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Evaluation of abnormal liver associated enzymes

Evaluation of abnormal liver associated enzymes. Objectives. Define “liver associated enzymes” Differentiate: Hepatocellular vs. cholestatic Radiographic/pathology images Specific liver diseases. Liver associated enzymes & assessment of liver function. Commonly used in reference to:

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Evaluation of abnormal liver associated enzymes

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  1. Evaluation of abnormal liver associated enzymes

  2. Objectives Define “liver associated enzymes” Differentiate: Hepatocellular vs. cholestatic Radiographic/pathology images Specific liver diseases

  3. Liver associated enzymes& assessment of liver function • Commonly used in reference to: • Alanine aminotransferase (ALT) • Aspartate aminotransferase (AST) • Alkaline phosphatase (AP) • Gamma glutamyl transpeptidase (GGT) • Bilirubin • Markers of synthetic capacity • Albumin/pre-albumin • Prothrombin time/INR

  4. Aminotransferases • Elevation reflects hepatocyte injury • ALT relatively liver specific • AST may be found in skeletal and cardiac muscle, blood cells • Hepatocellular injury ALT:AP >5 • If ALT/AST elevation >1000 • Ischemia, virus, toxin, less commonly CBD stone, AIH

  5. Alkaline Phosphatase (AP) • Found in liver, bone, placenta, neoplasms • AP increased 3x in adolescence/ also increased in late pregnancy • AP half-life 1 week (remain elevated after relief of biliary obstruction) • AP elevations seen with infiltrative hepatic disorders • Cholestatic injury ALT:AP ratio <2

  6. Gamma Glutamyl Transpeptidase • GGT derived primarily from hepatocytes and biliary epithelia • Useful to confirm hepatic origin of AP (may also use a 5’ nucleotidase) • Microsomal enzyme inducible by ETOH, Coumadin and anticonvulsants

  7. Bilirubin • Derived primarily from the catabolism of hemoglobin • Water soluble, conjugated “direct” • Impaired biliary excretion (obstruction) • Bilirubin in urine always conjugated • Water insoluble, unconjugated “indirect” • Increased production with hemolysis, ineffective erythropoiesis, hematoma resorbtion • Increased LDH, decreased haptoglobin, increased AST, increased retic count • Hemolysis will not elevate bilirubin >5 mg/dl

  8. Albumen • Serum concentration falls with hepatic parenchymal disease • Half Life 20 days • Negative acute phase reactant • May be depressed with poor nutrition, renal losses (nephrotic syndrome)

  9. History • Duration of LAE abnormality • Acute <6 months • Chronic >6 months • Medication history (with special attention to new medications) • Cholestasis with estrogens, anabolic steroids, erythromycin, amoxicillin-clavulanate • Family history of liver diseases • 2-3 generations/second degree relatives

  10. History • Jaundice (bilirubin >3 mg/dl) • Arthralgias • Weight loss • Changes in urine color (direct bilirubin only)

  11. Physical Exam • Temporal/proximal muscle wasting • Spider Nevi • Palmer erythema • Gyncomastia • Dupuytren’s contractures • Testicular atrophy

  12. Up to 42% of those with this condition have elevated LAE Associated with neuropathy May have iron and folate deficiency Unknown

  13. NAFLD/NASH • Macro vs. microvesicular fatty change • Less than 20-30 grams of ETOH per day • Metabolic syndrome • TPN • Drugs: amiodarone, tamoxifen, glucocorticoids, estrogens • ALT>AST

  14. NAFLD • Diagnosis • Echogenic liver by ultrasound • Liver <15 HU/spleen • Liver biopsy • Treatment: • Modification of risk factors • Pioglitazone/Vitamin E • Gastric Bypass

  15. Alcoholic Liver Disease • AST:ALT ratio >2 (established disease) • Elevations in AP/GGT • Macrocytic anemia • Thrombocytopenia • Elevated triglycerides • Higher rates Caucasians/lesser for Asians

  16. Alcoholic Liver Disease • Discontinuation of ETOH/Detox program • Monitor for complications: • Pancreatitis • Cirrhosis, HCC and decompensations • Maddrey discriminant function 4.6 x (PT-PT control) + bilirubin >32 give 4 week course of prednisolone • Pentoxifylline 400mg TID • No ETOH 6 months->transplant evaluation

  17. Hepatitis A • Fecal-Oral transmission • High rates daycare/prisons • Associated with contaminated water and shellfish • Liver injury secondary to host immune response

  18. Hepatitis A • Children <5 asymptomatic 90% • Adults 70-80% symptomatic • If >40 1% mortality >50 2-3% mortality • Usually aminotransferases normalize by 2 months • No increase in severity with pregnancy or increased fetal loss/abnormalities

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

  20. Hepatitis B • Prevalence 5% of world population • 1-1.25 million in U.S. chronically infected as indicated by HBsAg positive • Most common in SE Asia/ China/ Philippines/ Middle East/ Africa • Lower prevalence: safe sex/vaccination • Only DNA Virus

  21. Hepatitis B • Chronic infection more likely when exposed as child • Increased vertical transmission with high viral load and HBeAg positive mothers • Rare fulminant hepatic failure (encephalopathy within 8 weeks of onset of sxs)

  22. Hepatitis B Serologies

  23. Hepatitis B • Universal immunization of 11-12 year olds • HBIG used for neonatal prophylaxis, post exposure prophylaxis, post transplant prophylaxis • Therapy with interferons or nucleoside analogues

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

  25. Hepatitis C • RNA virus • 3-4 million persons infected in U.S. • 50-85% of infections become chronic • Decreasing incidence due to improved medical practices, blood donor screening, syringe exchange programs • Not efficiently spread via sexual relations • Majority of patients asymptomatic

  26. Extrahepatic manifestations • Membranoproliferative glomerulonephritis • Essential mixed cryoglobulinemia • Porphyria cutanea tarda • Leukocytoclastic vasculitis • Lichen planus • Diagnosis • Enzyme immunoassay (EIA) screen • Virologic confirmation via PCR amplification

  27. Hepatitis C • Genotype 1 • Telaprevir, Boceprevir therapy approved FDA May 2011 • Response guided therapy • Still requires Peg-IFN/RBV • Genotype 2,3 • Peg-IFN/RBV • 24 weeks therapy

  28. Hepatitis E • Endemic disease geographically distributed around the equatorial belt • High fatality rate (0.5-4%) with pregnant women at a fatality rate of 20% • Fecal-oral/rain season transmission • Dx by anti-HEV IgM

  29. Autoimmune Hepatitis • Etiology-viral, drug, toxic or environmental agent that resembles a self antigen (molecular mimicry) • Type 1 AIH-most common in U.S./all ages • >75% female • ASMA/ANA • Acute onset 40%-rarely fulminant • If UC consider PSC overlap

  30. Autoimmune Hepatitis • Type 2 • Affects mainly children (2-14 years) • In Europe 20% adults/ U.S. 4% adults • Antibodies to LKM-1

  31. Autoimmune Hepatitis • Predominantly hepatocellular inflammation • Fatigue, abd pain, hepatomegaly • AP elevated in 81% however usually less than 2x normal (only 10%>4x normal) • Elevated gammaglobulinemia 92% usually IgG

  32. Autoimmune Hepatitis • Treat if: • Aminotransferases > 10 fold normal • Aminotransferases > 5 fold normal with immunoglobuline >2 x normal • Incapacitating symptoms • Bridging necrosis by liver biopsy • Pediatric patients

  33. 47 year-old WM with chronic elevation of LAE and joint pain otherwise asymptomatic What is the disease and likely genetic mutation? Unknown

  34. Hemochromotosis • Prevalence of 1:200-300 Northern European descent • AR homozygous mutation C282Y >80% • Smaller proportion C282Y/H63D • Increased intestinal iron absorption

  35. Hemochromotosis • Diabetes • Heart failure (cardiomyopathy) • Arthralgias • Amenorrhea/impotence • Increased skin pigmentation

  36. Hemochromotosis • Phlebotomy to ferritin <50 ng/ml • Usually 0.5-1 unit of PRBC each week • Each unit of PRBC=250 mg of iron • Ferritin will drop 30 ng/ml for every unit of PRBC removed • Deferoxamine(usually secondary iron overload)

  37. Wilson Disease • Prevalence 1:30:000 AR • Symptomatic usually 6-40 years • Chronic or fulminant liver disease • Mood disorder/movement disorder • Kayser-Fleischer ring/sunflower cataract • Hemolytic anemia

  38. Wilson Disease • AST>ALT (similar to ETOH) • Low AP • Elevated bilirubin • Low ceruloplasmin in 95% • Serum copper concentration low • Urinary copper elevated • Hepatic copper concentration >250 mcg/gram

  39. Wilson Disease • Treatment Penicillamine, trientine (primarily increase urinary excretion) • Zinc-induces metallothionein which binds copper in lumen • Liver transplant->fulminant hepatic failure

  40. Alpha-1 Antitrypsin Deficiency • Predisposes adults to liver disease and emphysema • Alpha-1 antitrypsin functions to protect tissues from proteases • Phenotype PiMM normal/ PiZZ 1:2000 • Dx with alpha-1 AT phenotype determination (alpha-1 AT level may be falsely elevated with inflammation)

  41. Alpha-1 Antitrypsin Deficiency • Avoid tobacco • Infusions of alpha-1 AT derived from pooled plasma • OLT recipient assumes Pi phenotype of donor

  42. Basilar emphysema

  43. Celiac Sprue • Small intestinal malabsorbtion after ingestion of gluten (wheat/rye/barley) • Highest in Celtic and Northern European populations 1:122-1:1000 • Classic sxs diarrhea, steatorrhea, weight loss, short stature • Extraintestinal-anemia (iron/folate/b-12), osteopenia, coagulopathy, infertility

  44. Celiac Sprue • Aminotransferase elevations found in 42% of celiac sprue patients • DX with anti tTG, endomysial antibodies • Associated with Dermatitis Herpetiformis • Autoimmune disease IDDM, thyroid disease, IBD, PBC • Increased rate of SI lymphoma • TX Gluten free diet

  45. Dermatitis HerpetiformisFitzpatrick's Color Atlas and Synopsis of Clinical Dermatology - 5th

  46. Ischemic Hepatitis • Preceded by hypotension/hypoxemia • Most common co-morbidity AMI/arrhythmia, sepsis • Significant elevation of aminotransferases and LDH (distinguish from viral hep) • Often with transient elevated Cr

  47. Budd-Chiari Syndrome • Impediment to flow from the hepatic veins to right atrium • May present as chronic, acute or fulminant liver dysfunction • Ascites, tender hepatomegaly • Hepatocellular injury>cholestasis

  48. Budd-Chiari Syndrome • DX-doppler ultrasound • absence of waveform in the hepatic veins • hypertrophy of the caudate lobe • Alternative modalities=CT/MRI • Tx- thrombolytics, anticoagulation, surgical portocaval shunt, TIPS-bridge to OLT, balloon angioplasty

  49. Sclerosing Cholangitis • Intrahepatic and extrahepatic bile duct stricturing, fibrosis and inflammation • Name the association->

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

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