Follow up of elevated liver enzymes
The term 'liver function tests' (LFT) is a misnomer. Only gamma glutamyl transferase (GGT) is specific for liver. Aspartate amino transferase (AST) is also found in muscle; lactate dehydrogenase (LD) has many sources including red blood cells, cardiac and skeletal muscle; and alkaline phosphatase (ALP) is found in bone and intestine as well as liver.
Only bilirubin and albumin measure function; bilirubin the excretory function and albumin the synthetic function. Because of this, although elevated LFTs do associate with liver inflammation, chronic liver disease is frequently associated with only mild to moderate enzyme elevations. For example, low albumin and or raised bilirubin without an elevation of liver enzymes may accompany cirrhosis.
Serum bilirubin is useful in the investigation and monitoring of hepatocellular disease and haemolysis.
Bilirubin is the product of haem breakdown. It is conjugated in the liver and excreted in the bile. Total bilirubin is made up of conjugated and unconjugated fractions. In most cases total bilirubin is sufficient to screen for abnormalities. Unconjugated bilirubin can also be measured; however it is mostly used to investigate neonatal jaundice.
An increase in total bilirubin may result from haemolysis or liver disease. When red cell breakdown overwhelms the hepatic excretory capacity, increased bilirubin levels result.
This is characterised by an increase in total bilirubin and a normal conjugated fraction. It is seen in haemolysis and in megaloblastic anaemia, but the most common cause is Gilbert syndrome.
Gilbert syndrome is an inherited decrease in the ability to conjugate bilirubin, which results in an isolated mild increase in bilirubin concentration in an otherwise normal person. It is surprisingly common and is associated with no adverse effects.
Liver disease is associated with increased bilirubin concentration when excretion via the biliary tree is blocked or when liver function is severely compromised. Common biliary tree obstructions include gallstones and pancreatic mass. In the absence of obstruction, bilirubin increases only when the liver’s ability to conjugate and excrete is severely decreased.
Occasionally, an increase in bilirubin is the most important sign of severe liver disease in the MBA. Normal levels of bilirubin may present in uncomplicated cirrhosis, early in the course of liver failure, or with hepatic metastases.
Liver enzyme patterns help to differentiate between hepatocellular disease and biliary disease.
Hepatocellular disease is characterised by an increase in transaminase enzymes, AST and AST. Impaired hepatocellular function will also affect synthesis of albumin and coagulation factors as well as bilirubin metabolism. When damage is extensive and prolonged, albumin and INR will be abnormal.
Involvement of the biliary tract is characterised by an increase in ALP and GGT.
Cellular enzyme levels increase in serum when cells are damaged. Increases in ALT and AST, the transaminases, can range from 2 to 100 fold. While the magnitude of the increase is not a good indicator of liver function, there are some useful rules of thumb.
Rules of thumb
Surveys have shown that in asymptomatic people isolated increases in ALT or AST that persist for 6–9 months, will be the result of some significant recognisable liver disease 85% of the time.
Increases above 500 U/L are often associated with acute hepatitis.
Increased ALT/AST may also be due to fatty liver (non-alcoholic hepatosteatosis), adverse medication effects, infection (hepatitis, A, B, or C, CMV or EBV), haemochromatosis, autoimmune disease, and less frequently other inherited disorders.
ALT is usually greater than the AST, when reversed, alcohol is often the cause.
AST and LD are present in liver but are ubiquitous in cells. Increased levels are often the result of haemolysis, in vivo or in vitro, or muscle cell death, either cardiac or skeletal. We discover an unexpected myocardial infarction every year via increased AST and LD levels. Measuring total creatine kinase (CK) for myopathy or troponin for myocardial infarction are good next steps. LD is a sensitive indicator of haematologic disease with the highest LDs measured, (~10,000 U/L) in pernicious anaemia.
GGT is a membrane bound enzyme that is readily induced. Medication, particularly anti-convulsants, alcohol, and obesity cause isolated increases in GGT.
ALP can be more difficult to interpret because it comes not only from the liver but also bone, intestine, and placenta. An isolated increase in ALP level is not likely from the liver. An increase in liver ALP is also usually associated with an increase in GGT. Both are increased in cholestasis the causes of which include heart failure, biliary tract disease, generalised liver disease, adverse medication effects, and metastases.
Where to now?
Many drugs are capable of causing liver damage, hence drug and alcohol history is essential to investigation.
Usually the next step in investigating increased liver enzyme levels is ultrasound of the liver to exclude fatty liver, serology testing for hepatitis and serum iron studies to screen for haemachromatosis.
Occasionally other tests are useful to determine the cause of hepatic dysfunction:
- autoimmunity anti nuclear (ANF) anti mitochondrial (AMA) anti smooth muscle (ASM) anti liver kidney-microsomal (LKM) and anti neutrophil cytoplasmic (ANCA) antibodies
- alpha 1 antitrypsin
- malignancy alpha feto protein (AFP)
The importance of non-specific liver enzyme abnormalities cannot be over emphasised. Recognising the patterns; isolated, biliary, hepatocellular, or mixed is a good starting point for identifying the cause of a patient's illness.