Abnormal Liver Function Tests

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  • Evaluation of Abnormal Liver Function TestsJoshua A. Hodge, Maj, USAF, MCStaff Family PhysicianAndrews AFB, MD

  • OverviewBackgroundTransaminasesAlkaline phosphataseBilirubinOther liver labsSummary

  • BackgroundLiver function tests ordered routinely1-4% of asymptomatic patients have abnormal valuesComponentsTransaminasesAlkaline phosphataseBilirubinOthers: albumin, protein

  • TransaminasesLocated in hepatocytesReleased after hepatocellular injury2 FormsAST Non-specific to liver: heart, skeletal muscle, bloodALTMore specific: elevated in myopathies

  • TransaminasesMay not be elevated in chronic liver diseaseHCV- apoptosisCirrhosisMinimal ALT elevations (
  • TransaminasesMild elevations more to comeMarked elevationsAcute toxic injury- ie tylenol, ischemiaAcute viral diseaseAlcoholic hepatitis

  • TransaminasesAST:ALT ratioElevated in alcoholic disease2:1If AST > 500 consider other causeNo alcohol use suggests cirrhosis

  • Mild TransaminitisAST/ALT < 5 times upper limit of normalEtiologiesHepatic: ALT-predominantChronic Hep C HemochromatosisChronic Hep B Medications/ToxinsAcute viral hep Autoimmune HepSteatosis Alpha1 Antitrypsin DefWilsons Disease Celiac Disease

  • Mild TransaminitisHepatic: AST predominantAlcoholSteatosisCirrhosisNon-hepaticHemolysisMyopathyThyroid diseaseStrenuous exercise

  • Elevated AST & ALT,
  • Hepatotoxic MedicationsAnalgesics- acetaminophen, NSAIDSAntimicrobialsAmox-clav, nitrofurantoin, sulfonamidesINHAzolesProtease InhibitorsAnticonvulsants- carbamazepine, valproic acid, phenyton

  • Hepatotoxic MedicationsCardiovascular- alpha-methyldopa, amiodarone, labetalolHyperglycemics- glyburide, troglidazonePsychiatric- trazadone, disulfiramHeparinPropylthiouracilStatinsZafirlukast

  • Hepatotoxic HerbalsChaparral leafEphedraGentianGermanderJin Bu HuanSenna, KavakavaScutellaria (skullcap)Shark cartilageVitamin A

  • Negative Serology- AsymptomaticStop EtOH & meds; wt loss; glucose controlRepeat LFTsObservationUltrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin, gliadin & endomysial AbLiver biopsyAbnormalNormal6 months

  • Negative Serology- Clinical Signs/Symptoms of Liver DiseaseConsider ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsinLiver biopsyAbnormal

  • Positive Serologies+ Hep C/B infectionObservation Hep A IgMFollow clinically, serial LFTsObservationPersistent elevated LFTs > 6 mosClinical improvement, LFTs normalize in
  • Serologic Tests for Viral HepatitisHAVHep A IgM- in acute infxnHep A IgG- in previous infxn or vaccinationHCVHCV Ab- during or after infectionHCV-RNA- during infectionDetectable prior to HCV Ab turning positive

  • Serologic Tests for Viral HepatitisHBVHep B Surface Ag- in active infxnHep B Surface Ab- in prior infxn or vaccinatedHep B Core Ab IgM- in active infxnHep B Core Ab IgG- in current or prior infxnHBV-DNA- in active infxnHep B e Ag & Ab- markers of viral presence and potential infectivity

  • SymptomsHBeAganti-HBeTotal anti-HBcIgM anti-HBcanti-HBsHBsAg0481216202428323652100Acute Hepatitis B Virus Infection with RecoveryTypical Serologic CourseWeeks after ExposureTitre

  • Alkaline PhosphataseProduced by biliary epithelial cellsNon-specific to liver: bone, intestine, placentaElevationsBiliary duct obstructionPrimary biliary cirrhosisPrimary sclerosing cholangitisInfiltrative liver disease- ie sarcoid, lymphomaHepatitis/cirrhosisMedications

  • MedicationsHormones- anabolic steroids, estrogen, methyltestosteroneAntimicrobials- augmentin, erythromycin, flucloxacillin, TMP-SMX, HIV medsCardiovascular- captopril, diltiazem, quinidineHyperglycemics- chlorpropamide, tolbutamidePsychiatric- fluphenazine, imipramine, iprindoleOthers- allopurinol, carbamazepine

  • Elevated Alk PhosRUQ us, med review, AMAAbnormal LFTsNormal LFTs, biliRUQ u/s for ductal dilatationGGT or 5-NNT ALT eval, liver bx, ERCP or MRCPOther sourceObservationLiver bxNo dilatation-+ERCPAMANoYesNeg AP > 6 mo

  • BilirubinProduct of hemoglobin breakdown2 FormsUnconjugated (indirect)- insoluble in hemolysis, Gilbert syndrome, medsConjugated (direct)- soluble in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc. No elevation until loss of > 50% capacity

  • Elevated BilirubinConjugated bili; Abnormal alk phos, ALT, ASTUnconjugated bili; Normal alk phos, ALT, ASTRUQ u/s to assess ductal dilatationHemolysis studies, review meds ALT eval, review meds, AMA, ERCP or MRCP, liver bxERCP or MRCP+-

  • Other Liver LabsAlbuminPoor marker of liver function- decreased by trauma, inflammatory conditions, malnutritionProthrombin time (PT)Insensitive: no change until liver loses 80% capacityAmmoniaNo correlation between brain & serum valuesOnly one contributor to encephalopathy

  • SummaryAlgorithms based on poor quality or absence of evidenceMost asymptomatic patients can safely be followed for a period of time to see if abnormalities resolveIf lab abnormalities persist be thoughtful with ordering

  • ReferencesAGA Clinical Practice Committee. AGA medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002;123:1364-66.AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002;123:1367-84.Bayard M, et al. Nonalcoholic fatty liver disease 2006;73:1961-8.Giboney PT. Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Physician 2005;71:1105-10.Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician 1999;59:

    Routine reasons to order: annual labs, insurance physical, blood bank, routine eval of non-hepatic diseaseAST made in cytosol and mitochondria. ALT in cytosol only. AST (aspartate aminotransferase) = SGOTALT (alanine aminotransferase) = SGPT

    ALT is present in other tissues but just in lower levelsHCV necrosis + apoptosis (programmed cell death)Do not follow normal bell shaped curve- skewed distribution with long tail at high endUp to 15% higher in African Americans and Hispanics

    There is also diurnal variation and day-to-day variation in valuesVit B6 (pyridoxine) depleted in alcoholics. B6 is coenzyme used by both AST and ALT. ALT is more strongly inhibited by vit B6 def. Also, alcohol causes mitochondrial damage releasing more AST (AST made in mitochondria but ALT is not)HCV is common and affects nearly 2% of population

    HBV prevalence is .1 -2.0%

    Steatosis/steatohepatitis- most common cause of elevated lfts- alcohol and nonalcoholic fatty liver disease but ALT predominant suggests no alcohol

    Hereditary hemochromatosis- one of most common genetic disease (1:200 1:400) and not uncommon cause of AST/ALT elevation- iron, ferritin, tibcAutoimmune hep- more common in females; 1:6000-7000; associated with thyroid disease & other autoimmune conditions- anti-nuclear antibodies, anti-smooth muscle abWilsons Disease- 1:30,000-300,000; lower serum ceruloplasmin; kayser-fleischer rings on slit-lamp (brown-green ring of copper deposit around the cornea)Alpha1 antitrypsin def- 1:1500-7600; decreased serum alpha one antitrypsinCeliac disease- antiendomysial & antigliadin absSigns/Sxs of liver disease: ascites, encephalopathy, coagulation problems, portal HTN, spider telangiectasias, testicular atrophy, gynecomastia, jaundice, hepatosplenomegaly

    Illegal drugs raise LFTs: anabolic steroids, PCP, ectasy, cocaine

    Serologies: HAV- HAV IgM; HBV- HBsAg, HBcIgM; HCV- HCV Ab or RNAOther agents: dantrolene, etretinate, halothane, nicotinic acid, phenylbutazoneSerologies: HAV- HAV IgM; HBV- HBsAg, HBcIgM; HCV- HCV Ab or RNA

    30Biliary duct obstruction: Delayed elevation when acute stone diseaseTakes several daysAST/ALT elevated initially (> 6X normal value)

    GGT = gamma glutanyl transferaseGGT elevated in isolation (normal LFTs) with alcohol use & anticonvulsant use (dilantin) without liver diseasePersistent elevated in asymptomatic women- think primary biliary cirrhosis (check antimitochondrial ab)Most mild elevations (50% excretory capacity

    Gilberts- Congenital enzyme def gluconyltransferase (decreased conjugation ability); bilis 2-3; up to 5% of population

    In liver disease conjugation ability usually remains intact and therefore see a predominance of conjugated bili and not unconjugated1st step: hx, physical and liver function tests

    Hemolysis studies: haptoglobin, cbc, peripheral smear, reticUnconjugated etiologies: hemolysis (ie hereditary spherocytosis), Gilbert syndrome- bili values usually 2-3 Albumin: isolated, low values = nonhepatic etiology; life is 3 weeks and values change slowly in relation to synthesis capacity; 2/3 is extravascular and extracellular so values very dependent on distribution

    Ammonia: not useful if known liver disease and encephalopathy; only useful if mental status changes of unknown etiology; values much higher in brain than serum; more accurate if arterial and not venous