Abnormal Liver Function Tests

Interpreting abnormal liver function tests and trying to diagnose any underlying liver disease is a common scenario in Primary Care. Abnormal liver function tests may be asymptomatic, and are often inadequately investigated - which may miss an early opportunity of identifying and treating chronic liver disease.¹
The primary problem may be the liver, or the abnormal results can be secondary to other problems elsewhere in the body.²

Alternatively there may be nothing wrong with the liver at all! Traditionally "normal" values are defined as being within ± 2 standard deviations meaning that 2.5% of a healthy population will have liver function tests outside the normal range. However, as liver disease is frequently asymptomatic, such a "healthy" population may have significant numbers of people with undiagnosed liver disease, and thus this argument should not be used as an excuse for inadequate investigation.

Liver function tests (LFTs) are readily available and are often included as a baseline investigation for a large number of different presentations. They usually consist of:

• Bilirubin:
  • Bilirubin is derived from the breakdown of haem in the red blood cells within the reticuloendothelial system.
  • The unconjugated bilirubin then binds albumin and is taken up by the liver.
  • In the liver it is conjugated which then makes it water soluble and thus allows it to be excreted into the urine.
  • Normally total serum bilirubin is measured, however the unconjugated and conjugated portions can be determined by measures of the fractions of indirect bilirubin and direct bilirubin respectively.³
• Albumin - sensitive marker of hepatic function, but not useful in the acute stages as has a long half life (20 days).
• Total Protein
• Transferases - usually either Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST), rarely does a laboratory routinely provide both:
  • These enzymes normally reside inside cells (in cytoplasm) so raised levels usually represent hepatocellular damage. ALT is more specific to the liver, as AST is also found in cardiac and skeletal muscle and red blood cells.
  • Very high levels (>1000 IU/l) suggest drug induced hepatitis (e.g. paracetamol), acute viral hepatitis (A or B) , ischaemic or rarely autoimmune hepatitis.
  • The ratio of AST to ALT can give some extra clues as to the cause:
    In chronic liver disease ALT > AST, once cirrhosis established AST > ALT. The extremes of the ratio of AST:ALT can also be helpful: >2 suggests alcoholic liver disease, and a ratio of <1.0 suggests non-alcoholic liver disease.^2,4
• Gamma-glutamyl transferase (GGT) - also related to the bile ducts. Typically elevated in cholestasis (with elevated ALP), but if ALP normal suggests induction of hepatic metabolic enzymes (e.g alcohol or enzyme inducing drugs).
• Alkaline phosphatase (ALP) - comes mainly from the cells lining bile ducts but also in bone. Marked elevation is typical of cholestasis (often with elevated GGT) or bone disorders (usually normal GGT). Isoenzymes analysis may help identify source. It is physiologically increased when there is increased bone turnover (e.g. adolescence) and is elevated in the third trimester (produced by the placenta).

When basic liver function tests are abnormal, ensure a full history and examination is performed:

• The other transaminase - i.e. ensure you have both ALT and AST results. The ratio of AST to ALT may be useful for distinguishing fatty liver due to alcoholic and non-alcoholic aetiologies (see above)
• Prothrombin (INR) - sensitive marker of hepatic synthetic function
• Viral serology e.g. hepatitis B and C, CMV, EBV and possibly HIV
• Autoantibody screen e.g. anti-mitochondrial antibody, anti-smooth muscle antibody and anti-nuclear antibody
• Immunoglobulins (if not available, raised immunoglobulins may be suggested by a raised globulin fraction (total protein minus albumin))
• Serum ferritin and transferrin saturation
• α fetoprotein
• Copper / caeruloplasmin
• α 1 antitrypsin
• Imaging: ultrasound is non-invasive and helpful to detect structural abnormalities

Consider drug toxicity in all cases.⁶

Once results are obtained determine which of the following scenarios they fit in to:

• Rise in bilirubin alone - need to know if unconjugated hyperbilirubinaemia or conjugated hyperbilirubinaemia. Usually due to defects of hepatic excretion. It can be detected by measuring the direct bilirubin component of the total bilirubin (> 50% confirms the presence of conjugated hyperbilirubinaemia).
  Unconjugated -
  • Haemolysis - Check reticulocyte count, blood film, haptoglobins, LDH and may need direct Coomb's test. Liaise with haematologist.
  • Drugs
  • Gilbert's syndrome
  • Crigler-Najjar syndrome
  Conjugated -
  • Dubin-Johnson syndrome
  • Rotor syndrome
  • Chronic liver disease, (usually associated with other liver function test abnormalities)
• Obstructive picture or cholestasis - rise in ALP and GGT more than AST and ALT. This may be intrahepatic or extrahepatic (bilirubin will also be raised).
  • Intrahepatic -
    • primary biliary cirrhosis
    • drugs
  • Extrahepatic -
    • Gallstone in common bile duct
    • Head of pancreas neoplasm
    • Drugs e.g. erythromycin, tricyclic antidepressants, flucloxacillin, oral contraceptive pill and anabolic steroids
    • Cardiac failure - improves with treatment
    • Primary biliary cirrhosis - commoner in women and first sign is a rise in ALP
    • Primary sclerosing cholangitis
    • Neoplasm - primary (rarely) and secondaries
    • Familial (benign)
• Hepatitic picture Rise in AST and ALT more than ALP and GGT:
  • Alcohol - fatty infiltration and acute alcoholic hepatitis (usually associated with markedly deranged liver function).
  • Cirrhosis of any cause - alcohol being one of the commonest.
  • Medications e.g. Phenytoin, carbamazepine, isoniazid, statins, methotrexate, paracetamol overdose, amiodarone. (Transaminases may be >1000 IU/l).
  • Chronic hepatitis B and C.
  • Acute viral hepatitis e.g. hepatitis A, B and C and CMV infection.
  • Autoimmune hepatitis.
  • Neoplasms - primary or secondaries.
  • Haemochromatosis.
  • Metabolic - Glycogen storage disorders, Wilson's disease.
  • Ischaemic liver injury e.g. severe hypotension
  • Fatty liver disease (mild elevation in transaminases <100 IU/l).
  • Non-hepatic causes: Coeliac disease, haemolysis and hyperthyroidism.
• Isolated rise in individual enzymes e.g. ALP and GGT:
  • Isolated rise in GGT:
    • This is most commonly due to alcohol abuse, or enzyme inducing drugs.
    • An isolated rise can occur even if no major liver disease.
    • The rise is not related to the amount of alcohol intake.
    • Also many heavy alcohol users may have normal GGT.
    • Stopping alcohol for 4 weeks should rectify the abnormality.
  • Isolated rise in ALP:
    • Third trimester of pregnancy (comes from the placenta - a normal finding)
    • If isolated rise in ALP consider other sources e.g. bone or kidney
      In the elderly consider:
      • Fractures
      • Paget's disease of bone
      • Osteomalacia
      • Bony metastases
      ALP is not usually raised in myeloma or osteoporosis (without a fracture).
• Occasionally the liver enzymes e.g. ALP, GGT, AST or ALT may all be similarly elevated making it difficult to determine whether it is a cholestatic or hepatitic picture.

Any liver abnormalities with evidence of hepatic dysfunction e.g. low albumin, raised INR should be referred to a specialist.⁷

1. If slightly abnormal rise in liver function tests (i.e. less than twice upper limit of normal):
   • Repeat liver function tests in 6 months time.
   • If you suspect the cause to be alcohol related then inform the patient and ask them to abstain and repeat the tests.
   • Other lifestyle changes may help e.g. good DM control and weight loss.
   • If still abnormal perform further tests e.g. viral serology or ultrasonography.
   • If remain abnormal for longer than six months then consider referral to a specialist.
   • If the patient is unwell despite slightly abnormal LFT's then they may need to be referred more urgently.
2. Very abnormal liver function tests (i.e. more than twice upper limit of abnormal):
   • Organise further blood tests and imaging.
   • Refer to out-patients - if you suspect the cause may be malignancy then an urgent cancer referral should be made.⁷

Consider urgent referral for hospital admission if patient unwell, for example

• Severe jaundice
• Severe ascites
• Encephalopathy
• Septic

Otherwise out-patient referral for anyone less ill if indicated - but try to determine cause.