HAEMOGLOBINOPATHIES OLASINDE Y.T - PowerPoint Presentation

Slide1

HAEMOGLOBINOPATHIES

OLASINDE Y.T

MB;BS(Ilorin), FWACP(

Paed

)

Slide2

Outline

Intro /def

Normal haemoglobin structure / function

Classification of haemoglobinopathies

Structural Hb Variants

Thalassaemias

Epidemiology

Clinical features

Differentials

Management

Slide3

Normal haemoglobin structure

Haemoglobin = heme + globin

Slide4

Slide5

Normal haemoglobin structure

Heme

has one central iron (in the ferrous form), which is attached to four

pyrol

rings.

Globin

is the protein part and consists of four chains. In humans, there are two alpha chains and the other two may be beta, delta, gamma or epsilon depending on the type of

haemoglobin

.

The gene clusters are involved in the production of

haemoglobin

and are located on the short arm of chromosomes 16 (

α

chain)

and 11(

β

-like chains-

δ

,

γ

and

ε

)

Slide6

Normal haemoglobin structure

HbF

(α

2

γ

2

) is the main

haemoglobin

during

foetal

life. At approximately 1 mo of

foetal

life,

HbA

(α

2

β

2

) appears, but does not become the dominant

haemoglobin

until after birth, when

HbF

levels start to decline.

A minor

haemoglobin

, HbA

2

(α

2

δ

2

) appears shortly before birth and remains at a low level after birth.

The final

haemoglobin

distribution pattern that occurs in childhood is not achieved until about 6 mo of age.

The normal hemoglobin pattern is >95%

Hb

A, ≤3.5

Hb

A

2

, and <2.5%

Hb

F

Slide7

Functions of the haemoglobin

Oxygen carrying molecule

Hb binds oxygen to form oxyhaemoglobin; the weak bond between the two allows oxygen to be released easily in the tissue.

Carbon dioxide carrier

Colour of blood

Buffer in the body

Slide8

Haemoglobinopathies

Haemoglobinopathies are abnormalties in haemoglobin chain

Inherited usually as

autosomal

recessive.

Carriers (

heterozygotes

) have just one abnormal gene

usually asymptomatic

people who inherit an abnormal gene from both parents (

homozygotes

) express the disease.

Slide9

Classification

Thalassaemias

. Reduced or absent production of normal α or β-

globin

chains, leading to reduced levels of

HbA

, the main adult

Hb

.

Structural

haemoglobin

variants. Mostly result from single amino-acid substitutions in the

α

or

β

chains.

results from mutations in the genes for α or β

globin

chains

the stability or other functions of the

Hb

molecule is altered (e.g. sickle

Hb

(

HbS

)).

Slide10

Epidemiology

Haemoglobinopathies

are the commonest genetic defect worldwide

It is estimated that 7% of world's population (420 million) are carriers, with 60% of

being in Africa.

300 000–400 000 babies with severe forms of these diseases are born each year

Populations at risk of having a

haemoglobinopathy

: Africa, the Mediterranean basin and Southeast Asia

South East Asia, there are 90 million carriers,

about 85 million in sub-Saharan Africa

and 48 million in the West Pacific region

Slide11

Structural haemoglobin variants

Although over 700 structural

haemoglobin

variants have been identified, only three (

Hb

S,

Hb

C, and

Hb

E) are of public health importance.

HbS: Valine substituted for glutamic acid

at position

β

6

HbC:

lysine substituted for

glutamic acid

at position

β

6

HbE: lysine

substituted for

glutamic acid

at position

β

26

Slide12

Haemoglobin

1

2

3

6

Position

7

26

63

67

121

146

A(normal)

Val

His

Leu

Glu

Glu

Glu

His

Val

Glu

His

S(sickle cell)

Val

C

Lys

G(San Jose)

Gly

E

Lys

M

Saskatoon

Tyr

M

Milwaukee

Glu

O(Arab)

Lys

Slide13

Structural haemoglobin variants

A combination/co-existence of the abnormal

haemoglobins

.

The homozygous state for the sickle-cell gene results in sickle-cell

anaemia

(

HbSS

)

heterozygous state for the sickle-cell and

HbC

genes results in

HbSC

disease

Others are

HbS

/

thalassaemia

,

HbE

/

thalassaemia

,

HbS

/D

punjab

, etc

Slide14

HbC

The mutation for

HbC

is at the same site as

Hb

S, with lysine instead of

valine

substituted for glutamine.

In the U.S.,

HbAC

occurs in 1/50 and

HbCC

occurs in 1/5,000 African-Americans.

HbAC

is asymptomatic.

HbCC

may result in mild

anaemia

,

splenomegaly

, and

cholelithiasis

.

Sickling

does not occur but

HbC

crystallizes, disrupting the red cell membrane

Slide15

HbC

heterozygous state for the sickle-cell and

Hb

C genes results in

HbSC

disease

milder than sickle-cell

anaemia

.

Slide16

HbE

Haemoglobin

E is the commonest structural

haemoglobin

variant globally

carrier rates may exceed 60% in regions like South East Asia

innocuous in its heterozygous and homozygous states

can interact with

β

thalassaemia

to produce a condition called

HbE

/

β

thalassaemia

the 2

nd

commonest

globin

mutation worldwide.

found almost exclusively in Southeast Asians, with a prevalence of 1/2,600 births

Slide17

HbD

At least 16 variants of

Hb

D exist;

only 1 (D Punjab), in combination with

Hb

S, produces symptoms of sickle cell disease.

Rare. Seen in 1–3% of Western Indians and in some Europeans with a tie to India.

Heterozygous D is clinically silent.

Homozygous D produces mild to moderate

anaemia

with

splenomegaly

Slide18

Thalassaemias

genetic disorders in the quantity of

globin

chain production (unlike SCD in which quality of

Hb

is affected).

β-thalassemia

: 2genes on chromosome 11

Deletion of one gene: partial

reduction (β

+

-

thalassaemia

aka β thalassemia minor ).

Deletion of the two genes: complete

absence of β-globin

chain(β

0

-thalassemia aka β thalassemia

major or Cooley’s

anaemia

)

α-thalassemia:

α-globin gene production is either absent or partially reduced.

Slide19

Epidemiology

3% of the world's population carries genes for β-

thalassemia

, and in Southeast Asia, 5–10% of the population carries genes for α-

thalassemia

Thalassaemia

has a high incidence in a broad band extending from the Mediterranean basin and parts of Africa, throughout the Middle East, the Indian sub-continent, South-East Asia, Melanesia and into the Pacific Islands.

The carrier frequency for β-

thalassaemia

in these areas ranges from 1% to 20%, while that for the milder forms of α-

thalassaemia

is much higher, ranging from 10–20% in parts of sub-Saharan Africa, through 40% or more in some Middle Eastern and Indian populations, to as high as 80% in northern Papua New Guinea and isolated groups in north-east India.

Slide20

Pathophysiology

The type of thalassemia carries the name of the reduced or underproduced or absent chain.

This leads to an excess of the normally produced chain, which accummulates as an unstable product and destroys the cell membrane.

Slide21

Pathophysiology

Two major features contribute to the pathogenesis of β-

thalassemia

:

inadequate β-

globin

gene production leading to decreased levels of normal hemoglobin (

HbA

)

an imbalance in α- and β-

globin

chain production.

there is an excess of α-

globin

chains relative to β- and γ-

globin

chains; α-

globin

tetramers (α

4

) are formed

Slide22

Pathophysiology

The excess α chains precipitate and form inclusions which interact with the red cell membrane, destroying the red cell.

There is shortened red cell survival, leading to

anaemia

and increased

erythroid

production.

The excess α chains also destroy the red cell precursors in the bone marrow, causing ineffective

erythropoeisis

.

Slide23

Pathophysiology

In the bone marrow,

thalassaemic

mutations disrupt the maturation of red blood cells, resulting in ineffective erythropoiesis; the marrow is hyperactive, but the patient has relatively few reticulocytes and severe

anaemia

.

Slide24

Pathophysiology

Some extra α chains combine with γ-

globin

chains to produce

HbF

(α

2

γ

2

). Thus, there is an elevated

HbF

level.

The δ-

globin

chains are also produced in increased amounts, leading to an elevated

Hb

A

2

(α

2

δ

2

).

Postnatally

, infants with

β-

thalassemia

become symptomatic because

Hb

A requires adequate production of

β-

globin

genes.

Slide25

Pathophysiology

In

α-

thalassaemia

, there are relatively fewer

α-

globin

chains and an excess of

β-

and

γ-

globin

chains.

These excess chains form Bart's

haemoglobin

(

γ

4

)

in

foetal

life and

HbH

(

β

4

)

after birth.

These abnormal tetramers lead to extra-vascular

haemolysis

.

Prenatally, a

foetus

with

α-

thalassaemia

may become symptomatic because

HbF

requires sufficient

α-

globin

gene production

Slide26

Pathophysiology

Deletion of 1

α

gene: silent carrier

2

α

genes:

α

-thalassemia trait; mild anaemia

Deletion of 3

α

genes the person manifests

α

-thalassaemia (HbH disease)

Deletion of 4

α

genes : not compartible with life.(Bart’s haemoglobin)

Slide27

Clinical features

severe

thalassemia

typical

facies

(maxillary hyperplasia, flat nasal bridge, frontal bossing),

pathologic bone fractures,

marked

hepatosplenomegaly

Cachexia

Splenomegally

; may be massive causing mechanical discomfort and secondary

hypersplenism

.

Features of ineffective

erythropoiesis

:

expanded

medullary

spaces (with massive expansion of the marrow of the face and skull),

extramedullary

hematopoiesis

, and a huge caloric need

Pallor,

hemosiderosis

, and jaundice may combine to produce a greenish brown complexion. As a result of the anemia, there is also an increase in iron absorption from the gastrointestinal tract, with toxicity leading to further complications. but the creation of excessive iron stores associated with

hemosiderosis

is a major concern in individuals with β-

thalassemia

.

Complications mostly as a result of increased iron deposition from repeated blood transfusions.

Slide28

Clinical features

β

-thalassaemia

β

-thalassaemia major (

β

+, Deletion of 4 genes)

Recurrent severe anaemia, jaundice, dark urine, failure to thrive, hepatosplenomegally, frontal bossing, cu coloured skin

Present in 2nd 6 months of life when HbF starts to decrease.

High HbF and HbA2

β

-thalassaemia minor(

β

o):mild. 1 chain deleted

Slide29

Clinical features

α-

thalassaemia

Prenatally,

Bart's

haemoglobin

(

γ

4

)

= foetal hydrops

Postnatally,

deletion of 1

α

gene= silent carrier

deletion of 2

α

genes= mild anaemia

deletion of 3

α

genes=HbH. severe anaemia, dark coloured urine, jaundice

deletion of 4

α

genes= incompartible with life

Slide30

Differentials

Microcytic anaemia

Fe deficiency

Pb poisoning

Al toxicity

SCD

Leukaemias

Slide31

Investigations

FBC

Hb

mcv, mch

Retic count but not in degree of anaemia (ineffective erythropoesis)

signs of haemolysis on PBF

Serum bilirubin

HPLC: Hb pattern

Urinalysis: urobilinogen, Hbnuria

Slide32

Treatment

Supportive

Blood transfusions

Iron chelation with desferoxamine in iron overload from too many blood transfusions.

Splenectomy if too recurrent blood transfusion

BM transplant curative

Slide33

Control

Neonatal screening and antenatal diagnosis have succeeded in reducing the frequency of new births of

thalassaemia

.

Specialized clinics provide optimum management of established cases.