Evaluation of abnormal liver Evaluation of abnormal liver associated enzymesassociated enzymes

Objectives

Define “liver associated enzymes”

Differentiate:– Hepatocellular vs. cholestatic

Radiographic/pathology images

Specific liver diseases

Liver associated enzymesLiver associated enzymes& assessment of liver function& assessment of liver function

Commonly used in reference to:Commonly used in reference to:– Alanine aminotransferase (ALT)Alanine aminotransferase (ALT)– Aspartate aminotransferase (AST)Aspartate aminotransferase (AST)– Alkaline phosphatase (AP) Alkaline phosphatase (AP) – Gamma glutamyl transpeptidase (GGT) Gamma glutamyl transpeptidase (GGT) – Bilirubin Bilirubin

Markers of synthetic capacityMarkers of synthetic capacity– Albumin/pre-albuminAlbumin/pre-albumin– Prothrombin time/INRProthrombin time/INR

AminotransferasesAminotransferases

Elevation reflects hepatocyte injuryElevation reflects hepatocyte injury

ALT relatively liver specificALT relatively liver specific

AST may be found in skeletal and cardiac AST may be found in skeletal and cardiac muscle, blood cells muscle, blood cells

Hepatocellular injury ALT:AP >5Hepatocellular injury ALT:AP >5

If ALT/AST elevation >1000If ALT/AST elevation >1000– Ischemia, virus, toxin, less commonly CBD Ischemia, virus, toxin, less commonly CBD

stone, AIHstone, AIH

Alkaline Phosphatase (AP)Alkaline Phosphatase (AP)

Found in liver, bone, placenta, neoplasmsFound in liver, bone, placenta, neoplasms

AP increased 3x in adolescence/ also AP increased 3x in adolescence/ also increased in late pregnancyincreased in late pregnancy

AP half-life 1 week (remain elevated after AP half-life 1 week (remain elevated after relief of biliary obstruction)relief of biliary obstruction)

AP elevations seen with infiltrative hepatic AP elevations seen with infiltrative hepatic disordersdisorders

Cholestatic injury ALT:AP ratio <2 Cholestatic injury ALT:AP ratio <2

Gamma Glutamyl TranspeptidaseGamma Glutamyl Transpeptidase

GGT derived primarily from hepatocytes GGT derived primarily from hepatocytes and biliary epitheliaand biliary epithelia

Useful to confirm hepatic origin of AP (may Useful to confirm hepatic origin of AP (may also use a 5’ nucleotidase)also use a 5’ nucleotidase)

Microsomal enzyme inducible by ETOH, Microsomal enzyme inducible by ETOH, Coumadin and anticonvulsantsCoumadin and anticonvulsants

BilirubinBilirubin

Derived primarily from the catabolism of Derived primarily from the catabolism of hemoglobinhemoglobin– Water soluble, conjugated “direct”Water soluble, conjugated “direct”

Impaired biliary excretion (obstruction)Impaired biliary excretion (obstruction)Bilirubin in urine always conjugatedBilirubin in urine always conjugated

– Water insoluble, unconjugated “indirect”Water insoluble, unconjugated “indirect”Increased production with hemolysis, ineffective Increased production with hemolysis, ineffective erythropoiesis, hematoma resorbtionerythropoiesis, hematoma resorbtionIncreased LDH, decreased haptoglobin, increased AST, Increased LDH, decreased haptoglobin, increased AST, increased retic countincreased retic countHemolysis will not elevate bilirubin >5 mg/dl Hemolysis will not elevate bilirubin >5 mg/dl

AlbumenAlbumen

Serum concentration falls with hepatic Serum concentration falls with hepatic parenchymal diseaseparenchymal disease

Half Life 20 daysHalf Life 20 days

Negative acute phase reactantNegative acute phase reactant

May be depressed with poor nutrition, May be depressed with poor nutrition, renal losses (nephrotic syndrome)renal losses (nephrotic syndrome)

HistoryHistory

Duration of LAE abnormalityDuration of LAE abnormality– Acute <6 monthsAcute <6 months– Chronic >6 monthsChronic >6 months

Medication history (with special attention to Medication history (with special attention to new medications)new medications)– Cholestasis with estrogens, anabolic steroids, Cholestasis with estrogens, anabolic steroids,

erythromycin, amoxicillin-clavulanateerythromycin, amoxicillin-clavulanate

Family history of liver diseases Family history of liver diseases – 2-3 generations/second degree relatives2-3 generations/second degree relatives

HistoryHistory

Jaundice (bilirubin >3 mg/dl)Jaundice (bilirubin >3 mg/dl)

ArthralgiasArthralgias

Weight lossWeight loss

Changes in urine color (direct bilirubin Changes in urine color (direct bilirubin only)only)

Physical ExamPhysical Exam

Temporal/proximal muscle wastingTemporal/proximal muscle wasting

Spider NeviSpider Nevi

Palmer erythemaPalmer erythema

GyncomastiaGyncomastia

Dupuytren’s contracturesDupuytren’s contractures

Testicular atrophyTesticular atrophy

Unknown

Up to 42% of those with this condition have elevated LAE

Associated with neuropathy

May have iron and folate deficiency

NAFLD/NASHNAFLD/NASH

Macro vs. microMacro vs. microvesicularvesicular fatty change fatty change

Less than 20-30 grams of ETOH per dayLess than 20-30 grams of ETOH per day

Metabolic syndromeMetabolic syndrome

TPNTPN

Drugs: amiodarone, tamoxifen, Drugs: amiodarone, tamoxifen, glucocorticoids, estrogensglucocorticoids, estrogens

ALT>ASTALT>AST

NAFLDNAFLD

DiagnosisDiagnosis– Echogenic liver by Echogenic liver by

ultrasoundultrasound– Liver <15 HU/spleenLiver <15 HU/spleen– Liver biopsyLiver biopsy

Treatment:Treatment:– Modification of risk factors Modification of risk factors – Pioglitazone/Vitamin EPioglitazone/Vitamin E– Gastric BypassGastric Bypass

Alcoholic Liver DiseaseAlcoholic Liver Disease

AST:ALT ratio >2 (established disease)AST:ALT ratio >2 (established disease)

Elevations in AP/GGTElevations in AP/GGT

Macrocytic anemiaMacrocytic anemia

ThrombocytopeniaThrombocytopenia

Elevated triglyceridesElevated triglycerides

Higher rates Caucasians/lesser for Asians Higher rates Caucasians/lesser for Asians

Alcoholic Liver DiseaseAlcoholic Liver Disease

Discontinuation of ETOH/Detox programDiscontinuation of ETOH/Detox program

Monitor for complications:Monitor for complications:– PancreatitisPancreatitis– Cirrhosis, HCC and decompensationsCirrhosis, HCC and decompensations

Maddrey discriminant function 4.6 x (PT-PT Maddrey discriminant function 4.6 x (PT-PT control) + bilirubin >32 give 4 week course of control) + bilirubin >32 give 4 week course of prednisoloneprednisolone

Pentoxifylline 400mg TIDPentoxifylline 400mg TID

No ETOH 6 months->transplant evaluationNo ETOH 6 months->transplant evaluation

Hepatitis AHepatitis A

Fecal-Oral transmissionFecal-Oral transmission

High rates daycare/prisonsHigh rates daycare/prisons

Associated with contaminated water and Associated with contaminated water and shellfish shellfish

Liver injury secondary to host immune Liver injury secondary to host immune responseresponse

Hepatitis AHepatitis A

Children <5 asymptomatic 90%Children <5 asymptomatic 90%

Adults 70-80% symptomatic Adults 70-80% symptomatic

If >40 1% mortality >50 2-3% mortalityIf >40 1% mortality >50 2-3% mortality

Usually aminotransferases normalize by 2 Usually aminotransferases normalize by 2 months months

No increase in severity with pregnancy or No increase in severity with pregnancy or increased fetal loss/abnormalitiesincreased fetal loss/abnormalities

Hepatitis AHepatitis A

Relapsing hepatitis resolution 4-15 weeks with Relapsing hepatitis resolution 4-15 weeks with recurrence recurrence Prolonged cholestasis (rare)Prolonged cholestasis (rare)Diagnosis IgM anti-HAV with clinical features of Diagnosis IgM anti-HAV with clinical features of diseasediseaseMay consider Immunoglobulin if exposure within May consider Immunoglobulin if exposure within 2 weeks (vaccine alone usually effective)2 weeks (vaccine alone usually effective)Vaccine 2 doses immunity 90-98%Vaccine 2 doses immunity 90-98%Treatment supportive care rare need in Treatment supportive care rare need in cholestasis for cholestyraminecholestasis for cholestyramine

Hepatitis B Hepatitis B

Prevalence 5% of world populationPrevalence 5% of world population

1-1.25 million in U.S. chronically infected 1-1.25 million in U.S. chronically infected as indicated by HBsAg positive as indicated by HBsAg positive

Most common in SE Asia/ China/ Most common in SE Asia/ China/ Philippines/ Middle East/ AfricaPhilippines/ Middle East/ Africa

Lower prevalence: safe sex/vaccinationLower prevalence: safe sex/vaccination

Only DNA VirusOnly DNA Virus

Hepatitis BHepatitis B

Chronic infection more likely when Chronic infection more likely when exposed as childexposed as child

Increased vertical transmission with high Increased vertical transmission with high viral load and HBeAg positive mothers viral load and HBeAg positive mothers

Rare fulminant hepatic failure Rare fulminant hepatic failure (encephalopathy within 8 weeks of onset (encephalopathy within 8 weeks of onset of sxs)of sxs)

Hepatitis B Serologies

Hepatitis B Hepatitis B

Universal immunization of 11-12 year oldsUniversal immunization of 11-12 year olds

HBIG used for neonatal prophylaxis, post HBIG used for neonatal prophylaxis, post exposure prophylaxis, post transplant exposure prophylaxis, post transplant prophylaxisprophylaxis

Therapy with interferons or nucleoside Therapy with interferons or nucleoside analoguesanalogues

Unknown

shiny, flat, polygonal, violaceous papules.Courtesy of Beth G Goldstein, MD and Adam O Goldstein, MD.

Hepatitis C Hepatitis C

RNA virusRNA virus3-4 million persons 3-4 million persons infected in U.S.infected in U.S.50-85% of infections become chronic50-85% of infections become chronicDecreasing incidence due to improved Decreasing incidence due to improved medical practices, blood donor screening, medical practices, blood donor screening, syringe exchange programssyringe exchange programsNot efficiently spread via sexual relationsNot efficiently spread via sexual relationsMajority of patients asymptomaticMajority of patients asymptomatic

Extrahepatic manifestationsExtrahepatic manifestations

Membranoproliferative glomerulonephritisMembranoproliferative glomerulonephritis

Essential mixed cryoglobulinemiaEssential mixed cryoglobulinemia

Porphyria cutanea tardaPorphyria cutanea tarda

Leukocytoclastic vasculitisLeukocytoclastic vasculitis

Lichen planusLichen planus

DiagnosisDiagnosis– Enzyme immunoassay (EIA) screenEnzyme immunoassay (EIA) screen– Virologic confirmation via PCR amplificationVirologic confirmation via PCR amplification

Hepatitis C Hepatitis C

Genotype 1Genotype 1– Telaprevir, Boceprevir therapy approved FDA Telaprevir, Boceprevir therapy approved FDA

May 2011May 2011– Response guided therapyResponse guided therapy– Still requires Peg-IFN/RBVStill requires Peg-IFN/RBV

Genotype 2,3 Genotype 2,3 – Peg-IFN/RBVPeg-IFN/RBV– 24 weeks therapy24 weeks therapy

Hepatitis E Hepatitis E

Endemic disease geographically Endemic disease geographically distributed around the equatorial beltdistributed around the equatorial belt

High fatality rate (0.5-4%) with pregnant High fatality rate (0.5-4%) with pregnant women at a fatality rate of 20%women at a fatality rate of 20%

Fecal-oral/rain season transmissionFecal-oral/rain season transmission

Dx by anti-HEV IgMDx by anti-HEV IgM

Autoimmune HepatitisAutoimmune Hepatitis

Etiology-viral, drug, toxic or environmental Etiology-viral, drug, toxic or environmental agent that resembles a self antigen agent that resembles a self antigen (molecular mimicry)(molecular mimicry)

Type 1 AIH-most common in U.S./all agesType 1 AIH-most common in U.S./all ages

>75% female>75% female

ASMA/ANAASMA/ANA

Acute onset 40%-rarely fulminantAcute onset 40%-rarely fulminant

If UC consider PSC overlapIf UC consider PSC overlap

Autoimmune HepatitisAutoimmune Hepatitis

Type 2Type 2

Affects mainly children (2-14 years)Affects mainly children (2-14 years)

In Europe 20% adults/ U.S. 4% adultsIn Europe 20% adults/ U.S. 4% adults

Antibodies to LKM-1Antibodies to LKM-1

Autoimmune HepatitisAutoimmune Hepatitis

Predominantly hepatocellular inflammationPredominantly hepatocellular inflammation

Fatigue, abd pain, hepatomegalyFatigue, abd pain, hepatomegaly

AP elevated in 81% however usually less AP elevated in 81% however usually less than 2x normal (only 10%>4x normal)than 2x normal (only 10%>4x normal)

Elevated gammaglobulinemia 92% usually Elevated gammaglobulinemia 92% usually IgGIgG

Autoimmune HepatitisAutoimmune Hepatitis

Treat if:Treat if:

Aminotransferases > 10 fold normalAminotransferases > 10 fold normal

Aminotransferases > 5 fold normal with Aminotransferases > 5 fold normal with immunoglobuline >2 x normalimmunoglobuline >2 x normal

Incapacitating symptomsIncapacitating symptoms

Bridging necrosis by liver biopsy Bridging necrosis by liver biopsy

Pediatric patientsPediatric patients

Unknown

47 year-old WM with chronic elevation of LAE and joint pain otherwise asymptomatic

What is the disease and likely genetic mutation?

HemochromotosisHemochromotosis

Prevalence of 1:200-300 Northern Prevalence of 1:200-300 Northern European descentEuropean descent

AR homozygous mutation C282Y >80%AR homozygous mutation C282Y >80%

Smaller proportion C282Y/H63DSmaller proportion C282Y/H63D

Increased intestinal iron absorptionIncreased intestinal iron absorption

HemochromotosisHemochromotosis

DiabetesDiabetes

Heart failure (cardiomyopathy)Heart failure (cardiomyopathy)

ArthralgiasArthralgias

Amenorrhea/impotenceAmenorrhea/impotence

Increased skin pigmentationIncreased skin pigmentation

HemochromotosisHemochromotosis

Phlebotomy to ferritin <50 ng/ml Phlebotomy to ferritin <50 ng/ml

Usually 0.5-1 unit of PRBC each weekUsually 0.5-1 unit of PRBC each week

Each unit of PRBC=250 mg of ironEach unit of PRBC=250 mg of iron

Ferritin will drop 30 ng/ml for every unit of Ferritin will drop 30 ng/ml for every unit of PRBC removedPRBC removed

Deferoxamine (usually secondary iron Deferoxamine (usually secondary iron overload)overload)

Wilson DiseaseWilson Disease

Prevalence 1:30:000 ARPrevalence 1:30:000 AR

Symptomatic usually 6-40 years Symptomatic usually 6-40 years

Chronic or fulminant liver diseaseChronic or fulminant liver disease

Mood disorder/movement disorderMood disorder/movement disorder

Kayser-Fleischer ring/sunflower cataract Kayser-Fleischer ring/sunflower cataract

Hemolytic anemiaHemolytic anemia

Wilson Disease Wilson Disease

AST>ALT (similar to ETOH)AST>ALT (similar to ETOH)Low APLow APElevated bilirubin Elevated bilirubin Low ceruloplasmin in 95%Low ceruloplasmin in 95%Serum copper concentration lowSerum copper concentration lowUrinary copper elevatedUrinary copper elevatedHepatic copper concentration >250 Hepatic copper concentration >250 mcg/grammcg/gram

Wilson Disease Wilson Disease

Treatment Penicillamine, trientine Treatment Penicillamine, trientine (primarily increase urinary excretion)(primarily increase urinary excretion)

Zinc-induces metallothionein which binds Zinc-induces metallothionein which binds copper in lumencopper in lumen

Liver transplant->fulminant hepatic failureLiver transplant->fulminant hepatic failure

Alpha-1 Antitrypsin DeficiencyAlpha-1 Antitrypsin Deficiency

Predisposes adults to liver disease and Predisposes adults to liver disease and emphysemaemphysema

Alpha-1 antitrypsin functions to protect Alpha-1 antitrypsin functions to protect tissues from proteasestissues from proteases

Phenotype PiMM normal/ PiZZ 1:2000Phenotype PiMM normal/ PiZZ 1:2000

Dx with alpha-1 AT phenotype Dx with alpha-1 AT phenotype determination (alpha-1 AT level may be determination (alpha-1 AT level may be falsely elevated with inflammation)falsely elevated with inflammation)

Alpha-1 Antitrypsin DeficiencyAlpha-1 Antitrypsin Deficiency

Avoid tobaccoAvoid tobacco

Infusions of alpha-1 AT derived from Infusions of alpha-1 AT derived from pooled plasmapooled plasma

OLT recipient assumes Pi phenotype of OLT recipient assumes Pi phenotype of donordonor

Basilar emphysemaBasilar emphysema

Celiac SprueCeliac Sprue

Small intestinal malabsorbtion after Small intestinal malabsorbtion after ingestion of gluten (wheat/rye/barley)ingestion of gluten (wheat/rye/barley)

Highest in Celtic and Northern European Highest in Celtic and Northern European populations 1:122-1:1000populations 1:122-1:1000

Classic sxs diarrhea, steatorrhea, weight Classic sxs diarrhea, steatorrhea, weight loss, short statureloss, short stature

Extraintestinal-anemia (iron/folate/b-12), Extraintestinal-anemia (iron/folate/b-12), osteopenia, coagulopathy, infertilityosteopenia, coagulopathy, infertility

Celiac SprueCeliac Sprue

Aminotransferase elevations found in 42% Aminotransferase elevations found in 42% of celiac sprue patientsof celiac sprue patients

DX with anti tTG, endomysial antibodiesDX with anti tTG, endomysial antibodies

Associated with Dermatitis HerpetiformisAssociated with Dermatitis Herpetiformis

Autoimmune disease IDDM, thyroid Autoimmune disease IDDM, thyroid disease, IBD, PBCdisease, IBD, PBC

Increased rate of SI lymphomaIncreased rate of SI lymphoma

TX Gluten free diet TX Gluten free diet

Dermatitis HerpetiformisDermatitis Herpetiformis

Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology - 5thFitzpatrick's Color Atlas and Synopsis of Clinical Dermatology - 5th

Ischemic HepatitisIschemic Hepatitis

Preceded by hypotension/hypoxemiaPreceded by hypotension/hypoxemia

Most common co-morbidity Most common co-morbidity AMI/arrhythmia, sepsisAMI/arrhythmia, sepsis

Significant elevation of aminotransferases Significant elevation of aminotransferases and LDH (distinguish from viral hep)and LDH (distinguish from viral hep)

Often with transient elevated CrOften with transient elevated Cr

Budd-Chiari SyndromeBudd-Chiari Syndrome

Impediment to flow from the hepatic veins Impediment to flow from the hepatic veins to right atriumto right atrium

May present as chronic, acute or fulminant May present as chronic, acute or fulminant liver dysfunctionliver dysfunction

Ascites, tender hepatomegalyAscites, tender hepatomegaly

Hepatocellular injury>cholestasisHepatocellular injury>cholestasis

Budd-Chiari SyndromeBudd-Chiari Syndrome

DX-doppler ultrasoundDX-doppler ultrasound– absence of waveform in the hepatic veinsabsence of waveform in the hepatic veins– hypertrophy of the caudate lobehypertrophy of the caudate lobe

Alternative modalities=CT/MRIAlternative modalities=CT/MRI

Tx- thrombolytics, anticoagulation, surgical Tx- thrombolytics, anticoagulation, surgical portocaval shunt, TIPS-bridge to OLT, portocaval shunt, TIPS-bridge to OLT, balloon angioplastyballoon angioplasty

Sclerosing CholangitisSclerosing Cholangitis

Intrahepatic and extrahepatic bile duct Intrahepatic and extrahepatic bile duct stricturing, fibrosis and inflammationstricturing, fibrosis and inflammation

Name the association->Name the association->

Primary sclerosing cholangitis

Portal bile duct with periductal sclerosis associated with degeneration of the bile duct epithelium. Courtesy of Robert Odze, MD.

Secondary Sclerosing cholangitisSecondary Sclerosing cholangitis

Cholangiographic pattern may be seen with:Cholangiographic pattern may be seen with:– NeoplasmNeoplasm

CholangiocarcinomaCholangiocarcinoma

HCCHCC

MetsMets

– IschemiaIschemia– Chronic Pancreatitis Chronic Pancreatitis – HIV (cmv, cryptosporidium)HIV (cmv, cryptosporidium)– CholedocholithiasisCholedocholithiasis

PSCPSC

80% have IBD (more commonly UC)80% have IBD (more commonly UC)– Consider rectal/sigmoid biopsyConsider rectal/sigmoid biopsy

3-6% of UC patients have PSC Present 3-6% of UC patients have PSC Present with jaundice, pruritus, abd painwith jaundice, pruritus, abd pain

AP usually elevated 3-5x may be 20xAP usually elevated 3-5x may be 20x

May have increased direct bilirubinMay have increased direct bilirubin

P-ANCA 65%-84%P-ANCA 65%-84%

PSCPSC

DX by ERCP (gold DX by ERCP (gold standard)standard)

Histology onion skin Histology onion skin fibrosisfibrosis

Elevated copper due Elevated copper due to impaired secretionto impaired secretion

Biopsy may detect Biopsy may detect small duct PSCsmall duct PSC

PSCPSC

If sudden deterioration suspect If sudden deterioration suspect cholangiocarcinomacholangiocarcinoma

Therapy possible benefit UDCATherapy possible benefit UDCA

Liver transplantLiver transplant

Harrison's Principles of Internal Medicine - 16th Ed. Harrison's Principles of Internal Medicine - 16th Ed.

Objectives

Define “liver associated enzymes”

Differentiate:– Hepatocellular vs. cholestatic

Radiographic/pathology images

Specific liver diseases

ReferencesReferences

(1) Davern T., Scharschmidt B., Biochemical (1) Davern T., Scharschmidt B., Biochemical liver tests. Sleisenger and Fordtran’s liver tests. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease (2002). 7Gastrointestinal and Liver Disease (2002). 7 thth edition pp 1227-1239edition pp 1227-1239..

(2) UpToDate online Pratt DS.,Approach to the (2) UpToDate online Pratt DS.,Approach to the patient with abnormal liver function tests. Last patient with abnormal liver function tests. Last revision April 2006revision April 2006(3) Braunwald E., Houser S., Fauci A., Longo D., (3) Braunwald E., Houser S., Fauci A., Longo D., Kasper D., Jameson J., Approach to the patient Kasper D., Jameson J., Approach to the patient with liver disease. Harrison’s Principles of with liver disease. Harrison’s Principles of Internal Medicine (2001). 15Internal Medicine (2001). 15 thth edition pp 1707- edition pp 1707-1737.1737.

Zachary and William BassettZachary and William Bassett