vHeme Synthesis
qPorphyrias (Disorders Of Heme Synthesis)
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vGlobin SynthesisqAbnormal Hb variants/
Hemoglobinopathies(Disorders of Globin Synthesis)
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Hemoglobin BreakdownqFormation and Fate of Bilirubin
qHyperbilirubinemia
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Jaundice : Causes Types and DiagnosisHemoglobin Biosynthesis
Hemoglobin biosynthesis
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includes biosynthesis of:vHeme
vGlobin Polypeptide chains
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Amount of Hb biosynthesized=6.25 gm/day
Site For Hemoglobin
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BiosynthesisOrgans Involved In
Hb Biosynthesis
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Bone Marrow-
Immature Erythrocytes ? 85%
Liver ? 15 %
Requirements For
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Hemoglobin Biosynthesis
Normal biosynthesis of
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Hemoglobin depends upon anQuality and Quantity of :
qAmino acids
--- Content provided by FirstRanker.com ---
qMineralsqVitamins
Heme Biosynthesis
OR
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Porphyrin Pathway
Biosynthesis
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OfFerroprotoporphyrin
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Site For Heme BiosynthesisOrgans
Bone Marrow-
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Immature Erythrocytes ? 85%Liver ? 15 %
Cellular Site
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Mitochondrial MatrixCytosol
Requirements For
Heme Biosynthesis
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Metabolic Precursors for Heme Biosynthesis:
? Glycine and Succinyl-CoA
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Vitamins (5 Hematopoietic Vitamins):vPantothenic acid (Vitamin B5)
vPyridoxine (Vitamin B6)
vFolate (Vitamin B10)
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vCyanocobalamin (Vitamin B12)vVitamin- C (Ascorbic acid)
Minerals for Heme Biosynthesis:
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?Iron ( Fe++)?Copper (Cu++)
?Zinc ( Zn ++)
Stages and Steps
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OfHeme Biosynthesis
3 Stages Of Heme Biosynthesis
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1. Synthesis of -Amino Levulinic Acid( ALA)
(In Mitochondrial Matrix)
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2. Synthesis of CoproPorphyrinogen?III
( CPG-III)
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(In Cytoplasm)3. Synthesis of ProtoPorphyrin IX and
Incorporation of Fe++ to Form Heme
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(In Mitochondrial Matrix)
7 steps in Heme Biosynthesis
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Step 1 in Mitochondrial MatrixSteps 2,3,4 in Cytoplasm
Steps 5,6 and 7 in
Mitochondrial matrix
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?Important Intermediates of Heme
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Synthesis Pathway:-Aminolevulinic acid
(ALA)
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Porphobilinogen(PBG = Pyrrole derivative)
Uroporphyrinogen III
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( UPG? Heme precursor)Protoporphyrin IX
(Direct Heme precursor)
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-Aminolevulinic Acid (ALA)? Synthesis of Heme starts in Mitochondrial matrix
? Succinyl-CoA and Glycine undergo a condensation ALA
? Reaction is catalyzed by enzyme ALA Synthase
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? ALA Synthase requires?Vitamin B6 (PLP)
? Copper ions
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PLP used in first step ofHeme biosynthesis
activates Glycine.
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Presence of free Heme inhibitsthe synthesis of an enzyme
- ALA Synthase.
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This represents a Feedback
mechanism for Heme synthesis.
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This first step is a Rate limitingstep of Heme synthesis:
vStimulated by the presence of
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Globin chains.
vInhibited by the presence of free
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Heme groups.Rate of Heme
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biosynthesis has goodcoordination with
Globin synthesis.
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Porphobilinogen (PBG)
? ALA leaves the Mitochondria Reach Cytoplasm
? 2x ALA condense together to form Porphobilinogen (PBG).
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? Reaction is catalyzed by Porphobilinogen Synthase/(ALA dehydratase)
Mitochondrial -Aminolevulinic acid
(ALA) is transported to the cytoplasm,
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where
ALA Dehydratase /Porphobilinogen
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Synthase- Zinc containing enzyme.Dimerizes 2 molecules of ALA to produce
The Pyrrole ring compound is
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Porphobilinogen (PBG).PBG then biosynthesizes Porphyrin
ring.
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The reactions involved for its
synthesis are extremely complex
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but can be summarized as follows:The condensation of four PBG
molecules
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Form an asymmetric cyclicUroporphyrinogen III(UPG III).
Synthesis of UPG III requires the
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presence of two enzymes:
v Uroporphyrinogen I Synthase
v Uroporphyrinogen III Cosynthase
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During UPG synthesis thereinvolves the formation of
short-lived intermediate
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Hydroxy Methyl Bilane
(HMB).
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UPG I Synthase/PBGDeaminase /HMB Synthase
Transforms 4 molecules of PBG
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to linear Tetrapyrrole
Hydroxy Methyl Bilane
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(HMB)HMB spontaneously
cyclizes to form UPG III
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by UPG III CosynthaseConversion of
Uroporphyrinogen II Coproporphyrinogen II
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4 Acetate residues of
Uroporphyrinogen III are
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Decarboxylated into 4 Methylgroups Coproporphyrinogen III
Coproporphyrinogen III returns to
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the Mitochondria again.
UPG III is converted to Coproporphyrinogen III
(CPGIII) by Decarboxylation of the Acetate side
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chains
To Methyl groups under the influence of the
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enzyme Uroporphyrinogen Decarboxylase.CPG III enters the Mitochondria where it is
converted to Protoporphyrinogen IX (PPG IX) by an
--- Content provided by FirstRanker.com ---
unknown mechanism.This reaction is catalyzed by the enzyme
Coproporphyrinogen Oxidase.
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Coproporphyrinogen III Protoporphyrinogen IX
In Mitochondria CPG III is oxidized to
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PPG IX.Two Propionyl residues transformed
to Two Vinyl residues.
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Removal of two CO2 molecules.
Reaction catalyzed by CPG Oxidase.
Protoporphyrinogen is a
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colorless compoundIt contains Methylene
bridges in tetrapyrrole
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ring structure.
Methylene bridges of
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Protoporphyrinogenare oxidized to
Methenyl bridges to
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form ProtoPorphyrin
Protoporphyrinogen IX Protoporphyrin IX
? Oxidation of protoporphyrinogen IX produces the
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conjugated Methenyl bonds of Protoporphyrin IX
Final Formation of Heme
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? Fe2+ is incorporated into Protoporphyrin IX? Reaction is catalyzed by enzyme Ferrochelatase/Heme
Synthase to Form Heme.
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Iron is chelated within Porphyrin
ring to form Heme by catalytic
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activity of Ferrochelatase.
Heme is incorporated into
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Proteins to become biologicallyfunctional Hemoproteins.
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HemeMetalloPorphyrin /Ferroprotoporphyrin
Heme forms various: Hemoproteins
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Hemoglobin
Myoglobin
Cytochromes
Catalase and Peroxidase
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Tryptophan PyrrolaseChlorophyll is a Magnesium
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containing Porphyrin presentin plants.
Chlorophyll is involved in
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photosynthesis of plants.
Regulation Of Heme Biosynthesis
ALA Synthase is an
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Allosteric regulatory
Enzyme of Heme
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biosynthetic pathway.ALAS 1 occurs in Hepatocytes
ALAS 2 is found in Erythroid tissue
Rate of Heme biosynthesis is
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flexible.
Heme biosynthesis changes
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rapidly in response to a widevariety of external stimuli.
Mechanisms and Factors
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Regulating Heme BiosynthesisFeed Back Inhibition
Repression of ALA Synthase
Inhibition of transport of ALA
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Synthase from Cytosol to
Mitochondrial matrix.
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Erythropoietin levelsIron levels
ALA Synthase is a key regulatory
enzyme of Heme biosynthesis.
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It is an allosteric enzyme that is
inhibited by an end product-Heme
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(Feedback inhibition)Requires Pyridoxal Phosphate as
a coenzyme
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Erythropoietin Stimulates
Heme Biosynthesis
Erythropoietin is a Protein
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produced by Kidneys .
Erythropoietin stimulates
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the ALA Synthase activity.Erythropoietin Synthesis
increased in high altitude
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dwellers.
Erythropoietin decreased
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in chronic renal failure.(Associated with Anemia)
Iron Levels Affect Heme Synthesis
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The amount of cellularIron determines
The affinity for Iron
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Responsive Element-
Binding Protein(IRE-BP).
When Iron levels are low
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There is a high bindingaffinity of IRE-BP with
mRNA of ALA.
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Which serves to inhibit the
translation of ALA mRNA
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Results in decrease of Hemebiosynthesis.
When Iron levels are
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sufficient.
There is a low binding affinity
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of IRE-BP with mRNA of ALA.Thus allowing translation of
ALA mRNA
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Stimulation of Heme synthesis.
How Iron Levels Affect
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Heme Synthesis
Iron and Hemoglobin
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Iron deficient redblood cells
Low number of red
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blood cells
Note the hollow and
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blanched appearanceof the red blood cells.
If either Heme or Globin
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synthesis is impairedIron is not utilized and
accumulates in the RBC.
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When Heme
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biosynthesis is impairedIron is underutilized
Mitochondria or Nucleus
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of Erythroblasts becomeencrusted with Iron.
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A Sideroblast isa Nucleated Erythrocyte
Containing Iron granules in
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its cytoplasm in the bonemarrow.
Sideroblast
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Sideroblast is
an Erythroblast with Iron granules
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(Pappenheimer bodies) seen inbone marrow stained by
Prussian blue or Perl stains.
A precursor Red blood
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cell (Immature RBC)
with a ring of Iron
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around the nucleus iscalled a ringed
Sideroblast.
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Siderocyte
Siderocyte is a non-
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nucleated red cell withIron granules
(Pappenheimer bodies)
A mature RBC with an
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accumulated Iron is
termed as Siderocyte .
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Siderocytesare abnormally increased in :
Sideroblastic Anemia
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HemosiderosisHemoglobinopathies
The Iron within
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Sideroblasts and
Siderocytes can be
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visualized by staining withPrussian blue stain.
--- Content provided by FirstRanker.com ---
Ringed Sideroblast
RINGED SIDEROBLASTS AND
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SIDEROCYTE
Effect Of Drugs and Other
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Substances On Heme BiosynthesisCertain Drugs and
Steroid Hormones
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increases Hemebiosynthesis.
Ingestion of drugs like
--- Content provided by FirstRanker.com ---
Phenobarbitals ,Insecticides,
certain chemical carcinogen,
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Markedly increases ALASynthase (ALAS1 of Hepatocytes)
activity.
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This increases production of Heme.
The biosynthesized Heme in
response to drug administration
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Is used for production of
Cytochrome P450
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Cyt P450 ?A Hemoprotein isresponsible for drug detoxification.
Lead Poisoning Affects
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Heme Biosynthesis
and
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Causes AnemiaFollowing Enzymes of Heme biosynthetic
pathway are inhibited by Lead ions
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(Pb2+) in cases of Lead poisoning.ALA Dehydratase / Porphobilinogen
Synthase
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Ferrochelatase / Heme Synthase
Thus Lead
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poisoningInhibit Heme
biosynthesis and
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Leads to Anemia.
Porphyrins
Porphyrins are
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chemically cyclic tetra
Pyrrole ring structures
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with substitutedgroups.
Porphyrins has
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conjugated ring systemAlternate single and
double bonds (Methenyl
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bonds).
Porphyrins are colored and
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Fluorescent compounds withMethenyl bridges/ Methyne
bonds in it.
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The double bonds in Porphyrinsabsorb visible light and appear
colored compounds.
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The Conjugated bonds of
Porphyrins in UV light shows
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fluorescence intense reddishpink color.
Types Of Porphyrins
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Based on arrangements of
Substituted groups on
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Tetrapyrrole RingsTypes Of Porphyrins
Type I Porphyrins
Type III Porphyrins
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Type I Porphyrinshas symmetric
arrangements of
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substituted groups
in tetra pyrrole ring
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structure.Type III Porphyrins
have asymmetrical
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distribution of the
substituted groups in
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tetra pyrrole rings.Type III Porphyrins
are most predominant
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in biological system.ProtoPorphyrin IX is of
type III Porphyrins
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Fischer placed
ProtoPorphyrin in 9th
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series of 15 possible isomers.In Disorders of Porphyrias
Porphyrins are
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abnormally elevatedIn blood and excreted in
urine.
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PorphyriasGk- Porphyria= Purple
Porphyrias
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Disorders Due ToDefective
Heme Biosynthesis
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Porphyrinurias
What Are Porphyrias?
The Porphyrias are
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group of disorders
Associated to
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defective Hemebiosynthesis.
Basic Cause Of Porphyrias
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Metabolic block inHeme biosynthesis
leads to Porphyrias.
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Defect in any oneEnzyme of Heme
biosynthesis
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Defect in Enzyme of Heme
Biosynthesis may be:
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?Inherited?Acquired
Most of the Porphyrias
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are of AutosomalDominant inheritance .
Types and Classification
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Of Porphyrias
6 Common Types Of Porphyrias
S.No Type Of Porphyrias
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Enzyme Defect
1
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Acute IntermittentUPG I Synthase/
Porphyria (AIP)
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PBG Deaminase
2
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ErythropoieticUPG III Cosynthase
Porphyria
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3
Cutanea Tarda
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UPG Decarboxylase4
Coproporphyria
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CPG Oxidase
5
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Variegate PorphyriaPPG Oxidase
6
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Protoporphyria
Ferrochelatase
Pneumonic To Remember
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6 Type Of Porphyrias
All Elephants Can
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Catch Ved Pathak.Mitochondria
PORPHYRIAS
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GLYCINE + SuccinylCoA
Agent Orange
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ALA Synthased Aminolevulinic acid(ALA)
3p21/Xp11.21
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ALA-Dehydratase
ALA Dehydratase
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Deficiency9q34
Porphobilinogen (PBG)
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Porphyria
Acute intermittent
PBG Deaminase
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Porphyria
Hydroxymethylbilane
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11q23Uroporphyrinogen III
Congenital Erythropoietic
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Cosynthase
Porphyria
--- Content provided by FirstRanker.com ---
Uroporphyrinogen III10q26
Uroporphyrinogen
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Porphyria
Decarboxylase
--- Content provided by FirstRanker.com ---
Cutanea tardaCoprophyrinogen III
1q34
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Coproporphyrinogen
Herediatary
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oxidasecoproporphyria
Protoporphyrinogen IX
--- Content provided by FirstRanker.com ---
9
Protoporphyrinogen
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VariegateProtoporphyrin IX
Oxidase
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Porphyria
1q14
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FerrochelataseErythropoietic
Heme
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18q21.3
protoporphyria
Different Basis For
--- Content provided by FirstRanker.com ---
Classification Of Various
Types Of Porphyrias
On Basis Of Cause
--- Content provided by FirstRanker.com ---
Primary/Congenital Porphyrias
Secondary/Acquired Porphyrias
On Basis Of Organ
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Hepatic Porphyria
Erythropoietic Porphyria
Inherited Porphyria
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Erythropoietic Porphyria - results fromexcessive production of Porphyrins in the
bone marrow.
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Hepatic Porphyria - results from
excessive production of Porphyrins in the
--- Content provided by FirstRanker.com ---
Liver.Acquired Porphyria
Lead Intoxication - interferes with
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Protoporphyrin synthesis
?Chronic Alcoholic Liver disease
--- Content provided by FirstRanker.com ---
On Basis Of SymptomsNeurological Porphyrias/Acute Porphyrias
Acute Intermittent Porphyria
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Coproporphyria
Variegate Porphyria
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?Autonomic Dysfunction?Abdominal pain
?Chest pain
?Confused Thoughts
?Depression and Psychosis
--- Content provided by FirstRanker.com ---
Photosensitive Porphyria/ChronicPorphyria
q Erythropoietic Porphyria
--- Content provided by FirstRanker.com ---
q Cutanea Tarda
Porphyrins below skin exposed to
--- Content provided by FirstRanker.com ---
sunlight showsvRedness
vSwelling
vItching
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vBurning SensationBiochemical Alterations
And
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Consequences Of Porphyrias
Enzyme Defect Of Heme
Pathway
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Blocks the Reaction Of Heme Pathway
Accumulates
--- Content provided by FirstRanker.com ---
PorphyrinsIntermediates of
Heme Pathways
--- Content provided by FirstRanker.com ---
High levels of Porphyrin in blood
,Tissues and Urine (Porphyrias)
Porphyrinogens are oxidized
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to Porphyrins.
Porphyrins are coloured
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pigments.Porphyrins are more stable
products.
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Accumulate in blood, tissues
and get excreted out through
--- Content provided by FirstRanker.com ---
urineEffects of Accumulated
Porphyrins and their Precursors
--- Content provided by FirstRanker.com ---
?Porphyria Sufferers ShowsqSevere Anemia
qNeurological Disturbances
qExtreme sensitivity to sunlight
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Porphyria sufferers has no
normal Heme biosynthesis.
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No normal Hb to transportOxygen to cells.
Hence suffer from Anemia.
--- Content provided by FirstRanker.com ---
Accumulation ofPorphyrinogens
in Brain and Skin can lead to:
--- Content provided by FirstRanker.com ---
qNeurological symptoms
q Photosensitivity
--- Content provided by FirstRanker.com ---
Enzyme block early inPorphyrin pathway prior to
formation of Porphyrinogens.
--- Content provided by FirstRanker.com ---
Accumulates ALA and PBG
Exhibits abdominal pain and
--- Content provided by FirstRanker.com ---
neuropsychiatric symptoms.Enzyme block occur later in
the Porphyrin pathway
--- Content provided by FirstRanker.com ---
Accumulates Porphyrinogens-CPG/PPG beneath skin.
Causes Photosensitivity
--- Content provided by FirstRanker.com ---
when Porphyrins exposed to
light about 400 nm.
--- Content provided by FirstRanker.com ---
The Porphyrins haveno useful function
Act as highly reactive
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oxidants, damaging to
tissues.
Porphyrins get excited at
--- Content provided by FirstRanker.com ---
400 nm.
Shows sharp absorption band
--- Content provided by FirstRanker.com ---
near 400nm (Soret band)Porphyrins reacts with
molecular Oxygen
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To form highly reactive
oxygen free radicals.
--- Content provided by FirstRanker.com ---
Injure Lysosomes and othercellular organelles.
Damaged Lysosomes release
--- Content provided by FirstRanker.com ---
their degradative enzymes .Causing variable degrees of
skin damage including
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scarring.
Porphyrias are characterized by
--- Content provided by FirstRanker.com ---
?Extreme sensitivity to light(exposure to sunlight causes
vesicular erythema),
--- Content provided by FirstRanker.com ---
? Excretes reddish-brown urine
? Possess reddish-brown teeth,
and ulcers
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Destruction of cartilage andbone
Causing the deformation of the
--- Content provided by FirstRanker.com ---
nose, ears, and fingers.
Mental aberrations, such as
--- Content provided by FirstRanker.com ---
hysteria, manic-depressivepsychosis, and delirium.
Porphyrias are cruelly referred to
--- Content provided by FirstRanker.com ---
as a Vampire's disease.
Thought to be a cause of the
--- Content provided by FirstRanker.com ---
madness of King George III.Can be caused by lead poisoning:
The fall of the Roman Empire!
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Porphyria
--- Content provided by FirstRanker.com ---
Diagnosis Of PorphyriasPorphyrias are rare, but
frightening conditions:
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Hard to diagnose and there is
no cure for Porphyrias.
Porphyrins Excreted
--- Content provided by FirstRanker.com ---
In Urine and Feces
Uroporphyrin excreted in
--- Content provided by FirstRanker.com ---
urine.ProtoPorphyrin excreted in
feces.
--- Content provided by FirstRanker.com ---
Coproporphyrin excreted
either in urine /feces.
--- Content provided by FirstRanker.com ---
Porphyrins are Coloredand Fluorescent.
Porphyrias are diagnosed by analysis of
--- Content provided by FirstRanker.com ---
Porphyrins in the laboratory.Spectrophotometry
Fluorometry
--- Content provided by FirstRanker.com ---
Woods lamp- Fluorescence in aqueouslayered viewed.
Based on quantitative Ehrlich's reagent
--- Content provided by FirstRanker.com ---
Watson Schwartz
Hoesch Test
Defective enzymes of
--- Content provided by FirstRanker.com ---
Porphyrias can be assayed
by various methods.
--- Content provided by FirstRanker.com ---
Enzyme Assay- HPLC.Acute Intermittent
Porphyria
--- Content provided by FirstRanker.com ---
(AIP)Acute Intermittent Porphyria
vThe most common type of
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Porphyria.
vAutosomal Dominant trait.
vSymptoms more common in
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females than males.
Acute Intermittent Porphyria
Type Of Porphyria-
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Acute/Hepatic/
Neurological Porphyria
Enzyme Defect Of AIP
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UPG I Synthase/PBG Deaminase
Biochemical Alteration In AIP
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No conversion of PBG toUPG III.
PBG and -ALA are
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abnormally elevated in
blood, tissues and urine.
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Manifestations Of AIPALA and PBG
accumulates in CNS.
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This causes excitation ofvisceral pain fibers
Leads to acute pain crises.
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ALA blocks the
action of GABA.
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Possess neurologicalsymptoms.
Symptoms of AIP are Acute
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and Intermittent.Symptoms does not occur
before puberty and shown at
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Adolescence.
(Due to Steroidal Hormone action)
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Person with AIP hasAffected GIT, Heart and Brain.
Abdominal colic pain
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No abdominal tenderness
Vomiting, Constipation
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Tachycardia, HypertensionNeuro toxicity
Behavioral changes, seizures
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AIP symptoms gets aggravatedduring:
vInfections
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vFastingvIntake of drugs
Diagnostic Test For AIP
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Watson and Schwartz Testusing Woods lamp ( UV lamp)
Detects urine Porphobilin.
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Treatment of AIPInfusion of Hematin
Represses ALA Synthase
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synthesis.Administration Of
Glucose.
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High cellular Glucose
prevents induction of ALA
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Synthase.Use of Sunscreens that
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filter out visible light,Can be used in
management of
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Photosensitive Porphyrias
The Madness of Inbreeding
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King George III : Severe abdominal pain, mental confusion,dark urine.
Enzyme Defects Responsible for The Porphyrias
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TypeEnzyme Involved
Major Symptoms
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Laboratory tests
Acute intermittent Uroporphyrinogen
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Abdominal painurinary Porphobilinogen
Porphyria
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synthase
Neuropsychiatric
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CongenitalUroporphyrinogen
Photosensitivity
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urinary uroporphyrin
Erythropoietic
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III CosynthasePorphyria
Porphobilinogen
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Porphyria cutanea
UPG
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Photosensitivityurinary uroporphyrin
tarda
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Decarboxylase
Porphobilinogen
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Variegate PorphyriaPPG Oxidase
Photosensitivity
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urinary uroporphyrin
Abdominal pain
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Neuropsychiatricfecal coproporphyrin
fecal Protoporphyrin
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ErythropoieticFerrochelatase
Photosensitivity
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fecal Protoporphyrin
protoporphyria
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red cell ProtoporphyrinGlobin Biosynthesis
The biosynthesis of Hemoglobin
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Globin Polypeptide chains isunder genetic control.
Using Protein synthetic machinery.
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Globin chain biosynthesis occurs
in cytosol on Polyribosomes.
Number And Types Of Globin
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Chains Biosynthesized
In Human Life
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6 different types of Globin chains areassociated with Normal Hb variants :
Globin
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Globin
Globin
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GlobinGlobin
Globin
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To biosynthesize these 6 types ofGlobin chains
Human being normally carry
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8 functional Globin genes
Arranged in two duplicate gene
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clusters.
Globin Gene Clusters
The -like cluster located on the
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short arm of chromosome 11
The -like cluster is located on
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the short arm of chromosome 16Globin polypeptide
chain biosynthesis
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begins in the yolk sac
At about 3 weeks' of
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gestation.Ontogeny of Globin Synthesis
Ontogeny of Globin Synthesis
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TimeRegion
Type of Globin
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Normal Hb Variant
Gene
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Type of Hb3 weeks of
Yolk Sac
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&
(Hb Gower I ( )2
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Gestation5 weeks of
Yolk Sac
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&
Hb Portland ( )2
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GestationHb G
ower II ( )
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2
6-30 weeks of
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Liver & spleen& &
Hb F ( )2
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Gestation
30 weeks of
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LiverHb A2 ( )2
Gestation
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At Birth
Bone Marrow
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& &Hb A ( )2
Hb F ( )2
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Synthesis of GlobinPrimary Structure Of
Globin
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The primary structure of globin
refers to the amino acid
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sequence of the various chaintypes.
Numbering from the N-terminal
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end identifies the position of
individual amino acids.
The specific number
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,and sequence of amino
acids in Globin chains
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Is very important for thenormal structure and
function of Hemoglobin.
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Secondary Structure of Globin
The secondary structure of all Globin
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chain types comprised of:9 Non-helical sections joined by 8
Helical sections.
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The Helical sections of Globin Chains
are identified by the letters A-H
While the non helical are
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identified by a pair of letters
corresponding to the adjacent
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helicese.g. NA (N-terminal end to the
start of A helix), AB (joins the A
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helix to the B helix) etc.
Tertiary Structure of Globin
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The secondary structure isfurther folded and bended on
its own to form 3 dimensional
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subunit.
To form a Tertiary structure of
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Globin.Heme gets incorporated in
the Heme pocket formed
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inside each Globin subunit.Quaternary Structure Of Hb
It is native conformational
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state of Hb/ Functional
form of Hb.
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Four subunits of tertiary
structure ,non covalently
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linkedTo form quaternary level
of organization of Hb.
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Assembly Of Hemoglobin
Although Heme and Globin
synthesis occur separately within
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developing red cell precursors,
Their rates of synthesis are
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carefully coordinated to ensure
optimal efficiency of Hb
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assembly.Synthesis of Hemoglobin
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HEMOGLOBIN SYNTHESISNormal structure of Hb
includes the structure and
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proportion of Globin chains
Which are necessary for the
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normal function of
Hemoglobin
Decreased Concentration of
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Hemoglobin in the red blood
cells
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Caused due to any abnormalityResults into a clinical
situation called Anemia
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Mechanisms RegulatingHemoglobin Synthesis
Formation of Hemoglobin is
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regulated by severalmechanisms:
The rate of Globin
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biosynthesis is
directly related to the
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rate of Hemebiosynthesis.
Heme stimulates
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Globin biosynthesis byInactivating an
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inhibitor of Globintranslation.
Negative feedback of
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Heme.
High concentrations of
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HemePrevent the mitochondrial
import of the first enzyme in
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Heme synthesis, ALA
Synthase ( ALAS).
The Concentration Of Iron
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An Iron Responsive Element-
binding protein (IRE-BP)
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binds to mRNAIron Response Elements (IRE-
BP) affects the translation of the
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mRNA for ALAS, Ferritin and
Transferrin receptors.
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Low Iron Levels =Low Heme Synthesis
Sufficient Iron Levels=
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Adequate Heme SynthesisDisorders Associated
To
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Globin Chain SynthesisOf Hemoglobin
Hemoglobinopathies
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Caused By
Abnormal Hb Variants
What are Abnormal Hb variants ?
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Abnormal Hb variants are
Hemoglobin's with:
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Normal Heme and Altered Globin ChainAbnormal Hb variants are
structurally abnormal
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The Abnormal Hb variants may
be abnormal functionally
Approximately 400
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abnormal Hb variants
are detected out.
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But not all abnormal Hbvariants affect the
normal function of Hb.
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Basic Cause For Formation Of
Abnormal Hb Variants
Mutations In Globin Genes
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Altered /Mutated
Globin Genes leads to
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form Abnormal Hbvariants.
Abnormal Hb Variants
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Occurs due to Mutation
in Globin Genes.
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Leads to defectiveGlobin chain synthesis.
Formation Of
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Abnormal Hb VariantsLeads To
Hemoglobinopathies
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What are Hemoglobinopathies?
Hemoglobinopathies are
genetic disorders
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associated to
Structurally and
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Functionally Abnormal
Hemoglobin variants.
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Structurally and
Functionally Abnormal
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Hb variants in human
body leads to
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HemoglobinopathiesTypes Of
Abnormal Hemoglobin
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Variantsand
Hemoglobinopathies
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Broadly two types
of Hb abnormalities
Qualitative
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Hb Abnormalities:
Mutations in Structural
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Globin genese.g. HbS-Sickle cell anemia.
Quantitative
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Hb Abnormalities:
Mutations in Regulatory
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Globin Genese.g. a Thalassemia
b Thalassemia
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QualitativeAbnormal Hb variants:
Caused due to mutations in structural
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Globin gene.
Has altered amino acid sequence in
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Globin polypeptide chain.Has altered Globin subunits in Hb
structure
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But Has Normal Heme Structure.
Examples of Common
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Abnormal Hb variantsAnd Corresponding
Hemoglobinopathy
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Due to Structural Globin Gene
Mutations
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ORSymptomatic Abnormal
Hb Variants
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Abnormal HbGlobin
Amino acid Altered
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Variants
Gene/Chain
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In Globin ChainAltered
Hb S
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6 GLU VAL
Sickle cell Hb
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Hb C6 GLU LYS
Cooley's Hb
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Hb D
121 GLU GLN
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Punjab HbHb E
26 GLU LYS
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Hb M
87 HIS TYR
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Hb has Fe+3Proximal
If noted most common abnormal Hb
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variants has:
Altered Globin genes and Globin
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chains.Substitution of Polar amino acid
"GLUTAMATE" with another amino
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acid.
Non Symptomatic
Abnormal Hb Variants
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Abnormal Hb Variants
?Hb P
?Hb Q
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?Hb N?Hb J
Consequences Of
Abnormal Hb Variants
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Presence of
Symptomatic Abnormal Hb Variants
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In RBCsAlters normal structure and
function of Hb
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Alters morphology of RBC's
Make RBC's fragile.
Causes Hemolysis, reduces Hb
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content and affects its function.Leads to Hemolytic Anemia
Increases Unconjugated serum
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BilirubinCauses Hemolytic Jaundice
Possess Splenomegaly -
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Increased function of Spleen toremove defective Erythrocytes
from the blood circulation.
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Detection Of
Abnormal Hb Variants
CBC and Blood Film Evaluation
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Solubility TestElectrophoresis
(Cellulose Acetate and Citrate Agar)
DNA Technology- PCR based
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techniques:DNA Finger Print Technique
Hybridization Technique
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Hemoglobinopathy-AntenatalDiagnosis
Check the Test partners of
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heterozygous or affected
individuals
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Antenatal diagnosis from DNAis obtained by chorionic villus
sampling, or by Amniocentesis
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CommonAbnormal Hb Variant
Causing
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Hemoglobinopathy
Sickle Cel Hemoglobin (HbS)
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Hb S is most
commonly occurring
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abnormal Hb variant.
Hb S leads to Hemoglobinopathy
Sickle Cell Anemia
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Biochemical Defect TO Form HbS
Formation of
Sickle Cell Hemoglobin (HbS)
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Is a classic example of
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point mutation(Transversion)
Point mutation is a
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substitution of
Nitrogen base in a
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normal Globin genesequence.
Substitution Of Nitrogen
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Base Which Forms Hb SAltered Nitrogen base
sequence in Beta Globin gene.
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There is substitution of
Nitrogen base Thymine to
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Adenine (T to A).On transcription of mRNA it
has altered codon, GAG to
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GUG
Altered amino acid
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substitution in the beta Globinchain.
Glutamate substituted by
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Valine
On translation at 6th position
of Globin chain polar amino
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acid GLU is substituted by
non polar amino acid VAL .
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This transforms HbA1 to HbS.Deoxystate of HbS
Affects Solubility
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HbS ? Is sickle cell Hb.Altered HbS affects
the solubility of Hb
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at Deoxystate in RBCs.HbS at low oxygen tension /
deoxy state forms Deoxy HbS.
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DeoxyHb S looses its polarity
/solubility
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Deoxy HbS forms protrusion onthe globin chain.
Sticky patch appears on HbS at
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deoxy state.
Each Hb S fits into this
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complementary site of another
globin chain.
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Many Hb S polymerizes insidethe RBC's
Forming a network of fibrous
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polymers.
HbS aggregates into long, rigid
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polymers are called Tactoids.
This makes HbS relatively
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insoluble and non functional.EM of Red
Blood Cell
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showing
`Tactoids'
Tactoids stiffen and distort
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the red blood cells.
RBC's changes morphology
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and appear sickled/crescentshaped.
Thus HbS Leads To
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Sickling of Erythrocytes and
hemolysis.
Sickled Erythrocytes
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may return to their
original shape when
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oxygenated.Effect of Sickled RBC's
And its
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Associated Complications
HbS Causes
Reduction of RBC life span to
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just 20 days.
Sickling of RBC's
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Distortion and lysis of RBC'sHemolysis
Sickling distorts and make
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RBC's fragile.
After several sickling
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episodes of RBC'sThere is irreversible damage
to RBC membrane.
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Thus Sickling Of RBC'scauses Sickle Cell
Anemia/Hemolytic
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Anemia.
Sickled cells are phagocytized
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by macrophages.In the spleen, Liver or bone
marrow.
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Sickling of RBC'smakes blood viscous
Lowers the rate of
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blood circulation.
Sickled cells has
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increased tendency toadhere to blood vessels.
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Rigid sickled cells unable tosqueeze out through small
capillaries
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Sickled cells get trapped in
small capillaries and block
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them.Sickling produces localized
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Anoxia/Tissue HypoxiaOxygen deprivation in the
tissues.
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Lowers ATP production in
cells.
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Anoxia in turn leads toincreased sickling process.
Sickling causes pain
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and infarction (death)of cells in tissues.
Sickling causes
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Spleen Dysfunction
Making the spleen
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non functionalSickling Increases
susceptibility towards tissue
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infectionPremature death of
individuals before 20 years
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due to infections.
Factors Increasing
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Sickling Of RBC'sExtent of RBC's sickling
is related to
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Amount of Hb Spresent in Erythrocytes.
Conditions Creating Hb S in Deoxy
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state:
Decreased pO2
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Increased pCO2Decreased pH
Increased 2,3 BPG
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Dehydration
Sickle Cel Anemia
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Sickle Cell Anemia is a genetic disorder
due to presence of abnormal Hb variant
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HbSIt is a Commonest type of a
Hemoglobinopathy
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It is a type of Hemolytic Anemia due to
Sickling of Erythrocytes
Inheritance of Sickle Cell Anemia
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Sickle Cell Disease is an
Autosomal recessive
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disorderPrevalence and Incidence
Prevalence of HbS
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Tropical areas
Africa
South America
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Incidence of HbS1:5000 births.
Biochemical Defect
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To CauseSickle Cell Anaemia
Sickle Cell Anemia is caused by
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a point mutation in structural
beta Globin gene
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Characterized by the presenceof abnormal HbS in
Erythrocytes.
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Hb S in Deoxy state promotesformation of hard, sticky,
sickled-shaped red blood
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cells ? Sickling of RBCs.
Types of Sickle Cell Anemia
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HbSS
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HbSS is sickle cell diseaseHomozygous state
Full blown disease
100% HbS concentration.
Both Globin genes of 2
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chromosomes are
mutated.
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Globin chain hasalteration at 6 Glu to Val
HbAS
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HbAS is sickle cell trait
Heterozygous state.
50% HbA1 and 50 % HbS
Symptoms are mild and less
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severe.
Fatality can be delayed.
Sickle cell trait offers
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protection from
Malarial parasites-
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Plasmodium falciparum.Hb SC Disease
Another red cell sickling disease
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Individual has mutant genes forboth Hb S and Hb C.
Has significant clinical variability
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Less severe anemiaLess painful crises.
Effects And Complications
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Of
Sickle Cell Anemia
Sickle Cell Anemia
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Leads To
Hemolytic Anemia
Hemolytic Jaundice
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Sickle Cell Anemia
Main Clinical Features
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?Hemolysis?Occlusion of blood
vessels by sickled red
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cellsHemolysis /Lysis of Sickled RBC
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Low Oxygen transport to tissues(Hemolytic Anemia)
Hemolytic Jaundice
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Tissue HypoxiaTissue Infarction
Tissue Infection
Painful Crisis
Fatality in severe cases
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Site of
Clinical Features Management
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SicklingBone
Painful crises
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Pain relief and hydrationHydroxyurea
Lung
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Acute chest
Transfusion regimen, pain
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syndromerelief and hydration
Brain
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Stroke
Transfusion regimen.
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HeartMyocardial
Transfusion regimen, pain
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infarction
relief and hydration
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SpleenAcute splenic
Transfusion, pain relief
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sequestration
and hydration
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SpleenHyposplenism
Pneumovax
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Retina
Proliferative
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Retinal surveil ance.retinopathy
Laser
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`Tactoids' form at low oxygentension
Stiff Sickled red cells occlude
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small blood vesselTissue Hypoxia and Infarction
Tissue Infections
Symptoms are more severe
Fatality confirmed
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Sudden death during
intensive training
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Hematuria, Isosthenuria(Renal Papillary Necrosis)
Infected RBC has incomplete life
cycle of parasites.
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Sickled erythrocytes efficiently
phagocytized and destroyed.
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Low K+ ion concentration in Hb Sis unfavorable for malarial
parasites to develop.
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Diagnosis of Sickle Cell Anemia
Sickling Test-
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Using Sodium Dithionitereducing agent on blood
smear
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Watch microscopically for
sickled RBC's.
Sickle Cel Anemia ? Blood film
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Sickle
Cel s
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ErythroblastsHowel -
Jol y Body
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Electrophoresis
Hb S is confirmed with
--- Content provided by FirstRanker.com ---
Cellulose AcetateElectrophoresis
--- Content provided by FirstRanker.com ---
At Alkaline pH during
Electrophoresis.
--- Content provided by FirstRanker.com ---
Hb S is less negativelycharged than Hb A1.
Hb S moves in a
--- Content provided by FirstRanker.com ---
position between Hb
A1 and Hb A2.
Hb S migrates more slowly
--- Content provided by FirstRanker.com ---
towards anode than Hb A1.
Altered mobility of HbS is due
--- Content provided by FirstRanker.com ---
to absence of negativelycharged Glutamate residue.
Sickle Cell Anemia - Treatment
--- Content provided by FirstRanker.com ---
Adequate hydration
Analgesics to relive pain
Aggressive Antibiotic therapy
--- Content provided by FirstRanker.com ---
to arrest the infection.Ingestion of 0.01 M of
Potassium or Sodium
--- Content provided by FirstRanker.com ---
Cyanate.Prevents sickling of RBC's and
its complications.
--- Content provided by FirstRanker.com ---
Opiates and hydration
for painful crises
--- Content provided by FirstRanker.com ---
Pneumococcalvaccination
Retinal surveillance
--- Content provided by FirstRanker.com ---
Hydroxyurea an antitumor drugUsed in therapy of Sickle cell
anemia.
--- Content provided by FirstRanker.com ---
Increases circulating levels of Hb FDecreases Sickling
Decreases painful crises
Reduces mortality
--- Content provided by FirstRanker.com ---
Blood Transfusionfor serious
manifestations
--- Content provided by FirstRanker.com ---
Support with Folate,
Iron chelation.
--- Content provided by FirstRanker.com ---
Stem cell transplantThalassemias
Thalassemia's are
--- Content provided by FirstRanker.com ---
HemoglobinopathiesCaused due to
defect/mutations in
--- Content provided by FirstRanker.com ---
Regulatory Globin
genes of Globin chain
--- Content provided by FirstRanker.com ---
synthesis.Individual suffering from
Thalassemia's has
--- Content provided by FirstRanker.com ---
Structurally andfunctionally unfavorable
abnormal Hb variants.
--- Content provided by FirstRanker.com ---
Thalassemias are
--- Content provided by FirstRanker.com ---
Autosomal recessiveblood disorders.
Thalassemias are
--- Content provided by FirstRanker.com ---
Characterized with AnemiaThalassemias mostly
occur in regions of
--- Content provided by FirstRanker.com ---
Mediterranean sea.
Also termed as
--- Content provided by FirstRanker.com ---
Mediterranean Anemia.Thalassemias are also
prevalent
--- Content provided by FirstRanker.com ---
In Arab,Americans, andAsians
In populations where
--- Content provided by FirstRanker.com ---
Malaria is endemic
Causes Of Thalassemias
Thalassemias due to
--- Content provided by FirstRanker.com ---
Regulatory Gene mutations
is a quantitative abnormality
--- Content provided by FirstRanker.com ---
of Hemoglobin.Mutations in Regulatory
Genes of Globin chain
--- Content provided by FirstRanker.com ---
synthesis.
Suppression of Globin
--- Content provided by FirstRanker.com ---
chain synthesis.Reduced/Absent of one or
more of Globin polypeptide
--- Content provided by FirstRanker.com ---
chain synthesis of Hb.Globin chains has normal amino
acid sequence.
--- Content provided by FirstRanker.com ---
Alpha Thalassemia ?
reduced alpha chain synthesis
--- Content provided by FirstRanker.com ---
Beta Thalassemia ?reduced beta chain synthesis
+ Reduced production of chains
--- Content provided by FirstRanker.com ---
0 complete absence of chains
Compensatory
--- Content provided by FirstRanker.com ---
Globin chain synthesisoccurs in Thalassemias.
--- Content provided by FirstRanker.com ---
Unbalanced production ofGlobin chains in
Thalassemias causes
--- Content provided by FirstRanker.com ---
Erythrocytes to be small,
hypochromic and sometimes
--- Content provided by FirstRanker.com ---
deformed.
Blood Picture Of Thalassemia
There occurs intracellular
--- Content provided by FirstRanker.com ---
accumulation of unmatched
Globin chains in the developing
--- Content provided by FirstRanker.com ---
ErythrocytesPrecipitation of the Proteins,
which leads to cell destruction in
--- Content provided by FirstRanker.com ---
the bone marrow.
Infective Erythropoiesis.
Mature functional RBC's
--- Content provided by FirstRanker.com ---
do not reach the
peripheral blood to carry
--- Content provided by FirstRanker.com ---
oxygen.Types of Thalassemia
Thalassemia Minor
--- Content provided by FirstRanker.com ---
Heterozygous StateAsymptomatic
Thalassemia Major
--- Content provided by FirstRanker.com ---
Homozygous TypeLethal at birth or in childhood.
Has many complications
Early and Continuous treatment
--- Content provided by FirstRanker.com ---
of Thalassemia allows survival toyoung adulthood .
-Thalassemia
--- Content provided by FirstRanker.com ---
Suppression of Globingenes
No/reduced globin chains
--- Content provided by FirstRanker.com ---
synthesis.
Compensatory more /
--- Content provided by FirstRanker.com ---
globin chains synthesized.Abnormal Hb in -Thalassemia
vHbH ? 4
--- Content provided by FirstRanker.com ---
vHb Bart - 4?Affect normal function of Hb
?Anemia
?Fetal death
--- Content provided by FirstRanker.com ---
Types Of Alpha Thalassemias/ Normal
/-
--- Content provided by FirstRanker.com ---
Mild microcytosis
/- -
--- Content provided by FirstRanker.com ---
Mild microcytosis-/-
-/- -
--- Content provided by FirstRanker.com ---
Hemoglobin H disease- -/- -
Hemoglobin Barts Disease ? Hydrops Fetalis
--- Content provided by FirstRanker.com ---
Silent Carriers of
Thalassemia
--- Content provided by FirstRanker.com ---
Out of 4 Gene there is missingof only 1 Gene.
Remaining 3 genes produces
--- Content provided by FirstRanker.com ---
sufficient chains for normal
Hb production.
--- Content provided by FirstRanker.com ---
1-2 % of Hb Bart in cord blood.Thalassemia Trait
2 Genes are deleted
Shows mild microcytic
--- Content provided by FirstRanker.com ---
hypochromic anemia
Occasionally Hb H inclusions
Cord blood contains 2-10% of Hb Bart.
--- Content provided by FirstRanker.com ---
Hb H inclusions can be seen
in RBC's after supra vital
--- Content provided by FirstRanker.com ---
stain.Cord blood contains 10-20%
Hb Bart.
--- Content provided by FirstRanker.com ---
Hb H DiseaseType of Thalassemia where 3
genes absent
--- Content provided by FirstRanker.com ---
Hb H present-Tetramer of chains.
Alters shape of RBC's
Shorten RBC life span.
Moderate hemolytic anemia.
--- Content provided by FirstRanker.com ---
Hb Bart Disease
Most clinically severe form
Thalassemia.
--- Content provided by FirstRanker.com ---
Where all 4 genes deletedTotal absence of chain
biosynthesis
Hb Bart major Hb found-
--- Content provided by FirstRanker.com ---
tetramer of chains.
Hydrops Fetalis
(Fetal Anemia causes Edema)
--- Content provided by FirstRanker.com ---
Hb Bart has extremely high
Oxygen affinity
--- Content provided by FirstRanker.com ---
Allows Oxygen transport but norelease at tissues.
Hypoxia
--- Content provided by FirstRanker.com ---
Still born infants/ die shortlyafter birth.
Beta Thalassemia
--- Content provided by FirstRanker.com ---
Beta ThalassemiaSuppression of Globin gene.
Reduced/ no production of
--- Content provided by FirstRanker.com ---
beta globin chains.Compensatory / Globin
chains biosynthesized.
--- Content provided by FirstRanker.com ---
Abnormal Hb in beta Thalassemia:HbF (22)
HbA2(22)
--- Content provided by FirstRanker.com ---
Types Of Beta Thalassemia
Beta Thalassemia minor
--- Content provided by FirstRanker.com ---
? heterozygous (or trait)Beta Thalassemia major
- homozygous
--- Content provided by FirstRanker.com ---
Beta Thalassemia TraitNo symptoms
Mild microcytic anemia
--- Content provided by FirstRanker.com ---
Beta Thalassemia MajorNo beta chain produced
(no HbA)
--- Content provided by FirstRanker.com ---
Cooley's Anemia
Homozygous disease
Beta Thalassemia Major
--- Content provided by FirstRanker.com ---
Crippling disease ofchildhood
Persistent HbF in age above 1
--- Content provided by FirstRanker.com ---
year
Reduced unloading of oxygen at
--- Content provided by FirstRanker.com ---
tissues.Premature destruction of RBC's.
Severe hypochromic
--- Content provided by FirstRanker.com ---
microcytic anemia occursgradually in the first year of life
Bone Marrow expansion
--- Content provided by FirstRanker.com ---
HypersplenismHepatosplenomegaly
MCV low
Severe Anemia
--- Content provided by FirstRanker.com ---
ReticulocytosisExtreme Poikilocytosis
(Different Shape ) and
--- Content provided by FirstRanker.com ---
Anisocytosis (Different Size).HPFH
Hereditary Persistence of
--- Content provided by FirstRanker.com ---
Fetal Hb (HPFH)It is a Genetic heterogeneous
disorder
--- Content provided by FirstRanker.com ---
Caused due to deletions of
Genes in chromosome 11.
--- Content provided by FirstRanker.com ---
Exhibits total absence ofand Globin chain synthesis.
Hb F(2 2) is the
--- Content provided by FirstRanker.com ---
predominant Hb present.
HPFH patients are
asymptomatic
--- Content provided by FirstRanker.com ---
If they are sedentary
and slow workers.
--- Content provided by FirstRanker.com ---
Diagnosis Of Thalassemia's
PCR based methods.
--- Content provided by FirstRanker.com ---
Gene MappingFor families that carry
a Thalassemia trait.
--- Content provided by FirstRanker.com ---
Genetic counselingand genetic testing is
recommended
--- Content provided by FirstRanker.com ---
Treatment Of Thalassemias
Repeated / frequent
--- Content provided by FirstRanker.com ---
blood transfusions.(After every 3- 4
months)
--- Content provided by FirstRanker.com ---
Due to repeated blood transfusionsin patients of Beta Thalassemia.
There exhibits Iron overload
--- Content provided by FirstRanker.com ---
Iron toxicity is noted since Iron isone way element
Iron once entered in blood do not get
--- Content provided by FirstRanker.com ---
excreted out.
Iron gets accumulated in functional
--- Content provided by FirstRanker.com ---
tissues.Tissue dysfunctions,
Growth failure and death
--- Content provided by FirstRanker.com ---
occurs before puberty due to
Iron toxicity.
--- Content provided by FirstRanker.com ---
However Iron chelation-Reduces Iron toxicity.
Folate supplementation
--- Content provided by FirstRanker.com ---
for promotion ofErythropoiesis
Azacytidine ? Drug used
--- Content provided by FirstRanker.com ---
with limited success
Bone marrow
--- Content provided by FirstRanker.com ---
transplantationStem cell transplant
Gene therapy
--- Content provided by FirstRanker.com ---
Abnormal Hb Variants
With Increased Oxygen Affinity
--- Content provided by FirstRanker.com ---
Hb BartHb H
Hb Chesapeake
Hb Rainier
--- Content provided by FirstRanker.com ---
Catabolism/Breakdown Of Hb
OR
--- Content provided by FirstRanker.com ---
Formation and Fate Of BilirubinOR
How Bilirubin is Formed and
--- Content provided by FirstRanker.com ---
Excreted ?
Catabolism of Hemoglobin
begin after destruction of
--- Content provided by FirstRanker.com ---
RBC's.
RBC destruction is normally
--- Content provided by FirstRanker.com ---
the result of senescence(Old/Aged).
Red cell destruction
--- Content provided by FirstRanker.com ---
usually occurs after a
mean life span of
--- Content provided by FirstRanker.com ---
120 days.The old red blood
cells are removed
--- Content provided by FirstRanker.com ---
Extravascularly byMacrophages of R.E
System.
--- Content provided by FirstRanker.com ---
Reticuloendothelial
system (RES), specially of
--- Content provided by FirstRanker.com ---
Spleen, Bone marrow andLiver are involved in RBC
destruction.
--- Content provided by FirstRanker.com ---
Essentials for ErythrocyteMembrane Integrity
Continuous supply of Glucose to
--- Content provided by FirstRanker.com ---
Erythrocytes
Continuous and uninterrupted
--- Content provided by FirstRanker.com ---
Glycolysis in RBCsContinuous minimal ATP
production in RBCs
--- Content provided by FirstRanker.com ---
RBC aging is characterized by:
Decreased Glycolytic enzyme
activity
--- Content provided by FirstRanker.com ---
Which leads to decreased
Glycolysis and ATP production
--- Content provided by FirstRanker.com ---
Subsequent loss of deformabilityand membrane integrity of RBCs.
Each day ~ 1% of the
--- Content provided by FirstRanker.com ---
RBCs are removedand replaced.
Approximately 2- 3 million old
--- Content provided by FirstRanker.com ---
RBCs removed and same amt
of new red blood cells enter
--- Content provided by FirstRanker.com ---
the circulation per second.This maintains constant RBC
count in blood.
--- Content provided by FirstRanker.com ---
80-90% of aged RBC destructionis Extravascular
Occurs mainly in the
--- Content provided by FirstRanker.com ---
Macrophages, Mononuclear
phagocytic cells of Spleen
--- Content provided by FirstRanker.com ---
Spleen is grave yard for RBC'sSmall amount occurring in the
RE system of Liver and Bone
--- Content provided by FirstRanker.com ---
marrow.
10-20 % of RBC destruction
--- Content provided by FirstRanker.com ---
is Intravascular, occurringin the lumen of the blood
vessels.
--- Content provided by FirstRanker.com ---
Senescent /old RBC'sin RES are lysed to
release its contents-
--- Content provided by FirstRanker.com ---
Hemoglobin (Hb)
Hb is degraded to:
--- Content provided by FirstRanker.com ---
Globins Amino AcidsRecycled Metabolism
Heme Bilirubin
--- Content provided by FirstRanker.com ---
excreted out of the body.Fe2+ Transported as
Transferrin
--- Content provided by FirstRanker.com ---
Iron stored as Ferritin
and reused in the next
--- Content provided by FirstRanker.com ---
Heme biosynthesisNot only Hb but
other Hemoproteins
--- Content provided by FirstRanker.com ---
containing Heme
groups are degraded
--- Content provided by FirstRanker.com ---
by the same pathway.Extravascular Erythrocyte
--- Content provided by FirstRanker.com ---
DestructionExtravascular Erythrocyte Destruction
is a normal pathway.
--- Content provided by FirstRanker.com ---
80-90% Erythrocytes destructed in
this manner.
--- Content provided by FirstRanker.com ---
Outside the circulatory system.Inside the phagocytic cells of Spleen,
Liver and Bone marrow.
--- Content provided by FirstRanker.com ---
Extravascular destruction of
RBCs
Intravascular Erythrocyte
--- Content provided by FirstRanker.com ---
Destruction
Erythrocytes destructed in
--- Content provided by FirstRanker.com ---
circulatory system.Normally 10 -20% erythrocytes
destructed in this manner.
--- Content provided by FirstRanker.com ---
Hb is directly released into blood
stream.
--- Content provided by FirstRanker.com ---
Hb in blood is bound toHaptoglobin.
Prevents renal excretion of
--- Content provided by FirstRanker.com ---
plasma Hb
Circulating Hb is removed
--- Content provided by FirstRanker.com ---
by Liver.Intravascular destruction of RBCs
--- Content provided by FirstRanker.com ---
Globin chains are broken
down to amino acids
--- Content provided by FirstRanker.com ---
Which are reutilized for
general protein synthesis
--- Content provided by FirstRanker.com ---
in the body.Heme part is
catabolized to
--- Content provided by FirstRanker.com ---
Bilirubin andexcreted out of the
body.
--- Content provided by FirstRanker.com ---
Microsomal enzyme Heme
Oxygenase of RE cells acts on
--- Content provided by FirstRanker.com ---
HemeRequires NADPH+H+ as a coenzyme
Cleaves Methenyl bridge of
--- Content provided by FirstRanker.com ---
cyclic tetrapyrrole ring of Porphyrin.
Forms Biliverdin ? A linear tetra
--- Content provided by FirstRanker.com ---
Pyrrole ring structure.
Iron is released in Ferrous is
oxidized to Ferric and
--- Content provided by FirstRanker.com ---
transported by Transferrin.
CO released is expired out.
--- Content provided by FirstRanker.com ---
Enzyme Biliverdin ReductaseReduces Methenyl bridges of Biliverdin
to Methylene bridges.
--- Content provided by FirstRanker.com ---
Reduces Biliverdin (Green bile pigment )
to Bilirubin ( Yellow bile pigment).
--- Content provided by FirstRanker.com ---
NADPH+H+ is used as reducing equivalentfor this reduction reaction by Biliverdin
Reductase.
--- Content provided by FirstRanker.com ---
Albumin Transports UnconjugatedBilirubin Through Blood.
1 gram of Hb yields 35 mg
--- Content provided by FirstRanker.com ---
of Bilirubin.
Daily 250-300 mg of
--- Content provided by FirstRanker.com ---
Bilirubin is produced by anadult.
Bilirubin formed in RE cells of a
--- Content provided by FirstRanker.com ---
Spleen after Heme catabolism andreleased in the blood circulation is:
Non polar
--- Content provided by FirstRanker.com ---
InsolubleFree or Unconjugated Bilirubin
Albumin a polar moiety
--- Content provided by FirstRanker.com ---
helps in transporting thisnon polar Bilirubin
--- Content provided by FirstRanker.com ---
Through aqueous phase ofblood circulation up to
Liver.
--- Content provided by FirstRanker.com ---
Albumin has two bindingsites for Bilirubin.
?High affinity binding site
--- Content provided by FirstRanker.com ---
?Low affinity binding siteBilirubin first tightly binds
to high affinity binding site
--- Content provided by FirstRanker.com ---
of Albumin.
25 mg of Bilirubin tightly
--- Content provided by FirstRanker.com ---
binds with Albumin in 100 mlblood.
Bilirubin bound
--- Content provided by FirstRanker.com ---
with AlbuminPrevents urinary
excretion of
--- Content provided by FirstRanker.com ---
Bilirubin in urine.
Drugs like Sulfonamides,
--- Content provided by FirstRanker.com ---
Penicillin, SalicylatesCompete with Bilirubin
for its binding to
--- Content provided by FirstRanker.com ---
Albumin.
Hypoalbuminemia
affects transport
--- Content provided by FirstRanker.com ---
and excretion of
Bilirubin.
--- Content provided by FirstRanker.com ---
Hypoalbuminemia maylead to retention of
Unconjugated Bilirubin
--- Content provided by FirstRanker.com ---
in blood circulation.
May cause Bilirubin
--- Content provided by FirstRanker.com ---
Encephalopathy.Facilitated transport
system helps in uptake of
--- Content provided by FirstRanker.com ---
Bilirubin in sinusoidalsurface of Hepatocytes.
Ligandin and Protein
--- Content provided by FirstRanker.com ---
Y of Hepatocytes
Prevent efflux of
--- Content provided by FirstRanker.com ---
Bilirubin back intoblood stream.
Conjugation Of Bilirubin
--- Content provided by FirstRanker.com ---
In LiverNon polar Bilirubin
entered in Liver
--- Content provided by FirstRanker.com ---
Undergoes conjugation
reaction
--- Content provided by FirstRanker.com ---
Conjugating agent is twomolecules of UDP-
Glucuronic acid
--- Content provided by FirstRanker.com ---
In presence of conjugatingenzyme UDP Glucuronyl
Transferase
--- Content provided by FirstRanker.com ---
Forms Conjugated Bilirubin-
Bilirubin Diglucuronide.
--- Content provided by FirstRanker.com ---
Conjugated Bilirubin is:Polar
Soluble form
Readily excretable form.
--- Content provided by FirstRanker.com ---
Conjugated Bilirubin is carriedthrough Bile via common bile duct
and excreted in the intestine
--- Content provided by FirstRanker.com ---
Secretion of Bilirubin into the
bile occurs by an active
--- Content provided by FirstRanker.com ---
transport mechanism.
Conjugated Bilirubin reaches terminal
--- Content provided by FirstRanker.com ---
ileum and large intestine.Glucuronides are removed by specific
bacterial enzymes- Glucuronidase.
--- Content provided by FirstRanker.com ---
Bilirubin is reduced to colorless
compound Stercobilinogen in
--- Content provided by FirstRanker.com ---
intestine.Small amount of Stercobilinogen is
reabsorbed and re excreted through
--- Content provided by FirstRanker.com ---
the Liver ? Enterohepaticcirculation.
Stercobilinogen is partly reabsorbed
--- Content provided by FirstRanker.com ---
enters in blood circulation is excreted
in urine as Urobilinogen and Urobilin.
--- Content provided by FirstRanker.com ---
Most of theStercobilinogen of
intestine is oxidized to
--- Content provided by FirstRanker.com ---
Stercobilin a orange
yellow colored
--- Content provided by FirstRanker.com ---
compound.Stercobilin is a
major excretable
--- Content provided by FirstRanker.com ---
form of Bilirubin infeces.
Futher Fate of Bilirubin
--- Content provided by FirstRanker.com ---
Bilirubin (Bil) is released from RES into the blood.
BUT! Bil is only poorly soluble in plasma, and therefore
during transport it is bound to albumin (Unconjugated
--- Content provided by FirstRanker.com ---
Bilirubin").
--- Content provided by FirstRanker.com ---
LIVERIn the hepatocytes, Bil is conjugated by 2 molecules of
glucuronic acid bilirubin diglucuronide (soluble in
--- Content provided by FirstRanker.com ---
water, ,,conjugated Bil")BILE
--- Content provided by FirstRanker.com ---
INTESTINE
Bilirubin is reduced to urobilinogen and stercobilinogen
--- Content provided by FirstRanker.com ---
BLOOD
CELLS
--- Content provided by FirstRanker.com ---
Stercobilin
excreted in
--- Content provided by FirstRanker.com ---
UrobilinHemoglobin
feces
--- Content provided by FirstRanker.com ---
excreted in
urine
--- Content provided by FirstRanker.com ---
GlobinUrobilinogen
Heme
--- Content provided by FirstRanker.com ---
formed by bacteria
KIDNEY
--- Content provided by FirstRanker.com ---
O2reabsorbed
Heme
--- Content provided by FirstRanker.com ---
INTESTINE
into blood
--- Content provided by FirstRanker.com ---
oxCyOgenase
Biliverdin IX
--- Content provided by FirstRanker.com ---
via bile duct to intestines
NADPH
--- Content provided by FirstRanker.com ---
BiliverdinBilirubin diglucuronide
reductase
--- Content provided by FirstRanker.com ---
(water-soluble)
NADP+
--- Content provided by FirstRanker.com ---
2 UDP-glucuronic acidBilirubin
Bilirubin
--- Content provided by FirstRanker.com ---
LIVER
(water-
--- Content provided by FirstRanker.com ---
(water-insoluble)via blood
insoluble)
--- Content provided by FirstRanker.com ---
to the
liver
--- Content provided by FirstRanker.com ---
Catabolism of HemoglobinNormal Red Cell Breakdown
--- Content provided by FirstRanker.com ---
HemoglobinHeme
Globin
--- Content provided by FirstRanker.com ---
Iron
Protoporphyrin
--- Content provided by FirstRanker.com ---
Amino acidsCO
Bilirubin
--- Content provided by FirstRanker.com ---
Transferrin
Expired air
--- Content provided by FirstRanker.com ---
(free)Liver
conjugation
--- Content provided by FirstRanker.com ---
Erythroblast
Bilirubin Glucuronides
--- Content provided by FirstRanker.com ---
Urobilin(ogen)Stercobilin(ogen)
Urine
--- Content provided by FirstRanker.com ---
Feces
Red Blood Cell Turnover
--- Content provided by FirstRanker.com ---
What Is Bilirubin ?Bilirubin is
Metabolic waste, an end product of Heme
--- Content provided by FirstRanker.com ---
catabolism
Formed in cells of RE system mainly in Spleen
--- Content provided by FirstRanker.com ---
Richly present in BileYellow colored Bile pigment
Carried through Bile for its excretion through
--- Content provided by FirstRanker.com ---
feces.
Recently a research
study has depicted
--- Content provided by FirstRanker.com ---
Bilirubin has an
Antioxidant capacity.
--- Content provided by FirstRanker.com ---
Bilirubin is majorly
excreted out through
--- Content provided by FirstRanker.com ---
feces in the form ofStercobilin.
(Yellow Orange pigment)
--- Content provided by FirstRanker.com ---
Types Of BilirubinFree/ Unconjugated /Indirect
Bilirubin
--- Content provided by FirstRanker.com ---
Non polar / insoluble form
Formed in RES- Spleen ,
--- Content provided by FirstRanker.com ---
LiverPresent in blood circulation
before entry into Liver cells.
--- Content provided by FirstRanker.com ---
Bilirubin Diglucuronide /Conjugated/
Direct Bilirubin
--- Content provided by FirstRanker.com ---
Polar/ Soluble form of
Bilirubin
--- Content provided by FirstRanker.com ---
Unconjugated Bilirubin istransformed to conjugated
Bilirubin in Liver.
--- Content provided by FirstRanker.com ---
Bilirubin-diglucuronide = Conjugated Bilirubin
is soluble in water "Direct Bilirubin"
Conjugated Bilirubin is formed
--- Content provided by FirstRanker.com ---
after conjugation reaction,
Conjugated with Glucuronate
Conjugated Bilirubin is
--- Content provided by FirstRanker.com ---
readily mixed with bile and
excreted out through feces.
--- Content provided by FirstRanker.com ---
Normal LevelsSerum Bilirubin
S.
--- Content provided by FirstRanker.com ---
Type Of Bilirubin
Normal
--- Content provided by FirstRanker.com ---
NoRanges
1
--- Content provided by FirstRanker.com ---
Total Bilirubin
0.2- 1 mg %
--- Content provided by FirstRanker.com ---
Direct+ Indirect2 Unconjugated/Indirect 0.2-0.8 mg%
Bilirubin
--- Content provided by FirstRanker.com ---
3
Conjugated / Direct 0- 0.2 mg%
--- Content provided by FirstRanker.com ---
BilirubinIn normal healthy
conditions there is
--- Content provided by FirstRanker.com ---
No conjugatedBilirubin in
circulating blood.
--- Content provided by FirstRanker.com ---
When Is Conjugated Bilirubin
is present in blood?
--- Content provided by FirstRanker.com ---
During obstruction in commonbile duct (CBD)
(Obstructive Jaundice)
--- Content provided by FirstRanker.com ---
Forms of BilirubinBilirubin - In Bile
Urobilin ? In Urine
Stercobilin - In Stool
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia
Hyperbilirubinemia
Increased levels of serum
--- Content provided by FirstRanker.com ---
Total Bilirubin
Above 1 mg% is termed
--- Content provided by FirstRanker.com ---
as Hyperbilirubinemia.Types Of Hyperbilirubinemia
Unconjugated
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia
Conjugated
--- Content provided by FirstRanker.com ---
HyperbilirubinemiaBiphasic Hyperbilirubinemia.
Causes of Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Over production Of BilirubinLess excretion of Bilirubin
Leads to retention of Bilirubin in
--- Content provided by FirstRanker.com ---
blood causing
Hyperbilirubinemia.
Causes of Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Hemolytic anemia
Hepatitis
--- Content provided by FirstRanker.com ---
Biliary duct stoneexcess
hemolysis
--- Content provided by FirstRanker.com ---
Unconjugated Bilirubin
Unconjugated
--- Content provided by FirstRanker.com ---
conjugated Bilirubin(in blood)
Bilirubin
--- Content provided by FirstRanker.com ---
(in blood)
conjugated Bilirubin
--- Content provided by FirstRanker.com ---
(in blood)(released to bile duct)
conjugated Bilirubin
--- Content provided by FirstRanker.com ---
(in blood)
Causes of Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
1.Conditions whichform excess Bilirubin
than the excreting
--- Content provided by FirstRanker.com ---
capacity of body.
Abnormal excessive intravascular
hemolysis
--- Content provided by FirstRanker.com ---
Overproduction of Bilirubin from Heme
catabolism.
--- Content provided by FirstRanker.com ---
More than the capacity of Liver toconjugate and excrete
Leads to Unconjugated
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia.
2.Conditions which
--- Content provided by FirstRanker.com ---
block excretion ofBilirubin out of the
body.
--- Content provided by FirstRanker.com ---
Failure of diseased Liver toconjugate and excrete
Bilirubin through bile.
--- Content provided by FirstRanker.com ---
In viral hepatitis
Leads to biphasic
Hyperbilirubinemia.
--- Content provided by FirstRanker.com ---
Obstruction to the flow of bile
Due to obstruction in bile duct.
Regurgitation of bile in systemic
--- Content provided by FirstRanker.com ---
blood circulation.Leads to conjugated
Hyperbilirubinemia.
--- Content provided by FirstRanker.com ---
3.Congenital / Inheriteddefects in uptake and
excretion of Bilirubin by
--- Content provided by FirstRanker.com ---
Liver
Leads to congenital
Hyperbilirubinemia.
--- Content provided by FirstRanker.com ---
4.Hypoalbuminemia / high
drug concentration in blood
Affects Bilirubin transportation
--- Content provided by FirstRanker.com ---
by Albumin
Retains Bilirubin in blood
Leads to Unconjugated
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia.
Diagnosis of Hyperbilirubinemia
Diagnosis of Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Vanden Bergh's Reaction
Quantitative estimation of
serum:
--- Content provided by FirstRanker.com ---
Total Bilirubin
Unconjugated Bilirubin
Conjugated Bilirubin
Types of Vanden Bergh's Reaction
--- Content provided by FirstRanker.com ---
Direct Vanden Bergh's Reaction
Estimates serum Conjugated
--- Content provided by FirstRanker.com ---
Bilirubin (soluble form)Serum Conjugated Bilirubin +
Diazo Reagent = Pink Azobilirubin
--- Content provided by FirstRanker.com ---
In the Direct Vanden BerghReaction soluble form of a Bilirubin
is directly and immediately
--- Content provided by FirstRanker.com ---
reacted with the Diazo Reagent.
Conjugated Bilirubin requires no
--- Content provided by FirstRanker.com ---
solubilizing agent.Hence Conjugated Bilirubin is
also termed as Direct Bilirubin
--- Content provided by FirstRanker.com ---
Indirect Vanden Bergh's Reaction
Estimates Serum Unconjugated
--- Content provided by FirstRanker.com ---
Bilirubin (Insoluble form)Serum Unconjugated Bilirubin +
Methanol/Surfactant (solubilizing
--- Content provided by FirstRanker.com ---
agent)+ Diazo Reagent = Pink
Azobilirubin
In an Indirect Vanden Bergh
--- Content provided by FirstRanker.com ---
Reaction
Insoluble form of Unconjugated
--- Content provided by FirstRanker.com ---
Bilirubin is first solubilized with asolubilizing agent (Methanol)
Then the solubilized form reacts with
--- Content provided by FirstRanker.com ---
Diazo reagent to form a pink
Azobilirubin complex
--- Content provided by FirstRanker.com ---
Unconjugated Bilirubin indirectlyreacts with the Diazo Reagent.
Since Unconjugated Bilirubin
--- Content provided by FirstRanker.com ---
requires solubilizing agent for
reaction with Diazo reagent.
--- Content provided by FirstRanker.com ---
Hence Unconjugated Bilirubin isalso termed as Indirect Bilirubin
Results and Significance
--- Content provided by FirstRanker.com ---
OfVanden Bergh's Reaction
S.No
--- Content provided by FirstRanker.com ---
Results of
Type of Hyperbilirubinemia/
--- Content provided by FirstRanker.com ---
Vanden BerghJaundice
1
--- Content provided by FirstRanker.com ---
Direct Vanden Conjugated Hyperbilirubinemia
Bergh's Reaction
--- Content provided by FirstRanker.com ---
Obstructive JaundicePositive
2
--- Content provided by FirstRanker.com ---
Indirect Vanden
Unconjugated
--- Content provided by FirstRanker.com ---
Bergh's ReactionHyperbilirubinemia.
Positive
--- Content provided by FirstRanker.com ---
Hemolytic Jaundice
3
--- Content provided by FirstRanker.com ---
Both Direct and Biphasic HyperbilirubinemiaIndirect Vanden
means
--- Content provided by FirstRanker.com ---
Bergh's Reaction
Both conjugated and
--- Content provided by FirstRanker.com ---
positiveUnconjugated Bilirubin
increased.
--- Content provided by FirstRanker.com ---
Hepatic Jaundice.
Significance Of
Vanden Bergh's Reaction
--- Content provided by FirstRanker.com ---
I. Quantitatively Estimates serum
Total, conjugated and
--- Content provided by FirstRanker.com ---
Unconjugated Bilirubin.II. From the levels of serum total
Bilirubin- Diagnoses Jaundice
--- Content provided by FirstRanker.com ---
III. From the serum levels of Direct and
Indirect Bilirubin levels-
--- Content provided by FirstRanker.com ---
Differentiate- Type of JaundiceIV. From the values of serum Bilirubin-
Indicate-Severity of Jaundice
--- Content provided by FirstRanker.com ---
Jaundice/Icterus ConditionJaundice is a
pathological/Clinical
--- Content provided by FirstRanker.com ---
condition
Characterized by
--- Content provided by FirstRanker.com ---
HyperbilirubinemiaIn Jaundice Total
Serum Bilirubin levels
--- Content provided by FirstRanker.com ---
are more than 2.5 mg %.High circulating
Bilirubin more than
--- Content provided by FirstRanker.com ---
2.5 mg% in blood
and tissues causes
--- Content provided by FirstRanker.com ---
jaundice.Jaundice is a yellow
--- Content provided by FirstRanker.com ---
discoloration to:Skin
Sclera of eyes
Nails
--- Content provided by FirstRanker.com ---
Mucous membraneCauses and Types Of Jaundice
Basic Cause and Consequence
--- Content provided by FirstRanker.com ---
Of JaundiceDefect in Heme catabolism
vOverproduction of Bilirubin
--- Content provided by FirstRanker.com ---
Defect in Bile excretion
?Less excretion of Bilirubin
--- Content provided by FirstRanker.com ---
Retains Bilirubin in blood andbody
--- Content provided by FirstRanker.com ---
JaundiceTypes Of Jaundice
Hemolytic/Pre Hepatic /Retention/
--- Content provided by FirstRanker.com ---
Acholuric JaundiceHepatic/Infectitious Jaundice
Obstructive/Post Hepatic/
--- Content provided by FirstRanker.com ---
Regurgitation /Choluric/CholestaticJaundice.
Neonatal Physiological Jaundice
--- Content provided by FirstRanker.com ---
Neonatal Pathological Jaundice
Erythroblastosis Foetalis
--- Content provided by FirstRanker.com ---
Breast Feeding JaundiceBreast Milk Jaundice
Sub Clinical Jaundice/ Latent
--- Content provided by FirstRanker.com ---
Jaundice-Serum Bilirubin levels between 1-3
mg%
--- Content provided by FirstRanker.com ---
Clinical Jaundice-
Serum Bilirubin levels more than
--- Content provided by FirstRanker.com ---
3 mg%.Hemolytic/ Prehepatic
/Retention Jaundice
--- Content provided by FirstRanker.com ---
Due to abnormal excessive
intravascular
--- Content provided by FirstRanker.com ---
hemolysis(premature) .Characterized by Unconjugated
Hyperbilirubinemia.
--- Content provided by FirstRanker.com ---
Healthy Body RBC Destruction
Normal human body brings approx.
--- Content provided by FirstRanker.com ---
200 billion RBC lysis per day
v 160 billion is Extravascular Lysis
v 40 billion is Intravascular lysis
--- Content provided by FirstRanker.com ---
Intravascular destruction of RBCs
Conditions Causing Abnormal
Excessive Intravascular Hemolysis
--- Content provided by FirstRanker.com ---
Sickle Cell Anemia
Thalassemia's
Glucose-6-Phosphate Dehydrogenase
--- Content provided by FirstRanker.com ---
deficiencyMismatched blood transfusion
Malaria
Burns
--- Content provided by FirstRanker.com ---
SpherocytosisDrug interactions
Excessive abnormal intravascular
hemolysis
--- Content provided by FirstRanker.com ---
Increased Heme catabolism
Increased Unconjugated Bilirubin
in blood
--- Content provided by FirstRanker.com ---
Levels of the Unconjugated Bilirubin
more than normal capacity of Liver
--- Content provided by FirstRanker.com ---
to conjugate and excrete (3 gm/day).Unconjugated Bilirubin is in
queue to enter Liver for
--- Content provided by FirstRanker.com ---
conjugation and excretion.
Thus there occurs retention of
--- Content provided by FirstRanker.com ---
Unconjugated Bilirubin inblood.
Laboratory Findings
--- Content provided by FirstRanker.com ---
InHemolytic Jaundice.
Blood Investigations
--- Content provided by FirstRanker.com ---
Results of Vanden Bergh's
Reaction
--- Content provided by FirstRanker.com ---
Total Bilirubin IncreasedIndirect Bilirubin Increased
Direct Bilirubin Normal
Urine Investigations
--- Content provided by FirstRanker.com ---
Ehrlich's Test for urineUrobilinogen ? Positive
Urine Urobilin increased.
--- Content provided by FirstRanker.com ---
Hays sulfur test for Bile salts-Negative
Fouchet's Test for Bilirubin-
--- Content provided by FirstRanker.com ---
Negative
Stool Appearance
--- Content provided by FirstRanker.com ---
Dark brown color feces inHemolytic Jaundice
Due to more Stercobilin
--- Content provided by FirstRanker.com ---
excreted out in feces.
Bone Marrow Examination
Hyperplasia of Bone marrow
--- Content provided by FirstRanker.com ---
Reticulocytosis in Peripheralblood smear
Immature form of RBC's
--- Content provided by FirstRanker.com ---
increased in blood circulation.
Hepatic/ Infectitious Jaundice
--- Content provided by FirstRanker.com ---
Liver Parenchymal damageDue to Viral Hepatitis
Biphasic
Hyperbilirubinemia.
--- Content provided by FirstRanker.com ---
Conditions Affecting LiverParenchymal Damage
Viral infection of Liver
--- Content provided by FirstRanker.com ---
( Viral Hepatitis)Liver Cirrhosis- Alcoholism
Drug Effects:
vRifampicin -affect cellular
--- Content provided by FirstRanker.com ---
uptake of Bilirubin by Liver cells
vNovobiocin -affect conjugation
--- Content provided by FirstRanker.com ---
of Bilirubin in Liver.Causes Of Biphasic
Hyperbilirubinemia in Hepatic
--- Content provided by FirstRanker.com ---
JaundiceIn Hepatitis damage and
inflammation of Liver parenchymal
--- Content provided by FirstRanker.com ---
cells.
This impairs and delays the
--- Content provided by FirstRanker.com ---
conjugation and excretion of Bilirubinby Liver.
This retains Unconjugated Bilirubin
--- Content provided by FirstRanker.com ---
in blood.
Inflammation of Hepatocytes
and intra hepatic obstruction
--- Content provided by FirstRanker.com ---
in hepatitis
Leaks out conjugated
--- Content provided by FirstRanker.com ---
Bilirubin in blood.Thus biphasic
Hyperbilirubinemia is noted.
--- Content provided by FirstRanker.com ---
In Hepatic Jaundice
there is a Marginal
--- Content provided by FirstRanker.com ---
increaseIn both serum
Unconjugated and
--- Content provided by FirstRanker.com ---
Conjugated Bilirubin
Laboratory Findings
In
--- Content provided by FirstRanker.com ---
Hepatic Jaundice
Blood Investigations
--- Content provided by FirstRanker.com ---
Results of Vanden Bergh's ReactionTotal Bilirubin increased
Indirect Bilirubin increased (Marginal)
Direct Bilirubin increased (Marginal)
--- Content provided by FirstRanker.com ---
Serum SGPT/ALT and SGOT/AST
activity increased.
Urine Investigations
--- Content provided by FirstRanker.com ---
Ehrlich's Test for urine
Urobilinogen ? Normal
--- Content provided by FirstRanker.com ---
Urine Urobilin normal.Hays sulfur test for Bile salts-
may be positive in severe cases.
--- Content provided by FirstRanker.com ---
Fouchet's Test for Bilirubin-maybe positive in severe cases.
Stool Appearance
--- Content provided by FirstRanker.com ---
Normal/ slightly pale colored
feces in Hepatic Jaundice.
Obstructive/ Post hepatic /
--- Content provided by FirstRanker.com ---
Regurgitative Jaundice
Due to obstruction in bile
--- Content provided by FirstRanker.com ---
flow to reach small intestine.Characterized with
Conjugated
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia.
Conditions Causing Obstructive
--- Content provided by FirstRanker.com ---
JaundiceObstruction of Bile duct due to
Gall stones in Common Bile
--- Content provided by FirstRanker.com ---
Duct(CBD).Narrowing of bile duct due to
surgery.
--- Content provided by FirstRanker.com ---
Tumor of head of Pancreas.
Enlargement of lymph glands
near Gall bladder /bile duct.
--- Content provided by FirstRanker.com ---
Causes Of Conjugated
Hyperbilirubinemia In Obstructive
--- Content provided by FirstRanker.com ---
Jaundice.Partial/ Complete Obstruction of
bile duct
--- Content provided by FirstRanker.com ---
Regurgitation of bile into systemiccirculation
Bile contains bile salts and bile
--- Content provided by FirstRanker.com ---
pigment- Bilirubin .
Hydrophilic Conjugated Bilirubin
--- Content provided by FirstRanker.com ---
is now in blood circulation.In Obstructive Jaundice
Bile get excreted out through urine.
--- Content provided by FirstRanker.com ---
Bile salts and conjugated Bilirubinpresent in urine.
Dark yellow colored urine noted
--- Content provided by FirstRanker.com ---
due to presence of Bilirubin occurs in
Obstructive Jaundice patients.
Laboratory Findings
--- Content provided by FirstRanker.com ---
In
Obstructive Jaundice.
--- Content provided by FirstRanker.com ---
Blood InvestigationsResults of Vanden Bergh's
Reaction
--- Content provided by FirstRanker.com ---
Total Bilirubin increased
Indirect Bilirubin normal
Direct Bilirubin increased
Serum ALP activity increased.
--- Content provided by FirstRanker.com ---
Urine InvestigationsEhrlich's Test for urine
Urobilinogen ? Negative
--- Content provided by FirstRanker.com ---
Urine Urobilin decreased.
Hays sulfur test for Bile salts-
Significantly Positive
--- Content provided by FirstRanker.com ---
Fouchet's Test for Bilirubin-
Significantly Positive
--- Content provided by FirstRanker.com ---
Stool AppearanceClay colored stools due to
absence of Stercobilin in feces of
--- Content provided by FirstRanker.com ---
Obstructive Jaundice.
Fatty stools due to excretion of
--- Content provided by FirstRanker.com ---
Lipids in feces(Absence of Bile salts in intestine).
Neonatal
--- Content provided by FirstRanker.com ---
Physiological JaundiceNeonatal - Physiological Jaundice
Noted in premature, low
--- Content provided by FirstRanker.com ---
birth weight infants.
After 1- 7 days of birth.
Causes
--- Content provided by FirstRanker.com ---
Immature hepatic system
in premature born infants
--- Content provided by FirstRanker.com ---
Poor uptake andconjugation of
Unconjugated Bilirubin
--- Content provided by FirstRanker.com ---
from blood by Liver
Low levels of Conjugating Enzyme
UDP- Glucuronyl Transferase
--- Content provided by FirstRanker.com ---
Delays the conjugation andexcretion of Bilirubin
Consequences
--- Content provided by FirstRanker.com ---
Physiological Jaundice exhibitsUnconjugated
Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Serum Bilirubin may raise up to
20 mg % or more
--- Content provided by FirstRanker.com ---
Unconjugated Bilirubin ishydrophobic
It can easily cross blood brain
--- Content provided by FirstRanker.com ---
barrier to enter central nervous
system.
--- Content provided by FirstRanker.com ---
Leading to Kernicterus(Bilirubin Encephalopathy)
Bilirubin accumulates in
--- Content provided by FirstRanker.com ---
Neurons of Basal Ganglia,Hippocampus Cerebellum
Medulla of Brain.
This causes necrosis of
--- Content provided by FirstRanker.com ---
nerve cells and brain
damage.
--- Content provided by FirstRanker.com ---
SymptomsFits/ Convulsions
Mental Retardation
Encephalitis
--- Content provided by FirstRanker.com ---
Spasticity(Skeletal muscle tightness and
stiffness)
Treatment
--- Content provided by FirstRanker.com ---
Phototherapy at 450 nm.
Exchange transfusions of blood
(When Serum Bilirubin > 20 mg%)
--- Content provided by FirstRanker.com ---
During Phototherapy baby is
exposed to uv light
--- Content provided by FirstRanker.com ---
The Bilirubin is transformed tosolubilized form of Bilirubin
--- Content provided by FirstRanker.com ---
Which is readily excretable outthrough urine.
?Blue / white UV light induces
--- Content provided by FirstRanker.com ---
isomerization?Of non polar , insoluble form of
Unconjugated Bilirubin ?Z isomer
--- Content provided by FirstRanker.com ---
?To water soluble, polar form of
Bilirubin- E isomer.
--- Content provided by FirstRanker.com ---
The phototherapyshould be exposed to
child's skin
--- Content provided by FirstRanker.com ---
Breast feed the child
every 2 to 3 hours
--- Content provided by FirstRanker.com ---
(10 to 12 times a day).Feeding prevents
dehydration and helps Bilirubin
--- Content provided by FirstRanker.com ---
to excrete out the body.Phototherapy will continue until
the baby's serum Bilirubin
--- Content provided by FirstRanker.com ---
levels are low enough to be
safe.
--- Content provided by FirstRanker.com ---
Neonatal-Pathological JaundiceErythroblastosis Foetalis
Hemolytic condition in
--- Content provided by FirstRanker.com ---
neonatesExtrinsic Cause of Hemolysis
Exhibits Unconjugated Hyper
--- Content provided by FirstRanker.com ---
Bilirubinemia
Cause
--- Content provided by FirstRanker.com ---
Caused due to Rh incompatibilityWhen Rh ? ve mother
conceives Rh + ve baby.
--- Content provided by FirstRanker.com ---
This causes excessive
hemolysis of Erythrocytes at
--- Content provided by FirstRanker.com ---
the time of birth.Neonatal
Pathological Jaundice
--- Content provided by FirstRanker.com ---
Non-Hemolytic CauseBreast Feeding Failure
Jaundice
--- Content provided by FirstRanker.com ---
Jaundice caused in new
born infants.
--- Content provided by FirstRanker.com ---
Due to insufficient/lackin breast feeding of milk
Infants born by cesarean
--- Content provided by FirstRanker.com ---
section are at higher riskfor this condition.
Due to no normal
--- Content provided by FirstRanker.com ---
Lactation phase.
Inadequate quantities of
--- Content provided by FirstRanker.com ---
milk reached to infantsbody.
Decreases body fluids
--- Content provided by FirstRanker.com ---
,lowers bowel movements
,impair to remove
--- Content provided by FirstRanker.com ---
Bilirubin from an infantsbody.
Proper feeding
--- Content provided by FirstRanker.com ---
prevents dehydrationHelps Bilirubin to
excrete out of the body
--- Content provided by FirstRanker.com ---
without its retention.
Condition of breast feeding
--- Content provided by FirstRanker.com ---
Jaundice can be ameliorated byFrequent breast feeding
sessions of sufficient
--- Content provided by FirstRanker.com ---
duration(10-12 /day)
This stimulate adequate milk
--- Content provided by FirstRanker.com ---
production by mothers breast.Extra fluids are helpful for babies who
have not been getting enough breast
--- Content provided by FirstRanker.com ---
milk.Nursing more often (up to 12 times a day)
Will increase the baby's fluid levels
--- Content provided by FirstRanker.com ---
Can cause the Bilirubin level to drop.Breast Milk Jaundice
Breast Milk Jaundice
--- Content provided by FirstRanker.com ---
Non Organic Cause
Breast milk Jaundice is more of a
--- Content provided by FirstRanker.com ---
biochemical problemProbably caused by
factors/chemicals present in the
--- Content provided by FirstRanker.com ---
Breast milk.
These may block certain Proteins/
--- Content provided by FirstRanker.com ---
Enzymes in the infant Liver thatmetabolize Bilirubin.
Breast Milk Jaundice tends to
--- Content provided by FirstRanker.com ---
run in families
It occurs equally often in Males
--- Content provided by FirstRanker.com ---
and FemalesAffects 0.5 % to 2.4% of all
newborns.
--- Content provided by FirstRanker.com ---
Hypothesized MechanismsIncreased levels of Epidermal
Growth Factor (EGF) in Breast
--- Content provided by FirstRanker.com ---
milk.
Increased Bilirubin uptake from
--- Content provided by FirstRanker.com ---
the gut (enterohepaticcirculation) in breast fed babies.
In a new born Liver, activity of
--- Content provided by FirstRanker.com ---
Glucuronyl Transferase is only at 0.1-
1% of adult levels
--- Content provided by FirstRanker.com ---
Conjugation of Bilirubin in infants isreduced in comparison to adults.
Further inhibition of Bilirubin
--- Content provided by FirstRanker.com ---
conjugation by other agents leads
to increased levels of Bilirubin in the
--- Content provided by FirstRanker.com ---
blood.Breast-milk of some women contains a
metabolite of Progesterone called
--- Content provided by FirstRanker.com ---
3-Alpha-20-beta Pregnanediol.This metabolite inhibits the action of
the conjugating enzyme Uridine Di
--- Content provided by FirstRanker.com ---
Phospho (UDPGA) Glucuronyl
Transferase.
--- Content provided by FirstRanker.com ---
This brings poor conjugation andsubsequent excretion of Bilirubin.
An enzyme in breast milk called
--- Content provided by FirstRanker.com ---
Lipoprotein Lipase produces increased
concentration of non esterified free
--- Content provided by FirstRanker.com ---
fatty acidsThat inhibit Hepatic UDP Glucuronyl
Transferase
--- Content provided by FirstRanker.com ---
Which again leads to decreased
conjugation and subsequent excretion of
--- Content provided by FirstRanker.com ---
Bilirubin.Mothers taking drugs like Novobiocin,
Steroidal derivatives or Rifampicin
--- Content provided by FirstRanker.com ---
Drugs secreted through breast milkInfant fed by this milk has drug inhibitory
effect on Bilirubin metabolism.
--- Content provided by FirstRanker.com ---
Delay in Bilirubin uptake andconjugation in infants Liver.
Leads to Unconjugated Hyperbilirubinemia.
--- Content provided by FirstRanker.com ---
Management Of
Breast Milk Jaundice
--- Content provided by FirstRanker.com ---
Temporary stoppage of breastmilk feeding
Till the drug is cleared away
--- Content provided by FirstRanker.com ---
from the breast fed milk.
Congenital Hyperbilirubinemia
Congenital Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Genetic defects in Bilirubin
uptake, conjugation and
--- Content provided by FirstRanker.com ---
excretion of BilirubinLeads to elevated levels of
Bilirubin in infants blood and
--- Content provided by FirstRanker.com ---
body tissues.
Congenital Defect
Type Of
--- Content provided by FirstRanker.com ---
Disorders
Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Gilbert'sDefect in
Unconjugated
--- Content provided by FirstRanker.com ---
Syndrome
uptake
--- Content provided by FirstRanker.com ---
Hyperbilirubinemiaof
Bilirubin
--- Content provided by FirstRanker.com ---
by Liver
cells
--- Content provided by FirstRanker.com ---
Congenital DefectType Of
Disorders
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia
Crigler
--- Content provided by FirstRanker.com ---
CompleteUnconjugated
Najjar
--- Content provided by FirstRanker.com ---
absence of
Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
Syndrome-Ienzyme
UDP-
--- Content provided by FirstRanker.com ---
Glucuronyl
Transferase
Congenital Defect
--- Content provided by FirstRanker.com ---
Type Of
Disorders
--- Content provided by FirstRanker.com ---
HyperbilirubinemiaCrigler
Partial
--- Content provided by FirstRanker.com ---
Unconjugated
Najjar
--- Content provided by FirstRanker.com ---
absence ofHyperbilirubinemia
Syndrome-
--- Content provided by FirstRanker.com ---
enzyme
II
--- Content provided by FirstRanker.com ---
UDP-Glucuronyl
Transferase
--- Content provided by FirstRanker.com ---
Congenital Defect
Type Of
--- Content provided by FirstRanker.com ---
DisordersHyperbilirubinemia
Dubin
--- Content provided by FirstRanker.com ---
Defect in
Conjugated
--- Content provided by FirstRanker.com ---
Johnson's HepaticHyperbilirubinemia
Syndrome/ excretion
--- Content provided by FirstRanker.com ---
of
Deposition of Bilirubin
--- Content provided by FirstRanker.com ---
Black Liver conjugatedin Liver
Jaundice
--- Content provided by FirstRanker.com ---
Bilirubin
Congenital Defect
Type Of
--- Content provided by FirstRanker.com ---
Disorders
Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
RotorsUnknown
Conjugated
--- Content provided by FirstRanker.com ---
Syndrome Autosomal
Hyperbilirubinemia
--- Content provided by FirstRanker.com ---
RecessiveInheritance Deposition of Bilirubin
in Liver
--- Content provided by FirstRanker.com ---
Conditions Causing
Unconjugated Hyperbilirubinemia
Conditions Causing
--- Content provided by FirstRanker.com ---
Unconjugated Hyperbilirubinemia
Hemolytic Jaundice
Hepatic Jaundice
--- Content provided by FirstRanker.com ---
Neonatal/ Physiological JaundiceBreast Milk Jaundice
Gilbert's Syndrome
Crigler Najjar Syndrome
Hypoalbuminemia
--- Content provided by FirstRanker.com ---
High Drug Concentration lowering Albuminactivity.
Conditions Causing Conjugated
--- Content provided by FirstRanker.com ---
Hyperbilirubinemia
Obstructive Jaundice
Hepatic Jaundice
--- Content provided by FirstRanker.com ---
Dubin Johnson's SyndromeRotors Syndrome
Differential Diagnosis Of Jaundice
Parameters
--- Content provided by FirstRanker.com ---
Hemolytic
Hepatic
--- Content provided by FirstRanker.com ---
ObstructiveJaundice
Jaundice
--- Content provided by FirstRanker.com ---
Jaundice
Serum Bilirubin Indirect Bilirubin/
--- Content provided by FirstRanker.com ---
BiphasicDirect Bilirubin/
Unconjugated
--- Content provided by FirstRanker.com ---
Both Direct
Conjugated
--- Content provided by FirstRanker.com ---
Bilirubinand
Bilirubin
--- Content provided by FirstRanker.com ---
increased
Indirect
--- Content provided by FirstRanker.com ---
IncreasedBilirubin
Increased
--- Content provided by FirstRanker.com ---
Urine
Increased
--- Content provided by FirstRanker.com ---
Normal orAbsent or
Urobilinogen
--- Content provided by FirstRanker.com ---
Decreased
Decreased
--- Content provided by FirstRanker.com ---
Urine BilirubinAbsent
May present in
--- Content provided by FirstRanker.com ---
Present in high
and Bile Salts
--- Content provided by FirstRanker.com ---
small amountsamounts
Fecal Stercobilin
--- Content provided by FirstRanker.com ---
Increased
Normal or
--- Content provided by FirstRanker.com ---
In traces orColor Of Feces
Dark color feces
--- Content provided by FirstRanker.com ---
Decreased
absent
--- Content provided by FirstRanker.com ---
Clay coloredfeces
Serum ALT
--- Content provided by FirstRanker.com ---
Normal
Significantly
--- Content provided by FirstRanker.com ---
May be slightlyactivity
Increased
--- Content provided by FirstRanker.com ---
increased
Serum ALP
--- Content provided by FirstRanker.com ---
NormalMay slightly
Significantly
--- Content provided by FirstRanker.com ---
activity
increased
--- Content provided by FirstRanker.com ---
IncreasedQuestions
SHORT NOTES
--- Content provided by FirstRanker.com ---
Outline of Heme BiosynthesisPorphyrias: Types , Causes
and Consequences
--- Content provided by FirstRanker.com ---
Acute Intermittent Porphyria(AIP).
Catabolism of Hb /Fate &
--- Content provided by FirstRanker.com ---
Formation of Bilirubin.Jaundice & its types.
Vanden-Berg's Reaction
--- Content provided by FirstRanker.com ---
and its significance.Name the enzymes of Heme
Biosynthesis inhibited during
--- Content provided by FirstRanker.com ---
lead poisoning. What is its
consequence?
--- Content provided by FirstRanker.com ---
Comparison between abnormalHb derivatives & abnormal Hb
variants.
--- Content provided by FirstRanker.com ---
Abnormal Hb variantsHemoglobinopathies
Sickle Cell Anemia
Thalassemias
Thalassemia
--- Content provided by FirstRanker.com ---
ThalassemiaName the Bile pigments &
give the significance of their
--- Content provided by FirstRanker.com ---
presence in blood & urine.
Laboratory reports of
--- Content provided by FirstRanker.com ---
Obstructive Jaundice.When and Why Bilirubin
comes in Urine Explain?
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Neonatal JaundiceBreast Milk and Breast
Feeding Jaundice
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CongenitalHyperbilirubinemias
Write the defect & type of
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Hyperbilirubinemia in
Crigler's Najjar Syndrome-I
Crigler's Najjar Syndrome-II
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Gilbert's Disease.Dubin Johnson Syndrome.
THANK YOU
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