Liver Investigations

Liver Investigations

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Liver function tests (LFTs) are readily available and are often included as a baseline investigation for a large number of different presentations. Liver function tests (LFTs), are a group of blood tests that detect inflammation and damage to the liver. They can also check how well the liver is working. Liver enzyme testing includes ALT, AST, alkaline phosphatase; true liver function tests (LFTs) include PT, INR, albumin, and bilirubin.

Doctor may conduct liver enzyme and liver function tests if:

Ÿ  Taking a medication that can harm the liver

Ÿ  Have liver disease

Ÿ  Have symptoms of liver or bile system disease (abdominal pain, nausea and vomiting, or yellow skin)

Ÿ  Drink alcohol excessively

The liver filters and processes blood as it circulates through the body. It metabolizes nutrients, detoxifies harmful substances, makes blood clotting proteins, and performs many other vital functions. The cells in the liver contain proteins called enzymes that drive these chemical reactions.

When liver cells are damaged or destroyed, the enzymes in the cells leak out into the blood, where they can be measured by blood tests. Liver tests check the blood for two main liver enzymes:

Aspartate Aminotransferase (AST), formerly called SGOT. The AST enzyme is also found in muscles and many other tissues besides the liver. Alanine Aminotransferase (ALT), formerly called SGPT. ALT is almost exclusively found in the liver. If a liver damage is most likely present ALT and AST are found together in elevated amounts in the blood.

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·         Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST)

 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 (eg 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 nonalcoholic liver disease.

Another of the liver's key functions is the production of bile, which helps digest fat. Bile flows through the liver in a system of small tubes (ducts), and is eventually stored in the gallbladder, under the liver.

Alkaline Phosphatase is by far the most commonly tested of the three. If alkaline Phosphatase and/or 5' nucleotidase and GGT are elevated, a problem with bile flow is most likely present. Bile flow problems can be due to a problem in the liver, the gallbladder, or the tubes connecting them.

When bile flow is slow or blocked, blood levels of certain liver enzymes rise

                  Alkaline phosphatase (ALP)

 It 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). Isoenzyme analysis may help identify source. It is physiologically increased when there is increased bone turnover (eg adolescence) and is elevated in the third trimester of pregnancy (produced by the placenta).

 Gamma-glutamyl transferase (GGT)

It 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).

  5' Nucleotidase

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. Albumin - sensitive marker of hepatic function, but not useful in the acute stages as it has a long half life (20 days).

Total protein.

Interpreting abnormal liver function tests (LFTs) and trying to diagnose any underlying liver disease is a common scenario in Primary Care. Abnormal LFTs may be asymptomatic, and are often inadequately investigated - which may miss an early opportunity of identifying and treating chronic liver disease.

The primary problem may be the liver, or the abnormal results can be secondary to other problems in the body.  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 LFTs 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.

When basic LFTs are abnormal, ensure a full history and examination is performed:

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History and examination of a patient with abnormal LFTs

Full history - include:

·         Recent travel.

·         Transfusions.

·         Drugs, including paracetamol overdose and herbal remedies.

·         Tattoos.

·         Unprotected sexual intercourse.

·         Drug history (including herbal remedies).

·         Alcohol.

·         Occupation.

·         Diabetes mellitus, obesity, hyperlipidaemia (all associated with fatty liver disease).^[5^]

·         Family history.

Full examination - look especially for:

·         Stigmata of chronic liver disease, eg icteric skin and mucous membranes, palmar erythema, bruising, spider naevi, gynaecomastia.

·         Hepatomegaly.

·         Splenomegaly.

·         Ascites.

·         Obesity (associated with a fatty liver).

·         Any clues to the underlying cause, eg lymphadenopathy.

·         Features suggestive of hepatic encephalopathy.

Further tests will also be needed to try to find out the underlying cause:

·         The other transaminase - ie 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 nonalcoholic aetiologies (see above).

·         Prothrombin (INR) - sensitive marker of hepatic synthetic function.

·         Viral serology, eg hepatitis B and C, cytomegalovirus (CMV), Epstein-Barr virus and possibly HIV.

·         Autoantibody screen, eg antimitochondrial antibody, anti-smooth muscle antibody and antinuclear 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/ceruloplasmin.

·         α1-antitrypsin.

·         Imaging: ultrasound is noninvasive and helpful to detect structural abnormalities.

·         Patients should be identified for Jaundice, Dubin-Johnson Syndrome, Gilbert's Syndrome and Rotor's Syndrome

Interpretation

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

1.      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 hyperbilirubinaemia is usually due to Haemolysis – (check reticulocyte count, blood film, haptoglobins, LDH and may need direct Coombs' test. Liaise with haematologist). Drugs, Gilbert's syndrome or Crigler-Najjar syndrome are the other posibilities.

Conjugated hyperbilirubinaemia is usually due to Dubin-Johnson syndrome, Rotor syndrome, Chronic liver disease, (usually associated with other liver function test (LFT) abnormalities).

·         Rise in ALP and GGT more than AST and ALT

Is an indication of Obstructive picture or cholestasis . This may be intrahepatic (Primary biliary cirrhosis,Drugs) or extrahepatic (bilirubin will also be raised).

Extrahepati conditions:

·         Gallstone in common bile duct.

·         Head of pancreas neoplasm.

·         Drugs, eg erythromycin, tricyclic antidepressants, flucloxacillin, oral contraceptive pill and anabolic steroids.

·         Cardiac failure - improves with treatment.

·         Primary biliary cirrhosis - more common in women and the first sign is a rise in ALP.

·         Primary sclerosing cholangitis.

·         Neoplasm - primary (rarely) and secondaries.

·         Familial (benign).

·         Rise in AST and ALT more than ALP and GGT

It shows a Hepatitic picture.

·         Alcohol - fatty infiltration and acute alcoholic hepatitis (usually associated with markedly deranged liver function).

·         Cirrhosis of any cause - alcohol being one of the most common.

·         Medications, eg phenytoin, carbamazepine, isoniazid, statins, methotrexate, paracetamol overdose, amiodarone. (Transaminases may be >1000 IU/L).

·         Chronic hepatitis B and C.

·         Acute viral hepatitis, eg 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, eg 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

Isolated rise in GGT:

·         This is most commonly due to alcohol abuse, or enzyme-inducing drugs.

·         An isolated rise can occur even if there is 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, eg 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, eg ALP, GGT, AST or ALT may all be similarly elevated making it difficult to determine whether it is a cholestatic or hepatitic picture.

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Management plan

Any liver abnormalities with evidence of hepatic dysfunction, eg low albumin, raised INR, should be referred to a specialist.^[7]

·         If slightly abnormal rise in liver function tests (ie less than twice upper limit of normal):

·         Repeat liver function tests (LFTs) 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, eg good diabetes mellitus control and weight loss.

·         If still abnormal, perform further tests, eg viral serology or ultrasonography.

·         If remaining 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.

·         Very abnormal LFTs (ie more than twice the upper limit of abnormal):

·         Organise further blood tests and imaging.

·         Refer to outpatients - if you suspect the cause may be malignancy then an urgent cancer referral should be made.^[7^]

Consider urgent referral for hospital admission if a patient is unwell; for example:

·         Severe jaundice

·         Severe ascites

·         Encephalopathy

·         Septic

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