06-02-23 - Liver function and LFTs

Question 1

Learning outcomes

Answer 1

• How to make use of biochemical testing to aid in a diagnosis
• Highlight the limitations of biochemical testing which are useful but seldom diagnostic.
• Understand why good practice includes taking a good clinical history.

Question 2

What type of organ is the liver?

What are the 2 blood supplies of the liver?

What are the functional units of the liver?

What does each liver consist of?

Where are Kupffer cells located?

Answer 2

• The liver is Both a metabolic and excretory organ
• 2 blood supplies of the liver:
  1) Hepatic artery – oxygenated blood
  2) Portal vein – nutrient rich blood
• The functional unit of the liver is a lobule
• Each lobule is composed of hepatocytes (parenchymal cells) arranged in plates, in contact with bloodstream on one side & bile canaliculi (“little canals”) on the other
• Between the plates are vascular spaces (sinusoids) containing Kupffer cells (phagocytic macrophages)

Question 3

What are 4 different functions of the liver?

Answer 3

• 4 different functions of the liver:

1) Metabolic functions
* Carbohydrates, Hormones, Lipids, Drugs & Proteins

2) Storage
* Glycogen, vitamins, iron

3) Protective
* Detoxification and elimination of toxic compounds
* Kupffer cells ingest bacteria & other foreign material from blood.

4) Bile production and excretion
* Formed in biliary canaliculi, emulsifies fats & provides route for waste removal

Question 4

What are 7 different classifications of liver disease?

Answer 4

• 7 different classifications of liver disease:

1) Infection
* Viral (Hepatitis A-E, CMV)
* Bacterial
* Parasitic

2) Toxic / Drug induced

3) Autoimmune

4) Biliary tract obstruction
* Tumours
* Gallstones

5) Vascular

6) Metabolic
* Haemochromatosis – Iron overload, causes darkening of the skin
* Wilson’s disease – Copper overload
* Hereditary hyperbilirubinemias – elevated bilirubin

7) Neoplastic
* An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should.

Question 5

What are 3 causes of acute hepatitis?

What are 3 outcomes of acute hepatitis?

Answer 5

• 3 causes of acute hepatitis:
  1) Poisoning (paracetamol)
  2) Infection (Hepatitis A-C)
  3) Inadequate perfusion
• 3 outcomes of acute hepatitis:
  1) Resolution – majority of cases
  2) Progression to acute hepatic failure
  3) Progression to chronic hepatic damage

Question 6

What are 3 common causes of chronic liver disease?

What are 3 unusual causes of chronic liver disease?

Answer 6

• 3 common causes of chronic liver disease:
  1) Alcoholic fatty liver
  2) Chronic active hepatitis
  3) Primary biliary cirrhosis
• 3 unusual causes of chronic liver disease:
  1) α-1 AT deficiency
  2) Haemochromatosis
  3) Wilson’s disease

Question 7

What is cholestasis?

What are 2 causes of cholestasis?

What is the result of cholestasis?

What can this also be due to?

Answer 7

• Cholestasis is the consequence of failure to produce or excrete bile
• 2 causes of cholestasis:
  1) Failure by hepatocytes – intrahepatic cholestasis
  2) Obstruction to bile flow – extrahepatic cholestasis
• Both of these can occur together
• The result of cholestasis is accumulation of bilirubin in the blood leading to jaundice.
• Jaundice may also be due to excessive haemolysis – bilirubin is unconjugated and does not appear in the urine

Question 8

What are 4 effects of liver failure?

Answer 8

• 4 effects of liver failure:

1) Inadequate synthesis of albumin leading to oedema & ascites

2) Inadequate synthesis of clotting factors resulting in bruising

3) Inability to eliminate bilirubin causing jaundice

4) Inability to eliminate nitrogenous waste
* e.g. ammonia, giving rise to hepatic encephalopathy, a poorly defined neuropsychiatric disorder
* This can present with lip biting and flapping movements

Question 9

What is an LFT?

What are 3 questions we look to answer with an LFT?

What 4 markers are tested for in a Fife LFT panel?

What 2 markers are available for testing separately?

Answer 9

• An LFT is a liver functions test (also referred to as a hepatic panel) which is a groups of blood tests that provide information about the state of a patient’s liver
• 3 questions we look to answer with an LFT:
  1) Is liver disease present?
  2) What is the aetiology?
  3) What is the severity?
• 4 markers tested for in a Fife LFT panel:
  1) Alb – albumin
  2) ALT – Alanine transaminase
  3) ALP – Alkaline phosphatase
  4) Bil – bilirubin
• 2 markers are available for testing separately:
  1) ygT -
  2) AST – Aspartate transaminase

Question 10

What are 3 pros of testing for albumin?

What are 3 cons of testing for albumin?

What should we be mindful of when testing for albumin?

How can albumin be depleted?

Answer 10

• 3 pros of testing for albumin:
  1) Main plasma protein
  2) Produced by the liver
  3) Used as an assessment of liver synthetic function
• 3 cons of testing for albumin:
• Low albumin also found in:
  1) Post-surgical/ITU patients due to redistribution
  2) Significant malnutrition
  3) Nephrotic syndrome
• When testing for albumin, we should be mindful of what happened to the patient in the previous few days
• Constant vomiting can deplete albumin

Question 11

How do we test for ALT and AST?

What is a pro of testing for ALT and AST?

What are 2 cons of testing for ALT and AST?

Answer 11

• We test for ALT and AST separately (very sensitive markers)
• ALT – Alanine transaminase
• AST – Aspartate transaminase
• A pro of testing for ALT and AST is they are cytoplasmic enzymes which are sensitive markers of acute damage to hepatocytes
• 2 cons of testing for ALT and AST:

1) Non-specific: found in cardiac muscle & erythrocytes as well as the liver
* Have to determine if raised ALT/AST is due to heart/liver or something else

2) Also raised in e.g. – skeletal muscle disorders, – MI

Question 12

When is synthesis of alkaline phosphatase (ALP) increased?

What are 2 pros of testing for ALP?

What are 2 cons of testing for ALP?

Answer 12

• Synthesis of alkaline phosphatase (ALP) is increased in response to cholestasis (reduced or stopped bile flow from liver)
• 2 pros of testing for ALP:
  1) Used to look for biliary epithelial damage & obstruction
  2) Increased in liver disease due to increased synthesis in response to cholestasis
• 2 cons of testing for ALP:

1) ALP isoenzymes also present in bone, gut & placenta.
* Elevated in pregnancy and growth spurts of children

2) Raised in:
* Physiological states e.g., pregnancy, childhood
* Bone is broken or in some bony diseases
* Induced by some drugs

Question 13

What is ygT a sensitive marker for?

What are 2 pros of testing for ygT?

What are 3 cons of testing for ygT?

Answer 13

• ygT is a sensitive marker for alcohol intake
• Good to monitor ygT along with alcohol intake
• 2 pros of testing for ygT:
  1) Also used to look for biliary epithelial damage & obstruction.
  2) “Super”-sensitive
• 3 cons of testing for ygT:
  1) Also present in bone, biliary tract, pancreas & kidney.
  2) Affected by ingestion of alcohol and drugs such as phenytoin .
  3) May be over-sensitive? (why it has been dropped as a proper test)

Question 14

What are 3 pros of testing for bilirubin?

What is a con of testing for bilirubin?

Answer 14

• 3 pros of testing for bilirubin:

1) Breakdown product of haemoglobin: Unconjugated bilirubin taken up by liver & conjugated then excreted in bile.

2) Raised bilirubin results in clinical jaundice.

3) Used as an indicator of cholestasis.

• Con of testing for bilirubin:
• Also raised in:

1) Haemolysis

2) Hereditary hyperbilirubinaemias e.g. Gilbert’s syndrome.
* Gilbert’s syndrome affects men more can women
* Can occur in people that don’t have as much conjugative jaundice as other people
* Not really harmful and causes non-harmful jaundice

Question 15

What are 2 advantages of current LFTs?

What are 5 disadvantages of current LFTs?

Answer 15

• 2 advantages of current LFTs:
  1) Cheap, widely available, interpretable
  2) Direct subsequent investigation (e.g. imaging – US, X-ray, MRI, CT)
• 5 disadvantages of current LFTs:
  1) Do not assess liver “function”
  2) Lack of complete organ specificity
  3) Lack of disease specificity
  4) May be “over-sensitive”
  5) >40 years old, many newly discovered diseases for which they have no diagnostic value

Question 16

Describe the flow chart for Investigation of the patient with hyperbilirubinaemia (in picture)

Answer 16

Question 17

Describe the marker levels for acute and chronic hepatocellular damage and cholestasis (in picture)

Answer 17

Question 18

Case 1

Answer 18

• 24-year-old woman, on no medication, presented with mild jaundice, malaise and a history of heavy menstrual periods (menorrhagia)
• All investigations normal except bilirubin of 48µmol/L (RI<21) and microcytic anaemia
• Started on Fe supplements for anaemia
• 2 months later, anaemia resolved and bilirubin 28µmol/L
• 6 weeks later returned with chest infection, serum bilirubin = 58 µmol/L
• Fluctuating hyperbilirubinaemia due to Gilbert’s syndrome
• Common autosomal dominant disorder found in up to 7% of population
• Characterised by intermittent mild jaundice evident during periods of fasting and illness
• Due to conjugating defect in liver – conjugated bilirubin may be helpful.
• Benign & no treatment required
• Consider genetic testing
• What is the aetiology?
• Next steps:
• Guided by symptoms, history & initial LFT’s:

1) Hepatitis serology for viral causes or autoantibodies for specific diseases e.g. chronic active hepatitis, PBC

2) Imaging – obstruction, hepatomegaly

3) Specific proteins e.g. α-1 antitrypsin deficiency

4) Iron studies – Haemochromatosis (common)

5) Caeruloplasmin /Cu studies – Wilson’s disease (rare)

6) α-fetoprotein – hepatocellular carcinoma

7) Liver biopsy

Question 19

Case 2

Answer 19

• Case 2
• 49yr old female with pneumonia and septicaemia.
• Started on erythromycin and 5 days later became jaundiced & complained of pruritis.
• She had a previous history of renal stones.
• (LFT in picture)
• Differential diagnosis - ? obstructive jaundice – stones - ? Drug induced cholestasis
• Ultrasound scan equivocal
• ERCP revealed no abnormality
• Erythromycin medication ceased and cholestatic process resolved.
• Consider introduction or change of medication

Question 20

Case 3

Answer 20

Case 3
* 39yr old female presented with chest infection and generally feeling unwell
* Admitted to IV drug use
* Protein 75 g/L (60-80)
* GGT 101 U/L (7-33)
* Albumin 44 g/L (35-50)
* ALT 194 U/L (5-55)
* ALP 79 U/L (30-130)
* Bil 14 umol/L (<21)
* Hepatitis serology positive

• What is the severity?
• Pattern recognition
• LFT’s may be normal or mildly increased in patients with chronic disease e.g. cirrhosis
• Small changes may be significant (e.g. decompensation, long-standing chronic disease)
• Some quite marked increases may be of no apparent consequence, however,
• Long term consequences may be as yet unknown.

Question 21

Case 4

Answer 21

• Case 4
• The following LFT’s are from a 40-year-old man with known alcoholic liver disease
• Protein 75 g/L (60-80)
• γ-GT 780 U/L (7-50)
• Albumin 36 g/L (35-50)
• ALT 104 U/L (5-55)
• ALP 178 U/L (30-130)
• Bilirubin 36 µmol/L (<21)
• Effects of alcohol on the liver can vary from an isolated elevation of γGT to liver damage resulting in fatty infiltration, alcoholic hepatitis or cirrhosis.
• Consider - what if at his last review albumin was 40 g/L and bilirubin 25 µmol/L ?
• This small reduction means they are decompensating

Question 22

How common is liver disease?

When it often identified?

How does this affect mortality and cost to the NHS?

Answer 22

• Liver disease is on the increase:
• 3rd most common cause of death in men < 65 years
• Likely to rise further due to alcohol consumption & obesity
• Often identified late, leading to:
  1) Increased mortality
  2) Increased costs to the NHS

Question 23

What is an intelligent LFT (ILFT)?

What does it combine?

When might it be used?

Answer 23

• The intelligent Liver Function Testing (iLFT) pathway is a novel, automated system designed to improve early diagnosis of liver disease
• Consists of a combination of published diagnostic guidelines and expert opinion (panel).
• The ILFT is a combination of biochemistry, haematology & serology in conjunction with liver ultrasound
• ILFTS may be used in patients with abnormal LFT’s in whom the cause is unclear: – Patients with frank jaundice excluded

Question 24

What are 4 elements of the ILFT?

Answer 24

• 4 elements of the ILFT:

1) Patient specific data
* Age, gender, BMI, features of metabolic syndrome (diabetes, high BP), alcohol intake

2) LFT & FBC performed
* ALT, albumin, bilirubin, alk phos, yGT & platelets.

3) ALT, Alk phos & yGT all normal
* No further tests.

4) Any of ALT, Alk phos & yGT abnormal:
* Aetiology screen - Hepatitis serology, liver immunology, ferritin, alpha1 antitrypsin, caeruloplasmin, AST and
* Fibrosis staging - FIB4 score (Age, AST, ALT & platelet count) - NAFLD fibrosis score (Age, BMI, impaired fasting glucose /frank diabetes, AST, ALT, Albumin, platelets)
* Addition of ELF (Enhanced Live Fibrosis Test: P3NP, hyaluronic acid & TIMP-1) when NAFLD or FIB4 are raised provides further clarification.

Question 25

Describe the flowchart for the ILFT (in picture).

What number of outcomes are there from an ILFT?

Answer 25

• Describe the flowchart for the ILFT (in picture)
• 31 possible outcomes from an ILFT, with advice as to how to follow up.

Question 26

Study data for ILFTs

Answer 26

• Study data for ILFTs:
• 378 cases reviewed.
• 55 found to be jaundiced & excluded.
• Diagnostic agreement in 82.4% of cases using automated pathway.
• 6.4% unnecessarily referred to specialist (fail safe).
• 5 patients (1.5%) were inappropriately referred to GP:
• 2 had disease which is usually self-limiting
• 1 would have been picked up via US result.

Question 27

Case 5

Answer 27

• Case 5
• A 65 year man
• 2 month history of lethargy
• 2 week history of dark urine and upper abdominal discomfort
• Clinically jaundiced - referred to hospital.
• History
• PMH:
• No medications
• Diverticulitis 1 year ago when LFT’s were normal
• Nil else of note, no blood transfusions
• Retired consultant engineer
• Widower
• Teetotal
• No history of foreign travel
• Keen golfer
• LFTs:
• Bilirubin 142 µmol/L (<21)
• ALT 380 U/L (5-55)
• yGT 210 U/L (7-50)
• Alkaline phosphatase 412 U/L (30-130)
• Other investigations
• Liver ultrasound & abdominal CT normal.
• Biopsy showed normal architecture with pronounced cholestasis and inflammation.
• LFT’s improved over 2 weeks.
• Toxic reaction to an unknown toxin.
• Later
• Patient called to say the he had noticed for the first time a sign in the club house at his local golf course (used in Vietnam)
• “Patrons are advised not to lick golf balls as 2,4-phenoxyacetic acid (agent orange) is in use as a selective weedkiller. This substance is toxic if ingested.”
• Later still
• 4 months later the patient requested repeat liver function tests as he was sceptical of the diagnosis.
• When weedkiller was reapplied to the golf course, he had resumed licking his balls for 1 month.
• Later results
• Bilirubin 51 µmol/L (<21)
• ALT 145 U/L (5-55)
• yGT 120 U/L (7-50)
• Alkaline phosphatase 210 U/L (30-130)
• Diagnosis - Golf ball liver