Liver Function T est

Dr.Badhrinath J.

What ??

• No test can accurately assess Liver’s total functional capacity

• LFT, preferably called as Liver Biochemical tests• Distinguish Liver Disorders• Severity and progression of Liver disease• Monitoring the therapy.

• Battery of tests used for evaluation and Management of patients with Liver Disorders

Hepatic Lobule

Lobule of Liver

Lobule

Cell Types• Parenchymal Cells

• Hepatocytes• Cytoplasmic = LDH, AST, ALT• Mitochondrial = ASTm

• Canalicular = ALP, GGT

• Bile Duct Epithelial Cells- active role in the secretion and absorption of biliary components and regulation of the extracellular matrix composition

Cell Types• Sinusoidal Cells

• Hepatic Sinusoidal Endothelial Cells- (secrete PGs,IL-1,IL-6,TNF-α,Endothelin)

• Kupffer Cells (Specialised Macrophages,removal toxic ,foreign substances in portal blood)

• Peri-Sinusoidal Cells• Hepatic Stellate Cells (Vit A storage, Hepatic

Fibrosis)• Pit Cells(NK cells of liver,Tumour Cell killing

activity,removal of virus infected cells,growth&diff, Liver Graft Rejection)

Functions of Liver

• Metabolic Functions

• Excretory Functions

• Protective functions & detoxification

• Hematological and synthetic functions

• Storage functions

• Serum enzymes

The Function of Liver

1. Metabolic Functions

Liver actively participates in carbohydrate metabolism, lipid, protein, mineral and vitamin metabolisms.

2. Excretory Functions

Bile pigments, bile salts and cholesterol are excreted in bile into intestine.

3. Protective functions & detoxification

Kupffer cells of liver perform phagocytosis to eliminate foreign compounds. For example ammonia is detoxified to urea and metabolism of xenobiotics (detoxification).

Clearance of hormones such as insulin, parathyroid hormone, oestrogen, cortisol

4. Hematological and synthetic functions

Liver participates in formation of blood (particularly in embryo)

• Synthesis of plasma proteins (albumin and prothrombin), hormones e.g angiotensinogen, insulin-like growth factor and triiodothyronine.

• Destruction of erythrocytes by excreting its end products (Bilirubin)

5. Storage functions

Glycogen, vitamins A, D and B12

6. Serum enzymes

Acting as markers of liver damage

Test to assess liver function

•Liver function tests(LFT) are helpful to detect the abnormalities and extent of liver damage.

•Typically the LFT comprises of:•Synthetic Functions

• Albumin• Prothrombin Time

• Liver Injury• Transaminases – AST & ALT • Alkaline PO4ase

• Bilirubin, usually fractionated• Gamma Glutamyl Transpeptidase (GGT)

Bilirubin• Bilirubin is a breakdown product of heme

(ferroprotoporphyrin IX)

• Bilirubin formed in the reticuloendothelium is lipid soluble and virtually insoluble in water.

• Transported to liver by binding to albumin.

• After conjugation in hepatocytes, excreted via bile.

Bilirubin

• Elevated Total serum bilirubin correlates with poor outcomes in alcoholic hepatitis -- a critical component of the model for end-stage liver disease (MELD) score

• The presence of conjunctival icterus suggests a total serum bilirubin level of at least 3.0 mg/dL

• Tea- or cola-colored urine may indicate the presence of bilirubinuria and thus conjugated hyperbilirubinemia.

Bilirubin

• Total bilirubin: 1.0-1.5 mg/dl

• Conjugated bilirubin (Direct ; glucuronide): 0.2-0.9 mg/dl

• Unconjugated bilirubin ( Indirect; bilirubin - albumin complex): 0.8-1.2 mg/dl

Isolated Bilirubin

Transaminases• Tests of liver injury

• Hepatocytes contain high levels of enzymes that can leak into the plasma when there is liver injury

• Enzymes found in hepatocytes are:• Cytoplasmic = LDH, AST, ALT• Mitochondrial = ASTm

• Canalicular = ALP, GGT

• Below normal-chronic kidney disease on hemodialysis caused in part by vitamin B6 deficiency.

Alanine Aminotransferase (ALT)

• The test is primarily used to diagnose liver disease, to monitor the course of treatment for hepatitis, active postnecrotic cirrhosis, and the effect of drug therapy.

• The level of ALT abnormality is increased in conditions where cells of the liver have been inflamed or undergone cell death

• As the cells are damaged, the ALT leaks into the bloodstream leading to a rise in the serum levels

• Any form of hepatic cell damage can result in an elevation in the ALT

• ALT level may or may not correlate with the degree of cell death or inflammation

• ALT is the most sensitive marker for liver cell damage. ALT differentiates between hemolytic jaundice and jaundice due to liver disease.

Alanine Aminotransferase (ALT)

• serum glutamic-pyruvic transaminase (SGPT)

• Increased ALT levels are found in the following conditions:

- Hepatocellular disease

- Active cirrhosis (mild increase)

- Metastatic liver tumor

- Obstructive jaundice or billiary obstruction (mild to moderate increase)

- viral, infectious or toxic hepatitis (30-50x normal)

Aspartate Aminotransferase (AST)• serum glutamic oxaloacetic transaminase (SGOT).

• Also reflects damage to the hepatic cell

• It is less specific for liver disease

• It may be elevated and other conditions such as a myocardial infarct and muscle disease

• Although AST is not a specific for liver as the ALT, ratios between ALT and AST are useful to physicians in assessing the aetiology of liver enzyme abnormalities

• Viral heptitis, mononucleosis, and acute hepatotoxicity typically show elevations in ALT that are equal to or greater than AST elevations (AST/ALT less than or equal to 1.0)

• ALT is elevated to a lesser degree than AST in alcoholic liver disease and cirrhosis, passive congestion, bile duct obstruction, or metastatic tumor to the liver (AST/ALT greater than 1.0)

Asymptomatic Transaminases

Alkaline Phosphatase

• The primary value of an elevated serum level of alkaline phosphatase of liver -recognition of cholestatic disorders.

• 4 fold elevation of serum ALP -approximately 75% of patients with chronic cholestasis, both intrahepatic or extrahepatic

Alkaline Phosphatase• Source: liver, bone, placenta and intestine.• ↑ ALP activity in liver disease are the result of increased

synthesis of the enzymes by cells lining the bile canaliculli, usually in response to cholestasis (intra or extra-hepatic).

• Also in infiltrative diseases of liver, when space occupying ↑lesions (e.g tumours) are present.

• Growing bones need ALP.• ↑ serum ALP by osteoblast-rapid growth of bone (growth,

healing of fracture, bone cancer, Paget’s disease,rickets).• For pregnant women, ALP is produce by the placenta.• ALP from the intestine is increased in a person with

inflammatory bowel disease such as ulcerative colitis.

Approach on ALP

Isolated ALP Cholstatic enzymes

Gamma Glutamyl Transferase (GGT)

Enzyme• GGT is used by the body to synthesize glutathione tri peptide

• GGT is present in liver, kidney, pancreas, intestinal cells and prostrate glands

• Elevated levels (> 10 - 30 IU/l) are observed in :

chronic alcoholism, pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease and in diabetes mellitus

• In liver diseases, GGT elevation parallels that of ALP

• In alcoholic liver disease GGT levels may be parallel to alcohol intake

Albumin•Albumin

• Most abundant protein in serum [ 300-500g]• ↓albumin

• Impaired synthesis (malnutrition, malabsorption, hepatic dysfunction, cirrhosis)

• Loss (ascites, protein losing-nephropathy, enteropathy)

• May result in peripheral oedema/unreliable in ascites• ↑albumin

• Unusual – can occur in dehydration or as artifact fm tourniquet use

Albumin• Unreliable as a marker of hepatic synthetic function in acute

liver injury due to long serum half life 14-21 days

• Serum albumin levels less than 3 g/dL in a patient with newly diagnosed hepatitis should raise suspicion of a chronic process

• Serum albumin is an excellent marker of hepatic synthetic function in patients with chronic liver disease and cirrhosis

Prothrombin Time• Measure of the rate at which prothrombin is

converted to thrombin, reflecting the extrinsic pathway of coagulation.

• Synthesis of prothrombin Factor- II,V, VII, X.

• Factor VII-shortest serum half-life 6hrs

• Most useful in diagnosis of acute liver disease

• PT INR is useful for monitoring oral anti-coag therapy Warfarin, not very useful for liver disease

• Causes of prolonged P.T• hepatic dysfunction,• congenital deficiency of clotting factors, • vitamin K deficiency (vitamin K is required for normal

functioning of factors II, VII, IX, and X)• disseminated intravascular coagulation (DIC).

• DIC identified by measuring a factor VIII level in serum.

• Vitamin K deficiency -subcutaneous administration of vit K (e.g., 10 mg) leads to improvement in P.T by 30%.

Ceruloplasmin• Cu containing enzyme (ferroxidase) in serum

• ↓ in Wilson’s d/s

• Associated with chronic hepatitis (occ acute) and

may have neurologic/ psychiatric sequelae

α -Fetoprotein• One of the major plasma proteins in foetal life

• Function not known, similar structure to albumin

• Falls thru-out gestation (~10,000 ng/mL at birth) and by age one yr (<10 ng/mL – adult levels)

• In acute hepatic injury AFP ↑ 10 – 20X upper ref limits

• Abt 10% pt with viral hepatitis have ↑ AFP

• Fibrosis post chronic liver d/s, AFP ↑

• Used to screen and diagnose HCC & hepatoblastoma

TESTS TO DETECT HEPATIC FIBROSIS

• liver biopsy is the standard for the assessment of hepatic fibrosis.

• noninvasive measures of hepatic fibrosis have been developed.

• measures include single serum biochemical markers and multiparameter tests aimed at detecting and staging the degree of hepatic fibrosis.

• hyaluronan is the best to date

Hyaluronan• Hyaluronan is a glucosaminoglycan produced in

mesenchymal cells .

• Typically degraded by hepatic sinusoidal cells,

• serum levels of hyaluronan are elevated in patients with cirrhosis as a result of sinusoidal capillarization .

• A fasting hyaluronan level greater than 100 mg/L had a sensitivity of 83% and specificity of 78% for the detection of cirrhosis.

• useful for identifying advanced fibrosis in patients with chronic hepatitis C, chronic hepatitis B, ALD, and NASH

QUANTITATIVE LIVER FUNCTION TESTS

• Evaluate the excretory or detoxification capacity of the liver more specifically than the serum bilirubin level.

• lack of specificity and often cumbersome methodology have limited their widespread acceptance

• Indocyanine green (ICG)

• galactose elimination capacity

• Caffeine clearance tests

• Lidocaine metabolite formation

• 14C and 13C aminopyrine breath tests

Take home message• initial evaluation : assess in clinical context

• classified in 3 groups1. synthetic function : albumin, clotting

time2. cholestasis : bilirubin, ALP, GGT3. hepatocyte injury : AST, ALT

LIVER BIOCHEMICAL TESTING

• Liver biochemical tests have been used to • monitor for and assess the severity of drug-

induced liver injury,• assess operative risk, • identify candidates for liver transplantation,• direct donor organ allocation. • Post-op Graft Rejection

Thank you