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Evaluation of Liver Injury Mark J. Czaja Liver Research Center Albert Einstein College of Medicine Bronx, N.Y. Liver Function Tests • • • • • • Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Lactate dehydrogenase (LDH) Alkaline phosphatase Bilirubin Albumin Mechanisms of Liver Dysfunction • Direct cellular injury • Blockage in bile flow • Impaired blood flow Direct Cellular Injury - HCV Infection Blockage in Bile Flow - Biliary Atresia Impaired Blood Flow - CHF Consequences of Liver Injury liver cell injury liver cell death proliferation matrix deposition sufficient inadequate recovery liver failure altered architecture cirrhosis Types of Liver Tests • True tests of liver function • Biochemical markers of liver injury • Biochemical markers of specific liver diseases Testable Biochemical Liver Function • Ability to transport organic anions • Capacity to metabolize certain substances • Capability to synthesize various proteins Steps in Organic Anion Transport • Delivery and uptake • Metabolic alteration • Secretion and excretion Bilirubin • Tetrapyrole • Toxic in neonates - kernicterus • Derived from: Senescent RBC (70-80%) Hemoproteins (20-30%) Ineffective erythropoiesis Bilirubin Formation heme heme oxygenasebiliverdin biliverdin reductase bilirubin Transport: hydrophobic due to internal H-bonding circulates bound to albumin Bilirubin Metabolism Plasma Bile Hepatocyte Alb UCB BMG BDG UCB ligandin glucuronyl BMG BMG transferase BDG BDG Bilirubin Elimination Intestine • BMG (20%) + BDG (80%) +UCB (trace) • Deconjugated to urobilinogen • Excreted or reabsorbed (20%) Urine • BMG and BDG • No UCB Measurement of Serum Bilirubin • • • • Normal concentration < 1 mg/dl Conjugated < 5% Jaundice if > 3 mg/dl Detected by diazo reaction - cleaved to colored azo-dipyrole Conjugated reacts rapidly (direct) Unconjugated reacts slowly (indirect) Differential Diagnosis I • Prehepatic • Intrahepatic Congenital Acquired • Posthepatic Differential Diagnosis II • Unconjugated hyperbilirubinemia Increased bilirubin production (hematological) Decreased uptake (drug) Decreased conjugation (congenital) • Conjugated hyperbilirubinemia Congenital Drug Liver disease Biliary obstruction Inherited Disorders Causing Unconjugated Hyperbilirubinemia • Crigler-Najjar syndrome Type 1 – absent GT Type 2 – reduced GT activity • Gilbert’s syndrome – reduced GT activity due to genetic defect in TATAA element of GT promoter Inherited Disorders Causing Conjugated Hyperbilirubinemia • Dubin-Johnson syndrome – mutations in multidrug resistance associated protein 2 (MRP2) • Rotor’s syndrome – genetic defect Hepatic Metabolic Capacity • Clearance must depend on total functional mass or metabolic activity • Hepatic drug metabolism [14C]amino-pyrine breath test • Galactose elimination • Not used clinically Hepatic Synthetic Capacity • Most major plasma proteins are made in the liver • Decreased hepatocytes = decreased protein synthesis and release • Albumin and coagulation factors are clinically important Albumin • 50% of all synthesized hepatic protein • Determinant of plasma oncotic pressure • Important transport protein Serum Albumin Levels • Long half-life of 20 days • Large hepatic synthetic reserve • Decreased with persistent, large injury • Decreased in chronic liver disease • Poor prognostic sign Non-hepatic Causes of Hypoalbuminemia • Severe malnutrition • Renal or GI loss Glomerulopathy, HIV enteropathy • High catabolism Infections, burns Coagulation Factors • Half-lives of hours to days • Liver synthesizes I, II, V, VII, IX, and X • Large synthetic reserve Prothrombin Time (PT) • PT detects abnormalities in I, II, V, VII and X (extrinsic pathway) • PT is increased in liver disease • Best prognostic indicator Acute liver disease Chronic liver disease Non-hepatic Causes of Elevated PT • Congenital coagulation factor deficiencies • Consumptive coagulopathies • Vitamin K deficiency (II, VII, IX, X) To Rule Out Vitamin K Deficiency • Any patient with an elevated PT • Parental vitamin K for 3 days • Normalization of PT - vitamin K deficiency • Failure to normalize - hepatocellular disease Serum Immunoglobulins • Not produced by hepatocytes • Frequently elevated in liver disease • Secondary to inflammatory process • ? produced by antigen shunting Biochemical Markers of Liver Injury Liver Enzymes • Low levels always present in serum • Leak out from cell after injury • Very sensitive • Magnitude of abnormality does not correlate well with degree of injury Aspartate Aminotransferase (AST) • Serum glutamic-oxaloacetic transaminase (SGOT) • Transfers an a-amino group of aspartate to a-keto group of ketoglutaric acid • Present in skeletal muscle, kidney, brain Alanine Aminotransferase (ALT) • Serum glutamic-pyruvic transaminase (SGPT) • Transfers an a-amino group of alanine to a-keto group of ketoglutaric acid • Present principally in liver AST and ALT • Elevated in most liver diseases • Highest levels are in acute liver diseases • Only slight elevations in chronic liver diseases • Usually increase in parallel AST/ALT in Alcoholic Hepatitis • Transaminases rarely exceed 300 • AST:ALT >2 Factors Affecting AST/ALT • Depressed by pyridoxine (vit. B6) deficiency • Decreased by uremia and renal dialysis AST/ALT Controversies • Should lower normal limits be used in females? Females < 30 vs. males < 40 • Are the normal limits too high? Females < 20 and males < 30 Lactate Dehydrogenase (LDH) • Component of classic LFT’s • Highly non-specific Tests of Impaired Hepatic Excretion Increased In • Cholestasis • Intra-hepatic biliary tract obstruction • Extra-hepatic biliary obstruction Alkaline Phosphatase • Hydrolyzes phosphate esters at alkaline pH • Also present in bone, kidney, placenta, intestine • Mainly liver and bone in adults • Increased in children from bone growth • Placental form during pregnancy Elevated Alkaline Phosphatase • Can occur in any liver disease • Highest with cholestasis or biliary tract obstruction • Elevated in infiltrative diseases • Due to increase synthesis and secretion Alkaline Phosphatase Isoenzymes Source Heat Inactivation 5' NT GGTP Liver Moderate + + Bone Rapid - - Placenta Slow - - Intestine Slow - - 5'-Nucleotidase • Hydrolyzes 5'- adenosine monophosphate • Mainly present in liver • Increases along with alkaline phosphatase g-Glutamyl Transpeptidase (GGTP) • • • • Transfers g-glutamyl groups Widely distributed Sensitive correlate to alkaline phosphatase Non-specific (alcoholism, MI, DM, pancreatic disease, renal failure) Biochemical Markers of Specific Liver Diseases Etiology-specific Liver Tests • • • • • Viral hepatitis serologies Serum ferritin level Ceruloplasmin level Alpha1-antitrypsin level Antimitochondrial antibody titer Viral Hepatitis Serology • HAV – anti-HAV IgM and IgG • HBV – HBsAg, anti-HBsAg, and anti-HBcAg • HCV – anti-HCV, HCV RNA Serum Ferritin • Widely distributed storage protein • Levels reflect body iron stores • Elevated in primary hemochromatosis • Elevated in acute inflammation and cirrhosis Serum Ceruloplasmin • Copper-binding protein • Decreased in 95% of patients with Wilson’s disease • 20% of heterozygotes have decreased levels a1-Antitrypsin • Inhibits serum trypsin • Major component of a1-globulin • Deficiency cause of neonatal hepatitis Antimitochondrial Antibody (AMA) • Directed against mitochondrial enzyme pyruvate dehydrogenase complex • Positive in 90% of patients with primary biliary cirrhosis Interpretation of Abnormal LFT’s • Examine multiple tests • Consider non-hepatic causes • Determine the most abnormal tests Hepatocellular vs. Cholestatic Test Hepatocellular Cholestatic ALT/AST 2-3 NL-1 Alk Phos NL-1 2-3 Bilirubin NL-3 NL-3 Albumin NL-3 NL PT NL-3 NL Case 1 25 yo IVDA c/o 1 week of nausea, vomiting, and myalgias. Physical exam revealed jaundice. • ALT 2045 (15-45) • AST 2300 (15-45) • Alk Phos 273 (50-150) • Bili 3.9 (0.1-1.0) • Alb 4.2 (3.5-5.5) • PT 11.5 (10-12) Hepatocellular W/U H&P EtOH, medications, transfusions Risk for viral hepatitis Risk factors for NASH Etiology-specific LFT’s USG and liver biopsy Autoimmune features HBV Infection - HBcAg Staining Case 2 67 yo c/o several months of weight loss, and 1 week of nausea, vomiting, and myalgias. Physical exam revealed cachexia and jaundice. • ALT 75 (15-45) • AST 115 (15-45) • Alk Phos 650 (50-150) • Bili 10.2 (0.1-1.0) • Alb 4.2 (3.5-5.5) • PT 11.0 (10-12) Cholestatic W/U H&P medications, gallstones, weight loss USG normal AMA liver biopsy dilated ducts ERCP Pancreatic Carcinoma - ERCP