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Home , Alanine transaminase, Bilirubin, Blood test, Elevated transaminases, Ferritin, Liver function tests

clinical function tests

Penelope Coates

This article forms part of our ‘Tests and results’ series for 2011 which aims to provide information rarely, may form ‘macro’ complexes about common tests that general practitioners order regularly. It considers areas such as indications, with immunoglobulins or other large molecules, what to tell the patient, what the test can and cannot tell you, and interpretation of results. resulting in reduced clearance and a falsely high result. In patients with extremely high Keywords: ; liver ; gastrointestinal diseases levels, substrate exhaustion may lead to a falsely low result. to prevent degradation samples should be protected from light if high levels of Liver function tests (LFTs) are a panel of are suspected. Some methods give falsely low markers (Table 1) used to assess results if the specimen is haemolysed. and monitor several diseases. However, is routinely measured by they are not all true tests of liver function dye binding. Different dyes are used – with and abnormalities may not reflect liver variable specificity, particularly in the low . , therefore it is preferable to use the same laboratory for repeat tests. When should LFTs be ordered? Indications for liver function testing include What do the results mean? investigating and patients with It is helpful to classify results as typical of suspected , at risk patient groups, or (interruption to flow between monitoring malignancy; and before initiating and the and the gut) or consistent with monitoring hepatotoxic (Table 2). hepatocellular damage (Table 3). There is no cost effectiveness data for the use Raised (ALT and AST) suggest of LFTs1,2 and by definition 2.5% of the healthy hepatocellular injury. Marked increases (over population may have an abnormal result at any 10 times the upper reference limit) suggest one time, usually mild. an acute or severe insult, for example drugs, acute viral or . Mildly elevated What to tell the patient? transaminases (up to five times the upper Patients should be aware that a is reference limit) suggest , alcohol, fatty required. No special preparation, such as fasting, liver or (Table 3). Alcohol often is necessary. Results are often available within results in a higher AST:ALT ratio than other forms 24 hours, although they may be slower in remote of liver damage. levels do not areas and may be quicker in urgent situations. directly correlate to the degree of liver damage, Liver function tests attract a Medicare rebate for example in where levels may drop to (see Resources for a link to a fact sheet for within the . patient information). is not specific to the liver, it is also produced in bone, intestine and What laboratory factors can affect placenta. A concurrent raised GGT suggests liver results? origin. Common causes of a raised ALP and GGT Enzyme gamma-glutamyl (GGT), are cholestasis and enzyme induction by alcohol alkaline phosphatase (ALP), aspartate or medication. transaminase (AST), and transaminase isolated raised ALP is typically due to bone (ALT) levels involve a monitored reaction and disease (eg. Paget disease in patients over

Reprinted from Australian Family Vol.40, No. 3, march 2011 113 clinical Liver function tests the age of 50 years, deficiency, ALP is over 1.5 times the upper reference limit. raised GGT is due to alcohol excess, and 30% of metastasis). On request the laboratory may Gamma-glutamyl transferase is most useful alcohol abusers will have a normal GGT. Levels quantify ALP liver and bone isoforms if the to confirm the liver origin of ALP. It is associated remain elevated for 2–3 weeks after cessation of clinical context is unclear and when the total with alcohol use, although only 70% of isolated heavy drinking or liver injury. Bilirubin increases in both cholestatic and Table 1. Liver function tests and their site of origin hepatotoxic liver disease. In adults, raised Bilirubin Haem bilirubin is usually predominantly conjugated. Conjugated in liver Unconjugated hyperbilirubinaemia in adults Albumin Synthesised in liver: half life about 20 days is usually due to Gilbert syndrome or to Total Includes albumin, immunoglobulins and carrier : haemolysis. Gilbert syndrome is a common variable proportion synthesised in liver benign impairment in bilirubin conjugating GGT Originates from the canalicular (bile) surface of hepatocyte ability, affecting up to 5% of the population, ALP Originates from the canalicular (bile) surface of hepatocyte with a persistent isolated increase in bilirubin Also from bone (produced during bone formation), intestine up to 2–3 times the upper reference limit. Levels and placenta AST Originates from the hepatocyte , hepatocyte increase during acute illness or fasting and mitochondria and from muscle (skeletal and cardiac) further investigation is unnecessary. ALT Originates from the hepatocyte cytoplasm low albumin can indicate severe liver disease, but is more often from other causes Table 2. Indications for liver function tests including physiological (eg. ), Indication Examples , , and protein losing History or examination findings • History of poisoning (eg. ) states. Total protein can be useful to estimate suggest liver disease • on examination the fraction, increased in inflammation. • History of alcohol abuse In cirrhosis, low albumin and increased bilirubin • Signs of including are associated with reduced survival. • Family history of haemochromatosis When should I repeat LFTs and for populations at • Contact tracing in cases of hepatitis what constitutes a change? high risk of blood borne • Indigenous patients infection • Illicit drug use Interpretation and follow up vary with clinical • Previous transfusion context and results. In selected settings, Significant nonliver disease • Malignancies isolated, unexpected minor abnormalities may be that may effect liver function • Hypoxia repeated within a short time frame Monitoring medications • (eg. 1 week.) Almost a third of results will return • to the normal range on repeat testing3 and obviously a persistent abnormality is more likely Table 3. Classification of liver function test abnormalities to be due to significant . Pattern Laboratory features Common causes monitoring patients with existing liver Cholestasis ALP >200 IU/L • Biliary obstruction disease or hepatotoxic effects of medications ALP more than three • Pregnancy (needs further assessment) should be done no more often than monthly if times ALT • Drugs (eg. erythromycin, oestrogen) the patient is otherwise stable. Three monthly • Infiltration (eg. malignancy) testing is appropriate for some medications (eg. Hepatocellular ALT >200 IU/L • Infection (eg. , C, A; EBV; methotrexate). damage ALT more than three CMV) Daily testing may be appropriate for very times ALP • Alcohol (AST often >2 times ALT) acute toxic or hypoxic insult, although twice • Fatty liver weekly is more common. • Drugs (eg. paracetamol*) transaminases ALT and AST have large • Metal overload (eg. hereditary normal within-subject variability such that serial haemochromatosis, copper overload) results are only significant if they differ by more • Hypoxia (LD usually >1.5 times AST) than 30%. Similarly, a significant change for • Autoimmune GGT is more than 20%, ALP more than 15%, and * Patients with pre-existing liver disease, including alcohol abuse, are vulnerable to bilirubin more than 40%. Albumin has very low paracetamol even at a standard dose5 intraindividual variation.

114 Reprinted from Australian Family Physician Vol.40, No. 3, march 2011 Liver function tests clinical

Next steps? infection (affecting up to 3% of • Lab Tests Online – a patient focused site that explains individual tests. Available at www.labtest- 3 Follow up investigations are certainly the population), fatty liver, and hereditary sonline.org.au recommended for patients with severe or haemochromatosis. All patients with mildly • A useful patient handout is available at: www. persistent abnormalities, or with relevant clinical should be asked about patient.co.uk/health/Blood-Test-Liver-Function- Tests.htm. findings. These investigations are context risk factors for blood borne , and should specific. However, in a hepatotoxic picture have serological testing for hepatitis C and B. Author investigations such as hepatitis , Alcohol use should be reviewed as alcoholic Penelope Coates MBBS, FRACP, FRCPA, is and saturation are first line. Further hepatitis and nonalcoholic Clinical Director, Chemical Pathology, Institute of investigation may include tests for less common have almost identical biochemical and clinical Medical and Veterinary Science, Adelaide, South Australia. [email protected]. causes such as copper overload and autoimmune presentations. There is no biochemical test liver disease. In contrast, for cholestatic results to reliably identify or exclude alcohol abuse. Conflict of interest: none declared. the initial emphasis is usually on hepatic Overweight and obesity increase the risk of imaging with ultrasound. fatty liver by six-fold but need not be present to References 1 American Gastroenterological Association posi- make the diagnosis. Ultrasound shows a bright Case study 1 tion statement: evaluation of liver chemistry tests. hyperechoic liver texture, as typically seen in Gastroenterology 2002;123:1364–6. A woman, 35 years of age, complained 2. AGA Technical review on the evaluation of liver fatty liver. Hereditary haemochromatosis has of and dark . She chemistry tests. Gastroenterology 2002;123:1367– 4 was clinically mildly jaundiced. Her liver a frequency of 1:150 in Australia. Only 28% 84. of men and 1% of women homozygous for the 3. lazo M, Selvin E, Clark JM. Clinical implications function tests were as follows: of short-term variability in liver function test most common HFE mutation will become Albumin 36 g/L (34–48) results. Ann Intern Med 2008;148:348–52. overloaded, hence initial screening with fasting 4. Allen KJ, Gurrin LC, Constantine CC, et al. Protein 83 g/L (65–85) studies for ferritin and Iron-overload-related disease in HFE hereditary Total bilirubin 45 µmol/L (2–24) hemochromatosis. N Engl J Med 2008;358:221– is recommended. 30. GGT 439 U/L (<60) 5. Zimmerman HJ, Maddrey WC. Acetaminophen ALP 285 U/L (30–110) Case study 3 (paracetamol) with regular intake A man, 66 years of age, presented with of alcohol: analysis of instances of therapeutic ALT 49 U/L (<55) weight loss and fatigue. He had a normocytic misadventure. Hepatology 1995;22:767–73. AST 43 U/L (<45) anaemia. His LFTs were as follows: Albumin 22 g/L (34–48) The raised ALP relative to ALT suggests cholestasis and the high GGT confirms liver origin. Protein 59 g/L (65–85) The mild hyperbilirubinaemia confirms the clinical Total bilirubin 12 µmol/L (2–24) impression of jaundice. Biliary disease is highly GGT 926 U/L (<60) likely with gallstones the most likely differential ALP 527 U/L(30–110) diagnosis. However, this clinical picture may also ALT 104 U/L (<55) occur in drug reactions or infiltrative conditions. AST 96 U/L (<45) After a careful history, abdominal ultrasound is the most appropriate next investigation. The raised ALP relative to ALT again suggests cholestasis, but this time in the absence of Case study 2 jaundice. While medications may be responsible, A man, 39 years of age, had the following patient’s age, significant symptoms and low results as part of an insurance medical: albumin (biochemical evidence of severe Albumin 37 g/L (34–48) concurrent illness) suggest intrahepatic Protein 72 g/L (65–85) cholestasis from liver metastases as a likely Total bilirubin 13 µmol/L (2–24) . It would be unusual for this to be the GGT 46 U/L (<60) first indication of neoplastic disease. Again, as ALP 81 U/L (30–110) in many cases of cholestasis, ultrasound is an ALT 76 U/L (<55) appropriate next investigation. AST 44 U/L (<45) Resources Mild elevation in transaminases is not an • The Royal College of Pathologists of Australasia Manual of Pathology Tests – lists clinical problems uncommon incidental finding in asymptomatic and individual tests for the clinician. Available at patients. The commonest causes include chronic www.rcpamanual.edu.au

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