How to interpret liver function tests

1 PRACTICE TOOLSVol 1 September 2009 Clinical Pharmacist363By Gareth Nickless, DipClinPharm,MRPharmSMany pharmacists will, at somestage, have needed to interpret apatient s liver function tests (LFTs)and decide whether any of his or hermedicines required dose reduction orcessation. Although drug-induced liver disease isrelatively uncommon, medicines shouldalways be considered as a possible cause ofliver dysfunction (and pharmacists shouldbe vigilant for such events and report allsuspected reactions to the Medicines andHealthcare products Regulatory Agencyusing the yellow card scheme). Over 600medicines have been associated withhepatotoxic reactions. liver function assessmentLFTs involve detecting the levels of severalbiochemical markers in the advice on adjusting the doses ofmedicines for patients with renal disease isplentiful (eg, The renal drug handbook ),there is no equivalent publication forpatients with abnormal LFTs or hepaticdysfunction.

2 Furthermore, LFTs cannotquantify liver function in the same way thatcreatinine clearance quantifies renalfunction. Instead, practitioners rely oninformation in summaries of productcharacteristics, the British NationalFormulary and, where available, inpublished guidelines for treatment ofspecific diseases. Although abnormal LFTs can indicate ahepatobiliary problem that warrants furtherinvestigation, they should not be assessed inisolation. The presence of other signs andsymptoms of liver disease (eg, ascites,varices) should also be common biochemical markersmeasured in LFTs are explained below. commonly produced by liver cells. Inresponse to acute hepatocellular damage (eg,acute hepatitis), the levels of these enzymesin the bloodstream can rise significantly.

3 Transaminase levels are not usuallyaffected for patients with cholestasis;however, gallstones lodged in the commonbile duct can result in transaminaseenzymes and biliary enzymes (alkalinephosphatase [ALP] and gammaglutaryltransferase [GGT]) all being raised indicating hepatitis and levels may be normal (oronly marginally raised) in patients withcirrhosis since there is little remaininghealthy liver tissue to produce glutaryltransferaseProducedby hepatocytes and bile ducts, GGT is anenzyme for which levels can be raised 10-to 20-fold in patients with cholestasis. Itslevels can also be raised, but often less so, inpatients with cirrhosis. Alkaline phosphatase ALP isoenzymesare found in hepatocytes, bile canaliculiepithelial cells, bone and intestine.

4 RaisedALP levels are commonly seen in bothintra- and extrahepatic cholestasis, and inPaget s disease. If a patient s GGT is alsoraised, this can help to confirm whether araised ALP is of hepatobiliary level of serum carrierprotein albumin is useful for assessing aliver s synthetic function . Since albumin sPatients with abnormal liver function tests are encountered commonly by pharmacists. It is thereforehelpful to know how to amend patients treatments and when such amendments might be necessaryHow to interpret liver function tests Gareth Nicklessis lead clinical liaisontutor/practitioner at Wirral UniversityTeaching Hospital NHS Foundation SHORTP harmacists are likely to come acrosspatients whose liver function tests areabnormal.

5 However, assessing LFTsalone will not offer pharmacists the the likely cause of abnormalLFTs can help determine whether theabnormalities are caused by a medicine,or whether any doses of medicines needto be changed to by-product of haemmetabolism, bilirubin is conjugated byhepatocytes for excretion. Whenhepatocytes are damaged (due to acutehepatitis or cirrhosis), they are unable toperform this function sufficiently, resultingin raised levels of unconjugated bilirubinand, ultimately, jaundice. Serum bilirubin levels can also be raisedas a result of cholestasis a conditionwhere the movement of bile from the liverto the gallbladder is inhibited (this can becaused by intrahepatic factors, such as viralhepatitis or a bacterial abscess, orextrahepatic factors, such as gallstones).

6 Haemolysis, as seen in autoimmunehaemolytic anaemia, can also raisebilirubin enzymesAlanineaminotransferase (ALT) and aspartateaminotransferase (AST) enzymes are mostPARAMETERSCORE123 Bilirubin ( mol/L)<3535 50>50 Albumin (g/L)>3528 35<28 INR< > or Severe or easily treatedintractableGrade of hepaticencephalopathyNone1 23 4 Once all points have been tallied, chronic liver disease is classified as indicated below:POINTSCLASSONE-YEAR SURVIVALTWO-YEAR SURVIVAL5 6A100%85%7 9B81%57%10 15C45%35%Box 1: Child-Pugh scores to classify chronic liver diseaseCP, Sep, p363-66, how to_FAQ 26/8/09 10:38 Page 363 PRACTICE TOOLS364 Clinical PharmacistSeptember 2009 Vol 1 Rob Bouwman | a result, few drugs use this scoringsystem in their product information tosuggest specific dose reductions caspofungin is an exception whichrecommends a dose of 35mg daily (insteadof the usual 50mg daily) for patients withChild-Pugh class B of medicines on the liverMedicines can affect the liver in manyways, ranging from minor abnormalities ofreported LFTs to significant hepaticnecrosis.

7 In some cases, the reaction hasbeen serious enough to warrant amedicine s withdrawal from the market (eg,troglitazone the first marketedthiazolidinedione). Some reactions are predictable and occurin a dose-related manner (eg, in paracetamoloverdose) whereas others are idiosyncratic(eg, cholestasis caused by chlorpromazine).For most drugs, pre-existing liverdysfunction does not generally increase therisk of developing drug-induced liverdisease, although sodium valproate andmethotrexate are notable exceptions. Polypharmacy may increase the risk ofhepatotoxic reactions. For example, non-steroidal anti-inflammatory drugs are morelikely to cause liver disease if they areBox 2: How some medicines can affect liver function tests PenicillinsModerate and asymptomatic rises in serumtransaminases have been observed in patients taking have also been reports of cholestatic jaundice, especially forflucloxacillin and co-amoxiclav (due to the clavulanic acidcomponent).

8 Signs and symptoms usually occur during or shortlyafter a course of treatment, but may be delayed for two weeks orlonger after the course has finished. The risk is increased formales, elderly patients and those who receive a course of treatmentthat exceeds 14 days. This reaction is usually reversible, but canbe severe and potentially fatal. StatinsModerate rises of transaminases (ie, less than three timesthe upper limit of normal [ULN]) have been reported following theuse of all statins. This increase may be transient or sustained. Thegeneral advice from manufacturers is to discontinue therapy if therise is progressive (ie, more than three times the ULN andpersistent).

9 MethotrexateAbnormal LFTs and hepatic cirrhosis have beenreported from the use of methotrexate, therefore regular monitoringis required. If abnormal LFTs develop, treatment should bestopped. In some cases (eg, when patients have been taking aparticularly high dose), it may be possible to restart treatment at alower dose once the LFTs return to drugsModest rises in transaminases are notuncommon in patients with tuberculosis (TB). The British ThoracicSociety guidelines for the management of TB3recommendmonitoring LFTs for all patients with known chronic liver disease. Iftransaminases rise to more than five times the ULN, or bilirubinrises above the ULN, treatment with rifampicin, isoniazid andpyrazinamide should be stopped.

10 Once LFTs have recovered, these medicines can be restartedsequentially (as outlined in the guidelines) with LFTs beingmonitored daily. The National Institute for Health and ClinicalExcellence has recently published guidance on the management ofTB, but it does not suggest how treatment should be restarted insuch is an enzyme inducer and it is common forthree- to five-fold increases in gamma glutaryltransferase to beobserved during treatment. Hepatotoxicity that requires withdrawalof the drug is less common. If hypoalbuminaemia is observed inpatients who are taking phenytoin, more of the drug will beunbound in plasma. Consequently, a corrected concentration ofphenytoin should be calculated as follows: Corrected concentration =Measured plasma concentration ( mol/L)( serum albumin (g/L) / 44)+ medicinesIncreased use of herbal medicines has led totheir greater recognition as a cause of liver injury.