Liver Dr. Abdulrahman Al-Ajlan

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Liver is the largest internal organ in the body. It consists of two main lobes divided into right and left by the hepatic vein that together weigh from 1400 to 1600g in the normal adult.

The Liver

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The liver is complex organ, located in the upper right corner of the abdomen. The liver received approximately 15 ml of blood per minute from two major vessels:

* The hepatic artery supplies 25% of the total blood flow and provides most of the oxygen requirement.

* The portal vein drains most of the gastrointestinal tract (GI). It supplies 75% of the blood flow and transports the most recently absorbed material from the intestines to the liver.

Location:

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The liver is a vital organ, which has many vital roles.

The liver plays a major role in protein, carbohydrate and lipid homeostasis.

The liver stores glycogen, vitamins and iron.

It contains an extensive reticuloendothelial system for the synthesis and breakdown of blood cells.

Liver cells metabolize, detoxify and excrete both endogenous and exogenous compounds.

(Metabolism and execration of drugs and toxins)

Liver function

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A request for LFTs will provide results for Bilirubin, the aminotransferases and alkaline phosphatase in serum specimen.

Bilirubin: Bilirubin is composed of four pyrrole rings joined by methyl bridges and it’s the principal pigment in bile, which is derived from breakdown of Hb.

About 80 % of the Bilirubin formed daily comes from the degradation of Hb, whereas the remainder comes from the destruction of heme containing proteins (myglobin, cytochromes , catalase).

Liver Function Tests (LFTs)

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Iron

(Reused for synthesis of Hb, myoglobin ,

enzyme , stored in liver , bone marrow)

Hemoglobin

Protein (globin)

Is reused

Porphyrrin

(Is not recycle)

Bilirubin (Slightly soluble in plasma and is transported to the liver binding to

albumin)

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BloodBilirubin –

albumin complex

In the liver

Albumin

Bilirubin diglucuronide

Bilirubin monoglucuronide

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It is a yellow discoloration of the skin or sclera, this is due increase of bilirubin con in the blood upper the normal average.Free bilirubin will accumulate in the body fat, while the conjugated bilirubin accumulate in elastic tissues such as the eyeballs, the mucous membrane of the mouth, nose and the skin of the abdomen and chest.

Jaundice is not detectable until the con of bilirubin is greater than about 40µmol/L. Normal concentration of Bilirubin in plasma is less than 22µmol/L.

Jaundice may be due to diseases of the blood, of the liver or the bile ducts or pancreas.

Jaundice:

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1- Haemolysis. Due of ◦a)-The life span of RBC is less than the normal 120 days.

◦b)-Abnormal spherical shape of RBC (hereditary spherocytosis).

◦c) -Deficiency of glu-6-P dehydrogenase. The cells are destroyed when exposed to oxidant drugs.

◦e) - Sickle cell anemia.◦All these factors increase Hb breakdown produces bilirubin which overloads the conjugating mechanism.

The main reasons make the bilirubin levels in blood may raise:

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2-Failure of conjugating mechanism within the hepatocytes.

A- Gilbert s disease There is impairment in the ability of the liver cells to take up free bilirubin from the blood. The bilirubin levels in serum slightly high. The patient is slightly jaundiced, but all other liver function tests are normal {enzyme, etc}

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B- Najjar syndrome (deficiency of glucuronyl transferase)

The deficiency of this enzyme in infants leads to high level of free bilirubin, and there is no conjugated bilirubin. The infants become jaundiced shortly after birth.

In infant, free bilirubin is able to enter the brain (only in infants because the immature central nervous system). It is toxic to nerve cells; these children usually die within first year of live due brain damage.

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C-Physiological jaundice (jaundice in newborns)

Newborn infants (premature babies), often accumulate bilirubin because the activity of hepatic bilirubin glucuronyl transferase is low at birth and reaches about levels in about two weak, bilirubin enter the brain and causes damage of brain cells.

The new born with elevated level of bilirubin are treated with blue fluorescent light, which converts bilirubin to more polar (water soluble).

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3- Obstruction in the biliary system. Bile is excreted from the liver cells into

bile duct through canaliculi (tiny vessels or little channeles). Bile duct carries bile to the small intestine. Obstruction at any point will cause bile to back up. Some of the conjugated bilirubin is reabsorbed into the blood and jaundice results. The bile duct obstruction may be due to gallstones or a tumor.

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1-Partially block of the bile duct by gallstones.

Diagnosis: Alkaline phosphatase may be high, although serum bilirubin within the reference range.

Extrahepatic biliary obstruction

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2- Fully block of the bile duct. Diagnosis; If the blockage is complete, both bilirubin and alkaline phosphatase are raised.

The degree of obstruction reflected by the levels of alkaline phosphate.

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B. Intrahepatic biliary obstruction:

The bile canaliculi become blocked due cirrhosis, liver cancer or infection.

Diagnosis;It is lead to increase con of conjugated bilirubin in serum.

4- Diseases of the liver. Any disease that damages or destroys a large number of liver cells lead to decrease the capacity of the liver to covert free bilirubin to bilirubin glucuronide and jaundice will results.

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Glutamic Oxalacetic Transaminase (sGOT) or Aspartate Aminotransferase (AST)

Glutamic Pyruvic Transaminase (GPT) or Alanine Transaminase (ALT).

Alkaline Phosphatase (ALP) Gama Glutamyl Transpeptidase (GGT) or γGT

 

Enzyme Tests in Liver Disease:

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Bile:  It is consists of a watery mixture of

organic and inorganic compounds. phosphatidylcholine and bile salts are the most important organic components of bile.

Bile can either pass directly from the liver into the duodenum throw the common bile duct or be stored in the gallbladder when not needed immediately for digestion

Bile is composed of bile acids or salts bile pigment (biluribin esters) cholesterol and substances extracted from the blood

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Total bile production averages about three liters per day although only one liter is extracted

The bile acids cholic acid and chenodeoxycholic cholesterol

The bile acids are conjugated with the amine acids glycine or taurine forming bile salts (conjugated bile acids) are excreted into the bile canaliculi

During fasting and between meals ,a major of the bile acids pool is concentrated up ,to fold in the gallbladder ,bile acids reach the intestines when the gallbladder contracts after each meal ,about 500 to 600 ml of bile enter the duodenum each day .it is involved with the digestion and absorption of lipids

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Bile acids:   The bile acids contain 24 carbons with two

or three hydroxyl groups and a side chain that terminates in a carboxyl group

The most common bile acids are cholic chenodeoxycholic acid .bile and acids are synthesized in the liver by multi step pathway from cholesterol

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The molecule have both a polar and a non polar face and can act as emulsifying agent in intestine helping to prepare dietary tri-acylglycerol and other complex lipids for degradation by pancreatic digestive enzyme

  Bile salt:   Chenodeoxycholic acid +taurine  

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The main functional constituent of the bile are the salts which are involved in fat digestion and absorption from the small intestine. Fat of the bile salts in the intestine. They may be reconjugated and dehydroxylated (at postion7) by intestinal bacteria. 95% of bile salts are absorbed in the ileum and return to the liver where they may be reconjugated with glycine or taurine, however they are not rehydroxylated .those that laclc the 7α -hydroxylproup are called secondary bile salts

The liver recycles 95% of the bile salts each day .5% are lost in the feces

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Transaminase enzymesTransaminase that transfer of an amino group from one amino acid to an α-keto acid. Transaminase reactions are readily reversible and can used in the syntheses or the degradation of amino acids.

Enzyme test in liver disease

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Example, glutamic oxalacetic transaminase (GOT)

aspartate aminotransferase (AST). Or aminotransferase Example of transamintaion reaction

are : Oxaloacetic +glutamate

Aspartate + α –ketoglutarate Enzyme: Aspartate

aminotransaminase (AST) witch is also known as glutamate oxaloacetate transaminase (GOT)

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GOT or AST: It is found in highest concentration in the

liver and heart muscle and also skeletetal muscle it is clinical usefulness is largely restrict to the diagnosis of disease of the liver and heart the case of liver disease, large amount of GOT may be released into the blood very high levels are observed in a cute disease while lesser elevation are seen in chronic liver disease

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In case of infection hepatitis the level of GOT increase in the first stage of the illness and very high level during the height of the disease the level of GOT remains very high throughout the period of illness

The level of GOT increase to 100 times the upper adult reference limit in the following cases

-Acute vival or toxic hepatitis -Circulatory failure with “shock” and hypoxia -Myocardial infraction In some cases such as cirrhosis cholestatic jaundice

and skeletal muscle disease after trauma or surgery such as cardiac surgery the level GOT moderate increase

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Some chemical such us chlorine containing organic compounds are toxic to the liver

Carbon tetra chloride is a hepatotoxin chloroform less toxic

All these chemicals may causes damage to the liver

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Infectious mononucleosis: It is a virus disease and it is quite common

among young adults The most characteristic feature of the disease

is (sore throat) With enlarged lymph nodes in the neck and

fever and jaundice Diagnosis.   GOT levels are elevated in 80% of the

patient .the degree of elevation is less than in infectious or toxic hepatitis

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Glutamic pyruvic transaminase GPT Alanine +glutamate alanine +α-

ketoglutamate  This enzyme transfer the amino group

of alanine into α–ketoglutarate to form Glutamic acids

ALT is present in highest concentration in the liver and to a lesser extent in kidney skeletal muscle and heart .the level of ALT in serum occurs only in disease of the liver

GPT is measured conjugated with GOT to determine the source of GOT is the liver or the heart

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In case of infection hepatitis large amount of infectious hepatitis large amount of ALT and AST are released into blood circulation especially in sever acute hepatitis

GPT (ALT) level is usually equal to or slightly highest than GOT (AST) level

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Some of the liver disease which produces ALT (GPT) is

 1/ obstructive jaundice  When the out flow of bile from the liver into

the duodenum is blocked the level of GOT and GPT are moderately increased

The level of GOT in this case are if about the same level after a myocardial infract (coronary or heart attack) so an associated rise in GPT (ALT) may help to differentiate these two conditions

Cirrhosis and other liver disease In case of cirrhosis, the level of the ALT may

be normal or up twice the upper adult reference limit .so it is elevated to a lesser extent than GOT.

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In some cases the ration of GOT / GPT is used to diagnosing the nature of the liver disease :

 In acute hepatitis the ratio is 1 or less

Cirrhosis the ratio is usually about 2-5

In case of myocardial infraction GPT (ALT) is not elevated ordinarily Abnormal

ALT level would confirm the hypothesis that an elevated GOT is due to cardiac disease.

Slightly elevation of ALT may occur if the infraction of ALT may occur if the infraction destroys a very large volume of heart muscle

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Alkaline phosphatase (ALP) ALP is present in most of tissues but is used

most often in the clinical diagnosis of bone and liver disease

ALP synthesis by cells lining the bile canaliculi

In liver disease the activity of ALP increase due to the result of increased synthesis of the enzyme by cells lining the bile canaliculi

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Alkaline phosphatase (ALP) ALP is present in most of tissues but is used

most often in the clinical diagnosis of bone and liver disease

ALP synthesis by cells lining the bile canaliculi

In liver disease the activity of ALP increase due to the result of increased synthesis of the enzyme by cells lining the bile canaliculi

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There are a very large number of enzyme which catalyze the hydrolysis of most organic phosphate monoesters

Inhibition with l-phenylalanine is also of some use in isoenzyme

Investigation intestinal and placenta alkaline phosphatase are strongly inhibited by this amino acids while bone and liver alkaline phosphatase are not .

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Since bone is a source of the enzyme bony metastases and other diseases associated with increased osteoblastic activity may produce high levels of ALP in the absence of liver disease

The enzyme is found in placenta and pregnant women also have elevated levels especially in the third trimester of pregnancy.

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Gama – glutamyl transfpeptidase (GGT) or gamma GT Function of GGT It is an enzyme which catalyze the transfer of the

gamma glutamyl group from one peptide to another or to amino acid .also the specific function of this enzyme relates to the transport of aminoacids through cell membranes (recent hypothesis)

Gamma GT occurs mainly in the cells of liver, kidney pancreas and prostate

Plasma GGT activity is highest in men that in women GGt is measured in serum Causes of raised plasma GGT activity

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Indication of enzyme synthesis without damage by drugs or alcohol anticonvulsants or phenytion.

Disease of the liver such as: Those associated with obstruction of the bile flow Obstruction of the bile flow may be due to disease

of the duct it self or of the liver cell or of adjacent organs

These include inflammation of the walls of bile duct (cholangitis)

Inflammation of the gall bladder (cholecystitis ) Precipitation of bile within the smallest duct

(cholestasis) in case of vival hepatitis. In case of gall stones witch is blocked in large

duct (due to precipitated by cholesterol or bilirubin)

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Tumors with or outside liver, which compress and block the duct (such as spread of cancer from other organs to the liver or tumor of the biliary duct themselves or cancer of the pancreas

The highest level have been seen in cancer of the bile duct at the point where it enters the wall of the small intestine this disease lead to elevation of both GGT and alkaline phosphatase

Hepatocellular damage such us that due to infectious hepatitis (measurement of plasma transaminase activity is a more sensitive indicator of such conditions)

Very high plasma GGT activities out of proportion to those of the transaminase may be due to:

1/ induction by anticonvulsant drugs or by chronic alcohol intake

2/ alcoholic hepatitis 3/ cholestatic liver diseases

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Tumors with or outside liver, which compress and block the duct (such as spread of cancer from other organs to the liver or tumor of the biliary duct themselves or cancer of the pancreas

The highest level have been seen in cancer of the bile duct at the point where it enters the wall of the small intestine this disease lead to elevation of both GGT and alkaline phosphatase

Hepatocellular damage such us that due to infectious hepatitis (measurement of plasma transaminase activity is a more sensitive indicator of such conditions)

Very high plasma GGT activities out of proportion to those of the transaminase may be due to:

1/ induction by anticonvulsant drugs or by chronic alcohol intake

2/ alcoholic hepatitis 3/ cholestatic liver diseases

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It required pyridoxal phosphate, a member of the vitamin B6 groups, as coenzyme, the letter acting as the carrier of the –NH group.

Transaminase are widely distributed in the body. Only L-amino acids can undergo transamination.

 Lysine, praline, hydrosy prolone an threonine can not undergo transamination