METABOLISM OF
HEME
Submitted to: Pankaj
Dhiman Sir
Presented by:
Arushi Gupta (15)
Ishita sharma(30)
Kunal Chatterjee
(31)
Nidhi Bhalla (35)
Rajat Dhiman (41)
Sahil Sharma (47)
INTRODUCTION
Red blood pigment found in RBC.
Tetrameric protein
Chromoprotein
STRUCTURE OF
GLOBIN 2 alpha
Made of 4
polypeptide 2 beta
chain Linked by non-covalent
interaction
Normal level
Adult male=14-16g%
Adult female=13-15g%
Heme is present
in:
Myoglobin
Cytochromes
Peroxides
Catalase
Tryptophan pyrrolase
Nitric oxide synthase
STRUCTURE OF
HEME
Ferroprotoporphyrin
Derivative of PORPHYRIN
(cyclic compounds formed by fusion of 4
pyrrole
rings linked by methenyl (=CH-) bridges).
The pyrrole rings are named as I, II, III, IV.
The bridges as alpha, beta, gamma & delta.
Substitutions are denoted as 1-8.
Pyrrol
e rings
TYPE I: Substituent groups arranged symmetrically (1, 3, 5, 7) or (2, 4, 6, 8).
TYPE III: Substituent groups arranged asymmetrically (1, 3, 5, 8) or (2, 4, 6, 7).
Type III is most predominant in biological systems. Also called Series 9.
The usual substitutions are:Propionyl groupMethyl groupVinyl group
BIOSYNTHESIS OF HEME
Synthesized by almost all the tissues.
In the normoblasts.
The pathway is partly cytoplasmic and partly mitochondrial.
Occurs in 7 steps.
Some
Great
DoctorsPalpateHeartUnderCoverProducePure
Heme
STEP STEP
1 2
STEP
3
STEP
4
STEP
6
STEP 5
Regulation of Heme Synthesis
ALA synthase: regulated by repression mechanism. Heme inhibits
synthesis of ALA synthase by acting as co-repressor.
ALA synthase -allosterically inhibited by hematin.
Inhibition of transport of ALA synthase from cytosol to mitochondria.
Drugs like barbiturates, insectisides and carcinogens induce heme
synthesis.
The steps catalysed by ferrochelatase and ALA dehydratase:
inhibited by lead.
INH( Isonicotinic acid hydrazide): decreases the availability of
PLP.
PORPHYRIAS
WHAT ARE PORPHYRIAS?
A collection of metabolic disorders with abnormalities in
enzymes involved in Heme synthesis.
Increased production of porphyrins and their precursors
(ALA+PBG).
Not associated with jaundice.
CLASSIFICATION OF PORPHYRIAS
Porphyrias
Erythropoetic Hepatic
Chroni Acut
c e
Inherited as autosomal dominant disorders.
Congenital erythropoietic porphyria is an exception(autosomal
recessive).
Enzyme defect prior to the synthesis of the tetrapyrroles
manifest abdominal and neuropsychiatric signs,
Enzyme defects leading to the accumulation of tetrapyrrole
intermediates show photosensitivity.
Classified as inherited or acquired.
Acquired porphyria is rare
Deficient enzyme -
porphyria
relationship
Acute Intermittent Porphyria
(AIP)
Inherited autosomal dominant trait.
Due to decreased PBG-deaminase=
increased activity of ALA-synthase.
Urine is colorless = voided, but color
increases on standing (photo oxidation of
PBG to porphobilin).
SYMPTOMS OF AIP
Starvation and Drugs
Acute abdominal
pain
Light sensitivity
Congenital erythropoietic
porphyria
Deficiency of enzyme
uroporphyrinogen III
synthase.
Rare congenital disorder.
Patients are photosensitive (high
porphyrins).
Increased hemolysis.
Porphyria Cutanea Tarda
Cutaneous Hepatic Porphyria.
Chronic disease (deficiency of
uroporphyrinogen decarboxylase).
Uroporphyrin accumulates in urine.
Liver accumulates fluorescence.
Cutaneous photosensitivity.
Hereditary Coproporphyria
Defect in enzyme coproporphyrinogen oxidase.
Coproporphyrinogen lll and other intermediates (ALA and
PBG) prior to the blockade are excreted in urine and feces.
Patients are photosensitive.
Hematin (ALA synthase inhibitor) is used in treatment.
Variegate porphyria
Acute disease
Deficiency of
protoporphyrinogen
Oxidase.
Protoporphyrinogen IX and other
intermediates prior to blocking are
observed in urine.
Urine is colored.
Photosensitivity is observed.
Protoporphyria
Deficiency of ferrochelatase.
Protoporphyrin IX accumulates in
erythrocytes, bone marrow, and
plasma.
Photosensitive patients.
Reticulocytes and skin biopsy of
patients show red fluorescence.
Acquired Porphyrias
Due to lead poisoning and toxicity from other
compounds.
Lead inhibits ferrochelatase = decreased level of heme
with consequent increased activity of ALA synthase.
DIAGNOSIS
Presence of porphyrin
precursor (PBG) in urine is
detected using Ehrlich’s
reagent.
Urine under UV light =strong
RED fluorescence.
CATABOLISM OF HEME
Fate of
Conjugati bilirubin
on of
bilirubin
Uptake of -secretion of
bilirubin bilirubin into
by liver bile
-formation of
urobilin in
Formati intestine
on of
-excretion in
bilirubi urine and stool
n
FORMATION OF BILIRUBIN
UPTAKE & CONJUGATION IN LIVER
FATE OF BILIRUBIN
HYPERBILIRUBINEMIAS
serum bilirubin
>2 mg/dL
An elevated level of the pigment bilirubin in the blood is known as HYPERBILIRUBINEMIAS.
Sufficient elevation of bilirubin produces jaundice.
Hyperbilirubinemia is a biochemical finding but jaundice is a
clinical finding for increased bilirubin levels in the blood.
Based on the cause,
hyperbilirubinemias may be classified
into :
1. Congenital 3. Hemolytic Jaundice
Hyperbilirubinemia
s
5. Obstructive jaundice
2. 4. Hepatocellular jaundice
Acquired
Hyperbilirubinemias
Depending on the nature of bilirubin in blood, the
condition may be grouped into conjugated or
unconjugated hyperbilirubinemia.
Congenital hyperbilirubinemia
Abnormal uptake, conjugation or excretion of
bilirubin due to inherited defects.
congenital
Crigler Gilbert Dubin Rotor Lucey-
najjar syndrome Johnson syndrome Driscoll
syndrome syndrome
Type 1 Type 2
Syndromes of Hyperbilirubinemias
Crigler –najjar
syndrome
Deficiency of glucuronyl
transferase
Type 1 Type II
Complete absence of the Glucoronyl Enzyme deficiency is partial.
transferase No such symptoms appear
Jaundice appears within first 24hrs of life Not exceeds more than 20mg/dl
Unconjugated bilirubin level increases Death does not occurs.
more than 20mg/dl
Death occurs.
Dubin-Johnson Syndrome
Autosomal inherited recessive trait
Defective excretion of conjugated bilirubin.
Bilirubin gets deposited in liver (conjugated bilirubin increased).
Gilbert’s syndrome
Autosomal Inherited dominant trait
It is a combination of diseases
Impairment in conjugation due to reduced UDP-glucuronyl transferase
Decreased hepatic clearance of bilirubin
Rotors syndrome
Similar to Dubin – Johnson syndrome
Level of conjugated bilirubin is increased
Active transport system is defective
Lucey-Driscoll syndrome
An inhibitor of UDP-glucuronyl transferase is present
DIFFERENCE
TEST FOR BILE
PIGMENTS
GMELIN'S TEST
Bilinogen+conc= green fluorescence.
FOUCHET'S TEST
Urine + few ml 
Filter and filterate remain on filter paper
Add one drop of 
Green blue spot = +ve
VAN DEN BERGH TEST FOR BILIRUBIN
Bilirubin + diazonium salt= purple color complex
Conjugated bilirubin = direct reaction.
Unconjugated bilirubin = indirect reaction.
Ehrlich's test
PLASMA BILIRUBIN
Normal= 0.2– 1mg/dl
Hyperbilirubinemia= If the plasma bilirubin level exceeds 1 mg/dl
Jaundice= bilirubin level exceeds 2 mg/dl
Conjugated bilirubin = 0.2 to 0.4 mg/dl
Unconjugated bilirubin = 0.2 to 0.6 mg/dl
JAUNDICE
THREE TYPES :-
Haemolytic or Pre-hepatic.
Hepatocellular or Hepatic.
Obstructive or Post-hepatic
Jaundice.
PREHEPATIC JAUNDICE
Increased hemolysis
coupled with immature
hepatic system for the
uptake, conjugation and
secretion of bilirubin.
Neonatal jaundice
Because of the immature liver in newborn ,they do not have enough capacity to
remove the bilirubin that is present in the blood.
So absence of UDP-GT
Kernicterus
Rh incompatibility
1. KERNICTERUS
The activity of the enzyme UDP-glucuronyl transferase is low in the newborn.
serum cross the kernicterus mental
uncojugate bloodbrain retardation
d bilirubin barrier .
↑
Treatment: phenobarbital as it can induce bilirubin metabolising enzymes in liver
and phototherapy
PHOTOTHERAPY
Unconjugate Lumirubin
d bilirubin (non toxic)
(toxic)
2. RH INCOMPATIBILITY
HEPATIC JAUNDICE
Liver Drugs
cirhosis
Wilson’s
disease
Hepatitis Liver cancer
POST HEPATIC JAUNDICE
If there is complete obstruction, UBG
will be decreased in urine or is even
absent
Causes :-
Intrahepatic
cholestasis
Extrahepatic
obstruction
EXTRAHEPATIC OBSTRUCTION
DIAGNOSIS
OF JAUNDICE
