307 REVIEW Postgrad Med J: first published as 10.1136/pmj.79.932.307 on 1 June 2003. Downloaded from Evaluation of abnormal liver function tests J K Limdi, G M Hyde ............................................................................................................................. Postgrad Med J 2003;79:307–312 Interpretation of abnormalities in liver function tests is a sterile ear or body piercing, blood or blood product common problem faced by clinicians. This has become transfusions), medications used currently or pre- viously, herbal or alternative remedies, and occu- more common with the introduction of automated pational exposure to toxins (box 2). routine laboratory testing. Not all persons with one or Other factors such as diabetes, obesity and more abnormalities in these tests actually have liver hyperlipidaemia in non-alcoholic fatty liver dis- ease, and family history (for Wilson’s disease, disease. The various biochemical tests, their haemochromatosis, autoimmune disease) may be pathophysiology, and an approach to the interpretation significant. of abnormal liver function tests are discussed in this review. BILIRUBIN .......................................................................... Bilirubin is formed from the lysis of red cells (the haem component) within the reticuloendothelial system. Unconjugated bilirubin is transported to ommonly available tests include alanine the liver loosely bound to albumin. It is water transaminase (ALT) and aspartate insoluble and therefore cannot be excreted in Ctransaminase (AST), alkaline phosphatase urine. Conjugated bilirubin is water soluble and (ALP), gammaglutamyl transferase, serum bi- appears in urine. lirubin, prothrombin time, or international nor- Within the liver it is conjugated to bilirubin malised ratio and serum albumin (box 1). They glucoronide and subsequently secreted into bile reflect different functions of the liver—that is, to and the gut respectively. Intestinal flora breaks it excrete anions (bilirubin), hepatocellular integ- down into urobilinogen, some of which is rity (transaminases), formation and the subse- reabsorbed and either excreted via the kidney into quent free flow of bile (bilirubin and ALP), and urine or excreted by the liver into the gastro- protein synthesis (albumin). intestinal tract. The remainder is excreted in the Other tests are often performed by a specialist stool as stercobilinogen giving stool its brown and include hepatitis serology, iron and copper colour. α http://pmj.bmj.com/ studies, 1-antitrypsin levels, and autoantibodies. Serum bilirubin is normally mainly in an These relate to the possible aetiology of the unconjugated form reflecting a balance between abnormality. production and hepatobiliary excretion. Bilirubin The enzymes tested are most commonly raised production increases in haemolysis, ineffective in liver disease but some enzymes are also present erythropoiesis, resorption of a haematoma, and in other tissues and consequently may be raised rarely in muscle injury. In all these cases the in other conditions. bilirubin is mainly in an unconjugated form. When faced with an abnormality in an asymp- Conjugated hyperbilirubinaemia characteristi- on September 28, 2021 by guest. Protected copyright. tomatic patient it is imperative to establish that cally occurs in parenchymal liver disease and bil- there is an abnormality in the first place, that is iary obstruction. statistically significant (the normal value is the mean value in a group of healthy individuals ±2SD). The tests should be repeated and when UNCONJUGATED HYPERBILIRUBINAEMIA confirmed appropriate steps be taken. Unconjugated hyperbilirubinaemia (indirect bi- lirubin fraction >85% of total bilirubin) occurs CLINICAL ASSESSMENT with increased bilirubin production or in defects A detailed history should be taken and full physi- in hepatic uptake or conjugation, which in turn cal examination performed with a particular may be inherited or acquired (box 3). See end of article for emphasis on alcohol consumption, risk factors for Gilbert’s syndrome deserves particular men- authors’ affiliations viral hepatitis (intravenous drug use, sexual pro- tion. This is a common, benign disorder character- ....................... miscuity, homosexual relations, tattoos, non- ised by unconjugated hyperbilirubinaemia, which Correspondence to: is exacerbated by fasting. It does not require any Dr Jimmy K Limdi, specific treatment and the patient should be reas- Tameside General Box 1: Normal values sured. Hospital, Fountain Street, Ashton-under-Lyne • Alanine transaminase: 0–45 IU/l. OL6 9RW, UK; • Aspartate transaminase: 0–35 IU/l. ................................................. [email protected] • Alkaline phosphatase: 30–120 IU/l. Submitted • Gammaglutamyl transferase: 0–30 IU/l. Abbreviations: ALP, alkaline phosphatase; ALT, alanine 10 November 2002 • Bilirubin: 2–17 µmol/l. transaminase; AST, aspartate transaminase; ELISA, enzyne Accepted • Prothrombin time: 10.9–12.5 sec. linked immunosorbent assay; HbsAg, hepatitis B surface 12 January 2003 • Albumin: 40–60 g/l. antigen; HFE, haemochromatosis gene; NASH, ....................... non-alcoholic steatohepatitis www.postgradmedj.com 308 Limdi, Hyde Box 2: Clinical assessment Box 4: Common causes of raised transaminases Postgrad Med J: first published as 10.1136/pmj.79.932.307 on 1 June 2003. Downloaded from 1. Alcohol consumption. • Alcohol. 2. Risk factors for viral hepatitis: • Medications: non-steroidal anti-inflammatory drugs, antibi- • Intravenous drug use. otics, HMG Co-A-reductase inhibitors, antiepileptic drugs, • Sexual promiscuity. antituberculous drugs, herbal medications, illicit drug use. • Homosexual relations. • Non-alcoholic steatohepatosis. • Tattoos. • Chronic hepatitis B and C. • Non-sterile ear or body piercing. • Autoimmune diseases. • Blood or blood product transfusions. • Haemochromatosis. • Residence in developing nations. • Wilson’s disease. 3. Medications. • Congestive cardiac failure and ischaemic hepatitis. α 4. Occupational exposure to toxins. • 1-Antitrypsin deficiency. • Coeliac disease. • Endocrine disease: hypothyroidism, Addison’s disease. • Diseases of striate muscle. Box 3: Causes of isolated hyperbilirubinaemia • Glycogen storage diseases. (A) Unconjugated 1. Increased bilirubin production. • Haemolysis. warranted if repeated tests confirm abnormality. Very high • Ineffective erythropoiesis. levels should prompt further evaluation without delay. • Blood transfusion. Common causes are non-alcoholic fatty liver disease, • Resorption of haematomas. alcoholic liver disease, chronic hepatitis B and C, autoimmune α 2. Decreased hepatic uptake. liver disease, haemochromatosis, Wilson’s disease, 1- anti- • Gilbert’s syndrome. trypsin deficiency, and coeliac disease. • Drugs—for example, rifampicin. 3. Decreased conjugation. • Gilbert’s syndrome. CAUSES OF RAISED AMINOTRANSFERASES • Criggler-Najjar syndrome. Alcohol • Physiological jaundice of the newborn. A reliable history is helpful; in reality this can be difficult. A (B) Conjugated biochemical clue is the ratio of AST to ALT (2:1 at least), 1. Dubin-Johnson syndrome. reflecting the low level of activity of ALT in people with alco- 2. Rotor’s syndrome. holic liver disease. A gammaglutamyl transferase level of twice the normal with an AST/ALT ratio of 2:1 or more is highly suggestive of Disproportionate isolated unconjugated hyperbilirubinae- alcohol abuse.5 Gammaglutamyl transferase is not specific to mia may also be seen in fulminant Wilson’s disease. It is inter- alcohol and hence cannot be used as an isolated test.4 esting that the ALP is low in such situations. Haemolysis is Notably, AST levels of more than eight times normal and believed to result from copper release in the blood stream with ALT levels more than fives times normal are exceptionally rare 5 resulting red cell lysis. in alcoholic liver disease. Conversely ALT may be normal even http://pmj.bmj.com/ It is worth mentioning here that bilirubin levels of more in the face of severe alcoholic liver disease. Typically than 85 µmol/l in the presence of normal hepatic function aminotransferase levels are less than 300 U/l in alcohol cannot be explained by chronic haemolysis alone.12 induced liver injury unless of course other insults such as viral or Paracetamol induced liver injury are superimposed on alco- CONJUGATED HYPERBILIRUBINAEMIA (DIRECT holic liver disease, when serum aminotransferase levels may BILIRUBIN >50% OF TOTAL BILIRUBIN) exceed 1000 U/l. Very high aminotransferase levels are charac- This occurs in inherited or acquired defects in hepatic teristically seen in ischaemic liver injury, acute viral hepatitis, excretion. Bilirubin levels have prognostic significance in and drug or toxin induced liver injury and occasionally in on September 28, 2021 by guest. Protected copyright. alcoholic hepatitis, primary biliary cirrhosis, and in acute liver acute obstructing choledocholithiasis. failure. However a disproportionate rise in conjugated bilirubin has limited diagnostic value. As conjugated bilirubin Medication is excreted in urine, bilirubin levels rarely exceed 510 µmol/l in Several drugs may cause raised liver enzymes, commonly the absence of renal failure or haemolysis.3 non-steroidal anti-inflammatory drugs, antibiotics, statins, antiepileptics, and antituberculosis drugs (box 4). A specific AMINOTRANSFERASES inquiry should be made about herbal remedies, alternative These include AST and ALT. They are an excellent marker of medications, and substance abuse. The commonest