Evaluation of Liver Injury Mark J Czaja Liver
- Slides: 59
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 altered architecture recovery liver failure 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%) l Hemoproteins (20 -30%) l Ineffective erythropoiesis l
Bilirubin Formation heme biliverdin heme oxygenasebiliverdin bilirubin reductase Transport: hydrophobic due to internal H-bonding circulates bound to albumin
Bilirubin Metabolism Plasma Bile Hepatocyte Alb UCB BMG BDG UCB ligandin BMG transferase BDG glucuronyl
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 l l Conjugated reacts rapidly (direct) Unconjugated reacts slowly (indirect)
Differential Diagnosis I • Prehepatic • Intrahepatic Congenital l Acquired l • Posthepatic
Differential Diagnosis II • Unconjugated hyperbilirubinemia l l l Increased bilirubin production (hematological) Decreased uptake (drug) Decreased conjugation (congenital) • Conjugated hyperbilirubinemia l l Congenital Drug Liver disease Biliary obstruction
Inherited Disorders Causing Unconjugated Hyperbilirubinemia • Crigler-Najjar syndrome l Type 1 – absent GT l 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 (MRP 2) • Rotor’s syndrome – genetic defect
Hepatic Metabolic Capacity • Clearance must depend on total functional mass or metabolic activity • Hepatic drug metabolism [14 C]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 l Glomerulopathy, HIV enteropathy • High catabolism l 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 l l 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. B 6) deficiency • Decreased by uremia and renal dialysis
AST/ALT Controversies • Should lower normal limits be used in females? l Females < 30 vs. males < 40 • Are the normal limits too high? l 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 p. H • 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 Alpha 1 -antitrypsin level Antimitochondrial antibody titer
Viral Hepatitis Serology • HAV – anti-HAV Ig. M and Ig. G • HBV – HBs. Ag, anti-HBs. Ag, and anti-HBc. Ag • 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
a 1 -Antitrypsin • • Inhibits serum trypsin Major component of a 1 -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 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 Et. OH, medications, transfusions Risk for viral hepatitis Risk factors for NASH Etiology-specific LFT’s USG and liver biopsy Autoimmune features
HBV Infection - HBc. Ag 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 normal AMA liver biopsy USG dilated ducts ERCP
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