JANET LIM-DY, M.D., F,P.S.P. D.T.M.H.

EVALUATION OF EVALUATION OF LIVER FUNCTION LIVER FUNCTION

TESTSTESTS

Overview Overview 3 Systems involved in understanding liver function tests:

Hepatocyte

Biliary Tract: bili metabolism

•Proteins synthesis•Coagulation factors synthesis

RES: Immune sys. , Heme & globin metabolites

KREBS CYCLE

GLUCONEOGENESIS

GLYCOLYSIS

HMP-SHUNT

FA SYNTHESIS & BREAKDOWN

LIPOPROTEIN METABOLISM

AA & NUCLEIC ACID METABOLISM

2 GENERAL METABOLIC PATHWAYS:1. AA-CHO PATHWAY involves ALT & AST

2. UREA CYCLE NH4 ureaEnzyme OCT unique to

liver

LIVER FUNCTION TESTS

hepatic structure, cell integrity, function

Reasons for requesting LFT:1. For Diagnosis2. For Differentiation

Is Hepatic damage due to primary hepatocyte damage or biliary system obstruction?

3. Prognosis / Monitoring

LIVER FUNCTION TESTSLIVER FUNCTION TESTS

Liver EnzymesAminotransferases (ALT and AST)Lactate Dehydrogenase (LDH)Alkaline Phosphatase (Alk Phos) Glutamyl transferase (GGT)

TESTS FOR DISCLOSING TESTS FOR DISCLOSING HEPATIC DYSFUNCTIONHEPATIC DYSFUNCTION

TESTS FOR DISCLOSING TESTS FOR DISCLOSING HEPATIC DYSFUNCTIONHEPATIC DYSFUNCTION

Total Protein Albumin

Gamma GlobulinsAlpha Globulins

Clotting FactorsProthrombinTimeHEPATOBILIARY DYSFUNCTION Serum Bilirubin ( total & direct)

PATIENT PREPARATION & SPECIMEN COLLECTION

No special preparation requiredSerum : Preferred SpecimenHeparinized Plasma : Acceptable

2 major aminotransferasesAST(SGOT) – Aspartate transferaseALT(SGPT) – Alanine transferase

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: Liver Enzymes: TransaminasesTransaminases

Reaction catalyzed by ALT COOH CH3 COOH COOH | + | B6 | |

CH2 H C- CH2 C=O

| | | |

CH2 + COOH CH2 + COOH

| | pyruvate

C=O C-

| | COOH COOH

-ketoglutarate L-alanine L-glutamate

Liver Enzymes: Liver Enzymes: TransaminasesTransaminases

NH3

NH3

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 enzymeElevation of ALT activitypersist longer

TransaminasTransaminaseses

AST

AST

ALT

Reference value

ALT :

Males 10-40 U/L

Females 7-35 U/L

AST :

Males 15-40 U/L

Females 13-35 U/L

Transaminases In Transaminases In Hepatobiliary DiseasesHepatobiliary Diseases

Mild:

PM damaged

Mitochondrial AST released into serum:

Disproportionate elevation----

(De Ritis quotient)

Cytoplasmic AST & ALT released into serum

More severe:Mitochondrial membrane damaged

ASTALT

Hepatocellular injury

ALT

AST

AST

80%

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 damageHow to calculate AST/ALT ratio?

ex. AST= 52, ALT =67 52/67 = .75

AST / ALT > 2 ( 3:1 to 4:1) = ALDAST/ALT <1,most likely assoc. with other cause eg. Viral hep

acute hepatitis : ALT is more increased than AST (20 -100 x the upper limit)AST is 10x the upper limit5-10x the upper limit in liver Ca

Transaminases Transaminases

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 > 1AST value > 1000 = severe liver necrosis, AMI

TRANSAMINASESREMEMBER: Levels are often compared with results of other LFTs to help determine which form of liver d’s is presentIn most type of liver d’s ,ALT level > ASTAST/ALT ratio is lowAST : use for monitoring tx of potentiallyhepatotoxic drugs> 3x ULN stop tx

Possible Causes of Chronic Elevation:1. Alcohol or medication use2. ChronicViral Hepatitis3. Non-alcoholic fatty liver disease

4. Overweight (inc.ALT)

Transaminases In Transaminases In Asymptomatic Patients Asymptomatic Patients

Distribution of isoenzymes-

LD1

LD2

LD4

LD5

LIVER ENZYMES : LACTATE DEHYDROGENASE

LD

LDTRANSCardiac muscle, kidney,rbcLiver, skeletal muscle

LD1,LD2

LD1,LD2

LD4,LD5

LD4LD5

Cytoplasmic enzymeNon specific for liver

N value(TLD) =150 IU/l

LDTRANS

CPK

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

or+ elevated Alk.PO in the absence of other abn. Liver function tests (AST,ALT)

Total LD + alkaline Phosphatase: = space occupying lesions (e.g.) metastatic carcinoma1o hepatocellular carcinomaHemangioma (rarely)

Source of LD (LD5) : ?hepatocytestumorboth

LIVER ENZYMES : LD in Other Liver Diseases

ALKALINE PHOSPHATASE

Distribution:

liver *

Bone *

kidney

intestine

placenta

Each of w/c

contain distinct isoenzymes

ALP

ALP

ALP

ALP

ALP

Bulk *

Liver: exists predominantly in

biliary tract a marker for biliary

dysfunction

ALKALINE PHOSPHATASE

R.V.=20-105 U/L (adults)

Canalicular membrane Func.: facilitate transfer of metabolites across cell membranes ;lipid transport, & calcification process in bone synthesis

ALKALINE PHOSPHATASE

Clinical Application

Obstruction of BT from:

Stones in duct

Infections

SOL

ALP (> 10 x ULN)

Reason for Increase:

Synthesis + excretion of ALP

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

ALKALINE PHOSPHATASE

Clinical application

Hepatobiliary Ds

Bone Ds Other Conditions

Obstructive jaundice

Osteitis deformans

Healing fractures

Biliary cirhosis

Rickets Normal growth

Intrahep cholestasis

Osteomalacia Pregnancy

SOL(granuloma,abscess,metastatic ca)

Hyperthyroidism

Note: dec. ALP is seen in malnutrition

Viral hepatitis Metastatic bone ds

hypophosphotasia

Cirrhosis Osteogenic Sa

Conditions in Which the Serum ALP Conditions in Which the Serum ALP is is

Tissue distribution:

KidneyPancreasLiverProstrate

Ref.values: 3-35 U/L

GLUTAMYL TRANSFERASE (GGT)

GGT

GGTGGT

GGT3-30 U/L

> 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)

GLUTAMYL TRANSFERASE (GGT)

Increased Activity:Application:

Detecting Alcoholic Liver Ds

Liver metastasis in anicteric patient

Chronic obstruction of bile duct

Composed of :AlbuminGlobulins (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

Total serum protein

Functions:Major osmotically active component of vascular systemTransport protein( e.g. for bilirubin & thyroid hormone)

Synthesized by liver at 120 mg/kg/day

PROTEINS IN LIVER FUNCTIONALBUMIN

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

Heme Globin

Iron Protoporhyrin

Biliverdin

Liver

Recycled into new rbc’s

Unconjugatedbilirubin

Albumin

RESSenescent

rbc’s Amino acid pool

RES

+Heme oxygenase

Bilirubin reductase

+

Albumin

2%-5% renal excretion

Bilirubin glucoronide

Urobilinogen

Unconjugated bilirubin

Urobilin (fecal pigment)

Small intestine

20% reabosrobedIntestinal bacteria

Alkal;ine pH + β-glucoronidase

BileBilirubin uridine diphosphate

Glucoronyl transferase

BILIRUBIN METABOLISM

DISORDERS OF BILE PIGMENT METABOLISMReference 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.

JAUNDICE/ICTERUS

Bilirubin deposition in sclera and in skin

> 2.5 mg/dL (43 umol/L)

DISORDERS OF BILE PIGMENT METABOLISM

Impaired Bili Conjugation Physiologic jaundice of

NB Breast milk jaundice Genetic Def. Of bili UGT

(Criggler-Najar) Gilbert syndrome Diffuse Hepatocelular

Ds

UnconjugatedExcess Bilirubin Prodxn

Hemolytic AnemiaResorption of blood from internal hgeIneffective erythropoiesis(e.g.pernicious An,

thalassemia

Hepatic uptake Drug interference Some cases of Gilbert

syndrome

DISORDERS OF BILE PIGMENT DISORDERS OF BILE PIGMENT METABMETAB

(HYPERBILIRUBINEMIA)(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

DISORDERS OF BILE PIGMENT DISORDERS OF BILE PIGMENT METABMETAB

(HYPERBILIRUBINEMIA)(HYPERBILIRUBINEMIA)

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

CONDITION AST ALT

LD ALP TP

ALB BIL NH4

1 H H H H N N H N 2 N N N N-

slH

L L H H

3 N N N H N N N-H

N

4 N or

HN or H

H H N N N-H

N

5 sl H sl H

sl H

N-sl H

N N N-SlH

N

6 Very

HH H H L L H H

6 Fundamental Patterns of Liver Function 6 Fundamental Patterns of Liver Function TestsTests

The end

Good clinical history Complete P.E.