The liver

Presented by

Dr. Mohammad Saadeh

The requirements for the Clinical Chemistry

Philadelphia University

Faculty of pharmacy

Introduction

The liver is the largest organ in the body.

The liver is of vital importance in intermediary metabolism and in the

detoxification and elimination of toxic substance.

Introduction

Structure of liver:

1. 60% hepatocytes

2.30% kupffer cell (reticuloendothelial )

3.10% Supporting tissue

The liver performs an astonishingly

large number of tasks that impact all

body systems.

Liver have two channels that can

supply and oxygen nutriment :

hepatic artery and hepatic portal

vein .

The corresponding channels is

hepatic vein and bile ducts.

Functions of liver

① Excretory function: bile pigments, bile salts and cholesterol are

excreted in bile into intestine.

② Metabolic function: liver actively participates in carbohydrate,

lipid, protein, mineral and vitamin metabolisms.

③ Hematological function: liver is also produces clotting factors like

factor V, VII. Fibrinogen involved in blood coagulation is also

synthesized in liver. It synthesize plasma proteins and destruction of

erythrocytes.

④ Storage functions: glycogen, vitamins A, D and B12,and trace

element iron are stored in liver.

⑤ Protective functions and detoxification: Ammonia is detoxified to

urea. kupffer cells of liver perform phagocytosis to eliminate foreign

compounds. Liver is responsible for the metabolism of xenobiotic.

Liver function tests (LFTs)

Liver function tests (LFTs or LFs) are groups of blood tests that give

information about the state of a patient's liver and can contribute to making an

accurate diagnosis of the specific liver disorder.

LFTs are divided into:

true tests of liver function,

such as serum albumin, bilirubin, and Prothrombin time.

tests that are indicators of liver injury or biliary tract disease.

Typically the LFT comprises of:

1. Total protein.

2. Albumin and globulin.

3. (Prothrombin Time).

4. Transaminases such as AST & ALT.

5. Alkaline phosphatase.

6. Bilirubin.

7. Gamma Glutamyl Transpeptidase (GGT).

Liver function tests

Most common live disease:

Hepatitis: acute or chronic damage to and destruction of

liver.

Cirrhosis: fibrosis, shrinkage liver, decrease number and

function of hepatocellular.

Jaundice: high plasma concentration of bilirubin.

Cholestasis is defined as a decrease in bile flow due to

impaired secretion by hepatocytes or to obstruction of bile

flow through intra-or extrahepatic bile ducts.

Note: Obstruction bile duct may cause jaundice or cirrhosis.

Liver function tests

These biochemical investigation can assist in differentiating the

following:

Obstruction to the biliary tract.

Acute hepatocellular damage.

Chronic liver disease.

Liver cancer.

Classification of liver functions test

Classified based on the major functions of liver:

① Excretion: Measurement of bile pigments, bile salts.

② Serum enzymes: Transaminase (ALT, AST), alkaline phosphate (ALP),

5’-nucleotidase, LDH isoenzyme.

③ Synthetic function: Prothrombin time, serum albumin.

④ Metabolic capacity: Galactose tolerance and antipyrine clearance

⑤ Detoxification : urea.

1. Excretion : Bilirubin

• Bilirubin is the main bile pigment that is formed from the

breakdown of heme in red blood cells. The broken down

heme travels to the liver, where it is secreted into the bile by

the liver.

• Effective bilirubin conjugation and excretion depend on

hepatobiliary function and on the rate of RBC turnover.

1. Serum bilirubin:

Small amount of bilirubin circulates in the blood. Serum

bilirubin is considered a true test of liver function, as it

reflects the liver's ability to take up, process, and secrete

bilirubin into the bile.

Bilirubin metabolism serum bilirubin levels are reported as

1. Total bilirubin (conjugated and unconjugated) (normal value

= 0.3-1.2 mg/dl).

2. Direct bilirubin (conjugated bilirubin) (normal value ≤ 0.4

mg/dl), filtrated by glomerulurs.

Bilirubin is released by Hb breakdown and is bound to

albumin as water-insoluble indirect bilirubin (unconjugated

bilirubin), which is not filtrated by glomerulurs.

Unconjugated bilirubin travels to the liver, where it is

separated from albumin, conjugated with monoglucuronide

(25%) and diglucuronide (75%) (more water soluble), and

then actively secreted into bile as conjugated bilirubin (direct

bilirubin), which is filtrated by Glomerulurs.

Figure in the next slide

Bilirubin metabolism

indirect

bilirubin

direct

bilirubin

Binding with Glucuronic acid no yes

Reacting with the diazo reagent

Slow and indirect

Rapid and direct

solubility in water small large

Discharged via kidney no yes

Pass through the

membrane of cell yes no

Difference of two bilirubins

A. urobilinogen :

Conjugated bilirubin is excreted via bile salts to intestine. Bacteria in

the intestine break down bilirubin to urobilinogen for excretion in the

feces (normal value for fecal urobilinogen = 40 - 280 mg/day)

2. urine(/faeces)

Normally there are mere traces of urobilinogen in the urine. average

is 0.64mg , maximum normal 4mg/24 hours.

B. Urobilin

Urobilin is the final product of oxidation of urobilinogen by oxygen in

air. The amount change with the amount of urobilinogen excretion .

B. bilirubinurine:

Bilirubin is not normally present in urine and faese since bacteria in

intestine reduce it to urobilinogen.

The kidneys do not filter unconjugated bilirubin because of its avid

binding to albumin. (bilirubin-albumin complex is too large)

conjugated bilirubin can pass through glomerular filter.

Bilirubin is found in the urine in obstructive jaundice due to various

causes and in cholestasis.

Note:

Bilirubin in the urine may be detected even before clinical

jaundice is noted.

Who is a candidate for the test?

Bilirubin is used to diagnosis of jaundice.

There are three major causes of increased serum bilirubin

1. Hemolytic Jaundice, increases total bilirubin; direct bilirubin

(conjugated) is usually normal. Urine color is normal, and no

bilirubin found in urine.

2. Hepatic Jaundice, occur in viral hepatitis; may cause an

increase in both direct and indirect bilirubin. Urine color is dark,

and bilirubin is present in the urine.

3. Obstructive jaundice ( Cholestasis), may be intrahepatic or

extrahepatic, increase direct and indirect bilirubin. Urine color is

dark, and bilirubin is present in the urine.

Who is a candidate for the test? Bilirubin is used to diagnosis of jaundice.

Abnormal bilirubin levels can be found in many disorders, including:

blocked bile ducts

Cirrhosis

hepatitis

liver diseases

immature liver development in newborns.

Liver function tests

2. Serum enzymes

Examples:

Increase (total bilirubin and ALP) OR (ALP and GGT) are indices of

cholestasis (blockage of bile flow). vvi

Increase ALT and AST measure the integrity of liver cells. vvi

Albumin and Prothrombin time measure the liver synthetic capacity.

Standard group of test Property being assessed

Serum albumin, PT Protein synthesis

Serum bilirubin (total) Hepatic anion transport

Serum enzyme activity

ALT, AST Hepatocellular integrity

ALT, GGT Presence of cholestasis

Liver function tests

2. Serum enzymes

Alkaline phosphatase (ALP or GPT) (remember)

Clinical significance:

diagnosis of two groups of conditions; increase in hepatobiliary disease

(obstructive jaundice, cirrhosis, hepatitis and metastic) and bone disease

associated with increased osteoblastic activity (child's rickets with D vitamin

deficiency, Paget's disease, hyperparathyroidism with skeletal).

extraheptic biliary obstruction; example

• Stone in bile duct.

• Intrahepatic cholestasis.

• Biliary cirrhosis.

ALP Physiologically increase in; Pregnancy, Childhood, Fatty meals.

Liver function tests; 2. Serum enzymes γ-Glutamyl transferase (GGT): levels are elevated in:(remember)

Cholestasis

liver diseases such as alcoholic cirrhosis and drug such as phenytoin.

5' nucleotidase (5'NTD):(hydrolysis of a nucleotide into a nucleoside and a phosphate)

5' Nucleotidase (5'NTD) is another test specific for cholestasis or damage to

the intra- or extrahepatic biliary system

Elevated ALP and GGT or 5'NTD suggest that the liver is the source.

Aminotrasferases (remember)

1. AST (GOT) increased in

myocardial infarction.

Acute hepatitis (cell damage) Hepatobiliary diseases such as cirrhosis.

2. ALT (GPT) levels are elevated in:

liver diseases such as Acute hepatitis (cell damage), cirrhosis.

ALT is considered more liver-specific than AST.

increase level of calcium in plasma) multiple myeloma or leukemia, bone

disease, osteoporosis and Paget's disease.

normally: GPT or ALT is normal, AST or GOT is normal, GPT/GOT is

about 1.15.

Virus hepatitis: GPT↑, GOT is normal ,GPT/GOT＞1, even more

than 2.5.

chronic hepatitis : GPT↑ ,GOT ↑, GPT/GOT is about 1.

Liver cancer, cirrhosis, Alcohol-induced hepatitis: GPT↑ ,GOT ↑

GPT/GOT < 1, about 0.6~0.7.

Accute myocardial infarct : GPT/GOT < 1

Although AST=GOT is not a specific for liver as the ALT=GPT,

ratios between GPT and GOT are useful to physicians in assessing the

etiology of liver enzyme abnormalities.

Liver function tests

2. Serum enzymes

GPT and GOT is in the different distribution of the hepatocytes. GPT

exists primarily in the cytoplasm of liver cell. if there is a slight liver

cell damage, GPT firstly leak into the bloodstream, so that the serum

GPT increased.

The GOT mainly in the "mitochondria“ of liver cells, the

mitochondria are "bubble" in the liver cell cytoplasm. if there is a

slight liver cell damage, GOT don`t leak into the bloodstream.

When the GOT was significantly higher, mitochondria of liver cells are injuries.

Liver function tests 2. Serum enzymes

Lactate dehydrogenase (LDH) is an enzyme found in nearly all living

cells.

Increased levels of LD4 and LDH-5 in liver disease and skeletal muscle.

Example: jaundice and metastatic carcinoma, viral hepatitis.

Liver function tests 2. Synthetic function (plasma proteins)

Albumin (Alb) (normal value=4-6 g/dl)

Clinical significance:

Decrease serum level of albumin in:

Function: Maintains serum oncotic pressure.

Serve as transport agent.

Primarily manufactured by the liver so, liver disease can decrease

albumin levels.

globulins

Function as transport agents and play a role in certain immunological

mechanisms.

present, in early stage rise in β –globulins (transferrin, LDL, C3)

and in later stages γ-globulins (antibodies) shows rise.

Liver function tests 2. Synthetic function (plasma proteins) Prothrombin time (PT)

Prothrombin is a protein made by the liver. Prothrombin helps blood to

make normal clots.

Imcrease "prothrombin time" (PT) in liver disease.

Why?

The "prothrombin time" (PT) is one way of measuring how long it takes

blood to form a clot, and it is measured in seconds (such as 13.2

seconds). A normal PT indicates that a normal amount of blood-clotting

protein is available.

Disruption of bile flow results in inadequate absorption of vitamin K

from intestinal.

Good indicator of intrahepatic disease due to extra-hepatic

obstruction.