Liver Function TestLiver chemistry test Clinical implication of abnormality

ALT Hepatocellular damage

AST Hepatocellular damage

Bilirubin Cholestasis, impair conjugation, or biliary obstruction

ALP Cholestasis, infiltrative disease, or biliary obstruction

PT Synthetic function

Albumin Synthetic function

GGT Cholestasis or biliary obstruction

Bile acids Cholestasis or biliary obstruction

5`-nucleotidase Cholestasis or biliary obstruction

LDH Hepatocellular damage, not specific

Normal Laboratory Values

2 SD

Abnormal Normal

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

(times)

Marked

(times)

AST <2-3 2-3 to 20 >20

ALT <2-3 2-3 to 20 >20

ALP <1.5-2 1.5-2 to 5 >5

GGT <2-3 2-3 to 10 >10

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

Liver Function Test

AST and ALT

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

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

• level of transminase elevation

• predominant AST elevation

• rate of transaminase declination

AST, ALT

• Peak values of transaminase activity occur between the 7th and l2th days;

• activities then gradually decreaser,e aching normal levelsb ythe 3rd to 5th week if recovery is uneventful

• Persistenceo f increased A LT for more than 6 months after an episode of acute hepatitis is used to diagnose chronic hepatitis

• After AMI, increased AST activity appears in serum, as might be expected from the high AST concentration in heart muscle. AST activity also is increased in progressive muscu-

• The ratio seems to clearly identify the liver-cell "necrotic type" condition (i'e'' slight enzyme increase concomitant with relatively high activities of mitochondrial enzymes), typical of alcoholic hepatitis

• Several authors have described AST linked to immunoglobulins, or macro-AST

• The typical findings are a persistent increase of serum AST activity in an asymptomatic subiect, with the absence of any demonstrable pathology in organs rich in AS

• The increased AST activity might reflect decreased clearance of the abnormal complex from plasma. Macro-AST has no known clinical relevance

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

Rate of Transaminase Declination

rapid • ischemic• short half life drug• acute biliary tract

obstruction • fulminant hepatitis

slow• acute viral hepatitis• long half life drug• AIH• metabolic disease

ALT and AST < 5 timesALT 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

Common medication

• Acetaminophen overdose• Statins • NSAIDs• Antibiotics• Antiepileptics• Antituberculosis drugs• Herbal remedies, alternative

medications and substance abuse

ALT and AST < 5 times and AST predominant

• history alcohol intake (history from patient and family members)

• hemolysis studies

• aldolase

• CPK

• macro-AST

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)

Bilirubin

RE cell plasma hepatocyte

HEME UCB UCB

+

albumin

UCB+ligandin

BMG

BDG

bile

urobilinogen stercobilinogen

BilirubinUDP-glucoronyltransferase

• 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

Bilirubin

Isolated unconjugated hyperbilirubinemia

• IDB fraction > 85% of total bilirubin1. increase production :

• hemolysischronic hemolysis-not sustained increase of bilirubin >5 mg/dl in normal hepatic function

• ineffective erythropoiesis : folate, IDA• drug : rifampicin, ribavirin, probenecid• resolution of hematoma

2. defects in hepatic uptake/conjugation• Gilbert’s syndrome• Crigler-Najjar syndrome

Indirect Hyperbilirubinemia

Bilirubin AST, ALT Alb Glob PT

hemolysis 5 mg/dl increase AST N N N

Gilbert’s syndrome

5 mg/dl normal N N N

• 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

Conjugated hyperbilirubinemia

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

Alkaline phosphatase

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

Physiologic• >60 yr.• child and adolescent• pregnancy• blood group O• post meal (fatty meal)

Pathologic• intrahepatic • extrahepatic

Alkaline phosphatase

Alkaline phosphatase

Intrahepaticviral alcohol

drug pregnancy

PBC PSC

TPN sepsis

vanishing bile duct syndrome

benign recurrent cholestasis

benign post-op. cholestasis

paraneoplastic syndrome

venoocclusive disease

GVHD

Extrahepaticintraluminal 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

• 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

• TB• Fungal infection• HCC • Lymphoma• Metastatic malignancy• Amyloidosis • Sarcoidosis • Other granulomatous diseases

modest (up to 3x) rise in aminotransferase,

and up to 20x rise in ALP, bilirubin N-5x

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• Methylenedioxymethamphetam

ine• Oxaprozin• Pizotyline• Quinidine• Tolbutamide• TPN• Trimethoprim-

sulfamethoxazole

γ-glutamyltransferase (GGT)

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

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

Summary Hepatocellular necrosis Biliary obstruction Infiltration

toxin/ ischemia

viral alcohol complete partial

AST/ALT 50-100X 5-50X 2-5X 1-5X 1-5X 1-3X

ALP 1-3X 1-3X 1-10X 2-20X 2-10X 1-20X

Bilirubin 1-5X 1-30X 1-30X 1-30X 1-5X 1-5X

PT increase in severe,

unresponsive to vit K

increase,

responsive to vit K

normal

albumin increase in subacute/chronic usually normal, decrease in advance

normal

Albumin

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

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

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

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

misnomer– not effectively assess actual function – not always specific for the liver– limited information regarding presence or

severity of complication

Liver Function Test

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