Evaluation of Liver Injury Mark J. Czaja Liver Research Center Albert Einstein College of Medicine...

Evaluation of Liver InjuryEvaluation of Liver InjuryEvaluation of Liver InjuryEvaluation of Liver Injury

Mark J. CzajaMark J. Czaja

Liver Research CenterLiver Research Center Albert Einstein College of Medicine Albert Einstein College of Medicine

Bronx, N.Y.Bronx, N.Y.

Mark J. CzajaMark J. Czaja

Liver Research CenterLiver Research Center Albert Einstein College of Medicine Albert Einstein College of Medicine

Bronx, N.Y.Bronx, N.Y.

Liver Function TestsLiver Function TestsLiver Function TestsLiver Function Tests

• Alanine aminotransferase (ALT)Alanine aminotransferase (ALT)

• Aspartate aminotransferase (AST)Aspartate aminotransferase (AST)

• Lactate dehydrogenase (LDH)Lactate dehydrogenase (LDH)

• Alkaline phosphataseAlkaline phosphatase

• BilirubinBilirubin

• AlbuminAlbumin

• Alanine aminotransferase (ALT)Alanine aminotransferase (ALT)

• Aspartate aminotransferase (AST)Aspartate aminotransferase (AST)

• Lactate dehydrogenase (LDH)Lactate dehydrogenase (LDH)

• Alkaline phosphataseAlkaline phosphatase

• BilirubinBilirubin

• AlbuminAlbumin

Mechanisms of Liver DysfunctionMechanisms of Liver DysfunctionMechanisms of Liver DysfunctionMechanisms of Liver Dysfunction

• Direct cellular injuryDirect cellular injury

• Blockage in bile flowBlockage in bile flow

• Impaired blood flowImpaired blood flow

• Direct cellular injuryDirect cellular injury

• Blockage in bile flowBlockage in bile flow

• Impaired blood flowImpaired blood flow

Direct Cellular Injury - HCV InfectionDirect Cellular Injury - HCV InfectionDirect Cellular Injury - HCV InfectionDirect Cellular Injury - HCV Infection

Blockage in Bile Flow - Biliary Blockage in Bile Flow - Biliary AtresiaAtresia

Blockage in Bile Flow - Biliary Blockage in Bile Flow - Biliary AtresiaAtresia

Impaired Blood Flow - CHFImpaired Blood Flow - CHFImpaired Blood Flow - CHFImpaired Blood Flow - CHF

Consequences of Liver InjuryConsequences of Liver InjuryConsequences of Liver InjuryConsequences of Liver Injuryliver cell injuryliver cell injury

liver cell deathliver cell death

proliferationproliferation matrix depositionmatrix deposition

sufficientsufficient inadequateinadequate altered architecturealtered architecture

recoveryrecovery liver failureliver failure cirrhosiscirrhosis

Types of Liver TestsTypes of Liver TestsTypes of Liver TestsTypes of Liver Tests

• True tests of liver functionTrue tests of liver function

• Biochemical markers of liver injuryBiochemical markers of liver injury

• Biochemical markers of specific Biochemical markers of specific

liver diseasesliver diseases

• True tests of liver functionTrue tests of liver function

• Biochemical markers of liver injuryBiochemical markers of liver injury

• Biochemical markers of specific Biochemical markers of specific

liver diseasesliver diseases

Testable Biochemical Liver Testable Biochemical Liver FunctionFunction

Testable Biochemical Liver Testable Biochemical Liver FunctionFunction

• Ability to Ability to transport transport organic anionsorganic anions

• Capacity to Capacity to metabolizemetabolize certain substances certain substances

• Capability to Capability to synthesizesynthesize various proteins various proteins

• Ability to Ability to transport transport organic anionsorganic anions

• Capacity to Capacity to metabolizemetabolize certain substances certain substances

• Capability to Capability to synthesizesynthesize various proteins various proteins

Steps in Organic Anion TransportSteps in Organic Anion TransportSteps in Organic Anion TransportSteps in Organic Anion Transport

• Delivery and uptakeDelivery and uptake

• Metabolic alterationMetabolic alteration

• Secretion and excretionSecretion and excretion

• Delivery and uptakeDelivery and uptake

• Metabolic alterationMetabolic alteration

• Secretion and excretionSecretion and excretion

BilirubinBilirubinBilirubinBilirubin

• TetrapyroleTetrapyrole

• Toxic in neonates - kernicterusToxic in neonates - kernicterus

• Derived from:Derived from: Senescent RBC (70-80%)Senescent RBC (70-80%) Hemoproteins (20-30%)Hemoproteins (20-30%) Ineffective erythropoiesisIneffective erythropoiesis

• TetrapyroleTetrapyrole

• Toxic in neonates - kernicterusToxic in neonates - kernicterus

• Derived from:Derived from: Senescent RBC (70-80%)Senescent RBC (70-80%) Hemoproteins (20-30%)Hemoproteins (20-30%) Ineffective erythropoiesisIneffective erythropoiesis

Bilirubin FormationBilirubin FormationBilirubin FormationBilirubin Formation

hemehemehemeheme biliverdinbiliverdinbiliverdinbiliverdin bilirubinbilirubinbilirubinbilirubinhemehemehemeheme

oxygenaseoxygenaseoxygenaseoxygenase

biliverdinbiliverdinbiliverdinbiliverdin

reductasereductasereductasereductase

Transport: hydrophobic due to internal H-bondingTransport: hydrophobic due to internal H-bonding circulates bound to albumincirculates bound to albuminTransport: hydrophobic due to internal H-bondingTransport: hydrophobic due to internal H-bonding circulates bound to albumincirculates bound to albumin

Bilirubin MetabolismBilirubin MetabolismBilirubin MetabolismBilirubin Metabolism

UCBUCB

ligandinligandin

UCBUCB

ligandinligandin

glucuronyglucuronyllglucuronyglucuronyll

transferasetransferasetransferasetransferase

BMGBMG

BDGBDG

BMGBMG

BDGBDG

AlbAlb

UCBUCB

AlbAlb

UCBUCB

BMGBMG

BDGBDG

BMGBMG

BDGBDG

PlasmaPlasmaPlasmaPlasma HepatocyteHepatocyteHepatocyteHepatocyte BileBileBileBile

BMGBMG

BDGBDG

BMGBMG

BDGBDG

Bilirubin EliminationBilirubin EliminationBilirubin EliminationBilirubin Elimination

IntestineIntestine• BMG (20%) + BMG (20%) +

BDG (80%) BDG (80%) +UCB (trace)+UCB (trace)

• Deconjugated to Deconjugated to urobilinogenurobilinogen

• Excreted or reab-Excreted or reab-sorbed (20%)sorbed (20%)

IntestineIntestine• BMG (20%) + BMG (20%) +

BDG (80%) BDG (80%) +UCB (trace)+UCB (trace)

• Deconjugated to Deconjugated to urobilinogenurobilinogen

• Excreted or reab-Excreted or reab-sorbed (20%)sorbed (20%)

UrineUrine• BMG and BDGBMG and BDG

• No UCBNo UCB

UrineUrine• BMG and BDGBMG and BDG

• No UCBNo UCB

Measurement of Serum Measurement of Serum BilirubinBilirubin

Measurement of Serum Measurement of Serum BilirubinBilirubin

• Normal concentration < 1 mg/dlNormal concentration < 1 mg/dl• Conjugated < 5%Conjugated < 5%• Jaundice if > 3 mg/dlJaundice if > 3 mg/dl• Detected by diazo reaction - cleaved Detected by diazo reaction - cleaved

to colored azo-dipyrole to colored azo-dipyrole Conjugated reacts rapidly (direct)Conjugated reacts rapidly (direct) Unconjugated reacts slowly (indirect)Unconjugated reacts slowly (indirect)

• Normal concentration < 1 mg/dlNormal concentration < 1 mg/dl• Conjugated < 5%Conjugated < 5%• Jaundice if > 3 mg/dlJaundice if > 3 mg/dl• Detected by diazo reaction - cleaved Detected by diazo reaction - cleaved

to colored azo-dipyrole to colored azo-dipyrole Conjugated reacts rapidly (direct)Conjugated reacts rapidly (direct) Unconjugated reacts slowly (indirect)Unconjugated reacts slowly (indirect)

Differential Diagnosis IDifferential Diagnosis IDifferential Diagnosis IDifferential Diagnosis I

• PrehepaticPrehepatic

• IntrahepaticIntrahepatic CongenitalCongenital AcquiredAcquired

• PosthepaticPosthepatic

• PrehepaticPrehepatic

• IntrahepaticIntrahepatic CongenitalCongenital AcquiredAcquired

• PosthepaticPosthepatic

Differential Diagnosis IIDifferential Diagnosis IIDifferential Diagnosis IIDifferential Diagnosis II• Unconjugated hyperbilirubinemiaUnconjugated hyperbilirubinemia

Increased bilirubin production Increased bilirubin production (hematological)(hematological)

Decreased uptake (drug)Decreased uptake (drug) Decreased conjugation (congenital)Decreased conjugation (congenital)

• Conjugated hyperbilirubinemiaConjugated hyperbilirubinemia CongenitalCongenital DrugDrug Liver diseaseLiver disease Biliary obstructionBiliary obstruction

• Unconjugated hyperbilirubinemiaUnconjugated hyperbilirubinemia Increased bilirubin production Increased bilirubin production

(hematological)(hematological) Decreased uptake (drug)Decreased uptake (drug) Decreased conjugation (congenital)Decreased conjugation (congenital)

• Conjugated hyperbilirubinemiaConjugated hyperbilirubinemia CongenitalCongenital DrugDrug Liver diseaseLiver disease Biliary obstructionBiliary obstruction

Inherited Disorders Causing Inherited Disorders Causing Unconjugated HyperbilirubinemiaUnconjugated Hyperbilirubinemia

Inherited Disorders Causing Inherited Disorders Causing Unconjugated HyperbilirubinemiaUnconjugated Hyperbilirubinemia

• Crigler-Najjar syndrome Crigler-Najjar syndrome Type 1 – absent GTType 1 – absent GT

Type 2 – reduced GT activity Type 2 – reduced GT activity

• Gilbert’s syndrome – reduced GT Gilbert’s syndrome – reduced GT activity due to genetic defect in activity due to genetic defect in TATAA element of GT promoter TATAA element of GT promoter

• Crigler-Najjar syndrome Crigler-Najjar syndrome Type 1 – absent GTType 1 – absent GT

Type 2 – reduced GT activity Type 2 – reduced GT activity

• Gilbert’s syndrome – reduced GT Gilbert’s syndrome – reduced GT activity due to genetic defect in activity due to genetic defect in TATAA element of GT promoter TATAA element of GT promoter

Inherited Disorders Causing Inherited Disorders Causing Conjugated HyperbilirubinemiaConjugated Hyperbilirubinemia

Inherited Disorders Causing Inherited Disorders Causing Conjugated HyperbilirubinemiaConjugated Hyperbilirubinemia

• Dubin-Johnson syndrome – Dubin-Johnson syndrome – mutations in multidrug resistance mutations in multidrug resistance associated protein 2 (MRP2)associated protein 2 (MRP2)

• Rotor’s syndrome – genetic defectRotor’s syndrome – genetic defect

• Dubin-Johnson syndrome – Dubin-Johnson syndrome – mutations in multidrug resistance mutations in multidrug resistance associated protein 2 (MRP2)associated protein 2 (MRP2)

• Rotor’s syndrome – genetic defectRotor’s syndrome – genetic defect

Hepatic Metabolic CapacityHepatic Metabolic CapacityHepatic Metabolic CapacityHepatic Metabolic Capacity

• Clearance must depend on total Clearance must depend on total functional mass or metabolic activityfunctional mass or metabolic activity

• Hepatic drug metabolism - Hepatic drug metabolism - [[1414C]amino-pyrine breath testC]amino-pyrine breath test

• Galactose eliminationGalactose elimination

• Not used clinicallyNot used clinically

• Clearance must depend on total Clearance must depend on total functional mass or metabolic activityfunctional mass or metabolic activity

• Hepatic drug metabolism - Hepatic drug metabolism - [[1414C]amino-pyrine breath testC]amino-pyrine breath test

• Galactose eliminationGalactose elimination

• Not used clinicallyNot used clinically

Hepatic Synthetic CapacityHepatic Synthetic CapacityHepatic Synthetic CapacityHepatic Synthetic Capacity

• Most major plasma proteins are made Most major plasma proteins are made in the liverin the liver

• Decreased hepatocytes = decreased Decreased hepatocytes = decreased protein synthesis and releaseprotein synthesis and release

• Albumin and coagulation factors are Albumin and coagulation factors are clinically importantclinically important

• Most major plasma proteins are made Most major plasma proteins are made in the liverin the liver

• Decreased hepatocytes = decreased Decreased hepatocytes = decreased protein synthesis and releaseprotein synthesis and release

• Albumin and coagulation factors are Albumin and coagulation factors are clinically importantclinically important

AlbuminAlbuminAlbuminAlbumin

• 50% of all synthesized hepatic 50% of all synthesized hepatic proteinprotein

• Determinant of plasma oncotic Determinant of plasma oncotic pressurepressure

• Important transport proteinImportant transport protein

• 50% of all synthesized hepatic 50% of all synthesized hepatic proteinprotein

• Determinant of plasma oncotic Determinant of plasma oncotic pressurepressure

• Important transport proteinImportant transport protein

Serum Albumin LevelsSerum Albumin LevelsSerum Albumin LevelsSerum Albumin Levels

• Long half-life of 20 daysLong half-life of 20 days

• Large hepatic synthetic reserveLarge hepatic synthetic reserve

• Decreased with persistent, large injuryDecreased with persistent, large injury

• Decreased in chronic liver diseaseDecreased in chronic liver disease

• Poor prognostic signPoor prognostic sign

• Long half-life of 20 daysLong half-life of 20 days

• Large hepatic synthetic reserveLarge hepatic synthetic reserve

• Decreased with persistent, large injuryDecreased with persistent, large injury

• Decreased in chronic liver diseaseDecreased in chronic liver disease

• Poor prognostic signPoor prognostic sign

Non-hepatic Causes of Non-hepatic Causes of HypoalbuminemiaHypoalbuminemia

Non-hepatic Causes of Non-hepatic Causes of HypoalbuminemiaHypoalbuminemia

• Severe malnutritionSevere malnutrition

• Renal or GI lossRenal or GI loss Glomerulopathy, HIV enteropathyGlomerulopathy, HIV enteropathy

• High catabolismHigh catabolism Infections, burnsInfections, burns

• Severe malnutritionSevere malnutrition

• Renal or GI lossRenal or GI loss Glomerulopathy, HIV enteropathyGlomerulopathy, HIV enteropathy

• High catabolismHigh catabolism Infections, burnsInfections, burns

Coagulation FactorsCoagulation FactorsCoagulation FactorsCoagulation Factors

• Half-lives of hours to daysHalf-lives of hours to days

• Liver synthesizes I, II, V, VII, Liver synthesizes I, II, V, VII, IX, and XIX, and X

• Large synthetic reserveLarge synthetic reserve

• Half-lives of hours to daysHalf-lives of hours to days

• Liver synthesizes I, II, V, VII, Liver synthesizes I, II, V, VII, IX, and XIX, and X

• Large synthetic reserveLarge synthetic reserve

Prothrombin Time (PT)Prothrombin Time (PT)Prothrombin Time (PT)Prothrombin Time (PT)

• PT detects abnormalities in I, II, PT detects abnormalities in I, II, V, VII and X (extrinsic pathway)V, VII and X (extrinsic pathway)

• PT is increased in liver diseasePT is increased in liver disease

• Best prognostic indicatorBest prognostic indicator Acute liver diseaseAcute liver disease Chronic liver diseaseChronic liver disease

• PT detects abnormalities in I, II, PT detects abnormalities in I, II, V, VII and X (extrinsic pathway)V, VII and X (extrinsic pathway)

• PT is increased in liver diseasePT is increased in liver disease

• Best prognostic indicatorBest prognostic indicator Acute liver diseaseAcute liver disease Chronic liver diseaseChronic liver disease

Non-hepatic Causes of Non-hepatic Causes of Elevated PTElevated PT

Non-hepatic Causes of Non-hepatic Causes of Elevated PTElevated PT

• Congenital coagulation factor Congenital coagulation factor

deficienciesdeficiencies

• Consumptive coagulopathiesConsumptive coagulopathies

• Vitamin K deficiency (II, VII, IX, X)Vitamin K deficiency (II, VII, IX, X)

• Congenital coagulation factor Congenital coagulation factor

deficienciesdeficiencies

• Consumptive coagulopathiesConsumptive coagulopathies

• Vitamin K deficiency (II, VII, IX, X)Vitamin K deficiency (II, VII, IX, X)

To Rule Out Vitamin K DeficiencyTo Rule Out Vitamin K DeficiencyTo Rule Out Vitamin K DeficiencyTo Rule Out Vitamin K Deficiency

• Any patient with an elevated PTAny patient with an elevated PT

• Parental vitamin K for 3 daysParental vitamin K for 3 days

• Normalization of PT - vitamin K Normalization of PT - vitamin K deficiencydeficiency

• Failure to normalize - hepatocellular Failure to normalize - hepatocellular diseasedisease

• Any patient with an elevated PTAny patient with an elevated PT

• Parental vitamin K for 3 daysParental vitamin K for 3 days

• Normalization of PT - vitamin K Normalization of PT - vitamin K deficiencydeficiency

• Failure to normalize - hepatocellular Failure to normalize - hepatocellular diseasedisease

Serum ImmunoglobulinsSerum ImmunoglobulinsSerum ImmunoglobulinsSerum Immunoglobulins

• Not produced by hepatocytesNot produced by hepatocytes

• Frequently elevated in liver diseaseFrequently elevated in liver disease

• Secondary to inflammatory processSecondary to inflammatory process

• ? produced by antigen shunting? produced by antigen shunting

• Not produced by hepatocytesNot produced by hepatocytes

• Frequently elevated in liver diseaseFrequently elevated in liver disease

• Secondary to inflammatory processSecondary to inflammatory process

• ? produced by antigen shunting? produced by antigen shunting

Biochemical Biochemical Markers of Liver Markers of Liver

InjuryInjury

Biochemical Biochemical Markers of Liver Markers of Liver

InjuryInjury

Liver EnzymesLiver EnzymesLiver EnzymesLiver Enzymes

• Low levels always present in serumLow levels always present in serum

• Leak out from cell after injuryLeak out from cell after injury

• Very sensitiveVery sensitive

• Magnitude of abnormality does not Magnitude of abnormality does not

correlate well with degree of injurycorrelate well with degree of injury

• Low levels always present in serumLow levels always present in serum

• Leak out from cell after injuryLeak out from cell after injury

• Very sensitiveVery sensitive

• Magnitude of abnormality does not Magnitude of abnormality does not

correlate well with degree of injurycorrelate well with degree of injury

Aspartate Aminotransferase Aspartate Aminotransferase (AST)(AST)

Aspartate Aminotransferase Aspartate Aminotransferase (AST)(AST)

• Serum glutamic-oxaloacetic Serum glutamic-oxaloacetic transaminase (SGOT)transaminase (SGOT)

• Transfers an Transfers an -amino group of aspartate -amino group of aspartate to to -keto group of ketoglutaric acid-keto group of ketoglutaric acid

• Present in skeletal muscle, kidney, brainPresent in skeletal muscle, kidney, brain

• Serum glutamic-oxaloacetic Serum glutamic-oxaloacetic transaminase (SGOT)transaminase (SGOT)

• Transfers an Transfers an -amino group of aspartate -amino group of aspartate to to -keto group of ketoglutaric acid-keto group of ketoglutaric acid

• Present in skeletal muscle, kidney, brainPresent in skeletal muscle, kidney, brain

Alanine Aminotransferase Alanine Aminotransferase (ALT)(ALT)

Alanine Aminotransferase Alanine Aminotransferase (ALT)(ALT)

• Serum glutamic-pyruvic transaminase Serum glutamic-pyruvic transaminase (SGPT)(SGPT)

• Transfers an Transfers an -amino group of alanine -amino group of alanine to to -keto group of ketoglutaric acid-keto group of ketoglutaric acid

• Present principally in liverPresent principally in liver

• Serum glutamic-pyruvic transaminase Serum glutamic-pyruvic transaminase (SGPT)(SGPT)

• Transfers an Transfers an -amino group of alanine -amino group of alanine to to -keto group of ketoglutaric acid-keto group of ketoglutaric acid

• Present principally in liverPresent principally in liver

AST and ALTAST and ALTAST and ALTAST and ALT

• Elevated in most liver diseasesElevated in most liver diseases

• Highest levels are in acute liver Highest levels are in acute liver diseasesdiseases

• Only slight elevations in chronic Only slight elevations in chronic liver diseasesliver diseases

• Usually increase in parallelUsually increase in parallel

• Elevated in most liver diseasesElevated in most liver diseases

• Highest levels are in acute liver Highest levels are in acute liver diseasesdiseases

• Only slight elevations in chronic Only slight elevations in chronic liver diseasesliver diseases

• Usually increase in parallelUsually increase in parallel

AST/ALT in Alcoholic AST/ALT in Alcoholic HepatitisHepatitis

AST/ALT in Alcoholic AST/ALT in Alcoholic HepatitisHepatitis

• Transaminases rarely exceed 300Transaminases rarely exceed 300

• AST:ALT >2AST:ALT >2

• Transaminases rarely exceed 300Transaminases rarely exceed 300

• AST:ALT >2AST:ALT >2

Factors Affecting AST/ALTFactors Affecting AST/ALTFactors Affecting AST/ALTFactors Affecting AST/ALT

• Depressed by pyridoxine (vit. BDepressed by pyridoxine (vit. B66) )

deficiencydeficiency

• Decreased by uremia and renal dialysisDecreased by uremia and renal dialysis

• Depressed by pyridoxine (vit. BDepressed by pyridoxine (vit. B66) )

deficiencydeficiency

• Decreased by uremia and renal dialysisDecreased by uremia and renal dialysis

AST/ALT ControversiesAST/ALT ControversiesAST/ALT ControversiesAST/ALT Controversies

• Should lower normal limits be Should lower normal limits be

used in females?used in females? Females < 30 vs. males < 40Females < 30 vs. males < 40

• Are the normal limits too high?Are the normal limits too high? Females < 20 and males < 30Females < 20 and males < 30

• Should lower normal limits be Should lower normal limits be

used in females?used in females? Females < 30 vs. males < 40Females < 30 vs. males < 40

• Are the normal limits too high?Are the normal limits too high? Females < 20 and males < 30Females < 20 and males < 30

Lactate Dehydrogenase Lactate Dehydrogenase (LDH)(LDH)

Lactate Dehydrogenase Lactate Dehydrogenase (LDH)(LDH)

• Component of classic LFT’sComponent of classic LFT’s

• Highly non-specificHighly non-specific

• Component of classic LFT’sComponent of classic LFT’s

• Highly non-specificHighly non-specific

Tests of Impaired Hepatic Tests of Impaired Hepatic ExcretionExcretion

Increased InIncreased In

Tests of Impaired Hepatic Tests of Impaired Hepatic ExcretionExcretion

Increased InIncreased In

• CholestasisCholestasis

• Intra-hepatic biliary tract obstructionIntra-hepatic biliary tract obstruction

• Extra-hepatic biliary obstructionExtra-hepatic biliary obstruction

• CholestasisCholestasis

• Intra-hepatic biliary tract obstructionIntra-hepatic biliary tract obstruction

• Extra-hepatic biliary obstructionExtra-hepatic biliary obstruction

Alkaline PhosphataseAlkaline PhosphataseAlkaline PhosphataseAlkaline Phosphatase

• Hydrolyzes phosphate esters at Hydrolyzes phosphate esters at alkaline pHalkaline pH

• Also present in bone, kidney, placenta, Also present in bone, kidney, placenta, intestineintestine

• Mainly liver and bone in adultsMainly liver and bone in adults• Increased in children from bone growthIncreased in children from bone growth• Placental form during pregnancyPlacental form during pregnancy

• Hydrolyzes phosphate esters at Hydrolyzes phosphate esters at alkaline pHalkaline pH

• Also present in bone, kidney, placenta, Also present in bone, kidney, placenta, intestineintestine

• Mainly liver and bone in adultsMainly liver and bone in adults• Increased in children from bone growthIncreased in children from bone growth• Placental form during pregnancyPlacental form during pregnancy

Elevated Alkaline PhosphataseElevated Alkaline PhosphataseElevated Alkaline PhosphataseElevated Alkaline Phosphatase

• Can occur in any liver diseaseCan occur in any liver disease• Highest with cholestasis or biliary tract Highest with cholestasis or biliary tract

obstructionobstruction• Elevated in infiltrative diseasesElevated in infiltrative diseases• Due to increase synthesis and secretionDue to increase synthesis and secretion

• Can occur in any liver diseaseCan occur in any liver disease• Highest with cholestasis or biliary tract Highest with cholestasis or biliary tract

obstructionobstruction• Elevated in infiltrative diseasesElevated in infiltrative diseases• Due to increase synthesis and secretionDue to increase synthesis and secretion

Alkaline Phosphatase IsoenzymesAlkaline Phosphatase IsoenzymesAlkaline Phosphatase IsoenzymesAlkaline Phosphatase Isoenzymes

SourceSource Heat Heat InactivationInactivation 55' NT' NT GGTPGGTP

LiverLiver ModerateModerate ++ ++

BoneBone RapidRapid -- --

PlacentaPlacenta SlowSlow -- --

IntestineIntestine SlowSlow -- --

55'-Nucleotidase'-Nucleotidase55'-Nucleotidase'-Nucleotidase

• Hydrolyzes 5Hydrolyzes 5'-'- adenosine monophosphate adenosine monophosphate

• Mainly present in liverMainly present in liver

• Increases along with alkaline phosphatase Increases along with alkaline phosphatase

• Hydrolyzes 5Hydrolyzes 5'-'- adenosine monophosphate adenosine monophosphate

• Mainly present in liverMainly present in liver

• Increases along with alkaline phosphatase Increases along with alkaline phosphatase

-Glutamyl Transpeptidase-Glutamyl Transpeptidase(GGTP)(GGTP)

-Glutamyl Transpeptidase-Glutamyl Transpeptidase(GGTP)(GGTP)

• Transfers Transfers -glutamyl groups-glutamyl groups

• Widely distributedWidely distributed

• Sensitive correlate to alkaline phosphataseSensitive correlate to alkaline phosphatase

• Non-specific (alcoholism, MI, DM, Non-specific (alcoholism, MI, DM, pancreatic disease, renal failure)pancreatic disease, renal failure)

• Transfers Transfers -glutamyl groups-glutamyl groups

• Widely distributedWidely distributed

• Sensitive correlate to alkaline phosphataseSensitive correlate to alkaline phosphatase

• Non-specific (alcoholism, MI, DM, Non-specific (alcoholism, MI, DM, pancreatic disease, renal failure)pancreatic disease, renal failure)

Biochemical MarkersBiochemical Markersof Specific Liverof Specific Liver

Diseases Diseases

Biochemical MarkersBiochemical Markersof Specific Liverof Specific Liver

Diseases Diseases

Etiology-specific Liver TestsEtiology-specific Liver TestsEtiology-specific Liver TestsEtiology-specific Liver Tests

• Viral hepatitis serologiesViral hepatitis serologies• Serum ferritin levelSerum ferritin level• Ceruloplasmin levelCeruloplasmin level

• AlphaAlpha11-antitrypsin level-antitrypsin level

• Antimitochondrial antibody titerAntimitochondrial antibody titer

• Viral hepatitis serologiesViral hepatitis serologies• Serum ferritin levelSerum ferritin level• Ceruloplasmin levelCeruloplasmin level

• AlphaAlpha11-antitrypsin level-antitrypsin level

• Antimitochondrial antibody titerAntimitochondrial antibody titer

Viral Hepatitis SerologyViral Hepatitis SerologyViral Hepatitis SerologyViral Hepatitis Serology

• HAV – anti-HAV IgM and IgGHAV – anti-HAV IgM and IgG

• HBV – HBsAg, anti-HBsAg, HBV – HBsAg, anti-HBsAg,

and anti-HBcAgand anti-HBcAg

• HCV – anti-HCV, HCV RNAHCV – anti-HCV, HCV RNA

• HAV – anti-HAV IgM and IgGHAV – anti-HAV IgM and IgG

• HBV – HBsAg, anti-HBsAg, HBV – HBsAg, anti-HBsAg,

and anti-HBcAgand anti-HBcAg

• HCV – anti-HCV, HCV RNAHCV – anti-HCV, HCV RNA

Serum FerritinSerum FerritinSerum FerritinSerum Ferritin

• Widely distributed storage proteinWidely distributed storage protein

• Levels reflect body iron storesLevels reflect body iron stores

• Elevated in primary hemochromatosisElevated in primary hemochromatosis

• Elevated in acute inflammation and Elevated in acute inflammation and cirrhosiscirrhosis

• Widely distributed storage proteinWidely distributed storage protein

• Levels reflect body iron storesLevels reflect body iron stores

• Elevated in primary hemochromatosisElevated in primary hemochromatosis

• Elevated in acute inflammation and Elevated in acute inflammation and cirrhosiscirrhosis

Serum CeruloplasminSerum CeruloplasminSerum CeruloplasminSerum Ceruloplasmin

• Copper-binding proteinCopper-binding protein

• Decreased in 95% of patients Decreased in 95% of patients with Wilson’s diseasewith Wilson’s disease

• 20% of heterozygotes have 20% of heterozygotes have decreased levelsdecreased levels

• Copper-binding proteinCopper-binding protein

• Decreased in 95% of patients Decreased in 95% of patients with Wilson’s diseasewith Wilson’s disease

• 20% of heterozygotes have 20% of heterozygotes have decreased levelsdecreased levels

11-Antitrypsin-Antitrypsin11-Antitrypsin-Antitrypsin

• Inhibits serum trypsinInhibits serum trypsin

• Major component of Major component of 11-globulin-globulin

• Deficiency cause of neonatal Deficiency cause of neonatal hepatitishepatitis

• Inhibits serum trypsinInhibits serum trypsin

• Major component of Major component of 11-globulin-globulin

• Deficiency cause of neonatal Deficiency cause of neonatal hepatitishepatitis

Antimitochondrial AntibodyAntimitochondrial Antibody(AMA)(AMA)

Antimitochondrial AntibodyAntimitochondrial Antibody(AMA)(AMA)

• Directed against mitochondrial Directed against mitochondrial enzyme pyruvate enzyme pyruvate dehydrogenase complexdehydrogenase complex

• Positive in 90% of patients Positive in 90% of patients with primary biliary cirrhosiswith primary biliary cirrhosis

• Directed against mitochondrial Directed against mitochondrial enzyme pyruvate enzyme pyruvate dehydrogenase complexdehydrogenase complex

• Positive in 90% of patients Positive in 90% of patients with primary biliary cirrhosiswith primary biliary cirrhosis

Interpretation of Abnormal Interpretation of Abnormal LFT’sLFT’s

Interpretation of Abnormal Interpretation of Abnormal LFT’sLFT’s

• Examine multiple testsExamine multiple tests

• Consider non-hepatic causesConsider non-hepatic causes

• Determine the most abnormal testsDetermine the most abnormal tests

• Examine multiple testsExamine multiple tests

• Consider non-hepatic causesConsider non-hepatic causes

• Determine the most abnormal testsDetermine the most abnormal tests

Hepatocellular vs. Hepatocellular vs. CholestaticCholestatic

Hepatocellular vs. Hepatocellular vs. CholestaticCholestatic

TestTest HepatocellularHepatocellular CholestaticCholestatic

ALT/ASTALT/AST 2-32-3 NL-1NL-1

Alk PhosAlk Phos NL-1NL-1 2-32-3

BilirubinBilirubin NL-3NL-3 NL-3NL-3

AlbuminAlbumin NL-3NL-3 NLNL

PTPT NL-3NL-3 NLNL

Case 1Case 1Case 1Case 1

• ALT 2045 (15-45)ALT 2045 (15-45)• AST 2300 (15-45)AST 2300 (15-45)• Alk Phos 273 Alk Phos 273

(50-150)(50-150)


(50-150)(50-150)

• Bili 3.9 (0.1-1.0)Bili 3.9 (0.1-1.0)• Alb 4.2 (3.5-5.5)Alb 4.2 (3.5-5.5)• PT 11.5 (10-12)PT 11.5 (10-12)


25 yo IVDA c/o 1 week of nausea, vomiting, and myalgias. Physical

exam revealed jaundice.

25 yo IVDA c/o 1 week of nausea, vomiting, and myalgias. Physical

exam revealed jaundice.

Hepatocellular W/UHepatocellular W/UHepatocellular W/UHepatocellular W/U

H & PEtOH, medications, transfusions

H & PEtOH, medications, transfusions

Risk for viral hepatitis

Risk for viral hepatitis

Risk factors for NASH

Risk factors for NASH

Autoimmune features

Autoimmune features

Etiology-specific LFT’sEtiology-specific LFT’s

USG and liver biopsyUSG and liver biopsy

HBV Infection - HBcAg StainingHBV Infection - HBcAg StainingHBV Infection - HBcAg StainingHBV Infection - HBcAg Staining

Case 2Case 2Case 2Case 2


(50-150)(50-150)


(50-150)(50-150)



67 yo c/o several months of weight loss, and 1 week of nausea, vomiting, and myalgias. Physical exam revealed

cachexia and jaundice.

67 yo c/o several months of weight loss, and 1 week of nausea, vomiting, and myalgias. Physical exam revealed

cachexia and jaundice.

Cholestatic W/UCholestatic W/UCholestatic W/UCholestatic W/U

H & P medications, gallstones, weight loss

H & P medications, gallstones, weight loss

AMAAMA

USGUSG

ERCPERCP

liver biopsyliver biopsy

dilated ductsdilated ductsnormalnormal

Pancreatic Carcinoma - ERCPPancreatic Carcinoma - ERCPPancreatic Carcinoma - ERCPPancreatic Carcinoma - ERCP

Evaluation of Liver Injury Mark J. Czaja Liver Research Center Albert Einstein College of Medicine...

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