EVALUATION OF LIVER FUNCTION

TESTSGuide - Dr. Manohar Lal Prasad Presenter - Dr. Dhiraj Kumar

Source - Harrison’s principles of internal medicine 19th edition.Sleisenger and Fortrans textbook of gastrointestinal and liver disease.

LIVER FUNCTION TEST USED TO:

Detect presence of liver disesase

To know the extent of known liver diseases

Distinguish among different types of liver diseases

Follow the response to treatment

Liver function tests

Can be normal in pt. with serious liver diseases

Rarely suggests specific

diagnosis rather suggest

general categories of liver disease

Hepatocellular

Cholestatic , or infiltrative

They detect –liver cell damge,

interference with bile flow

Functions of liver

Metabolic functions

Excretory functions

Synthetic functions

Storage functions

Detoxification functions

Tests based on detoxification function:

Blood ammonia level

Tests based on excretory functions:

Sr. bilirubin Urine bilirubin

Urine and fecal

urobilinogen

Urine bile salts

Tests based on synthetic functions:

Plasma protein Prothrombin time

Tests based on metabolic functionsCarbohydrate metabolism• G

alactose tolerance test

Lipid metabolism• Sr

Cholesterol

Protein metabolism• S

r Protein

• Aminoaciduria

Enzymes in diagnosis of liver diseses

ENZYMES

•AST(SGOT)•ALT(SGPT)

ENZYMES•ALP•GGT•5’NT

Tests used in clinical practice

Sr . Bilirubin ALT(SGPT)

AST(SGOT) Alkaline phosphatase

Serum Albumin

Prothrombin time

Sr. Bilirubin• Breakdown product of porphyrin ring of heme containing

protein( myoglobin, cytochrome, peroxidase)• Two fractions:• Conjugated(Direct)(water soluble)(excreted by kidney)• Unconjugated (indirect)(water insoluble) (bound to

albumin)• Normal value- 1- 1.5mg/dl• In case of hyperbilirubinemia, if direct fraction <15% -

Unconjugated hyperbilirubinemia• Direct fraction- Upper limit of normal range is 0.3mg/dl

CAUSES OF HYPERBILIRUBINEMIA Isolated increase in unconjugated bilirubin is due to –1. Hemolytic disease2. Genetic disorders – crigler najjar and gilbert’s syndrome3. Neonatal jaundice/physiological jaundice

Isolated increase in conjugated bilirubin is due to –4. Cholestasis5. Genetic disorders – Dubin johnson syndrome and rotor’s

syndrome

Increase in both conjugated and unconjugated bilirubin is due to –

1. Intrahepatic /liver disorders

Degree of elevation of Sr bilirubin significant in:

Viral hepatitis

Alcoholic hepatitis

Drug induced liver disease

Model for End Stage Liver Disease(MELD) Score

• Criteria for listing a pt. for liver transplantation• Range of MELD score is 6 to 40• Liver tansplantation done in those pt who

have >15 MELD score• MELD score – bilirubin, creatinine, PT as INR• MELD score >= 21 high mortality in alcoholic

hepatitis

Urine Bilirubin:

Any bilirubin in urine- Conjugated bilirubin

Unconjugated fraction is water insoluble and albumin bound, hence not filtered

Phenothiazine give false positive

Recovering from jaundice urine bilirubin clears prior to Sr bilirubin

Bile salts:

• Are products of cholesterol metabolism• Facilitate absorption of fat from intestine• Primary bile salts- cholate & chenodeoxycholate,

produced in liver

• Metabolised by bacteria in intestine

• Produces secondary bile salts-lithocholate & deoxycholate

Bile salts

In cirrhosis- decreased ratio of primary to secondary bile salts

In cholestasis - secondary bile salts not formed – increased ratio of primary to secondary bile salts

Normally renal excretion of bile salt is negligible

Cholestasis increase renal excretion of bile salt

Measured by- Hay’s test, HPLC

BLOOD AMMONIA:Detoxification of ammonia

In liver – get converted to urea-excreted in kidney

In striated muscles- combines with glutamine – glutamic acid

Advanced liver disease •Significant muscle wasting•Contributes to hyperammonemia

Increased blood ammonia •Detect occult liver disease with mental status change

Increased blood ammonia •In severe portal hypertension•Portal blood shunts around liver

Increased arterial ammonia •Correlates with fulminant hepatic failure outcome

ENZYMES IN LIVER DISEASES

• Sr transaminases• Aspartate

aminotransferases (AST)(SGOT)

• Alanine aminotransferases (ALT)(SGPT)

• Alkaline phosphatase(ALP)• Gamma glutamyl

transpeptidase(GGT)• 5’ Nucleotidase(5’NT)

Sr enzyme test grouped in two categories:

Enzymes whose elevation reflect damage to hepatocytes

Enzyme whose elevation reflect cholestasis

Enzyme showing infiltrative pattern

Enzymes that reflect damage to hepatocytes:

Aspartate aminotransfersase(AST)(SGOT)

Alanine aminotransferases(ALT)(SGPT)

AST(SGPT) is found in liver > cardiac muscles > skeletal muscles> kidney> brain >pancreas> lungs> WBC >RBC

ALT(SGPT) is found primarily in liver.( more liver specific)

Normal range is 10-40 IU/L

• Sr aminotransferases upto 300 IU/L are non specific

• Minimal ALT elevation Fatty liver disease• If levels >1000 IU/L reflects extensive

hepatocellular injury seen in:1. Viral hepatitis2. Ischemic liver injury( prolonged hypotension

or acute heart failure3. Toxin/drug induced liver injuryIn most acute hepatocellular disorder ALT >=AST

AST/ALT Ratio:• Normal ratio 0.7 to 1.4• Useful in 1. Wilson disease 2. Chronic liver disease 3. Alcoholic liver disease• AST/ALT <1 seen in 1.Chronic viral hepatitis 2.NAFLD • AST/ALT >2:1 suggestive & 3:1 is highly suggestive of alcoholic

liver disease• In alcoholic liver disease : ALT rarely >300 & ALT often

normal( alcohol induced deficiency of PYRIDOXAL PHOSPHATE)

Aminotransf-erases

not increased

in obstructive jaundice

except

During the

acute phase

of biliary

obstruction

Due to passage of gall

stone into CBD

In this aminotran-sferases

1000-2000 IU/L

AST(SGOT)

• 2 forms 1. Cytosolic 2. Mitochondrial (mAST) – synthesized in precursor

form( pre-mAST)

converted to mature form• Account for 80% of total AST activity in liver cells• mAST/ total AST ratio- marker of chronic alcohol

consumption

• Isolated rise of ALT is seen in1. Chronic HepC infection2. Fatty liver• Isolated AST elevation1. Alcohol related 2. Drug induced liver injury3. Hemolysis4. Myopathic processesThese enzymes distinguish hepatocellular from cholestatic

jaundice• Increase in ALT and AST (>500 IU/L) in hepatocellular

jaundice than in cholestatic jaundice(>200 IU/L)• Persistence of elevated AST & ALT beyond 6 month in

case of hepatitis – chronic hepatitis

Enzymes showing cholestasis:• 3 enzymes are elevation in cholestasis 1. Alkaline phosphatase(ALP)2. 5’Nucleotidase(5’NT)3. Gamma glutamyl transpeptidases(GGT)

ALP & 5’NT – in or near bile canalicular membrane of hepatocytes

GGT located in ER & bile duct epithelial cells(less specific for cholestasis)

GGT (sometimes) used to identify occult alcohol use

• ALP isoenzyme is found in 1. Liver 2. Bone 3.Placenta 4. Small intestine• Physiological rise in ALP 1. Age >60 years ( 1-1.5 times)2. Blood type O & B (after eating a fatty meal

due to influx of intestinal ALP in blood)3. Children and adolescents ( rapid bone growth)4. Late in normal pregnancies( placental ALP)

• ALP < 3 times – any liver disease• ALP> 4 times 1. Cholestatic liver disease 2. Infiltrative liver disease(cancer & amyloidosis) 3. Pagets disease of bone( rapid bone turnover)If ALP is raised – source of isoenzyme by:1. Fractionation of ALP by electrophoresis2. Measure GGT &5’NT –elevated only in liver disease3. Different isoenzymes have different heat susceptibilityi. Increased heat stable fraction – MC from placentaii. Sensitive to heat inactivation- Bone ALP

Normal levels

Sr GGT 10 to 47 IU/L

Sr 5’ NT 2 to 17 IU/L

Sr ALP 39 to 117IU/L

Tests based on Biosynthetic function

Plasma proteins

Coagulation factors(Prothrombin time P.T.)

Plasma proteins• Liver is the sole source of plasma proteins except for

immunoglobulins( by plasma cells)• Sr albumin comprises 60% of all plasma proteins• Tests of plasma protein include:1. Total Sr protein2. Sr albumin 3. Sr globulin4. Sr A/G ratio5. Pre albumin6. Pro collagen III peptide 7. Ceruloplasmin

Albumin• Synthesized exclusively by hepatocytes• Long half life 18 – 20 days; 4% is degraded per day• Slow turn over – not a good indicator of acute or mild hepatic

dysfunction• In hepatitis , albumin < 3 mg/dl – Chronic liver disease like

cirrhosis, reflects liver damage and decreased albumin synthesis• Non hepatic cause of low albumin:1. Protein malnutrition2. Protein losing enteropathy3. Nephrotic syndrome4. Chronic infection(increased levels of IL-1, TNF, Cytokines- inhibit

albumin synthesis

Sr Globulin

• Made of alpha, beta , gamma globulin• Alpha & beta globulin produced primarily in hepatocytes• Gamma globulin produced by B lymphocytes• In Cirrhosis and Chronic hepatitis – gamma globulin is

increased ( Cirrhotic liver fails to clear bacterial antigen from intestine which come through hepatic circulation)

• Diffuse polyclonal IgG – Auto immune hepatitis• Increased IgM – Primary biliary cirrhosis• Increased IgA- Alcoholic liver disease

• Pre Albumin1. Level falls in liver diseases2. Half life 2 days3. Sensitive indicator of change in synthetic & catabolic function4. Useful in drug induced hepato toxicity• Ceruloplasmin 1. Acute phase protein2. Normal plasma level 0.2 – 0.4g/l• Decreased in Increased in 1. Wilson disease 1.Copper toxicity2. Menke’s disease 2. Pregnancy3. Aceruloplasminemia 3. OCPs4. Copper deficiency

Pro collagen III peptide

• Cleavage product of type III procollagen molecule• Radioimmuno assay• Increased when there is transformation of viable

hepatic tissue into connective tissue / fibrosis• Used in evolution of liver disease like:1. Chronic active hepatitis2. Liver fibrosis 3. Liver cirrhosis

Coagulation factors• Except factor VIII, clotting factors synthesized in

liver• Half life ranges 6 hrs( factor VII) to 5 days

(fibrinogen)• Measurement is single best measure of hepatic

synthetic function• Diagnosis and prognosis of acute parenchymal liver

diseases• Test – Prothrombin time(PT)• PT measures II, VII, IX, X activity - Vit K dependent

PT & INR• INR- Degree of anti coagulation on warfarin therpy• International Sensitivity index(ISI): INR standardise PT

measured according to thromboplastin reagent used in any lab expressed as ISI.

• ISI is used to calculate INR• PT is increased in 1. Hepatitis2. Cirrhosis3. Vit k deficiency- obstructive jaundice, fat malabsorption4. If PT > 5 times , not corrected by parenteral Vit k - poor

prognostic sign in acute viral hepatitis & other liver diseaseINR is part of MELD Score

LFT in Anti TB treatment• LFT should be preferred before starting anti TB treatment• With use of rifampicin & isoniazid , onset of liver damage

may be as soon as 10 days or may be upto 1yr after commencing therapy

• So LFT should be repeated routinely• High risk groups are –1. Malnourished 2. Children and elderly3. Known liver disease - Alcoholic liver disease - Hepatitis B &C

Percutaneous liver biopsyCan be performed bedside with LADone in• Hepatocellular disease of uncertain cause• Prolonged hepatitis with possibility of auto immune hepatitis• Unexplained hepatitis• Fever of known origin• Staging of malignant lymphomaContradiction of percutaneous liver biopsy• Significant ascites• Prolonged INRIn these conditions transjugular approach is done.

Transient Elastography (FibroScan)

• Ultra sound waves to measure hepatic stiffness non invasively

• Useful for early fibrosis in1. Chronic Hep C2. Primary Biliary Cirrhosis3. Hemochromatosis4. NAFLD5. Recurent chronic hepatitis after liver

transplantation

Evaluation of chronically abnormal liver tests