Date post: | 05-Jan-2016 |
Category: |
Documents |
Upload: | kevin-marsh |
View: | 230 times |
Download: | 2 times |
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 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
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.