentiate between conjugated and unconjugated hyperbilirubinaemia. Unconjugated bilirubin is water-insoluble and therefore doesn’t affect the colour of the patient’s urine. Conjugated bilirubin, however, can pass into the urine as urobilinogen, causing the urine to become darker. 1
In a similar fashion, the colour of the stools can be used to differentiate the causes of jaundice. In cholestasis, less conjugated bilirubin enters the gut, resulting in stools becoming pale (known as steatorrhoea). ¹
The combination of the colour of urine and stools can give an indication as to the cause of jaundice:
- Normal urine + normal stools = pre-hepatic cause
- Dark urine + normal stools = hepatic cause
- Dark urine + pale stools = post-hepatic cause (obstructive)
Causes of unconjugated hyperbilirubinaemia include:
- Haemolysis (e.g. haemolytic anaemia)
- Impaired hepatic uptake (drugs, congestive cardiac failure)
- Impaired conjugation (Gilbert’s syndrome)
Causes of conjugated hyperbilirubinaemia include:
- Hepatocellular injury
Albumin is synthesised in the liver and helps to bind water, cations, fatty acids and bilirubin. It also plays a key role in maintaining the oncotic pressure of blood.
Albumin levels can fall due to:
- Liver disease resulting in a decreased production of albumin (e.g. cirrhosis)
- Inflammation triggering an acute phase response which temporarily decreases the liver’s production of albumin
- Excessive loss of albumin due to protein-losing enteropathies or nephrotic syndrome
Prothrombin time (PT) is a measure of the blood’s coagulation tendency, specifically assessing the extrinsic pathway. In the absence of other secondary causes such as anticoagulant drug use and vitamin K deficiency, an increased PT can indicate liver disease and dysfunction. The liver is responsible for the synthesis of clotting factors, therefore hepatic pathology can impair this process resulting in an increased prothrombin time.
The ALT/AST ratio can be used to determine the likely cause of LFT derangement:
- ALT > AST is seen in chronic liver disease
- AST > ALT is seen in cirrhosis and acute alcoholic hepatitis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. The liver plays a significant role in gluconeogenesis and therefore assessment of serum blood glucose can provide an indirect assessment of the liver’s synthetic function. Gluconeogenesis tends to be one of the last functions to become impaired in the context of liver failure.
Step 5- Common patterns of LFT derangement
The table below demonstrates the typical LFT patterns associated with acute hepatocellular damage, chronic hepatocellular damage and cholestasis. A single arrow (↑) refers to a mild impairment and a double arrow (↑↑) refers to severe impairment.
|Acute hepatocellular damage||Chronic hepatocellular damage||
|ALT||↑↑||Normal or ↑||Normal or ↑|
|ALP||Normal or ↑||Normal or ↑||↑↑|
|GGT||Normal or ↑||Normal or ↑||↑↑|
|Bilirubin||↑ or ↑↑||Normal or ↑||↑↑|
Step 6- What to do next
Once the pattern of LFT derangement has been established, it is crucial to determine the cause.
Common causes of acute hepatocellular injury include:
- Poisoning (paracetamol overdose)
- Infection (Hepatitis A and B)
- Liver ischaemia
Common causes of chronic hepatocellular injury include:
- Alcoholic fatty liver disease
- Non-alcoholic fatty liver disease
- Chronic infection (Hepatitis B or C)
- Primary biliary cirrhosis
Less common causes of chronic hepatocellular injury include:
- alpha-1 antitrypsin deficiency
- Wilson’s disease
The liver screen
A ‘liver screen’ is a batch of investigations focused on ruling underlying causes of liver disease in or out.
A typical liver screen includes:
- Coagulation screen
- Hepatitis serology (A/B/C)
- Epstein-Barr Virus (EBV)
- Cytomegalovirus (CMV)
- Anti-mitochondrial antibody (AMA)
- Anti-smooth muscle antibody (ASMA)
- Anti-liver/kidney microsomal antibodies (Anti-LKM)
- Anti-nuclear antibody (ANA)
- Immunoglobulins – IgM/IgG
- Alpha-1 Antitrypsin – Alpha-1 Antitrypsin deficiency
- Serum Copper – Wilson’s disease
- Ceruloplasmin – Wilson’s disease
- Ferritin – Haemochromatosis
1. Roxe DM. Urinalysis. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 191. Available from: https://www.ncbi.nlm.nih.gov/books/NBK302/