Evaluation Of Elevated Liver Enzymes

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3/1/2021Evaluation ofElevated Liver Enzymes:What does this mean and what do I do next?Amelie Hollier, DNP, FNP‐BC, FAANPAdvanced Practice Education AssociatesSpeaker has norelationship to disclose.Objectives Able to discuss most common reasonsfor elevations in liver enzymes (20 mins) Able to evaluate elevations of liverenzymes and determine hepaticetiology (30 mins) Develop a methodical approach toevaluation of the patient with elevatedliver enzymes (20 mins)1

3/1/2021Outline Get to know the liver! Look at the liver labs in detail:ALT/AST, bilirubin, alkalinephosphatase, GGT, PT/INR, albumin An organized way to evaluate thepatientLet’s get toknow the Liver“Job Description”of the LiverMetabolizes drugsConverts glucose to glycogenProduces bileProduces proteins for blood plasma, clottingProduces proteins immune functionsProduces cholesterol, blood fatsConverts ammonia to ureaProcesses hemoglobinClears bilirubin2

3/1/2021Liver Function Tests ALT/AST Bilirubin, ALP, GGT PT/INR/AlbuminSo, if we want to knowhow a liver is working,we can order LFTs butLiver Function Tests ALT/AST measure of integrity ofliver Bilirubin, ALP, GGT measureexcretory function of liver PT/INR/Albumin measuresynthetic function of liver3

3/1/2021Quiz: About how many differentliver enzymes are there?1. Fewer than 102. About 103. Hundreds4. ThousandsBackgroundThere are THOUSANDS of Liver Enzymes!!!Generally grouped in to 2 Categories: Enzymes that indicate damage tohepatocytes (ALT, AST) Enzymes that reflect cholestasis (Alk, bili)A Look at the LiverLabs in Detail4

3/1/2021Background“Celebrity” Liver Enzymes:AST Aspartate aminotransferase, (SGOT)ALT Alanine aminotransferase, (SGPT)Take Home PointWho is your patient?Liver chemistries must be interpretedin the context of the patient's riskfactors for disease, symptoms, andhistory and physical examinationfindings.What are Normal Values?Normal ALT level in prospectively studiedpopulations without identifiable riskfactors for liver disease ranges from:29 to 33 IU/L for males19 to 25 IU/L for femalesage specific values for childrenKwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liverchemistries. Am J Gastroenterol. 2017;112:18‐35.5

3/1/2021So, why do elevations inALT, AST occur?Elevations in ALT, ASTLiver Enzymes: Sensitive indicators of liver cell injury ALT, AST found in hepatocytesSo, when do elevationsin ALT, AST occur?Liver Enzymes: In the presence of liver cell injury In most liver diseases Elevated in disorders that involve do NOTNECESSARILY involve the liver (heart failure,metastatic carcinoma)6

3/1/2021Quiz: Why are liverenzymes elevated inheart failure?Quiz: Why are liverenzymes elevated inmetastatic carcinoma?Quiz: Why are liverenzymes elevated innon‐liver relateddiseases?7

3/1/2021ALT, ASTAST found in: Liver, heart, skeletal muscleALT found in: Liver primarily, smallamounts in heart, kidney26 y/o female nurse who was recentlymarried presents with complaints ofweakness and fatigue for the past 3 days.She reports a neg home pregnancy test.CBC: normalhCG: negativeUA: Reddish brown, hematuria,nitrites neg, leukos negEarly Lab ResultsPatientNormal ValuesGlucose8270‐110 mg/dLTotal Protein7.56.0‐8.5 g/dLTotal Bilirubin0.40.1‐1.2 mg/dLAlbumin Level4.53.5‐5.5 g/dLAlkaline Phosphatase 8230‐120 U/LAST (SGOT)418 H0‐41 U/LALT (SGPT)174 H0‐45 U/L8

3/1/2021Take Home PointALT present primarily in the liver,so better marker of hepatocellularinjury than AST.Take Home Points AST present in the liver, cardiacmuscle, skeletal muscle, kidney,and brain Increase in AST without anelevation in ALT is suggestive ofcardiac or muscle diseaseNew Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.More Lab ResultsPatientNormal ValuesGlucose8270‐110 mg/dLTotal Protein7.56.0‐8.5 g/dLTotal Bilirubin0.40.1‐1.2 mg/dLAlbumin Level4.53.5‐5.5 g/dLAlkaline Phosphatase 8230‐120 U/LAST (SGOT)418 H0‐41 U/LALT (SGPT)174 H0‐45 U/LCK10,000 H22‐198 U/L9

3/1/2021What’s in yourdifferential diagnosisfor this patient?Take Home Point!Think liver disease with elevatedALT, AST, but don’t limit yourdifferential diagnosis to only liverdisease!Quiz: True or FalseA normal ALT, ASTexcludes liver disease.10

3/1/2021Elevations in ALT, AST Normal ALT, AST do NOT exclude liverdisease! Patients with cirrhosis commonly havenormal ALT, AST levels if there is nocontinuing injury to hepatocytes.Take Home Point!ALT, AST are NOT sensitivemeasures of liver disease.REAL HepatocellularInjuryALT, AST: Highest elevations ( 8 times ULN) usuallyoccur secondary to hepatocellular injury[hepatitis, hepatotoxicity fromacetaminophen, ischemic hepatitis (shockliver), autoimmune hepatitis ALT 10,000IU/L: think acetaminophen orshock liverNew Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.11

3/1/2021What affects ALT, AST? Day to day there are changes in ALT (5‐10%) Day to day there are changes in AST (10‐30%)Desai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompWhat else affects ALT,AST? Race and gender do! AST: 15% higher in African Americanmales NO other significant differences inwomen or other races Should we adjust AST for AfricanAmerican males?Desai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompWhat else affects ALT,AST? “Trunk fat” does! AST, ALT: 40‐50% higher in patients withabdominal adiposityDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiComp12

3/1/2021Quiz: Can liver injury beinduced by metabolicallyactive intra‐abdominalfat?Ruhl, CE, Everhart, JE. (2010). Trunk fat is associated with increased serum levels of alanine transferase in United States. Gastroenterology.138(4):1346.Abdominal Adiposity Trunk fat is a major bodycomposition determinant ofincreased ALTNew Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.Abdominal Adiposity Patients with elevated bodymass index and other featuresof metabolic syndrome, includingdiabetes mellitus, obesity,hyperlipidemia, or hypertension, withmild elevations of ALT should undergoscreening for NAFLD with ultrasoundNew Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.13

3/1/2021What else affects ALT,AST? Exercise can! AST: 3‐fold increase withstrenuous exercise ALT: lower in patients whoexercise at regular levels Enzymes increase morewith strength trainingDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompHow does hemodialysisaffect ALT, AST?Why do you need to know?How does hemodialysisaffect ALT, AST? Hemodialysis patients have falsely low ALT,AST levels These patients are at increased risk of liverdisease, including hepatitis C ULN is about 50% of healthy individuals!14

3/1/2021Elevated ALT, ASTDemonstrate injury tohepatocytesClinical PearlIf AST:ALT ratio is 3:1 orgreater THINK alcoholicliver disease, especially ifGGT is elevatedClinical PearlIn most hepatocellularinjury, ALT AST.15

3/1/2021Background“Celebrity” Liver Labs:BilirubinWhere does bilirubincome from?Bilirubin LevelALL conjugated bilirubin ALL unconjugated bilirubinSerum bilirubin level16

3/1/2021Bilirubin Level Normal serum bilirubin levelsmeans production clearance of bilirubinProduction ClearanceBilirubin LevelProduction ClearanceElevated Bilirubin levels Overproduction Impaired uptake, conjugation,excretion Leakage from damagedhepatocytes or bile ductsBilirubinIndirect bilirubin unconjugatedDirect bilirubin conjugated Elevated Direct hepatobiliary disease Elevated Indirect ? HepatobiliarydiseaseWallach, J. B. (2005). Interpretation of diagnostic tests. (8 ed., p. 422). Philadelphia,PA: Lippincott Williams & Wilkins.:17

3/1/2021Quiz: True or FalseA normal bilirubin levelexcludes liver disease.Bilirubin Level Bilirubin is NOT a sensitiveindicator of liver function ordysfunction Bili levels may be normal ina partially obstructed bileduct or severe liver injuryPatient has an ElevatedSerum Bilirubin LevelFirst Things First:Determine whether it isconjugated or unconjugatedHere’s Why:Almost 100% of bilirubin inhealthy people is unconjugated18

3/1/2021Elevated Serum Bili:Second Step, R ratioThe "R ratio" has been proposedto assess whether the pattern ofliver injury is hepatocellular,cholestatic, or mixed.New Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.Patient has an ElevatedSerum Bili LevelThe ratio is calculated using thisformula:R (ALT value ALT upper limit ofnormal [ULN]) (alkalinephosphatase value alkalinephosphatase ULN)New Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.R RatioInterpretationIf R ratio 5, hepatocellular injuryIf R ratio 2, cholestatic injuryIf R ratio 2‐5, a mixed patternNew Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests ‐ Medscape ‐Feb 01, 2018.19

3/1/2021Causes of ElevatedConjugated BilirubinHepatocellularDisease Hepatitis Pancreatitis Drug induced Hemochromatosis OthersCholestasis Pancreatic etiologies Malignancy Cholangitis Hepatitis and otherintrahepatic causesALWAYS HEPATOBILIARY DISEASECauses of ElevatedUnconjugated Bilirubin HemolysisIneffective erythropoiesisNeonatal jaundiceCrigler‐Najaar SyndromeGilbert’s SyndromeDecrease in hepatic uptake by drugs(rifampin)USUALLY NOT HEPATOBILIARY DISEASEGilbert’s Syndrome Characterized by elevated levels ofunconjugated hyperbilirubinemia Effects 7% of population Often misdiagnosed as hepatitis Bilirubin levels elevated but 3‐4 mg/dL Benign clinical entityUSUALLY NOT HEPATOBILIARY DISEASE20

3/1/2021HyperbilirubinemiaOnly direct bilirubin iswater solubleIt can be identifiedon urine dipstick!Take Home Point!Positive urine dipstick for bilirubin signifies thepresence of conjugated (direct) bilirubin.When patients with hepatobiliary diseaserecover, the urine bilirubin becomes negativebefore serum conjugated bilirubin.Background“Celebrity” Liver Enzymes:Alkaline Phosphatase21

3/1/2021Alkaline Phosphatase An enzyme that catalyzes the hydrolysis ofphosphate esters at an alkaline pH Found in liver, biliary tree, bone, placenta,intestine, kidney, WBCsAlkaline Phosphatase ALP levels are increased in tissues that areactive in metabolism (kidney, intestine, etc.) Clinical importance: most common elevationsare related to liver or bone issuesPatient has an elevated ALP.What’s the etiology?Fractionation of ALP is possible but . Expensive Have to wait for it to be performed22

3/1/2021Take Home Point!Fractionation of ALP is possible but .To help differentiate bone or liver: Order GGT, 5‐nucleotidase levels If normal, likely origin is the bone If elevated, likely origin is the liverQuiz:A pregnant patient isfound to have elevatedalkaline phosphataselevel. Is the etiologylikely to be pathological?Alkaline Phosphatase Elevations likely in pregnancy due to growthof placenta and fetal bone 2‐3 fold increase in 3rd trimester!!!23

3/1/2021Quiz:An adolescent is found tohave elevated alkalinephosphatase level. Is theetiology likely to bepathological?What else affects ALP?Elevations occur with high boneturnover: Healing fracturesOsteomalaciaHyperparathyroidismPaget disease of boneOsteogenic sarcoma (In adolescents?)Bone MetastasisDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompWhat else affects ALP?Elevations occur with liver and liverrelated issues: Cholestasis Infiltrative disease (lymphoma, leukemia,etc.) Liver lesions/masses Hepatitis, cirrhosis Many othersDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiComp24

3/1/2021What else affects ALP?Other Factors that can cause Elevations :Race/Gender: 15% higher in African American males 10% higher in African American femalesDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompWhat else affects ALP?Hemolysis Hemoglobin inhibitsenzyme activityDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompWhat else affects ALP?Smoking 10% higherDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiComp25

3/1/2021Quiz:A 35 year old femaletakes oralcontraceptives. Whateffect will this have onher ALP?What else affects ALP?Oral contraceptives 20% lowerDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompWhat else causesdecreased ALP? Wilson’s diseaseHypothyroidismPernicious anemiaEstrogen in post‐menopausal females Theophylline AlendronateDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiComp26

3/1/2021Take Home Point!Would prefer to measure ALP in a fasting state.Non‐fasting state may increase levelsslightly If elevated non‐fasting, repeat test, fasting. If remains elevated, investigateWhich of the following could be thecause of an elevated alkalinephosphatase level?1.2.3.4.5.6.AgePregnancyRecent healing fractureHyperthyroidismBone metastasisOverdose with acetaminophenSummary: What’s theEtiology of Elevated ALP? Elevations of other LFTs highlysuggestive of hepatobiliary origin If normal LFTs, measure 5nucleotidase (specific forhepatobiliary tree) If 5 nucleotidase not available, orderGGT (sensitive but not specific) Normal GGT or 5N indicates likelyetiology is boneDesai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiComp27

3/1/2021Background“Celebrity” Liver Enzymes:Gamma Glutamyl Transferase (GGT)GGT Found in hepatocytes,biliary epithelial cells,kidney, intestines,pancreas, spleen, heart,brain Consequently, notspecific for liverdiseaseGGT Elevated in 80‐95% ofpatients with acutehepatitis; regardless of type Not helpful in differentiatingdifferent types of liverdisease Most useful with elevatedALP to differentiate whetheretiology is bone or liver28

3/1/2021Background“Celebrity” Liver Labs:Prothrombin Time (PT)International Normalized Ratio (INR)PT/INR PT/INR is a measure of thefunction of the extrinsicpathway The factors are made in theliver PT will remain normal untilabout 80% of liver functionis compromised Therefore, neither sensitivenor specific for liver diseaseSummary: Etiology ofAbnormal PT/INR Decreases are seen in chronic liver disease inconjunction with other ABNORMAL liver tests Look at pattern of other abnormal tests29

3/1/2021Background“Celebrity” Liver Labs:AlbuminAlbumin Liver is the only organ that makes albumin Albumin makes up 60% of proteins in blood Main purpose is to regulate osmotic pressurein the blood Exerts osmotic effect and transports bilirubin,calcium and other electrolytes, progesterone,thyroxine, medicationsAlbumin Neither sensitive nor specific for liverdisease Half life is about 3 weeks; so its main use isin evaluation of the synthetic capacity ofthe liver in patients who have chronic liverdisease Many non‐hepatic diseases that areassociated with hypoalbuminemia:pregnancy, burns, malignancy, rapidrehydration30

3/1/2021Etiology ofHypoalbuminemia Decreases are seen in chronic liver disease inconjunction with other ABNORMAL liver tests Look at pattern of other abnormal testsLiver Function Tests ALT/AST measure of integrity of liver Bili, ALP, GGT measure excretoryfunction of liver PT/INR/Albumin measure syntheticfunction of liverLiver Function TestsElevationsALT/ASTDifferential Dx(liver function)Liver injury, hepatitis, NAFLD, acuteliver failure ( 10x ULN)Think bone disease, liver disease,obstructed bile ductsRBC destruction, liver disease, bile ductobstruction, Gilbert’s diseasePT (in setting ofCirrhosis, cancer originating in liver(liver injury)ALP(liver injury)Bilirubinabnormal LFTs) (liverfunction)AlbuminUsually normal in liver disease(liver function)31

3/1/2021Evaluation of the Patientwith Liver EnzymeElevationsQuiz:What’s the mostimportant part of initialevaluation of a patientwith elevated enzymes?History1. Exposure to hepatotoxins: Prescription meds OTC, illicit Herbal products Occupational/recreational exposureto toxins32

3/1/2021History2. Risk for viral hepatitis3. “Significant” EtOH consumption(difficult to get a good history)EtOH Consumption“Significant” EtOH consumption: 210 grams per week for men (15 drinks/week) 140 grams per week for women (10 drinks/week)The diagnosis and management of non‐alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association,American Association for the Study of Liver Diseases, and American College of Gastroenterology.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ, American Gastroenterological Association, AmericanAssociation for the Study of Liver Diseases, American College of Gastroenterology. Gastroenterology. 2012;142(7):1592.EtOH Consumption14‐gram (1 drink) equivalents of EtOH: 12 oz beer 5 oz wine 1.5 oz of 80 proof liquorThe diagnosis and management of non‐alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association,American Association for the Study of Liver Diseases, and American College of Gastroenterology.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ, American Gastroenterological Association, AmericanAssociation for the Study of Liver Diseases, American College of Gastroenterology. Gastroenterology. 2012;142(7):1592.33

3/1/2021Take Home Point!Look at ratio of abnormal AST, ALTRatio AST: ALT 2 Strongly consider EtOHRatio AST: ALT 1 Consider EtOH liver diseaseRatio AST: ALT 1 Seen in fatty liver, othersHistory4. Other Diseases/Conditions Right sided heart failure DM, obesity Pregnancy (gallstones) IBD Alpha‐1 antitrypsin deficiency Celiac disease Thyroid diseaseSummary of History1.2.3.4.Hepatotoxins?Risk of hepatitis?EtOH consumption?Other diseases/conditions?34

3/1/2021Physical Exam Muscle wasting Spider nevi, palmary erythema, gynecomastia,caput medusae (engorged periumbilical veins radiatingfrom the umbilicus secondary to severe portal hypertension) AscitesDupuytren’s contracturesEnlarged left supraclavicular nodeEnlarged liver, tender liverOthersLet’s Look atAbnormal Liver FunctionTestsKwo PY, Cohen SM, Lim JK. ACG clinical guideline:evaluation of abnormal liver chemistries. Am JGastroenterol. 2017;112:18‐35.First Step:What’s Elevated?This helps determine etiology! Elevated ALT, AST: think hepatocyteinjury Elevated Alkaline phosphatase:think cholestasis Isolated elevated bilirubin level35

3/1/2021Obviously If clues elicited in history and physicalexam point to a possible etiology,work it up.Obviously Exclude common conditions: DM,heart failure, thyroid disease,muscle disordersIF No Clue aboutEtiology of Elevations Extensive testing saves time andmoney but more false‐positives IF clues present, focused testingsaves time and money and preventsfalse‐positivesTapper EB, Saini SD, Sengupta N. Extensive testing or focused testing of patients withelevated liver enzymes. J Hepatol. 2017;66:313‐31936

3/1/2021Quiz:Asymptomatic, otherwise healthypatient with no obvious clues inhistory about AST/ALT elevations.How to 9Previous PatientQuestion Lab Values?Before initiating an evaluationof abnormal liver chemistries,repeat the panel or clarifyQuiz:Asymptomatic, otherwise healthypatient with no obvious clues inhistory about AST/ALT elevations?How to . Work up.2. Watch and wait for 4‐6months.37

3/1/2021Elevations in ALT, ASTEnzymeNormalMildModerateSevereAST10‐30 2‐3 ULN2‐3 to 20 20ALT2‐28 2‐3 ULN2‐3 to 20 20 Most common is mild to moderateelevations ( 8 times ULN) Refer severe elevations!!!Desai, S. (2004). Clinician’s Guide to laboratory medicine (3rd ed.). Hudson,OH: LexiCompALT, AST ElevationCommon Causes for Mild to ModerateElevations: Infectious Metabolic Alcohol or hepatotoxic drug use Autoimmune Hereditary liver diseaseALT, ASTMild to Moderate ElevationsInitial Workup: Screen for InfectiousHepatitis: Serology for Hepatitis A, B, C HBsAg, Anti‐HBs, anti‐HBc, anti‐HCV38

3/1/2021Nonalcoholic Fatty LiverDisease (NAFLD)Steatosis fatty liverNAFLD: hepatic steatosis presentwithout evidence of significanthepatic inflammationNASH: hepatic steatosis associatedwith hepatic inflammation (may lookjust like alcoholic steatohepatitis)ALT, ASTMild to Moderate ElevationsInitial Workup: Screen forNonalcoholic Fatty Liver Disease(NAFLD): Typically, ALT, AST 2‐5 times ULNALP may be 2‐3 times ULNSerum albumin, bili: usually normalSymptoms of metabolic syndrome, centralobesity, T2DM, dyslipidemiaO'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases,Practice Parameters Committee of the American College of Gastroenterology. Hepatology. 2010;51(1):307.Lazo M, Hernaez R, Eberhardt MS et al. Prevalence of Nonalcoholic Fatty Liver Disease in the United Status: TheThird National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 2013;178:38–45.Imaging with UltrasoundImaging for Nonalcoholic Fatty LiverDisease (NAFLD): Ultrasound: sensitivity 85%, specificity 94%Least expensiveLess sensitive in morbidly obeseUS: increased echogenicity; diffuse fattyinfiltrationHernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy andreliability of ultrasonography for the detection of fatty liver: a meta‐analysis.Hepatology. 2011;54(3):1082.39

3/1/2021Imaging with US vs CT, MRIImaging for Nonalcoholic Fatty LiverDisease (NAFLD): Detection ofsteatosisUSCTwithoutcontrastCT 008363Rofsky NM, Fleishaker H. CT and MRI of diffuse liver disease. Semin Ultrasound CT MR.1995;16(1):16.Vibration Controlled TransientElastography (VCTE)Used to grade fibrosis based on liverstiffness (quantitative andreproducible)Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy andreliability of ultrasonography for the detection of fatty liver: a meta‐analysis.Hepatology. 2011;54(3):1082.DiagnosisNonalcoholic Fatty Liver Disease(NAFLD): Demonstration of hepatic steatosis byimaging or biopsy Exclusion of other causes of steatosis Exclusion of “significant” EtOH consumptionO'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Associationfor the Study of Liver Diseases, Practice Parameters Committee of the American College ofGastroenterology. Hepatology. 2010;51(1):307.40

3/1/2021ALT, ASTMild to Moderate ElevationsInitial Workup: Screen forHemochromatosis: Serum iron, TIBCFe/TIBC 45% (then, get a serum ferritin)Serum Ferritin 200 ng/mL in menSerum Ferritin 150 ng/mL in womensupports diagnosisBacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and Management of hemochromatosis: 2011practice guideline by American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328.Quiz:Why don’t you order aserum ferritin initially?1. It costs too much.2. Serum ferritin is an acutephase reactant.Suppose Initial Workup: Inf hepatitis: Negative Hemochromatosis: Negative Fatty liver disease: NegativeNow what?41

3/1/2021What again? Review medication list (again) Assess EtOH use (again)ALT, AST ElevationRemember Common Causes: Infectious Metabolic Autoimmune Hereditary liver disease Alcohol or hepatotoxic drug useALT, AST ElevationSecond Level of Workup:Consider an autoimmune hepatitis Clue might be co‐existence of otherdiseases with autoimmune features:hemolytic anemia, ITP, DM type 1,thyroiditis, celiac sprue, ulcerativecolitisBjörnsson E, Talwalkar J, Treeprasertsuk S, Neuhauser M, Lindor K. Patients with typical laboratory features ofautoimmune hepatitis rarely need a liver biopsy for diagnosis. Clin Gastroenterol Hepatol. 2011;9(1):57.42

3/1/2021Autoimmune HepatitisCommon Presentation ALT, AST usually elevated Usually normal bili, ALP but canhave very high bili and ALP ifcholestatic presentationManns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli‐Vergani G, Vergani D, Vierling JM. Diagnosis and management ofautoimmune hepatitis, American Association for the Study of Liver Diseases. Hepatology. 2010;51(6):2193.Cholestatic InjuryFlow of bile is blocked Elevations in ALP,glutamyl transferase,bilirubin Elevations 8 fold Patient symptoms:pruritis, jaundice, darkurineAutoimmune HepatitisWorkup Total IgG or gamma globulin level Positive ANA (most common circulatingautoantibodies in Type 1 disease) Positive ASMA (antismooth muscleantibodies) 1:320 or greater; common in Type1 disease Anti‐liver/kidney microsomal‐1 (anti‐LKM‐1)antibodies (Type 2 disease)Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli‐Vergani G, Vergani D, Vierling JM. Diagnosis and management ofautoimmune hepatitis, American Association for the Study of Liver Diseases. Hepatology. 2010;51(6):2193.43

3/1/2021ALT, AST ElevationSecond Level of Workup:Consider Thyroid disease Hypothyroidism/Hyperthyroidism cancause elevations (constellation ofsymptoms and findings) TSH, free T4, T3 concentrations Might also be a clue to autoimmunehepatitisALT, AST ElevationSecond Level of Workup:Consider Celiac Disease Clue might be a history of diarrhea, IDA Anti‐tTG antibodies Moderately sensitive, highly specific foruntreated celiac diseaseHopper AD, Hadjivassiliou M, Hurlstone DP, Lobo AJ, McAlindon ME, Egner W, Wild G, Sanders DS. What is the roleof serologic testing in celiac disease? A prospective, biopsy‐confirmed study with economic analysis. ClinGastroenterol Hepatol. 2008;6(3):314.Suppose Second LineWorkup: Autoimmune Hepatitis: Negative Thyroid disease: Negative Celiac disease: NegativeNow what?44

3/1/2021ALT, AST ElevationWhat Other Causes? Infectious Metabolic Autoimmune Hereditary liver disease Alcohol or hepatotoxic drug useALT, AST ElevationThird Level of Workup: Consider Wilson’s Disease: abnormal coppertransport hepatolenticular degeneration (1in 30,000 people) Alpha‐1 antitrypsin deficiency Adrenal insufficiency Muscle disorders (Increased CK/aldolaselevels)Wilson’s DiseaseAbnormal LFTs Serum cerulplasmin level (low, 20mg/dL) Kayser‐Fleischer rings (slit lampeval): considered pathognomonicfor Wilson’s Disease45

3/1/2021Still Stumped?Liver BiopsySuppose Alk Phos isElevated?This helps with determining etiology! Elevated ALT, AST: think hepatocyteinjury Elevated Alkaline phosphatase:think cholestasis Isolated elevated bilirubin levelElevated AlkalinePhosphatase LevelHepatic in Etiology?46

3/1/2021Quiz:Is the elevated ALP ofhepatic ‐100 u/L4243350Ultrasound?Yes!Quiz:Is the elevated ALP ofhepatic ‐100 u/L2826350Ultrasound?Quiz:How would youdetermine if ALP is ofhepatic ‐100 u/L2826350GGT? Serum 5‐nucleotidase?47

3/1/20215 Nucleotidase, GGTelevated: Interpretation?Liver or Bone?EnzymeNormalPatientASTALTALPGGT5 nucleotidase10‐302‐2830‐100 u/L1‐70 u/L0‐11 U/L2826350140335 Nucleotidase, GGTWNL: Interpretation?Liver or Bone?EnzymeNormalPatientASTALTALPGGT5 nucleotidase10‐302‐2830‐100 u/L1‐70 u/L0‐11 U/L2826350403Suppose Bili isElevated?This helps with determining etiology! Elevated ALT, AST: think hepatocyteinjury Elevated Alkaline phosphatase:think cholestasis Isolated elevated bilirubin level48

3/1/2021Patient has an ElevatedSerum Bili LevelFirst Things First:Determine whether it isconjugated or unconjugatedHere’s Why:Almost 100% of bilirubin inhealthy people is unconjugatedCauses of ElevatedConjugated BilirubinHepatocellularDisease Hepatitis Pancreatitis Drug induced Hemochromatosis OthersCholestasis Pancreatic etiologies Malignancy Cholangitis Hepatitis and otherintrahepatic causesALWAYS HEPATOBILIARY DISEASEGilbert’s Syndrome Characterized by unconjugatedhyperbilirubinemia Effects 7% of population Often misdiagnosed as hepatitis Bilirubin levels elevated but 3‐4mg/dL Benign clinical entityUSUALLY NOT HEPATOBILIARY DISEASE49

3/1/2021Wrap Up!Remember your LiverEnzymes!!!!! ALT/AST measure of integrity of liver Bili, ALP, GGT measure excretory functionof liver PT/INR/Albumin measure syntheticfunction of liverWrap Up!Remember MostCommon Causes! InfectiousMetabolicAutoimmuneHereditary liver diseaseAlcohol or hepatotoxic drug useWrap Up!Remember to Look atwhat’s Elevated?This helps to determine etiology! Elevated ALT, AST: think hepatocyteinjury Elevated Alkaline phosphatase: thinkcholestasis Isolated elevated bilirubin level50

3/1/2021Thank you!For questions or to contactme:Dr. Amelie Hollieramelie@apea.comAdvanced Practice Education Associates51

3/1/2021 3 ALT/AST Bilirubin, ALP, GGT PT/INR/Albumin Liver Function Tests So, if we want to know how a liver is working, we can order LFTs but ALT/AST measure of integrity of liver

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In recent years, a new clinical form of liver failure has been recognised. Traditionally there were two types of liver failure: Acute liver failure (ALF), a rapid deterioration of the liver function in the absence of pre-existing liver disease, in the setting of an acute hepatic insult and chronic liver failure (CLF), a progressive

Nomenclature of Liver Disease Acute Liver Diseases: Acute Hepatitis: Hepatitic, Cholestatic, or Mixed Acute Liver Failure: - Jaundice -Encephalopathy - Coagulopathy Chronic Liver Diseases: Chronic inflammation with/without fibrosis Cirrhosis (stage 4 fibrosis) Liver Neoplasms Acute on top of Chronic Liver Diseases

Gene example Black and Liver B Locus is the gene responsible for the Black / liver coat colours: The B Locus has two alleles : B Black b Liver The black parent alleles are B / B (Black / Black) The liver parent alleles are b / b (liver / liver) The offspring is black and its alleles are B / b (Black / liver) The offspring inherited the black allele from the black

Restriction enzymes and DNA ligases represent the cutting and joining functions in DNA manipulation. All other enzymes involved in genetic engineering fall under the broad category of enzymes known as DNA modifying enzymes. These enzymes are involved in the degradation, synthesis and alteration of the nucle