Liver Function Test Piyanant Chonmaitree, MD. Department of Medicine Srinakharinwirot University

Liver Function Test Liver chemistry test Clinical implication of abnormality ALT Hepatocellular damage AST Bilirubin Cholestasis, impair conjugation, or biliary obstruction ALP Cholestasis, infiltrative disease, or biliary obstruction PT Synthetic function Albumin GGT Cholestasis or biliary obstruction Bile acids 5`-nucleotidase LDH Hepatocellular damage, not specific no single test provide accurate global assessment of hepatic function

Normal Laboratory Values Abnormal 2 SD mild elevation in 2.5% of normal population normal range included a small subset of patients with subclinical liver disease normal values = mean ± 2SD of normal population

Liver Function Test interpretation must be performed within the context of the patient’s risk factors, symptoms, concomitant conditions, medications, and physical findings rarely provide specific Dx, but rather suggest a general category of liver disease differing laboratories  differing normal values

Liver Function Test Mild (times) Moderate Marked AST <2-3 2-3 to 20 >20 ALT ALP <1.5-2 1.5-2 to 5 >5 GGT 2-3 to 10 >10

Liver Function Test should be evaluated and Rx in more expeditious manner marked abnormalities S&S of chronic liver disease or decompensation mild elevation is nonspecific and usually normal when repeated observe vs. additional evaluation must be made in context of clinical scenario different types of liver disease often associated with distinct pattern of biochemical abnormalities

Liver Function Test Advantages sensitive, noninvasive method of screening liver dysfunction pattern of laboratory test abnormalities to recognize type of liver disorder assess severity of liver dysfunction follow cause of liver disease Disadvantages lack sensitivity normal results in serious liver disease not specific for liver dysfunction seldom lead to specific diagnosis

Initial Approach history and physical examination algorithm approach useful mainly when no clinical clues history patient’s symptoms risk factors for liver disease concomitant conditions medications occupational exposure to hepatotoxins physical examination body habitus splenomegaly ascites cutaneous stigmata of chronic liver disease

Liver Function Test classified in 3 groups synthetic function : albumin, PT hepatocyte injury : AST, ALT cholestasis : bilirubin, ALP, GGT PT, albumin, bilirubin-most common tests used as prognostic factors

Albumin depend on nutrition, volume status, vascular integrity, catabolism, hormone, loss in stool and urine not specific for liver disease T1/2 19-21 D not reliable indicator of acute liver disease decrease : poor nutrition status, severe illness with protein catabolism, nephrosis, malabsorption, PLE, burns, heavy alcohol intake

Hypoalbuminemia globulin chol/TG Hb 1.decrease synthesis -protein malnutrition -chronic liver disease -chronic inflammation 2.increase loss -PLE -NS 3.increase Vd (ascites, overhydration) 4.increase turnover (catabolic state, steroid)

Globulin produced by stimulated B lymphocyte elevation in chronic liver disease chronic inflammation and malignant disease

Case 1 ผู้ป่วยหญิงอายุ 40 ปี มาด้วย ถ่ายเหลว 2 เดือนก่อน PE : T 37º C, markedly pale, no jaundice, koilonychia, glossitis, coarse hair, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] chol 80 mg/dl [<200] จงแปลผล LFT และบอกสาเหตุของความผิดปกติดังกล่าว

Case 2 ผู้ป่วยหญิงอายุ 40 ปี มาด้วย บวม 2 เดือนก่อน PE : T 37º C, not pale, no jaundice, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] chol 250 mg/dl [<200] จงแปลผล LFT และบอกสาเหตุของความผิดปกติดังกล่าว

Case 3 ผู้ป่วยหญิงอายุ 40 ปี มาด้วย ท้องบวม 2 เดือนก่อน PE : T 37.8º C, mildly pale, no jaundice no sign of chronic liver disease, liver and spleen not palpated, shifting dullness + LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 4.5 g/dl [1.5-3.5 g/dL] chol 100 mg/dl [<200] จงแปลผล LFT และบอกสาเหตุของความผิดปกติดังกล่าว

Case 4 ผู้ป่วยหญิงอายุ 40 ปี มาด้วย ท้องบวม 2 เดือนก่อน PE : T 37º C, mildly pale, no jaundice, spider nevi, palmar erythrema, liver and spleen not palpated, shifting dullness + LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 4.5 g/dl [1.5-3.5 g/dL] chol 100 mg/dl [<200] จงแปลผล LFT และบอกสาเหตุของความผิดปกติดังกล่าว

Prothrombin time liver synthesize coagulation factor except FVIII most present in excess, clotting abnormal occur only when substantial impairment in ability of liver to synthesis PT : FI, II, V, VII, IX and X T1/2 FVII 6 hrs. (shortest) prognosis : acute, chronic hepatocellular disease

Prothrombin time prolonged : vitamin K deficiency (malnutrition, malabsorption, antibiotics) massive transfusion congenital disease liver disease warfarin DIC

Prothrombin time in vit K deficiency, vit K 10 mg SC decrease prolong PT >30% within 24 hrs. INR : no advantage over PT

AST and ALT most frequent used markers of hepatocellular necrosis, but not correlate with eventual outcome decrease : recovery or poor prognosis poor prognosis : rapid fall with rising of bilirubin and PT after reaching peak, AST/ALT decrease at rate 10.5-11.7% per day

AST ALT catalyze transfer amino groups to form pyruvate catalyze transfer amino groups to form oxaloacetate cytosol (20%) and mitochondria (80%) cytosol T1/2 17 hr. (cytosol) 87 hr. (mitochondria) T1/2 47 hr. liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and RBC low concentration in other tissues

AST, ALT level of transminase elevation predominant AST elevation rate of transaminase declination

ALT and AST >15 times : acute hepatic injury 5-15 times : less useful <5 times : chronic hepatic injury improved acute hepatic injury

AST/ALT ratio < 1 : majority of liver disease >2 extrahepatic source alcoholic hepatitis ischemic and toxin acute Wilson’s disease : hemolysis cirrhosis >4 : fulminant Wilson’s disease

AST/ALT ratio

Rate of Transaminase Declination slow acute viral hepatitis long half life drug AIH metabolic disease rapid ischemic short half life drug acute biliary tract obstruction fulminant hepatitis

ALT and AST < 5 times ALT predominant Chronic hepatitis B, C Acute hepatitis (A-E, EBV, CMV) Steatohepatitis Hemochromatosis Medications/toxins Autoimmune hepatitis Alpha1-antitrypsin deficiency Wilson’s disease Celiac disease AST predominant Alcohol-related liver injury Steatohepatitis Cirrhosis Drug Nonhepatic Hemolysis Myopathy Thyroid disease Strenuous exercise Macro AST *almost any types of liver disease

Risk factor of chronic viral hepatitis injection drug use birth to mother with HBV blood transfusion prior to 1992 needle stick from a donor subsequently testing positive for HBV or HCV chronic hemodialysis unvaccinated health care workers homosexual body piercing or tattooing

Common medication Acetaminophen overdose Statins NSAIDs Antibiotics Antiepileptics Antituberculosis drugs Herbal remedies, alternative medications and substance abuse

ALT and AST < 5 times discontinue all nonessential medications if mild elevation and essential medications must be continued if liver enzyme elevations continue to rise, suspect medication should be stopped long-term effects of chronic, medication induced hepatotoxicity are lacking for many drugs

Case 5 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี ตรวจร่างกายปกติ LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงแปลผล LFT และบอก management ในผู้ป่วยรายนี้

Case 5.1 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี ไม่มีอาการผิดปกติใดๆ ไม่ดื่มสุรา ไม่กินยาใดๆ ไม่เคยได้รับเลือด ไม่เคยใช้สารเสพติด ตรวจร่างกายปกติ, BW 90 kg, Height 160 cm., truncal obesity LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงบอก management ในผู้ป่วยรายนี้

Diagnostic approach in mild elevations of the serum AST and ALT elevated ALT and AST < 5X history and PE, discontinue hepatotoxic medications confirm abnormality if an error is suspected liver chemistries, PT, albumin, CBC, hepatitis A, B and C serologies, Fe, TIBC, Ferritin lifestyle modification discontinue alcohol and hepatotoxic drug, weight loss, diabetes control consider U/S, ANA, ASMA, ceruloplasmin, alpha-1 antitrypsin consider as specific disease repeat liver chemistries observe U/S, ANA, ASMA, ceruloplasmin, alpha-1 antitrypsin liver biopsy negative, asymptomatic, no decompensation positive negative liver biopsy abnormal normal

Case 5.1 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี ไม่มีอาการผิดปกติใดๆ ไม่ดื่มสุรา ไม่กินยาใดๆ ไม่เคยได้รับเลือด ไม่เคยใช้สารเสพติด ตรวจร่างกายปกติ, BW 90 kg, Height 160 cm., truncal obesity LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] viral profile-negative

NAFLD/NASH NAFLD = macrovesicular steatosis with mild or without inflammation, no fibrosis NASH = NAFLD + inflammation/ ballooning/fibrosis alcohol <70 g/D in women, <140 g/D in men 2 hits hypothesis hyperinsulinemia  increased FFA in liver  steatosis hepatocyte necrosis and inflammation

NAFLD/NASH asymptomatic, vague RUQ pain, fatigue, malaise hepatomegaly, splenomegaly, spider angiomata, palmar erythema, ascites AST, ALT 2-4x, AST/ALT<1 1/3 ALP slightly elevated

NAFLD/NASH U/S –bright liver CT-lower density than spleen MRI-bright on T1W biopsy (gold standard) : macrovesicular steatosis, parenchymal inflammation, hepatocyte necrosis, ballooning hepatocyte degeneration

NAFLD/NASH weight reduction, exercise, control DM and dyslipidemia orlistat, sibutramine, Bariatric surgery avoidance of toxins : drugs, alcohol insulin sensitizing agents thiazolidinediones metformin

Case 5.2 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี มีประวัติ IVDU ตรวจร่างกายปกติ LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงบอก investigation เพิ่มเติมในผู้ป่วยรายนี้

Case 5.2 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี มีประวัติ IVDU ตรวจร่างกายปกติ LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] HBsAg positive antiHCV negative

ALT and AST < 5 times and AST predominant history alcohol intake (history from patient and family members) hemolysis studies aldolase CPK macro-AST

Case 6 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี ตรวจร่างกายปกติ LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 280 U/L [0-35 U/L] ALT 250 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงแปลผล LFT และบอก management ในผู้ป่วยรายนี้

Alcoholic hepatitis appropriate history of alcoholic consumption, serologic exclusion of other liver disease ♂ 40-80 g/D, ♀ 20-40 g/D 10-12 yrs. characteristic pattern AST rarely exceeds 300 IU/dl AST/ALT >1 in 92%, >2 in 70% pyridoxine deficiency alcohol induces release of mitochondrial AST GGT/ALP >2.5

Case 6 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี ดื่มสุรา ½ ขวดกลมต่อวัน 20 ปี ตรวจร่างกายปกติ LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 280 U/L [0-35 U/L] ALT 250 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงแปลผล LFT และบอก management ในผู้ป่วยรายนี้

Alcoholic hepatitis Rx abstinence alcohol drinking severe alcoholic hepatitis (DF >32) [DF = 4.6 x (PT-control) + serum bilirubin] glucocorticoid (no GI bleeding and active infection) improve survival, not reduce HRS pentoxyfilline reduce HRS

ALT and AST > 15 times Acute viral hepatitis (A-E, herpes) Medications/toxins Ischemic hepatitis Acute bile duct obstruction Autoimmune hepatitis Wilson’s disease Acute Budd-Chiari syndrome Hepatic artery ligation Heat stroke AST predominate : medication/toxin, ischemic >75 times : ischemic, toxic, viral (less common)

Case 7 ผู้ป่วยหญิงอายุ 40 ปี underlying disease AF, HT มาด้วย CHF LFT :TB 2 mg/dl [0.3-1 mg/dl] DB 1 mg/dl [0.1-0.3 mg/dl] AST 2500 U/L [0-35 U/L] ALT 2200 U/L [0-35 U/L] ALP 180 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงแปลผล LFT, DDx สาเหตุและบอก management ในผู้ป่วยรายนี้

Ischemic hepatitis low-flow hemodynamic state (shock liver, acute hepatic circulatory insufficiency) low-flow hemodynamic state hypotension, sepsis, cardiac arrhythmia, MI, HF, hemorrhage, extensive burns, severe trauma, heat stroke hypotension often not documented usually subclinical

Ischemic hepatitis sudden and massive (>2000) elevation of liver enzyme, tend to decrease rapidly and return normal within 1 wk. mild and transient elevation of bilirubin (80% < 2 mg/dl) and ALP extreme elevation LDH (>5000), ALT/LDH < 1.5 rare acute liver failure Rx and prognosis α underlying disease

Ischemic hepatitis

Case 8 ผู้ป่วยหญิงอายุ 40 ปี มาด้วย RUQ pain 12 ชั่วโมงก่อน LFT :TB 2 mg/dl [0.3-1 mg/dl] DB 1.5 mg/dl [0.1-0.3 mg/dl] AST 1200 U/L [0-35 U/L] ALT 1400 U/L [0-35 U/L] ALP 180 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงแปลผล LFT, DDx สาเหตุและบอก management ในผู้ป่วยรายนี้

Acute biliary obstruction aminotransferase peak early and decline rapidly over 24-72 hr. despite unresolved obstruction after aminotransferase decrease, bilirubin and ALP increase 25% of patients with AST > 10X

Acute biliary obstruction

Case 8 ผู้ป่วยหญิงอายุ 40 ปี มาด้วย RUQ pain 12 ชั่วโมงก่อน LFT :TB 2 mg/dl [0.3-1 mg/dl] DB 1.5 mg/dl [0.1-0.3 mg/dl] AST 1000 U/L [0-35 U/L] ALT 1300 U/L [0-35 U/L] ALP 180 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] U/S : bile duct dilatation with gall stone F/U LFT 72 hr. AST 300 U/L, ALT 600 U/L

LDH non specific rhabdomyolysis, MI, hemolysis, stroke, renal infarction, acute or chronic liver disease use in ischemic hepatitis : transient, massive elevation malignant infiltration of liver : sustained elevation with ALP

UDP-glucoronyltransferase Bilirubin UDP-glucoronyltransferase RE cell plasma hepatocyte HEME UCB UCB + albumin UCB+ligandin BMG BDG bile urobilinogen stercobilinogen

Bilirubin Direct bilirubin : reacted directly with reagent Indirect bilirubin : require addition of alcohol for color development Unconjugated bilirubin = indirect form Conjugated bilirubin = bilirubin mono and di-glucoronides

Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin hemolysis studies, review medications

Isolated unconjugated hyperbilirubinemia IDB fraction > 85% of total bilirubin increase production : hemolysis chronic hemolysis-not sustained increase of bilirubin >5 mg/dl in normal hepatic function ineffective erythropoiesis : folate, IDA drug : rifampicin, ribavirin, probenecid resolution of hematoma defects in hepatic uptake/conjugation Gilbert’s syndrome Crigler-Najjar syndrome

Case 9 ผู้ป่วยชายอายุ 30 ปี มาตรวจสุขภาพประจำปี LFT :TB 3 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 30 U/L [0-35 U/L] ALT 30 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] จงแปลผล LFT, DDx สาเหตุและบอก management ในผู้ป่วยรายนี้

Gilbert’s syndrome benign, unconjugated hyperbilirubinemia with otherwise normal liver chemistries up to 5% of normal population polymorphism in TATA box of gene encoding bilirubin UDP-GT impair ability to conjugate bilirubin prominent in fasting state, systemic illnesses, hemolysis, some medications

Gilbert’s syndrome Dx : asymptomatic, healthy mild unconjugated hyperbilirubinemia (<4 mg/dl) with otherwise normal liver chemistries test exclusion medications and hemolysis

Case 10 ผู้ป่วยชายอายุ 30 ปี มาด้วยอ่อนเพลีย 3 วันก่อน PE : T 38º C, markedly pale, mild jaundice, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 5.4 mg/dl [0.3-1 mg/dl] DB 0.8 mg/dl [0.1-0.3 mg/dl] AST 120 U/L [0-35 U/L] ALT 45 U/L [0-35 U/L] ALP 110 U/L [30-120 U/L] alb 3.6 g/dl [3.5-5.5 g/dl] glob 3.6 g/dl [1.5-3.5 g/dL] จงแปลผล LFT DDx สาเหตุและบอก management ในผู้ป่วยรายนี้

Indirect Hyperbilirubinemia AST, ALT Alb Glob PT hemolysis 5 mg/dl increase AST N Gilbert’s syndrome normal

Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin

Conjugated hyperbilirubinemia DB > 50% of total bilirubin can’t differentiate obstruction and parenchymal disease Delta fraction CB tightly bound to albumin tendency of hyperbilirubinemia to resolve more slowly than other biochemical tests rarely exceed 30 mg/dl, if no hemolysis, renal failure does not appear in urine, still react directly with diazo agent

Conjugated hyperbilirubinemia Bile duct obstruction Hepatitis Cirrhosis Medications/Toxins Primary biliary cirrhosis Primary sclerosing cholangitis Sepsis Total parenteral nutrition Intrahepatic cholestasis of pregnancy Benign recurrent cholestasis Vanishing bile duct syndromes Dubin-Johnson syndrome Rotor syndrome

Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin normal ALP, ALT, AST abnormal ALP, ALT, AST Rotor’s syndrome Dubin-Johnson syndrome

Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin normal ALP, ALT, AST abnormal ALP, ALT, AST Rotor’s syndrome AST, ALT ALP Dubin-Johnson syndrome predominate predominate hemolysis studies, review medications as elevated ALT evaluation U/S ERCP as elevated ALT evaluation review medications AMA, ERCP, liver biopsy / / present absent

Case 11 ผู้ป่วยชายอายุ 30 ปี มาด้วยจุกแน่นลิ้นปี่ 3 วันก่อน PE : T 37º C, not pale, mild jaundice, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 6.2 mg/dl [0.3-1 mg/dl] DB 4.8 mg/dl [0.1-0.3 mg/dl] AST 100 U/L [0-35 U/L] ALT 120 U/L [0-35 U/L] ALP 520 U/L [30-120 U/L] alb 3.6 g/dl [3.5-5.5 g/dl] glob 3.6 g/dl [1.5-3.5 g/dL] จงแปลผล LFT และบอก management ในผู้ป่วยรายนี้

Alkaline phosphatase family of isoenzyme catalyze hydrolysis of No. of P esters at alkaline pH require Zn for activity present in nearly all tissues (liver, bone, intestinal, placenta, kidney) liver ALP isoenzyme, 5’-nucleotidase, GGT microvilli of bile canaliculus associated with sinusoidal and canaliculus membrane, present in cytosol, secreted in bile

Alkaline phosphatase Physiologic >60 yr. child and adolescent pregnancy blood group O post meal (fatty meal) Pathologic intrahepatic extrahepatic CRF : abnormal elevation of intestinal AP isoenzyme

Alkaline phosphatase Intrahepatic Extrahepatic viral alcohol drug pregnancy PBC PSC TPN sepsis vanishing bile duct syndrome benign recurrent cholestasis benign post-op. cholestasis paraneoplastic syndrome venoocclusive disease GVHD Extrahepatic intraluminal obstruction : gall stones, ascariasis, hemobilia disease of BD : PSC, choledochal cyst, cholangioCA, AIDS cholangiopathy external compression : LN, GB CA, Mirizzi’s syndrome, CA pancreas, ampullar adenoma

Alkaline phosphatase in biliary obstruction induction of ALP synthesis 2° to enhanced translation of mRNA ALP levels, may not rise until 1-2 days T1/2 1 wk, take several days for levels to normalise after resolution in malignancy “Regan isoenzyme” no identifiable liver/bone involvement biochemical distinct from liver ALP associated variety of different CA ex lung CA may remain within normal range in extensive hepatic metastasis or extrahepatic bile duct obstruction nonspecific hepatitis : HD, RCC (bystander phenomenon)

Alkaline phosphatase initial evaluation : determine hepatic or nonhepatic origin, concomitant elevation of other serum LFT level not a reliable indicator of severity of underlying liver disease degree not help to distinguish intrahepatic and extrahepatic

Isolated hepatic ALP elevation Partial bile duct obstruction Medications Infiltrative liver disease Hepatic metastasis PBC PSC Hepatitis Cirrhosis Vanishing bile duct syndromes Benign recurrent cholestasis

Infiltrative diseases modest (up to 3x) rise in aminotransferase, and up to 20x rise in ALP, bilirubin N-5x TB Fungal infection HCC Lymphoma Metastatic malignancy Amyloidosis Sarcoidosis Other granulomatous diseases

Alkaline phosphatase ALP > 1000 : malignant biliary obstruction, sepsis, AIDS with systemic infection decrease : hypothyroidism, pernicious anemia, Zn deficiency, congenital, Wilson’s disease, severe hepatic insufficiency

Medications  elevation of bilirubin and ALP Anabolic steroid Allopurinol Amoxicillin-clavuronic acid Captopril Carbamazepine Chlorpropamide Cyproheptadine Diltiazem Erythromycin Estrogens Floxuridine Flucloxacillin Fluphenazine Gold salts Imipramine Indinavir Iprindole Nevirapine Methytestosterone Methylenedioxymethamphetamine Oxaprozin Pizotyline Quinidine Tolbutamide TPN Trimethoprim-sulfamethoxazole

Diagnostic approach in elevated serum alkaline phosphatase elevated ALP History and PE normal bilirubin, ALT, AST abnormal liver chemistries GGT or 5’nucleotidase U/S not hepatobiliary review medication AMA ERCP liver biopsy observation as elevated ALT evaluation, liver biopsy, ERCP yes no negative positive negative no duct dilatation > 6 months

Case 12 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี ตรวจร่างกายปกติ LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 320 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] จงแปลผล LFT และบอกสาเหตุของความผิดปกติดังกล่าว

γ-glutamyltransferase (GGT) catalyzed transfer of γ-glutamyl groups of peptides to other amino acid abundant in liver, kidney, pancreas, intestine, and prostate, spleen, heart, brain but not in bone T1/2 7-10 days 28 days in alcohol-associated liver injury located on membranes of cells with high secretory or absorptive activities

γ-glutamyltransferase (GGT) increase alcohol drug anticonvulsant (CBZ, phenytoin, and barbiturate), warfarin, OC almost all type of liver diseases COPD, renal failure, DM, hyperthyroidism, RA, AMI, pancreatic disease

Case 12 ผู้ป่วยหญิงอายุ 40 ปี มาตรวจสุขภาพประจำปี กินคุมกำเนิดอยู่ ตรวจร่างกายปกติ LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 320 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] GGT 86 [0-50] จงแปลผล LFT และบอกสาเหตุของความผิดปกติดังกล่าว

Summary Hepatocellular necrosis Biliary obstruction Infiltration toxin/ ischemia viral alcohol complete partial AST/ALT 50-100X 5-50X 2-5X 1-5X 1-3X ALP 1-10X 2-20X 2-10X 1-20X Bilirubin 1-30X PT increase in severe, unresponsive to vit K increase, responsive to vit K normal albumin increase in subacute/chronic usually normal, decrease in advance

Take home message initial evaluation : assess in clinical context classified in 3 groups synthetic function : albumin, clotting time cholestasis : bilirubin, ALP, GGT hepatocyte injury : AST, ALT

Liver Function Test Liver Chemistry Test misnomer not effectively assess actual function not always specific for the liver limited information regarding presence or severity of complication liver enzyme reflect hepatocyte integrity or cholestasis rather than liver function Liver Chemistry Test

Liver Function Test normal may have abnormal test normal value not ensure that patient is free of liver disease level of abnormality does not reflect severity but may help in DDx decrease in the value does not mean improvement limitation in sensitivity and specificity

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