Interpretation of deranged LFTs

Frequently, the college will put some sort of horrible LFT picture up for the candidates and ask them to make sense of it. The general trend of questions seems to be coma, flavoured with a recent history of discharge from an alcohol rehab institution of some sort. There is one specific question which is frequently repeated where the ammonia is also elevated, and the LFTs are raised in a non-specific pattern. Give six differentials, they usually ask.

The following SAQs have involved interpretation fo LFT derangement:

  • Question 23.2 from the second paper of 2015 (transaminitis)
  • Question 10.2 from the second paper of 2014 (pan-hepatitis, high ammonia)
  • Question 14 from the second paper of 2012 (the utility of serum ammonia)
  • Question 29.2 from the second paper of 2011 (pan-hepatitis, high ammonia)
  • Question 28.3 from the second paper of 2008 (list four causes of high ammonia)
  • Question 28 from the first paper of 2005 (pan-hepatitis, high ammonia)
  • Question 2c from the second paper of 2004 (diagnostic workup of unexplained LFT derangement)

For a short summary of deranged LFT interpretation, one cannot do better than the LITFL page by Mike Cadogan. As far as published resources go, the time-poor candidate may wish to quickly skim through the 2003 article by Limdi and Hyde. Another good guide to LFT interpretation by Giannini et al (2005) can be found hosted at And if one grows weary of well-written peer reviewed literature, one can burrow into the local chapter on laboratory tests of liver function, which covers the relevant sections of the CICM First Part Exam syllabus.  Assuming the senior CICM trainee has no need for such details, what follows is a list of tables to help generate differentials to answer the past paper SAQs.

The enzymes and metabolites

Alanine transaminase (ALT)

Previously referred to as glutamate-pyruvate transaminase (SGPT) or serum glutamic-pyruvic transaminase (SGPT), alanine aminotransferase in an enzyme that is found abundantly in the hepatocytes. Being a Kreb cycle enzyme, it is also found in other tissues (all of them!) but not in quite the same quanitites. The heart and the kidney have some, but the hepatic concentration of ALT exceeds theirs by abput 3000 times, making this a very liver-specific marker.  It is discussed in glorious detail by Kim et al (2008).

What is the point of it? It seems important. ALT catalyzes the transfer of amino groups to form α-ketoglutarate, as a part of the Cahill cycle (otherwise known as the alanine cycle). This cycle brings alanine to the liver, where ALT strips the amino group off it so as to make pyruvate out of it. Pyruvate is a useful metabolic fuel, and it gets burned. α-ketoglutarate gets the amino group and becomes glutamate, which is then deaminated again (with the amine group ultimately disappearing into the urea pool). Thus, one of the major puposes of ALT is to participate in the reclamation of amino acids as metabolic fuel substrates, and the other is as a part of the many stages of  ammonia excretion (where it eventually becomes urea). The plasma half-life of ALT is approximately 50 hours (Kim et al give 47 +/- 10), which is longer than AST.

Features of ALT as a diagnostic test:

  • Released after AST in hepatocellular injury
  • Rises to a higher level and is raised for longer than AST because of its longer half life.
  • Levels are usually lower when alcohol is responsble for the liver damage (acute or chronic)
  • Levels are unrelated to the degree of liver damage, and the exact level has no prognostic significance

Aspartate aminotransferase (AST)

Aspartate aminotransferase catalyses the reversible reaction which transfers an amino group to oxaloacetate, making it into aspartate. Aspartate can therefore end up being plugged into Krebs cycle as oxaloacetate, and The reversible reaction involving ASToxaloacetate can participate in de novo amino acid synthesis. It is ubiquitous. The reactions catalysed by this enzyme depend on Vitamin B6 as a cofactor.

AST has several isoforms, of which the mitochondrial form tends to have a longer half life. It is said that total AST has a half-life of only 17 hours, whereas for mitochondrial isoforms it is 87 hours (Giannini et al, 2005).

In a decreasing order of concentration, AST is found in the following tissues:

  • Liver
  • Cardiac muscle
  • Skeletal muscle
  • Kidneys
  • Brain
  • Pancreas
  • Lungs
  • Leukocytes
  • Erythrocytes

AST/ALT ratio

Some vague meaning can be derived from the difference between the ALT and AST:

Causes of a Raised ALT and AST

AST much higher than ALT

Hepatic causes:

  • Alcoholic hepatitis
  • Alcohol toxicity
  • Early ischaemic liver injury

Extrahepatic causes:

  • Rhabdomyolysis
  • Myocardial infarction

ALT much higher than AST

  • Later in ischaemic liver injury
  • Viral hepatitis
  • Toxic hepatitis (eg. paracetamol)

γ-glutamyl transferase (GGT)

γ-glutamyl transferase enjoys a thorough review by JB Whitfield (2001). Nobody should read that before the CICM fellowship, so in summary, its job is to join the γ-glutamyl from of glutathione with something else (be it an amino acid, a peptide or merely water). It is found in all sorts of tissues and is generally involved in making cysteine available to the cells, thereby participating in the neutralisation of oxidants. It is also peripherally involved in the transfer of amino acids across cell membranes. According to LITFL, it is produced in the renal tubules, liver, biliary tract, pancreas, lymphocytes, brain, and seminal vesicles. GGT is an induceable microsomal enzyme, and it can rise with various drugs, such as alcohol, barbiturates, phenytoin  and oral contraceptives. UpToDate reports that "elevated levels of serum GGT have been reported in a wide variety of clinical conditions, including pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes mellitus, and alcoholism". GGT is therefore a highly non-specific marker of biliary tract disease.

Isolated rise in GGT is fairly rare, and almost entrirely useless from a diagnostic viewpoint.

Causes of an isolated raised GGT
  • Myocarditis
  • Myocardial infarction
  • COPD
  • Renal failure


  • Phenytoin
  • Barbiturates
  • Alcohol
  • Flucloxacillin

Alkaline phosphatase (ALP)

Alkaline Phosphatase is actually up to 60 different isoenzymes, collectively measured as ALP. It is a non-liver specific enzyme which is found in all tissues, most notably bone, small intestine, leukocytes and the placenta. In fact, this enzyme is ubiquitous to most living things, including bacteria.  Functionally, it is a zinc-containing hydrolase which removes the phosphate group from various molecules, thereby allowing them to become less polar (and thus cross cell membranes, for example). Its name is derived from the fact that it is most effective in an alkaline environment. In the liver, alkaline phosphatase is found on the surface of the cells at the biliary canaliculi. The rise in serum ALP is usually associated either with enhanced synthesis (due to bile stasis) or release from canalicular cell surface (with deposition of bile salts). 

Causes of a Raised Alkaline Phosphatase

Physiological causes

  • Women in the third trimester of pregnancy.
  • Adolescents and children
  • Benign, familial
    (due to increased intestinal ALP).

Pathological causes

  • Hepatobiliary origin:
    • Bile duct obstruction.
    • Primary biliary cirrhosis.
    • Primary sclerosing cholangitis.
    • Drug induced cholestasis—for example, anabolic steroids.
    • Adult bile ductopenia.
    • Metastatic liver disease.
  • Extrahepatic origin
    • Bone disease: including bony metastases, rickets, Pagets disease
    • Sarcoidosis
    • Hyperthyroidism
    • Hodgkins lymphoma

Lactate dehydrogenase (LDH)

Lactate dehydrogenase (LDH) catalyses the  conversion of lactic acid to pyruvic acid, or the reverse reaction. It is found in essentially all cells. Five isoenzymes exist, but a differential titer is infrequently called for. As a marker of liver injury or dysfunction LDH is hopelessly unhelpful. Generally speaking, it is raised when all the other transaminases are raised, but it does not usually rise as high as AST or ALT.

Causes of a Raised Lactate Dehydrogenase

Spurious result

  • Haemolysed sample
  • Long sample transport time

Hepatic causes

  • Essentially any sort of liver damage, including cholestasis

Haematological causes

  • Haematological malignancy (a marker of its activity)
  • Haemolysis
  • Sickle cell anaemia

Cardiovascular causes

  • Myocardial infarction
  • Pulmonary embolism
  • Myocarditis
  • Shock (of any cause!)


Bilirubin is the endproduct of haem metabolism. It is essentially the same molecule as haem (i.e a tetrapyrrole porphyrin composed of four pyrrole rings) but it is unfolded, i.e. instead of making a neat ring the four pyrroles are in a chain instead. In the liver, bilirubin is cojugated into a water-soluble glucouronide.

Causes of an Isolated Raised Bilirubin

Unconjugated bilirubin

  • Increased bilirubin production.
    • Haemolysis.
    • Ineffective erythropoiesis.
    • Blood transfusion.
    • Resorption of haematomas.
  • Decreased hepatic uptake.
    • Gilbert’s syndrome.
    • Drugs—for example, rifampicin.
  • Decreased conjugation.
    • Gilbert’s syndrome.
    • Criggler-Najjar syndrome.
    • Physiological jaundice of the newborn.

Conjugated bilirubin

  • Failure to excrete conjugated bilirubin
    • Dubin-Johnson syndrome.
    • Rotor’s syndrome.
    • Sepsis
  • Biliary flow limitation (i.e. bile duct obstruction)


Ammonia is a product of deamination, and acts as the substrate for the urea cycle. As the synthesis of urea generally takes place in the liver, you can imagine that in liver failure the ammonia will be raised. The interpretation of serum ammonia levels is handled in detail elsewhere. In summary:

Causes of Hyperammonaemia, Arranged by Physiology

Pre-analytical error

  • Prolonged pre-transport time
  • Room temperature storage of sample

Increased substrate for ammoniagenesis

  • Excess protein catabolism:
    • Essential amino acid deficiency
    • Primary dietary carnitine deficiency
    • Steroids
    • Immobility
    • Severe exercise
    • Increased tissue turnover, eg haematological malignancy
  • Excess protein intake:
    • Weird diet
    • Parenteral nutrition

Bypass of normal metabolism

  • TIPS procedure
  • Portosystemic shunts

Acquired urea cycle defects

  • Fulminant hepatitis of any cause
  • Reye's syndrome
  • Drugs, eg. glycine or valproate

Congenital urea cycle defects

  • Inherited ura cycle defects
  • Organic aciduria
  • Fatty acid oxidation defects

Excess of exogenous ammonia

  • Ammonium chloride therapy
  • Excess generation of ammonia:
    • Gastric bypass
    • Urease-producing organisms
    • UTI

Reabsorption of excreted ammonia

  • Distal renal tubular acidosis
  • Ureteric diversion
  • Urinary tract infections
  • Vesicoureteric reflux
  • Bladder perforation

Patterns of derangement


The very term has attracted a scathing invective. In summary:

Causes of Raised Transaminase Levels


  • Ischaemic hepatitis
  • Portal vein thrombosis
  • Congestive heart failure
  • Veno-occlusive disease


  • Viral hepatitis
  • Pancreatitis


  • Malignant infiltration, eg. neoplasm


  • Alcoholic hepatitis
  • Paracetamol overdose
  • Amanita phalloides

Idiopathic / infiltrative

  • Fatty liver
  • NASH


  • Glycogen storage disease


  • Cholestasis of pregnancy
  • Cholestasis of prolonged fasting
  • Total parenteral nutrition


  • Hepatic laceration
  • Partial hepatectomy


  • Haemochromatosis
  • Wilson's disease
  • α1-antitrypsin deficiency

Cholestatic picture

The best resource for this is probably the 199 article by Assy et al, "Diagnostic approach to patients with cholestatic jaundice". In summary:

Causes of Cholestasis

Extrahepatic cholestasis

  • Choledocholithiasis
  • Malignant obstruction
  • Cholangitis
  • Pancreatitis
  • AIDS cholangiopathy
  • Primary Sclerosing Cholangitis

Intrahepatic cholestasis

  • Drug toxicity
  • Hepatitis
  • Cholestasis of pregnancy
  • Cholestasis of prolonged fasting
  • Total parenteral nutrition
  • Primary biliary cirrhosis
  • Primary Sclerosing Cholangitis

Diagnostic workup of an unexplained LFT derangement

The following tests will need to be ordered, in order of escalating expense, invasiveness and esotericims:

  • Albumin is a test of synthetic liver function, but is very nonspecific in critical illness.
  • Coags: APTT, PT, fibrinogen and mixing studies. These test the synthetic liver function. PT will be raised if the liver has stopped storing fat-soluble vitamins, and APTT will be raised if the synthetic function is so poor that clotting factor synthesis is impaired. Mixing studies help to demonstrate that the addition of healthy plasma corrects the factor deficiency.
  • Bilirubin differential (conjgated vs. unconjugated) helps discriminate biliary from nonbiliary causes of jaundice
  • Amylase and lipase (to exclude pancreatitis)
  • Ultrasound of the liver and biliary tree to rule out bile duct obstruction and any interruption of the hepatic vascular supply; and to look at the hepatic parenchymal texture (eg. fatty, cirrhotic, etc)
  • Hepatitis virus tests  to rule out acute hepatitis
  • Iron studies (to look for haemochromatosis)
  • Ceruloplasmin (if Wilson's disease is a realistic possibility)
  • Anti-smooth muscle antibodies (primary sclerosing cholangitis)
  • Anti-liver microsomal antibodies (autoimmune hepatitis)
  • Serum α-1 antitrypsin level (for deficiency)
  • Liver biopsy (gold standard)


Johnston, David E. "Special considerations in interpreting liver function tests." American family physician 59 (1999): 2223-2232.

Limdi, J. K., and G. M. Hyde. "Evaluation of abnormal liver function tests." Postgraduate medical journal 79.932 (2003): 307-312.

Hoekstra, Lisette T., et al. "Physiological and biochemical basis of clinical liver function tests: a review." Annals of surgery 257.1 (2013): 27-36.

Giannini, Edoardo G., Roberto Testa, and Vincenzo Savarino. "Liver enzyme alteration: a guide for clinicians." Canadian medical association journal 172.3 (2005): 367-379.

Kim, W., et al. "Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease." Hepatology 47.4 (2008): 1363-1370.

Pratt, Daniel S., and Marshall M. Kaplan. "Evaluation of abnormal liver-enzyme results in asymptomatic patients." New England Journal of Medicine 342.17 (2000): 1266-1271.

Whitfield, J. B. "Gamma glutamyl transferase." Critical reviews in clinical laboratory sciences 38.4 (2001): 263-355.

Balistreri, William F., et al. "Intrahepatic cholestasis: Summary of an American Association for the Study of Liver Diseases single‐topic conference." Hepatology 42.1 (2005): 222-235.

Assy, N., et al. "Diagnostic approach to patients with cholestatic jaundice." World journal of gastroenterology 5.3 (1999): 252-262.

Stellpflug, Samuel J. "Transaminitis: The Lab Test That Has Inflammation…." Journal of Medical Toxicology 7.3 (2011): 252-253.