LFT’s

Question 1

Why check LFT’s?

Answer 1

Why check LFTs?
LFTs are requested for two primary reasons:

• To confirm a clinical suspicion of potential liver injury or disease.

• To distinguish between hepatocellular injury (hepatic jaundice) and cholestasis (post-hepatic or obstructive jaundice).

Question 2

What blood tests are used to assess liver function?

Answer 2

What blood tests are used to assess liver function?
• Alanine transaminase (ALT)
• Aspartate aminotransferase (AST)
• Alkaline phosphatase (ALP)
• Gamma-glutamyltransferase (GGT)
• Bilirubin
• Albumin
• 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.

Question 3

LFT reference ranges

Answer 3

Reference ranges
Below is a summary of the reference ranges for LFTs, however, these often vary between laboratories, so make sure to check your local guidelines.
ALT 3-40 iu/l
AST 3-30 iu/l
ALP 30-100 umol/l
GGT 8-60 u/l
Bilirubin 3-17 umol/l
Albumin 35-50 g/l
PT 10-14 seconds

Question 4

Common causes of hepatocellular injury.
What LFT would indicate this?

Answer 4

Raised ALT / AST levels in the blood occur in pathologies that cause liver cell (hepatocyte) inflammation or damage. Therefore, raised ALT / AST levels are a marker of hepatocellular injury.

Common causes of hepatocellular injury include:
• Hepatitis (viral, alcoholic, ischaemic)
• Liver cirrhosis
• Drug / toxin-induced liver injury (e.g. paracetamol overdose)
• Malignancy (hepatocellular carcinoma)
Hint: The AST:ALT ratio can help determine the aetiology of hepatocellular injury, with a >2:1 ratio classical of alcoholic liver disease.2

Question 5

ALT/AST

Answer 5

ALT / AST
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are enzymes found within liver cells at high concentrations.
Raised ALT / AST levels in the blood occur in pathologies that cause liver cell (hepatocyte) inflammation or damage. Therefore, raised ALT / AST levels are a marker of hepatocellular injury.

Question 6

ALP

Answer 6

Serum alkaline phosphatase (ALP) is derived from biliary epithelial cells (cells lining the biliary tract) and bones. Raised ALP levels can therefore be caused by cholestasis or bone disease.

Question 7

GGT

Answer 7

Gamma-glutamyltransferase (GGT) is found in hepatocytes and also biliary epithelial cells.2 It is a non-specific but highly sensitive marker of liver damage and cholestasis.
ALP and GGT are interpreted together to localise the source of raised ALP in the blood.

Question 8

ALP and GGT results

Answer 8

• An ALP rise with normal GGT suggests bone disease (e.g. Paget’s disease, vitamin D deficiency, bony metastases)
• An ALP rise with associated GGT rise is more suggestive of cholestasis
Hint: An isolated GGT rise is classically associated with alcohol excess.

Question 9

What is cholestasis?

Answer 9

Cholestasis
Cholestasis describes an interruption in the bile flow from hepatocytes to the small intestine. Common causes include gallstone disease, external compression of the biliary tract (e.g. pancreatic malignancy) or medication side effects. Bilirubin may or may not be raised depending on the severity of cholestasis.

Question 10

Bilirubin

Answer 10

Bilirubin
Bilirubin is a waste product of haemoglobin breakdown. It is predominantly metabolised and excreted by the liver. Raised levels of bilirubin in the blood will lead to a yellowing of the skin, known as jaundice.
Hint: Jaundice is usually absent until the bilirubin level exceeds 50 micromol/L.

Question 11

Bilirubin metabolism

Answer 11

Bilirubin metabolism

• When red blood cells are broken down, unconjugated (insoluble) bilirubin is created as a waste product and binds to albumin in the bloodstream

• Hepatocytes take up unconjugated bilirubin and metabolise it to form conjugated (soluble) bilirubin

• Hepatocytes excrete conjugated bilirubin into the biliary tract, where it flows into the bowel lumen as bile

• Gut bacteria further metabolise bilirubin in bile to form urobilinogen, which is eventually excreted in the stools as stercobilinogen

• A small amount of urobilinogen is reabsorbed from the intestine into the portal venous system, and as urobilinogen is water-soluble, the kidney is able to excrete some of this into the urine.

Stercobilinogen gives stools their dark colour. Urobilinogen is colourless in the urine. However, if the urine is left exposed to the air, oxidation will occur, creating a dark colour. Under normal physiological conditions, urobilinogen will be present in the urine, however conjugated bilirubin will not be present.

Question 12

Causes of raised bilirubin

Answer 12

Raised levels of bilirubin in the blood can be caused by:
• Excess bilirubin production (pre-hepatic jaundice)
• A breakdown in bilirubin metabolism (hepatocellular jaundice)
• A blockage in the bile excretion pathway (cholestatic jaundice)

Question 13

Causes of predominantly unconjugated hyperbilirubinaemia:

Answer 13

Causes of predominantly unconjugated hyperbilirubinaemia:
• Pre-hepatic jaundice (e.g. haemolysis)
• Gilbert syndrome

Question 14

Causes of predominantly conjugated hyperbilirubinaemia:

Answer 14

Causes of predominantly conjugated hyperbilirubinaemia:
• Cholestasis

• Hepatocellular jaundice*
*Hepatocellular jaundice can initially cause a mixed conjugated/unconjugated jaundice, but at its most severe, unconjugated hyperbilirubinaemia is seen.

Question 15

What is the role of albumin?

Answer 15

Albumin
Albumin is synthesised in the liver and helps to bind water, cations, fatty acids and bilirubin. It also plays a crucial role in maintaining the oncotic pressure of blood. Albumin is used as a non-specificmarker of the synthetic function of the liver.

Question 16

Why would albumin levels fall?

Answer 16

Albumin levels can fall due to:
• Decreased albumin production: malnutrition, severe liver disease
• Increased albumin loss: protein-losing enteropathies, nephrotic syndrome
Hint: A decrease in the synthetic function of the liver indicates severe liver disease.
Albumin has a half-life of 20 days, so it will take time to decrease, even in severe liver disease. Further assessment of the synthetic function of the liver can be gained by ordering a coagulation screen, as the liver is also responsible for the synthesis of clotting factors.

Question 17

What LFTs are used to assess synthetic function of the liver?

Answer 17

Albumin
Decreased clotting factors/ increased PT time
Gluconeogenesis ability

Albumin is used as a non-specificmarker of the synthetic function of the liver.
Albumin levels can fall due to:
• Decreased albumin production: malnutrition, severe liver disease
• Increased albumin loss: protein-losing enteropathies, nephrotic syndrome
Hint: A decrease in the synthetic function of the liver indicates severe liver disease.
Albumin has a half-life of 20 days, so it will take time to decrease, even in severe liver disease. Further assessment of the synthetic function of the liver can be gained by ordering a coagulation screen, as the liver is also responsible for the synthesis of clotting factors.
Severe liver disease leads to decreased production of clotting factors and an increased prothrombin time (PT) / INR in the absence of other causes of coagulopathy.
The liver is also responsible for gluconeogenesis, and serum blood glucose assessment can also indirectly assess the liver’s synthetic function. However, gluconeogenesis tends to be one of the last functions to become impaired in liver failure.

Question 18

Pre hepatic jaundice

Answer 18

Pre-hepatic jaundice
Pre-hepatic jaundice occurs when increased red blood cell breakdown produces excess bilirubin. This can overwhelm metabolism/excretion pathways, leading to jaundice.

The most common cause of increased red blood cell breakdown is haemolysis. Bilirubin is unconjugated in the blood, as the hepatocytes have not yet metabolised it. The remainder of LFTs are generally normal, as the liver is otherwise working well.

Hint: In pre-hepatic jaundice, patients are often anaemic due to excess red blood cell breakdown. The diagnosis may be Gilbert’s syndrome if no anaemia is present.
Gilbert’s syndrome
Gilbert’s syndrome is a congenital disorder present in up to 5% of the population. It results from a deficiency of glucosyltransferase, the enzyme responsible for the conjugation of bilirubin within hepatocytes.
Gilbert’s syndrome classically presents following viral infection with raised bilirubin but normal LFTs/ full blood count. The disease is benign and requires no specific management.

Question 19

Gilbert’s syndrome

Answer 19

Gilbert’s syndrome
Gilbert’s syndrome is a congenital disorder present in up to 5% of the population. It results from a deficiency of glucosyltransferase, the enzyme responsible for the conjugation of bilirubin within hepatocytes.
Gilbert’s syndrome classically presents following viral infection with raised bilirubin but normal LFTs/ full blood count. The disease is benign and requires no specific management.

Question 20

Hepatocellular jaundice

Answer 20

Hepatocellular jaundice
Hepatocellular jaundice occurs when hepatocytes are damaged and dysfunctional, leading to an inability to metabolise unconjugated bilirubin from the bloodstream. This leads to high levels of unconjugated bilirubin in the blood. There will generally also be very high ALT / AST levels, marking hepatocyte damage.
Hint: Common causes of hepatocellular injury are covered above (hepatitis, cirrhosis, malignancy, drug or toxin insult). When liver injury is severe, there are not enough functioning hepatocytes to metabolise bilirubin, and jaundice will develop.

Question 21

Cholestatic (obstructive) jaundice

Answer 21

Cholestatic (obstructive) jaundice
Cholestasis is an interruption in bile flow from hepatocytes to the gut. When this interruption is severe, bilirubin levels will build up in the blood. The bilirubin has been metabolised in the liver, and thus the bilirubin in the blood is predominantly conjugated bilirubin. There will generally also be high ALP levels with associated high GGT, marking dysfunction of the biliary system.
Obstructive jaundice will classically lead to dark urine and pale stools. Bilirubin cannot enter the gastrointestinal tract due to cholestasis, leading to low stercobilinogen excretion in stools.
The bilirubin in the blood is conjugated and can be filtered by the kidneys. The presence of conjugated bilirubin gives the urine a very dark colour.

Hint: Stools may also be pale in hepatocellular jaundice, as there is decreased bilirubin metabolism/excretion, however as the bilirubin in the blood is unconjugated, it will not be able to pass into the urine. Therefore, the urine should remain a normal colour.

Question 22

Causes of cholestasis.

Answer 22

Causes of cholestasis
Cholestasis can occur due to either intrahepatic or extrahepatic biliary obstruction.

Causes of intrahepatic obstruction (obstruction of the hepatic bile canaliculi):
• Hepatitis
• Cirrhosis
• Malignancy
• Drugs (e.g. antibiotics, oral contraceptive pills, anabolic steroids)
• Pregnancy

Causes of extrahepatic obstruction (obstruction of hepatic ducts, or distal biliary tree):
• Gallstones
• Primary sclerosing cholangitis
• Intraluminal malignancy: cholangiocarcinoma
• Extraluminal malignancy causing duct compression: head of pancreas tumours

Question 23

Pre hepatic jaundice LFT’s

Answer 23

Raised bilirubin (anaemia) - haemolysis
Raised bilirubin (no anaemia) - Gilbert’s syndrome

Question 24

Hepatocellular jaundice LFT’s and causes

Answer 24

High unconjugated bilirubin
High ALT/AST

Common causes of hepatocellular injury are hepatitis, cirrhosis, malignancy, drug or toxin insult). When liver injury is severe, there are not enough functioning hepatocytes to metabolise bilirubin, and jaundice will develop.

Question 25

What is hepatocellular jaundice?

Answer 25

Hepatocellular jaundice occurs when hepatocytes are damaged and dysfunctional, leading to an inability to metabolise unconjugated bilirubin from the bloodstream. This leads to high levels of unconjugated bilirubin in the blood. There will generally also be very high ALT / AST levels, marking hepatocyte damage.

Question 26

Cholestatic (obstructive) jaundice LFT results

Answer 26

High bilirubin
High ALP/ GGT

Question 27

LFT interpretation method:
ALT/AST vs ALP/GGT

Answer 27

LFT interpretation method
Determine the pattern of LFT derangement

The pattern of ALT to ALP rise can indicate whether the pathology is primarily cholestatic or hepatocellular:

• 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 both hepatocellular injury and cholestasis

An isolated ALP rise without a GGT rise should raise your suspicion of bony pathology.

Question 28

3 stages of LFT interpretation:

Answer 28

Assess ALT/AST vs ALP/GGT

Assess bilirubin

Assess synthetic function ie albumin, PT and glucose

Question 29

Further investigations following LFT interpretation

Answer 29

Once the pattern of LFT derangement has been established, it is essential to determine the underlying cause.

If cholestasis is suspected, an ultrasound should be arranged to assess the biliary tree for a potential site/cause of biliary obstruction.

If hepatocellular injury is suspected, a liver ultrasound is generally arranged to assess for any structural lesions that may give clues as to the diagnosis. If the cause is unclear, a ‘liver screen’ may be ordered to investigate further.

Question 30

What is included in a liver screen?

Answer 30

Liver screen
A ‘liver screen’ is a batch of blood investigations to identify a wide range of potential causes of liver disease:

• 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)
• p-ANCA
• Immunoglobulins – IgM/IgG
• Alpha-1 Antitrypsin (to rule out alpha-1 antitrypsin deficiency)
• Serum Copper (to rule out Wilson’s disease)
• Ceruloplasmin (to rule out Wilson’s disease)
• Ferritin (to rule out haemochromatosis)