Download hydroxyurea therapy

PREVENTION OF SICKLE-CELL DISEASE BY
DTN FORMULA OF GENETIC COUNSELING
AND
TREATMENT BY
HYDROXYUREA THERAPY
DEFINITION
Sickle Cell Anemia the Clinical Expression
of Homozygosity for HbS is a Serious
Disease characterised by;
?
Unrelenting Hemolytic Anemia
?
Recurrent Episodes of Pain and
Fever
?
Pathological involvement of many
organs of the body
HISTORY
Sickle-cell disease has been known to the people of Africa for
hundreds of years.In west-Africa various ethnic groups give the
condition different names i.e. GA TRIBE, FAUTE TRIBE, EWE TRIBE
etc.
?
In 1910 a Chicago Physician James B . Herrick noted in an
Anemic patient unusual red cells “Sickle Shaped” the patient was a
West-Indies.
?
In 1940 Sherman( a student of John Hopkin Medical School)
proved that low oxygen tension altered the structure of
Heamoglobin.
?
In 1948 Janet Watson a Pediatric Haematologist in Newyork
found out that the paucity of sickle cell in peripheral blood of new
born was due to presence of HbF in the red cells.
?
HISTORY (Contd…)
?
Linus Pauling and Harvey Hano showed in 1948 the technique of
Protein Electrophoresis. They detected by electrophoresis that
sickle cell disease is due to a fault in a Protein.
?
In 1956 Vernom Inquam and J.A.Haunt at MRC in England showed
that in a sickle-haemoglobin glutamic acid at 6th position of beta
chain was replaced by valine.This made sickle cell disease the
first genetic disorder whose molecular basis was known.
?
In may 18th , 1995 the new England journal of medicine reported
that Hydroxyurea is the first agent that can prevent episodes of
Vasso-oclusive painful crisis , Hospitalisation, ACS(acute chest
syndrome), incidence of blood transfusion.
TYPES
Sickle cell disease is a genetically
transmitted Hereditary disease. If both
the parents are having the disease all
the offsprings born to them are likely to
inherit.
This disease is of two types;
1. Disease
2. Trait
PREVALENCE
This disease is found in the following
countries of the world
? Africa
? South America
? West-Indies
? India
? Saudi-Arabia
? Italy
? Greece
? Syria
In India a sickle cell belt prevails
in which the following states are
included.
? Jharkhand
? Orissa
? Chhatishgarh
? Madhya Pradesh
? Andhra Pradesh
? Karnatak
? Gujarat
In Orissa the following un-divided
Districts are in the sickle cell belt;
? Kalahandi
? Balangir
? Koraput
? Sambalpur
? Mayurbhanj
? Keonjhar
? Boudh-Phulbani
? Sundargarh
? Dhenkanal
? Ganjam
The following races residing in the above
Districts suffer from this disease ;
?SCHEDULE CASTE
?SCHEDULE TRIBE
?AGARIA
?TELI
?SUNDHI
?RAJPUT
?PAIKA
?BANKA
?GAUDA
?DUMAL
?
?
?
?
?
?
?
?
?
?
KURMI
CHASA
KULTHA
BHULIA
KAMARA
CHAMAR
MAHARANA
BADHEI
KUMBHAR
MALI
? The
disease cases suffer from
child hood with crisis and survive
with blood transfusions.
? The
trait cases almost lead a
normal life.
CAUSE OF SPREAD OF DISESASE
The spread is due to marriage between
? DISEASE
? DISEASE
? TRAIT
+
+
+
DISEASE
TRAIT
TRAIT CASES
This is happening in the above
mentioned innocent races without their
knowledge for the last hundreds of
years.
SOLUTION
To break this chain the DTN
formula of Genetic Counseling was
submitted to Govt. in 1994. If this
formula will be adopted the next
generation will be saved from dreaded
“DISEASE” cases.
STEP-1
The above mentioned races will be
made aware by extensive programmes
about the seriousness of the disease
how it is responsible for increased
infant and maternal mortality rate
among them. They will be educated
about the cause of spread of the
disease.
STEP-2
They will be informed to get their
blood examined by electrophoresis
machine in the pre-marital age.
STEP-3
The result of examination will divide the
society into 3 groups;
Result shortly known as
DISEASE
TRAIT
NORMAL
-------
D
T
N
Marriage will be allowed or disallowed in the
following manner
D +D
D+T
T+T
NOT ALLOWED
D+N
T+N
ALLOWED
N+N
* DISEASE - D, TRAIT - T, NORMAL - N
Genetic Explanation to the Formula
GENETICALLY
D
T
N
D
-------------- SS
-------------- AS
-------------- AA
+
D
SS
SS
SS
SS
SS
SS
D
+
T
SS
AS
AS
SS
AS
SS
T
+
T
AS
AA
AS
SS
AS
AS
This is happening in the above
mentioned innocent races without
their knowledge for the last hundreds
of years. Hence plenty of SS or
disease cases in the society.
If the DTN Formula will be
adopted…
D
+
SS
N
AA
AS
AS
AS
AS
T
+
N
AS
AA
AA
AS
AA
AS
N
+
N
AA
AA
A A
AA
AA
AA
HYDROXYUREA THERAPY
Hydroxyurea is a CHEMOTHERAPEUTIC
agent with potent effects on BONE
MARROW, producing HbF in the Red
Blood Cells.
TREATMENT DETAILS
? Baseline
measurements- at least 2 months of
baseline information on the HEMATOLOGIC status of
patients with sickle cell disease should be available
before starting treatment.
? Starting
dose-HYDROXYUREA can be started at a
dose of 10 mg/kg, orally, on a daily basis.
? Dose
escalation- the dose can be increased at a
rate of 5mg/kg/week as long as the HAEMATOLOGIC
values remain in an acceptable range.
? Maximum
? Trial
dose - 25mg/kg.Day
period - 6 to 9 months therapy to continue
before any decision on the efficacy of the treatment.
LEAMITING EFFECTS
? Platelet
count of less than 80,000/cu.mm
? Neutrophil count of less than 2,500/cu.mm.
? Haemoglobin of less than 6 gm/dl
? Hair loss, Gi Upset, rash.
Foetal haemoglobin level rises in almost all
patients but the response is variable.
?
Contraindications
Pregnancy
? Poor or erratic follow -up
? Allergy to hydroxyurea
? Use in children-many centres have advocated to use
in children above 2 years of age.
?
AN OVERVIEW OF HAEMOGLOBIN
? What
is haemoglobin ?
It is a protein carried by red cells. It picks
up oxygen from the lungs and delivers to the
peripheral tissues to maintain the viability of
cells. Hb is made from 2 similar proteins that
“stick together”. One is Alfa the other is Beta.
Before birth the Beta Protein is not expressed.
The Hb protein found only during foetal
development is Gamma, substitutes till birth.
Abv. - Hb for Haemoglobin.
HOW IS Hb MADE?
Like all proteins the “blueprint” for
Hb exists in DNA (the material that
makes up genes normally). An individual
has 4 genes that code for Alfa Protein or
Alfa Chains. 2 other genes code for Beta
Chains. (2 additional genes code for
Gamma Chains in the Foetus.) The Alfa
and Beta Chains are in equal numbers
despite
the
differing
number
of
genes.The protein chains join in
developing red cells and remain together
for the life of the red cell.
HOW DO ABNORMAL Hb ARISE?
The composition of Hb, is the same in all people. The genes
that code for Hb are identical through out the world.
Occasionally however one of the genes is altered by any of a
variety of “accident” that can occur in nature.These alterations
in the genes (called MUTATION) are very rare. Since genes are
inherited (half from mother and half from father) and they
contain the information needed to make a protein. If a mutation
produces an abnormal Hb. Gene in a person, the gene will be
passed on to their children. Most mutations in Hb produce no
problem. Occasionally however the alteration in the protein can
be problematic as it occurs in SICKLE CELL DISEASE and
THALASSAEMIA.
WHAT HAPPENS IF A Hb. GENE “ BURNS OUT ” ?
?
A separate gene determines the amino acid sequence of each
of the globins chains.
?
A single substitution in one type of Polypeptide Chain is
accounted for replacement of one Nucleotide in a RNA
Condone.
?
The abnormality of “Sickle Hemoglobin” can be attributed to a
change in a single purine base in the Condone which
specifies the 6th Amino acid of Beta Chain with the result that
Glutamic Acid is replaced by Valine.
?
This is called “Point Mutation” and accounts for several
inherited HAEMOGLOBINOPATHIES like:- Hb C,Hb E, Hb D,
Hb GUNHILL, Hb PUNJAB, Hb LEPORE, Hb FRIEBURG etc.
WHAT IS THALASSAEMIA?
?
Genes can suffer to an extend that they no longer produce
normal amount of HAEMOGLOBIN.
?
Usually one of the sets of Hb. Is affected:-the Alfa Gene
Set or the Beta Gene Set.
?
if Beta Globin Gene fails to produce a normal quantity of
beta chain the Alfa Gene Set will continue to produce a
normal quantity of Alfa Chain protien.
?
The result is that there is a imbalance in the amount of
Alfa Chain and Beta Chain Protein. This imbalance is
called “THALASSAEMIA”.
?
If beta gene set fails it is BETA THALASSEAMIA and Alfa
Gene Set failure is called ALFA THALASSAEMIA.
Why the disease is confined to a certain area?
? HAEMOGLOBINOPATHIES
occur as a
result of gene mutation.
? Very
high frequency for harmful
mutants are maintained in some
areas of the world probably by strong
selective pressure.
Red-Cell Dehydration in PATHOPHYSOLOGY
and treatment of Sickle Cell Disease
Abstract
Cells with a markedly increased Hbs concentration
are a prominent feature of sickle cell disease, as a
consequence of the loss of K-Cl and water from the
RBC. The extreme dependence of polymerization
kinetics on Hbs concentration means that these
dehydrated RBCs rapidly sickle when deoxygenated.
Blockade of k loss from the RBC should therefore
prevent the increase in Hbs concentration and reduce
RBC sickling.
TWO ION TRANSPORT PATHWAYS, THE K-CL COTRANSPORT AND
THE CA+ ACTIVATED K+ CHANNEL PLAY PROMINENT ROLES IN THE
DEHYDRATION OF RBC.
? Hence the possible THERAPEUTIC strategy may be inhibition
of K-CL co transport by increasing mg + in RBC,or the CA+
activated K channel by oral administration of CLOTRIMAZOLE.
? Deoxygenation leads to formation of Hbs polymers and cell
sickling.
? Kinetics of Hbs Polymerization shows a LATENCY PHASE
preceding the formation of polymer strands and their
explosive growth inside RBC.
? This LATENT PHASE(DELAY TIME) is inversely proportional
to the Hbs concentration in RBC.Small changes in Hbs
concentration markedly affect Hb polymerization and cell
sickling.
? The delay time plays a crucial role in the PATHOPHYSIOLOGY
of sickle cell disease.
REHYDRATION THERAPY
Contd..
? The time required for the RBC to move from arterial end to
cell-deoxygenating-then to venous end of the capillary network
is called CAPPILARY TRANSIT TIME.
? If the delay time is shorter than the capillary transit time,
sickling will occur in the capillaries—hence VASSO-OCLUSIVE
CRISIS.
? If the delay time is prolonged so that it exceeds the capillary
transit time Polymerization and Sickling will occur in the
venules---hence no vasso-oclusion and no crisis.
? One of the distinguishing characteristics of SICKLE RBC is
the presence of cell dehydration.
? The fraction of red cells containing dense dehydrated cells
with increased cell Hbs concentration, (to values of 40-50 gm/dl
compared with the normal 33gm/dl) has the highest percent of
irreversibly Sickle Cells(ISC),which maintain their deformed
shape even in the presence of normal oxygen tension.
NEWER THERAPIES
?
Hydroxyurea
?
Erythropoietin
?
Butyrate
?
Clotrimazole
?
Nitric Oxide
?
FluocorTM
?
Bone marrow transplantation
?
Gene replacement therapy
If the DTN formula will be obeyed Not a single SS or
“DISEASE” case will appear in the society. Let us join our hands to
save the next generation from dreaded “DISEASE” cases.To
elaborate more the “DISEASE” cases are very less about 0.1% and
trait cases are about 7-10% in the society. Hence for genetic
counseling we get about 90% normal cases. One should not be panic
and
let
us
proceed
for
examination
of
blood
for
Hb
-
ELECTROPHORESIS before marriage. Our target is the pre-marital
age group.Take a vow that each couple is to adopt DTN formula.
Special attention to be given for exclusion of THALASSAEMIA and
G-6-PD deficiency also. In the next generation “DISEASE” cases will
be nil. In subsequent generations trait cases will be also very less. It
may so happen that we will have to search for trait cases.
THANK YOU
P a d h y ,
-O r i s s a S ic k le C e ll D is e a s e s R e a s e r c h
P r o je c t , B h a w a n ip a t n a
S e n io r M e d ic in e S p e c ia lis t , N u a p a d a