Significance of Liver Function Tests By: Hildegarde Y. Vistal MD FPCP, FPSG, FPSDE

The liver performs a diverse array of biochemical, synthetic and excretory functions and as a result, no single biochemical test is capable of providing an accurate global assessment of hepatic function.

Tests are needed to: Detect disease Direct the diagnostic work-up Determine severity Assess prognosis Evaluate therapy

Classifications of the Liver function tests Markers of Hepatocellular necrosis Aminotransferases ALT (Alanine Transaminase or SGPT) AST (Aspartate Transaminase or SGOT) LDH (Lactate Dehydrogenase) Makers of Cholestasis GGTP (Gamma Glutamyl Transpeptidase) Alkaline Phosphatase Bilirubin Markers of Hepatic Synthetic Capacity Prothrombin Time Albumin

Markers of Hepatocellular necrosis Aminotransferases ALT (Alanine Transaminase or SGPT) - a cytosolic enzyme, that is liver specific - elevation is a result of leakage from damaged cells, reflecting hepatic injury AST (Aspartate Transaminase or SGOT) - present in both cytosolic and mitochondrial isoenzymes - also found in skeletal, cardiac muscle, kidney, brain, pancreas, and blood cells, -seen in hepatocytes *AST/ ALT Ratio - useful in differential diagnosis - ratio < or = to 1  acute liver injury - ratio > than 2 – alcholic hepatitis *Modest elevations - levels < 500 U/L *Marked elevations - levels > 500 U/L

Algorithm for managing a patient with an isolated increase in serum aminotransferase

Markers of Hepatocellular necrosis LDH (Lactate Dehydrogenase) - seen with skeletal and cardiac muscle injury, hemolysis, stroke and renal infarction - acute and chronic liver disease - very non-specific

Makers of Cholestasis GGTP (Gamma Glutamyl Transpeptidase) -derived from hepatocytes and biliary epithlia - found also in the kidneys, spleen, pancreas, heart, lung, and brain. - is a microsomal enzyme inducible by alcohol and drugs (anticonvulsants and warfarin)

Makers of Cholestasis Alkaline Phosphatase - present in a variety of tissues including liver, bone, intestine, kidney, placenta, leucocytes ( various neoplasms) - major sources are bone and liver * Levels up to 3 times normal are relatively non-specific * Striking elevations are seen with infiltrative hepatic disorders ( primary or metastatic tumors, intra or extra hepatic biliary obstruction)

Algorithm for managing a patient in an isolated increase in a serum Alkaline Phophatase

Makers of Cholestasis Bilirubin - organic anion derived from the catabolism of hemoglobin - production is accelerated by hemolysis, ineffective erythoropoeisis 1. Unconjugated Hyperbilirubinemia -indirect bilirubin, lipid soluble ( 85%) - results from increased bilirubin production or inherited or acquired defects in hepatic uptake or conjugation - seen in hemolysis 2. Conjugated Hyperbilirubinemia - direct bilirubin water soluble ( > 50%) - results of inherited or acquired defects in hepatic excretion - useful prognostically in patients with alcholic hepatitis, primary biliary cirrhosis, or accute liver failure

Algorithm for managing a patient with an isolated increase in serum total bilirubin.

Markers of Hepatic Synthetic Capacity Prothrombin Time - Liver plays a crucial role in hemostasis Differential Diagnosis Elevated PT 1. Vitamin K deficiency - malnutrtion - malabsortion - antibiotic use 2. Warfarin administration 3. DIC ( Factor VIII) 4. Liver Disease ( Normal or increase factor VIII) Prolongation of PT 1. Decompensated liver disease ( with hepatocellular dysfunction) 2. Chronic cholestatic disease

Markers of Hepatic Synthetic Capacity Albumin - 10 grams of albumin is synthesis and secreated by hepatocytes each day Factors that affect albumin levels 1. Nutritional and volume status 2. Vascular integrity 3. Catabolism 4. Hormonal Factors 5. Kidney disease 6. Liver disease - serum albumin level correlates with prognosis in chronic liver disease

Associated Liver Diseases Test (Normal Range) Basis of Abnormality Associated Liver Diseases Extrahepatic Source Aminotransferases (10-55 U/L, 0.17-0.92 ukat/L for ALT, 10-40 U/L, 0.17-0.67 ukat/L for AST) Leakage from damaged tissue Modest elevation- many types of liver disease Marked elevations- hepatitis (viral, autoimmune, toxic, and ischemic) AST/ALT > 2 with the value of each less than 300 U suggests alcoholic liver diseases or cirrhosis of any etiology ALT, relatively specific for hepatocyte necrosis AST, muscle (skeletal and cardiac), kidney, brain, pancreas, red blood cells Alkaline phosphate (45-115 U/L, 0.75-1.92 ukat/L) Overproduction and leakage into serum Modest elevations-many types of liver disease Marked Elevations- extra- and intrahe- patic cholestasis, diffuse infiltrating disease (e.g., tumor, MAC), occasionally alcoholic hepatitis Bone Growth or disease (e.g. tumor, fracture, Paget’s disease), placenta, intestine, tumors Gammaglutamyl transpeptidase (0-30 U/L, 0-0.50 ukat/L) ?Overproduction and leakage into serum Same as for alkaline phosphate; induced by ethanol, drugs GGTP/AP > 2.5 suggests (but not diagnostic of) alcoholic liver disease Kidney, spleen, pancreas, heart, lung, brain 5’-Nucleotidase (0-11 U/L, 0.02-0.18 ukat/L) Same as for alkaline phosphate Found in many tissues but serum elevation relatively specific for liver disease Bilirubin (0.0-1.0 mg/dL, 0-17 umol/L) Decreased hepatic clearance Marked Elevations- extra- and intrahe- patic bile duct obstruction, alcoholic, drug-induced or viral hepatitis, inherited hyperbilirubinemia Increased breakdown of hemoglobin (resulting from hemolysis, ineffective erythropoiesis, resorption of hematoma) or myoglobin (resulting from muscle injury) Prothrombin time (10.9-12.5 sec) or International Nromalized Ratio (INR) (0.9-1.2) Decreased synthetic capacity Acute or chronic layer liver failure (unresponsive to vitamin K) Biliary obstruction (usually responsive to vitamin K administration) Vitamin K deficiency (secondary to malabsorption, malnutrition, antibiotics), consumptive coagulopathy Albumin (4.0-6.0 g/dL, 40-60 g/L Decreased synthesis ?Increased catabolism Chronic liver failure Decreased in nephrotic syndrome, protein-losing enetrophaty, vascular leak, malnutrition, malignancy, aodinflamatory states.