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JANET LIM-DY, M.D., F,P.S.P. D.T.M.H. EVALUATION OF LIVER FUNCTION TESTS Overview 3 Systems involved in understanding liver function tests: •Proteins synthesis •Coagulation factors synthesis Hepatocyte Biliary Tract: bili metabolism RES: Immune sys. , Heme & globin metabolites KREBS CYCLE GLUCONEOGENESIS FA SYNTHESIS & BREAKDOWN LIPOPROTEIN METABOLISM AA & NUCLEIC ACID METABOLISM GLYCOLYSIS HMP-SHUNT 2 GENERAL METABOLIC PATHWAYS: 1. AA-CHO PATHWAY involves ALT & AST 2. UREA CYCLE NH4 urea Enzyme OCT unique to liver LIVER FUNCTION TESTS hepatic structure, cell integrity, function LIVER FUNCTION TESTS Reasons for requesting LFT: 1. For Diagnosis 2. For Differentiation Is Hepatic damage due to primary hepatocyte damage or biliary system obstruction? 3. Prognosis / Monitoring TESTS FOR DISCLOSING HEPATIC DYSFUNCTION Liver Enzymes Aminotransferases (ALT and AST) Lactate Dehydrogenase (LDH) Alkaline Phosphatase (Alk Phos) Glutamyl transferase (GGT) TESTS FOR DISCLOSING HEPATIC DYSFUNCTION Total Protein Albumin Gamma Globulins Alpha Globulins Clotting Factors ProthrombinTime HEPATOBILIARY DYSFUNCTION Serum Bilirubin ( total & direct) PATIENT PREPARATION & SPECIMEN COLLECTION No special preparation required Serum : Preferred Specimen Heparinized Plasma : Acceptable Liver Enzymes: Transaminases 2 major aminotransferases – Aspartate transferase ALT(SGPT) – Alanine transferase AST(SGOT) Catalyze reversibly the transfer of an amino gr.of either AST or ALT to alpha-ketoglutarate to yield glutamate plus the corresponding ketoacid of the starting a.a. Liver Enzymes: Transaminases Reaction catalyzed by ALT COOH | CH2 | CH2 + | C=O | COOH CH3 + | H C- NH3 | B6 COOH -ketoglutarate L-alanine COOH | CH2 | COOH | C=O | CH2 + COOH | pyruvate C- NH3 | COOH L-glutamate Transaminases AST AST ALT Distribution: ALT: liver (1o location) kidney & muscle (lesser quantity) more liver-specific cytoplasmic enzyme AST : in many body tissues, ex heart,liver,muscle,RBC brain,lung ,pancreas & kidney. cytoplasmic & mitochon drial enzyme Elevation of ALT activity persist longer Reference value ALT : Males Females AST : Males Females 10-40 U/L 7-35 U/L 15-40 U/L 13-35 U/L Transaminases In Hepatobiliary Diseases Hepatocellular injury AST Mild: AST PM damaged ALT Cytoplasmic AST & ALT released into serum ALT More severe: Mitochondrial membrane damaged Mitochondrial AST released into serum: AST 80% Disproportionate elevation---(De Ritis quotient) AST/ALT (DeRitis) ratio: to discriminate alcoholic hepatitis vs other liver diseases ; Sometimes help determine whether the liver is damaged or another organ has been damage How to calculate AST/ALT ratio? ex. AST= 52, ALT =67 52/67 = .75 AST / ALT > 2 ( 3:1 to 4:1) = ALD AST/ALT <1,most likely assoc. with other cause eg. Viral hep Transaminases acute hepatitis : ALT is more increased than AST (20 -100 x the upper limit) AST is 10x the upper limit 5-10x the upper limit in liver Ca Cirrhosis : ALT is more increased than AST, but as fibrosis progresses, ALTdec. In end stage = both enzymes are dec. Acute Fulminant hepatic failure,;AST : ALT > 1 AST value > 1000 = severe liver necrosis, AMI TRANSAMINASES REMEMBER: Levels are often compared with results of other LFTs to help determine which form of liver d’s is present In most type of liver d’s ,ALT level > AST AST/ALT ratio is low AST : use for monitoring tx of potentially hepatotoxic drugs > 3x ULN stop tx Transaminases In Asymptomatic Patients Possible Causes of Chronic Elevation: 1. Alcohol or medication use 2. ChronicViral Hepatitis 3. Non-alcoholic fatty liver disease 4. Overweight (inc.ALT) LIVER ENZYMES : LACTATE DEHYDROGENASE Cytoplasmic enzyme Non specific for liver Distribution of isoenzymesLD1 LD2 LD4 LD5 LD4 LD5 LD1,LD2 Cardiac muscle, kidney,rbc LD1,LD LD2 TRANS Liver, skeletal muscle LD LD4,LD5 N value(TLD) =150 IU/l LIVER ENZYMES : LD in Hepatitis Is slightly inc. but only transient ( low activity and short half life Large increment of total LD= 500 -1000 iu/l TRANS CPK LD or+ elevated Alk.PO in the absence of other abn. Liver function tests (AST,ALT) LIVER ENZYMES : LD in Other Liver Diseases Total LD + alkaline Phosphatase: = space occupying lesions (e.g.) metastatic carcinoma 1o hepatocellular carcinoma Hemangioma (rarely) Source of LD (LD5) : ? hepatocytes tumor both ALKALINE PHOSPHATASE Distribution: liver * Bulk * Bone * kidney intestine ALP ALP placenta ALP Each of w/c contain distinct isoenzymes ALP ALP ALKALINE PHOSPHATASE Canalicular membrane Func.: facilitate transfer of metabolites across cell membranes ;lipid transport, & calcification process in bone synthesis Liver: exists predominantly in biliary tract a marker for biliary dysfunction R.V.=20-105 U/L (adults) ALKALINE PHOSPHATASE Clinical Application Obstruction of BT from: Stones in duct Infections SOL ALP (> 10 x ULN) Reason for Increase: Synthesis + excretion of ALP ALKALINE PHOSPHATASE hepatocellular disease (due to inflam/necrosis of the ductular lining cells) Obst.Cholestasis (2x ULN,paralleling the rise of bili. ) Partial obst. Inc. ALP & normal bili (dissociated jaundice) CPC,liver-mod.elevated SOL of liver Clinical application Conditions in Which the Serum ALP is Hepatobiliary Ds Bone Ds Other Conditions Obstructive jaundice Osteitis deformans Healing fractures Biliary cirhosis Rickets Normal growth Intrahep cholestasis Osteomalacia Pregnancy SOL(granuloma,abs Hyperthyroidism Note: dec. ALP is cess ,metastatic ca) seen in malnutrition Viral hepatitis Metastatic bone ds Cirrhosis Osteogenic Sa hypophosphotasia GLUTAMYL TRANSFERASE (GGT) Tissue distribution: Kidney Pancreas Liver Prostrate GGT Ref.values: 3-35 U/L GGT GGT 3-30 U/L GGT GLUTAMYL TRANSFERASE (GGT) > 10x ULN in chronic cholestasis due to primary biliary cirrhosis or sclerosing cholangitis. > Inc. in 60-70% ---alcohol abuse; > most sensitive enzyme to determine liver damage from alcohol abuse > inc. in obst. disorders, SOL in the liver than w/ liver inj. > obese ; > high conc.of therapeutic drugs (acetaminophen,carbamazepine, Dilantine) Regulates the transport of a.a. across cell membranes by catalyzing the transfer of a glutamyl gr.from glutathione GLUTAMYL TRANSFERASE (GGT) Increased Activity: Application: Detecting Alcoholic Liver Ds Liver metastasis in anicteric patient Chronic obstruction of bile duct PROTEINS IN LIVER FUNCTION Total serum protein Composed of : Albumin Globulins (1,2, , immuno globulins) A/G ratio is 2:1 ; a reversal ratio favors renal / liver prob & chronic infect. Ref. Range: 6-7.8 g/dL (60% is albumin, 3.5-5 g/dL) PROTEINS IN LIVER FUNCTION ALBUMIN Functions: Major osmotically active component of vascular system Transport protein( e.g. for bilirubin & thyroid hormone) Synthesized by liver at 120 mg/kg/day Hepatitis : total protein and albumin are w/in their normal range Fulminant hep : abnormally Cirrhosis : low Albumin together with PT are better indices of severity and prognosis of liver disease Other Causes of dec. TP and ALB. Renal disease Protein losing enteropathy Malnutrition Chronic inflammatory diseases Severe burn An inc. in protein –Dehydration BILIRUBIN METABOLISM Senescent rbc’s RES Heme Globin RES Iron + Albumin Recycled into new rbc’s Liver Bilirubin uridine diphosphate Glucoronyl transferase Amino acid pool Protoporhyrin Heme oxygenase Biliverdin Bilirubin reductase Unconjugated + Albumin bilirubin 2%-5% renal excretion Bilirubin glucoronide Bile Small intestine Alkal;ine pH + β-glucoronidase Unconjugated bilirubin Intestinal bacteria Urobilinogen Urobilin (fecal pigment) 20% reabosrobed DISORDERS OF BILE PIGMENT METABOLISM Reference values: T serum bilirubin (A): 0.1 - 1 mg/dL (1.7 to 17 umol/L) Congugated Bilirubin (Direct): 0.3 mg/dL(5 umol/L) Unconjugated Bilirubin (Indirect): T Bilirubin – Conjugated Bilirubin BILIRUBIN Serum / plasma , fasting state;shld.be tested ASAP Interference factors: Hemolysis- false dec lipemic – false inc light – false dec. DISORDERS OF BILE PIGMENT METABOLISM JAUNDICE/ICTERUS Bilirubin deposition in sclera and in skin > 2.5 mg/dL (43 umol/L) DISORDERS OF BILE PIGMENT METAB (HYPERBILIRUBINEMIA) Unconjugated Excess Bilirubin Prodxn Impaired Bili Conjugation Physiologic jaundice of NB Hemolytic Anemia Resorption of blood from Breast milk jaundice internal hge Genetic Def. Of bili UGT Ineffective erythropoiesis (Criggler-Najar) (e.g.pernicious An, thalassemia Hepatic uptake Drug interference Some cases of Gilbert syndrome Gilbert syndrome Diffuse Hepatocelular Ds DISORDERS OF BILE PIGMENT METAB (HYPERBILIRUBINEMIA) Conjugated Dec. hepatic excretion of Bili Glucuronides Deficiency in canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome) In extrahepatic obst.,total bili rarely exceeds 25 ug/dl Ammonia Derived mainly from a.a. & nucleic acid metabolism Metabolized only in the liver Px preparation: fasting,plasma, arterial good venipuncture technique,no fist clenching R.V. 19- 16 ug/dl Alpha-feto protein An onco-fetal protein Marker of differentiation Synthesized by fetal yolk sac, hepatocytes Detectable during 4th wks. of pregnancy Increased in : HCC , benign liver ds ( cirrhosis ) Testicular Tumors (embryonal &yolk sac) Maybe inc. in breast,bronchial and colorectal Ca Ref.value : < 20ng/ml > 400 ng/dl =HCC Inc. neural tube defect 6 Fundamental Patterns of Liver Function Tests AST ALT LD ALP TP ALB BIL NH4 1 H H H H N N H N 2 N N N N-sl L H L H H 3 N N N H N N N-H N 4 N or H N or H H H N N NH N 5 sl N N 6 Very L L N- N SlH H H CONDITION H H sl H sl H Nsl H H H H The end Good clinical history Complete P.E.