Biochemistry of Jaundice – Problems and Mechanisms related to Jaundice

1. Explain why with hereditary defects in heme synthesis enzymes, the skin of patients has an increased sensitivity to solar radiation, and urine acquires a red color. The accumulation of what intermediate products of heme synthesis causes these symptoms?

In Jaundice, As we know, the synthesis of heme takes place in the cytosol and mitochondria of our cells. Acquisition of heme also occurs through intestinal absorption and intracellular transport. Hem is a component of various biological structures, mainly hemoglobin, others include myoglobin, cytochromase, catalease, heme peroxidase, and endothelial nitric oxide synthase. The most common type is heme B, which is found in hemoglobin which leads to derivations of other heme groups.
5′-Aminolevulinic acid synthase (ALA-S) is an enzyme regulated for heme synthesis in our body’s liver and erythroid cells. ALA Synthase has two forms, the first one is ALAS1, and the second one is ALAS2. All cells express ALAS1 while only liver and bone marrow express ALAS2. The gene for ALAS2 is on the X-chromosome.
An abnormality or mutation in 5-aminolevulinic acid synthase 2 (ALAS2) results in a disorder called X-linked sideroblastic anemia (hereditary disorder). It reduces protoporphyrin production and heme in our body. However, iron continues to enter the erythroblast resulting in accumulation in mitochondria and hence expression of the disease.
During the biosynthetic pathway, linear hydroxymethylbillane can spontaneously form a “defective” porphyrin ring when not immediately used as a substrate for uroporphyrinogen synthesis. If there is a deficiency of uroporphyrinogen III, the hydroxymethylbilan spontaneously stops and forms a separate molecule called uroporphyrinogen I. Copperorphyrinogen is formed as a result of uroporphyrinogen. Hem does not form from this molecule. Therefore linear hydroxymethylbil is an intermediate molecule responsible for these symptoms. This is the case of porphyria catania tarda – it is caused by decreased or decreased activity in uroporphyrinogen decarboxylase (UROD). It may be acquired or hereditary (autosomal dominant). Europorphyrin accumulates in the urine. Symptoms include photo sensitivity, hyperpigmentation, and liver injury. Treatment includes protection from sunlight, hydroxychloroquine, and phlebotomy.

2. What vitamins and at what stages are involved in the synthesis of heme ?

Synthesis of heme are described in total eight sages. In 1st step Glycine and succinyl-COA where succinyl-CoA is play a role as an intermediate in Krebs cycle, wher glycine can be makes from diet or by the metabolism of serine. aminovalenic acid synthase  enzyme which is known as vitamin B6-essential enzyme are helps to complete 1st step of heme synthesis by catalyzed.

3. What causes of jaundice do you know other than damage to hepatocytes , hemolysis and obstruction of the bile ducts?

Causes of Jaundice: –
1. Pre-Hepatic or Hemolytic (Unconjugated bilirubin): –
a. sickle cell,
b. drugs and toxins thalassemia,
c. SLE,
d. transfusion,
e. haemolytic disease of the newborn,
f. Abnormal RBCs,
g. Antibodies,
h. Hemoglobinopathies.

  1. Hepatocellular or Hepatic (Unconjugated + conjugated bilirubin) : –
    a. Hepatocellular liver damage (drugs, sepsis, pregnancy, TB)
    b. Hepatitis (viral, alcohol, non-alcoholic steatohepatitis, PBC)
    c. Gilbert’s Syndrome, Crigler-Najjar Syndrome
    d. Intrahepatic cholestasis
    e. Cirrhosis

  2. Post Hepatic or Obstructive (Conjugated bilirubin): –
    a. Structural disorder of bile duct
    b. Cholelithiasis
    c. Pancreatic Ca,
    d. Pancreatitis
    e. Congenital atresia of bile duct
    f. Bile duct obstruction (cholangio carcinoma/stricture)
    g. Primary sclerosing cholangitis


In other hand There is a neonatal jaundice which is a common type of jaundice and mostly occurs in newborn baby. In this UCB means Unconjucated Bilirubin cross the blood brain barer and damage the tissue of Brain. Some childes have a lot of RBCs and at that time they have less develop liver which didn`t work properly. Due to this situation bilirubin cannot proceed fastly and then they show their effect after birth.


4. Why in the midst of obstructive jaundice in patients there is a slowdown in blood coagulation?

In Jaundice there is resistant to suppress or inhibit plasma prothrombin depends on two factors, 1st liver damaging and other synthetic function disrupting and 2nd reducing or decreasing of absorption of Vit K from the intestinal tract.
Bile salts can be help in absorption of fat soluble substances from intestinal tract, and inhibition of jaundice can be reduce total amounts of bile salts distributed in the bile duodenum.
On other hand, reducing plasma prothrombin due to bstructive jaundice in which loss of appetite with less intake of vitamin K-containing foods.
Vit K are helps to synthesis of prothrombin which helps into coagulation and anticoagulation.

5. How does conjugated bilirubin get into the bloodstream normally?

In the bloodstream, Bilirubin is independent or un-deformed state; in bloodstream, bilirubin associated with albumin which is known as transported protein. If in liver, This Sugar are combines with glucosonic acid made of glucose, Concentrated are approximately 1,000 times of strength found in blood plasma. High excessive of bilirubin leaves the liver and then it goes to the gallbladder in which this is concentrated and mixed with other components of the bile. Formation of gall-stones are mainly held by bilirubin and infection in gallbladder can be occurs due to bacteria and af
ter that it convert into conjugated bilirubin to bilirubin and then into acid. Ca+ by free bilirubin can go out in the form of pigment stones, and due to this stones, passage of common bile duct can be block (between the liver, gallbladder and small intestine). When it goes to excessive the conjugated bilirubin is goes to bloodstream, and then it can show effect like the skin turns yellow.
When The transported channel (MRP2) didn t work properly then MRP 3 Channel protein where started. Actually MRP 3 Are Work all time but very less then MRP 2 so it didnt consider generally. But After closing MRP 2, we can show easily that MRP 3 are doing worked. So after that Conjugated Bilirubin means CB are going out in intercellular space and enters into blood stream because they created a concentration difference but due to presence of tight junction between cells. CB unable to cross them, then there a pressure generate due to continuously leakage of CB and then CB forcefully goes to Bloodstrem.
<h2><span style="font-size: small;">6. <b>How unconjugated bilirubin gets into the tissue if it cannot be transported by blood in its free form.</b></span></h2>
Unconjugated bilirubin are hydrophobic, not hydrophilic and due to this they are unable to go out through urine. There are Hepatic Transport Mechanism will work. Because There is no bilirubinuriya and UCB can
t go out by urine. So it increased Urobilinogen in urine due to more bilirubin reaches the intestine and more  urobilinogen is formed an reabsorbed.
HEPATIC TRANSPORT MECHANISM: – after the taken bilirubin from hepatic sinusoids into heptocytes, it have 2 types of mechanism:-
1. passive proliferation
2. receptor mediated endocytosis
The passive proliferation or diffusion are not energy consuming and it have a limitation of gradient Makes the bi lateral directions. Some mediated like carrier protein, activated transport of bilirubin are not good understable.


1. The doctor prescribed a ferrofolgamma drug containing ascorbic acid, iron sulfate, folic acid and vitamin B12 to a patient suffering from iron deficiency anemia. Justify the doctor’s recommendation, describing the role of each component of the drug in iron metabolism, heme and hemoglobin synthesis 

Vitamin C or water-soluble vitamin, are helps to increasing in iron absorbed in iron-deficiency anemia. Administration of water-soluble vitamin helps to increase iron availability for erythropoiesis, which can helps to improving the anemia response to treatment. water-soluble vitamin are a reduction agent which help to transformation of ferrous iron to ferrous iron, increasing absorption by digestion and brought iron without transferring, helps to iron for release from ferritin and hemosiderin and delaying ferritin conversion to hemosiderin, then administration of water-soluble vitamin can increase the quantity of iron available for erythropoiesis by obtaining it from deposits. The effect of administration of water-soluble vitamin which is known as hypoallerusplasia anemia is shown by the help of erythropoiesis stimulating agents (ESA). Functional deficit or hemochromatosis marker. The results of administration of water-soluble vitamin revealed an increased level of hemoglobin and transferrin saturation (TSAT) combined with a decrease of ESA.

Iron Sulfate: – Iron combines with porphyrin and globin chains to form hemoglobin, which is extremely important for transporting oxygen from the lungs to other tissues. Iron deficiency leads to a anaemia thanks to the formation of small erythrocytes with insufficient hemoglobin.

Folic acid is also a B complex that helps your body make red blood cells. If you’re doing not have enough red blood cells, then you have got got anemia. Red blood cells carry oxygen to any or all parts of your body. once you have got anemia, your blood cannot bring enough oxygen to any or all of your tissues and organs. Without enough oxygen, your body cannot function because it should. Low levels of folacin can cause pernicious anemia. With this condition, red blood cells are larger than normal. There are fewer of these cells. they’re also oval, not round. Sometimes these red blood cells don’t survive as long as normal red blood cells. Since folacin is biochemically inactive, it’s converted into tetrahydrofolic acid and methyltetrahydroflate by dihydrofolate reductase. The progenitors of these folic acids are transported by receptor-mediated endocytosis in cells where they’re required to stay up normal erythropoiesis, interconnect amino acids, methylate tRNA, and use the format and synthesize purine and thymidylate nucleic acids. is. Using cyanocobalamin as a cofactor, folacin can normalize high homocysteine levels by recharging methionine to homocysteine via methionine synthetase.

Vitamin B12 is used by the body in two forms, either as methylcobalamin or 5-deoxyadenosyl cobalamin. The enzyme methionine synthase requires methylcobalamin as a cofactor. This enzyme is usually involved within the conversion of the chemical compound homocysteine into methionine, while methionine, in turn, is required for DNA methylation. 5-deoxyadenosyl cobalin is also a cofactor required by the enzyme that converts L-methylmonyl COA to succinyl COA. This conversion could be a vital step within the extraction of energy from protein and fat. additionally, succinyl CoA is required for the assembly of hemoglobin, an oxygen-carrying substance in red blood cells.

1. A patient was admitted to the infectious diseases ward of the hospital with complaints of weakness, an elevated temperature of 38.5 ° C, and with pronounced icteric coloration of the skin and mucous membranes. Concentrations of direct and indirect bilirubin in the patient’s blood are increased. Direct bilirubin is present in the urine, the content of urobilin in the urine and stercobilin in the feces is reduced. What type of jaundice does the patient suffer from? To answer the question:

a) provide an outline of the formation of indirect bilirubin; 

Indirect bilirubin is formed by the breakdown of hemoglobin in red blood cells. The liver converts this bilirubin into direct bilirubin, which can then be released into the intestine by the gallbladder for later elimination. Bilirubin levels are therefore both a sign of destruction of red blood cells and proper functioning of the liver, gallbladder and bile ducts. A high level of total bilirubin (hyperbilirubinemia), which is mainly due to an increase in the indirect portion, may indicate a problem in hemolysis (breakdown) of red blood cells (for several reasons), a post-blood transfusion reaction. , Or cirrhosis liver.

b) write a reaction scheme for conjugation of bilirubin; 

first of all, After the complete life cycle of RBCs, it`s breaks into Heame and globin. In which Globin metabolised and makes Amino Acid. And Heme which is consists of iron and protophyrin, makes two product iron and protophyrin. After that protophyrin are convert into Unconjugated bilirubin which goes to liver by the help of Albumin protein and enzymes glucoronyl transferase . Aftert that in hepatic cells, UCB with the help of enzymes isomerase glucoronyl transferase this convert into conjugated bilirubin.

c) list the properties of direct and indirect bilirubin, explain causes toxicity unconjugated (indirect) bilirubin; 

Indirect bilirubin (Unconjugated): – Measurement of indirect bilirubin is underestimated by measurement of indirect bilirubin, as unconventional bilirubin (without / yet glucoronidation) reacts with diazosulf
anilic acid to form azobilirubin which is measured as direct bilirubin.

Direct bilirubin: – Direct bilirubin = Conjugated bilirubin + delta bilirubin

Conjugated bilirubin: – within the liver, bilirubin is conjugated with glucuronic acid by the enzyme glucuronitransferase, making it soluble in water: the conjugated variant is that the predominant quite bilirubin present within the “direct” bilirubin fraction. Most of it goes into the bile and is thus excreted within the bowel. Although most of the steroid is recombined to participate in enterohepatic circulation within the antralum, the conjugated bilirubin isn’t absorbed and instead passes into the colon. additionally, colonic bacteria decompose and metabolize bilirubin into colorless urobilinogen, which could lead to oxidation of urobilin and stercobilin. . Urobilin is excreted by the kidneys to grant urine its yellow color, and stercobilin is excreted as feces, giving the stool its characteristic brown color. A trace (~ 1%) of urobilinogen is reabsorbed into the enterohepatic circulation to be reabsorbed into the bile. The half-life of conjugated bilirubin is shorter than that of delta bilirubin.
Delta bilirubin: – Although direct and indirect bilirubin are used equally with conjugated and unrelated bilirubin, this is often often not quantitatively correct, because the direct fraction includes both conjugated bilirubin and ir bilirubin. Delta bilirubin is albumin-bound conjugated bilirubin. In other words, delta bilirubin may well be a form of bilirubin certain to albumin, which appears within the serum when the liver excretion of conjugated bilirubin is attenuated with sympathetic patients. additionally, direct bilirubin exceeds the conjugated bilirubin level due to unconjugated bilirubin, which reacts with diazosulfanilic acid, raising azobilirubin levels (direct bilirubin increases).

Uncontaminated hyperbilirubinemia during a newborn can cause the buildup of bilirubin in certain areas of the brain (especially the basal nucleus), resulting in various neurological deficits, seizures, abnormal reflexes and eye movements. Irreversible damage to areas may occur. Such neurological injury is known as kernicterus. The spectrum of clinical effects is termed bilirubin encephalopathy. Neurotoxicity of hyperbilirubinemia appears because the blood – brain barrier isn’t yet fully developed, [suspected – discussed] and bilirubin can freely pass into the cerebral interstitium, whereas increased blood bilirubin develops quite Individuals are protected. additionally to specific chronic medical conditions that will cause hyperbilirubinemia, newborns are generally at increased risk because they lack intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin within the feces (this Are substantially but the feces of a neonate. Who are adults). Conjugated bilirubin is instead converted into an undegraded form by the enzyme β-glucuronidase (in the intestine, this enzyme lining is found within the comb border of intestinal cells) and is reabsorbed via an outsized proportion of enterohepatic circulation.


d) Indicate the activity of which organ-specific hepatocyte enzymes are determined in the blood for the diagnosis of liver pathologies, and describe the basic principles underlying enzyme diagnostics 

Alanine Transmanase (ALT): Produced in hepatocytes, Very specific marker of hepatocellular injury, Relatively lower concentrations in other tissues more specific than AST, Levels fluctuate during the day, The increase may occur with the use of certain medications or during periods of strenuous exercise.

Aspartate transaminase (AST): Occurs in two isoenzymes, indistinguishable on standard AST assays, The mitochondrial isoenzyme is produced in hepatocytes and reacts to membrane stress similar to ALT, The cytosolic isoenzyme is present in skeletal muscle, heart muscle, and kidney tissue. Caution should be exercised in its use to evaluate hepatocellular damage, Usually rises in combination with ALT to indicate hepatocellular injury: a hepatic picture,

Alkaline phosphatase (ALP): A group of isoenzymes that act to destroy various types of molecules throughout the body, Produced in the membranes of bile ducts and canaliculi lining cells, Released in response to accumulation of bile salts or cholestasis, Non-liver production in kidney, intestine, leukocytes, placenta and bone, Physical growth in pregnancy or in growing children, Pathological enlargement with Paget’s disease, kidney disease, and bone metastases.

Gamma-glutamyl transferase (GGT): Present in liver, kidney, pancreas and intestine, It is found in the microsomes of hepatocytes and biliary epithelial cells, A biliary tract obstruction in the elevation of GGT with an increase in ALP is highly suggestive and is known as a cholestatic picture, Subject to increase with hepatic enzyme induction due to chronic alcohol use or drugs such as rifampicin and phenytoin .


1. A doctor recommended phototherapy for two newborns in whom jaundice was detected. In one child, the condition improved and the symptoms of jaundice disappeared. Irradiation with a blue-green light did not help the second child, so he was prescribed phenobarbital . However, this treatment was ineffective, and the child developed symptoms of encephalopathy. Justify the doctor’s recommendations and explain the results of treatment. For this:

a) explain the possible causes of the “physiological” jaundice of newborns; 

Excess bilirubin (hyperbilirubinemia) is the main cause of jaundice. Bilirubin, which is responsible for the yellowing of jaundice, is a normal part of the pigment released by the breakdown of “used” red blood cells. Newborns produce more bilirubin than adults because of overproduction in the first few days of life and rapid breakdown of red blood cells. Normally, the liver filters bilirubin from the bloodstream and releases it into the intestinal tract. The immature liver of a newborn often cannot remove bilirubin quickly, leading to an excess of bilirubin. Jaundice is called physical jaundice due to these common neonatal conditions, and it usually manifests on the second or third day of life.

b) indicate how the concentration of bilirubin in the blood, stercobilin and urobilin changes in the feces and urine of sick children, respectively; 

Bilirubin is a pigment that results from the breakdown of the hem part of hemoglobin. The liver conjugates bilirubin, making it soluble in water; And the conjugated form is excreted in the urine as urobilinogen, which gives urine its color. In the intestine, bilirubin is converted into stercobilinogen by bacteria. Stercobilinogen is absorbed and excreted by the liver or kidney. Stercobilin is oxidized to stercobilin, which is responsible for stool pigmentation.
Stercobilinogen (fecal urobilinogen) is a chemical produced by bacteria in the intestine. It is made up of broken hemoglobin. It is further processed to become chemical which gives the stool its brown color.
Urobilin and urobilinogen ,Urobilin and this is reduced form urobilinogen  and this is formed by the action of bacteria on bile pigments in the intestine.

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