liver function tests (LFTs)

see also:

• assessment of hepatic function
• liver diseases
• cirrhosis
• hepatomegaly
• hepatitis

• liver functions tests are commonly ordered as a screening test for patients with upper abdominal pain, jaundice (icterus), or for a variety of other presentations.
• ALT and AST are the main markers of liver damage, although thse can also be raised in muscle damage conditions
• glutamate dehydrogenase (GLDH) is a more liver-specific biomarker for detecting liver injury but is not currently available as a test ¹⁾
• bilirubin, AP and GGT tend to be raised in cholestatic conditions but can be raised due to other conditions
• serum albumin falls as a marker of acute phase reactions such as severe infection, but can also fall due to many other conditions (decreased production, increased renal protein losses, etc)

• LFTs may be abnormal for a range of aetiologies which can generally be grouped as follows:
  • acute hepatocyte damage:
    • this may be due to a viral or drug induced hepatitis, bacterial infections such as:
      • drug induced: alcohol, paracetamol overdose, etc
      • sepsis / septicaemia
      • Salmonella typhi (typhoid enteric fever)
      • hepatitis
      • cytomegalovirus (CMV)
      • EBV / glandular fever / infectious mononucleosis
      • ischaemic hepatitic necrosis
        • severe congestive cardiac failure
        • the shocked hypotensive patient
        • septic shock
      • neoplasia / cancer / tumours
      • heat illness and heat stroke, etc
      • rarely, Budd-Chiari syndrome (BCS)
    • the LFT's generally show a “hepatitic picture” of elevated ALT and AST (particularly if 10-fold increase compared to less than 2 fold increase in AP and GGT) +/- raised bilirubin with lesser or no elevations in GGT or AP
    • most of these conditions cause a similar rise in BOTH AST and ALT
      • levels > 50 fold increase may be seen in ischaemic hepatitic necrosis
      • levels > 25 fold increase often occur in viral or drug-induced hepatitis
      • acute liver failure typically is characterised by increases > 10-fold, plus abnormal clotting time
      • non-alcoholic fatty liver and haemochromatosis usually has < 4-fold increase
      • chronic hepatitis C infection usually has a < 2-fold increase but may be up to 10-fold increase
    • alcoholic liver disease may see rises up to 8-fold for AST and 5-fold for ALT
      • patients undergoing liver biopsy with a AST:ALT ratio > 2 are most likely to have hepatitis or cirrhosis due alcohol, particularly if ratio > 3, and if GGT is also raised ²⁾
    • hepatitic picture with thrombocytopenia:
      • Salmonella typhi (typhoid enteric fever)
      • HELLP syndrome in pregnancy
      • pre-eclampsia and eclampsia
      • viral haemorrhagic fevers and similar such as Severe fever with thrombocytopenia syndrome virus (SFTSV)
  • bile obstruction picture:
    • this is usually due to cholelithiasis but may occur with some drugs, particularly, alcohol, and from external compression on biliary tree such as via neoplasia / cancer / tumours
    • the LFT's generally show a “cholestatic picture” of elevated AP and GGT +/- raised bilirubin with lesser or no elevations in ALT or AST
  • impaired liver function:
    • this is generally demonstrated by a low albumin level (impaired synthesis capability) often with raised bilirubin +/- impaired clotting ability (impaired synthesis capability of clotting factors)
    • rarely, Budd-Chiari syndrome (BCS)
• “mixed picture” abnormal LFTs:
  • often the LFTs show a general increase in all four enzymes tested and this picture can be caused by aetiologies which cause either the hepatitic or cholestatic pictures
• NB. consider using a lower than “normal” range for patients on haemodialysis

• is there an obvious cause
  • sepsis / septicaemia
  • EBV / glandular fever / infectious mononucleosis
  • acute alcohol intake or picture of chronic alcohol abuse (AST:ALT ratio, history, etc)
  • pregnant:
    • consider HELLP syndrome in pregnancy, pre-eclampsia and eclampsia
  • overseas travel with fever:
    • Salmonella typhi (typhoid enteric fever)
    • dengue fever
    • malaria
    • hepatitis
    • etc
  • gastroenteritis:
    • cytomegalovirus (CMV)
    • Salmonella typhi (typhoid enteric fever)
  • hepatic venous congestion:
    • cardiac tamponade
    • congestive cardiac failure
• drug and alcohol history
  • if raised ALT with eosinophilia:
    • consider drug reaction with eosinophilia and systemic symptoms (DRESS) - usually starts 2-6wks after starting drug
• serology for viral hepatitis, EBV / glandular fever / infectious mononucleosis, consider cytomegalovirus (CMV)
• is patient obese and USS confirms non-alcoholic fatty liver disease
• if the above are non-diagnostic then:
  • iron studies to exclude haemochromatosis - suggested by transferrin saturation > 45% and high ferritin levels
  • hepatobiliary USS +/- CT scan to exclude neoplasia / cancer / tumours, etc.
  • re-check LFTs in 3-6 months
• if LFT's still deranged and no diagnosis then:
  • serum protein electrophoresis and if +ve, then ANA, anti-smooth muscle Abs, anti-liver/kidney microsomal Abs
  • TSH to exclude hypothyroidism and hyperthyroidism
  • consider coeliac disease, Wilson's disease
  • if LFT's persistently > 2-fold higher than normal, then consider liver biopsy although low yield and not without risks
  • still non-diagnostic consider referral or search for even more obscure diseases such as adrenal insufficiency

• the most common cause of “cholestatic picture” is biliary, thus a biliary USS is indicated to exclude cholelithiasis (gallstones) or CBD obstruction due to other causes
• USS shows dilated CBD:
  • extrahepatic cholestasis is the most likely cause of the abnormal LFTs and suggests conditions such as:
    • choledocholithiasis
    • Mirizzi syndrome (impacted cystic duct stone pressing on the CBD)
    • ascending cholangitis
    • pancreatitis
    • neoplasia / cancer / tumours
    • primary sclerosing cholangitis with an extrahepatic bile duct stricture
    • AIDS cholangiopathy
• if biliary USS normal:
  • it may still be extrahepatic cholestasis with normal CBD and intrahepatic duct diameters if either:
    • partial obstruction of the bile duct
    • scarred ducts preventing the ducts from dilating
      • eg. cirrhosis or primary sclerosing cholangitis
  • causes of intrahepatic cholestasis:
    • primary biliary cirrhosis (PBC) - check antimitochondrial antibodies and if +ve, consider liver biopsy
    • primary sclerosing cholangitis - consider MRCP to Dx
    • infiltrative diseases:
      • sarcoidosis, other granulomatous diseases, amyloidosis
      • neoplasia / cancer / tumours
    • drug toxicity
    • viral hepatitis
    • cholestasis of pregnancy
    • benign postoperative cholestasis
    • total parenteral nutrition
• NB. reduced hepatic perfusion in ageing results in reduced liver size and capacity and can cause a rise in GGT and AP levels with a fall in serum bilirubin levels while similar effects on the pancreas can cause low plasma lipase levels and possible exocrine pancreatic insufficiency and malnutrition

• an isolated raised GGT levels is usually not worth extensive Ix as it tends to be non-specific and occurs in:
  • pancreatic disease
  • myocardial infarction
  • renal failure
  • chronic obstructive pulmonary disease
  • diabetes mellitus
  • alcoholism
  • patients taking medications such as phenytoin and barbiturates

• ~half of total AP originates from bone
• exclude raised AP arising from bone:
  • children and adolescents with rapidly growing bones
  • those with healing bone fractures
  • those with bone disorders such as osteomalacia, osteoporosis, etc.
    • these patients may require work up for these bone conditions
    • in otherwise healthy non-pregnant adults, an ALP level > 72 IU/L may serve as a tentative threshold for recommending further assessments of osteoporosis³⁾, although more studies are needed
• isolated raised AP arising from the liver may occur in:
  • intrahepatic cholestasis (see above under Ix of cholestatic picture)
  • anabolic steroids
  • phenytoin

• see also jaundice (icterus)
• determine if bilirubin is mainly:
  • conjugated (“direct hyperbilirubinaemia”):
    • due to:
      • decreased excretion into the bile ductules
        • Dubin-Johnson syndrome
      • leakage of conjugated bilirubin from hepatocytes into serum
      • Rotor syndrome
  • unconjugated (“indirect hyperbilirubinaemia”):
    • due to:
      • bilirubin over-production:
        • haemolysis
          • haemolytic anaemia - check urine for Hb, and check blood reticulocyte count
          • emphysematous cholecystitis - mild to moderate unconjugated hyperbilirubinemia may be present because of haemolysis induced by clostridial infection
        • ineffective haematopoiesis
      • impaired bilirubin uptake into liver or conjugation:
        • Gilbert's disease (especially during periods of stress)
        • Crigler-Najjar syndrome
        • drugs

• see hypoalbuminaemia and nephrotic syndrome