Transcript HEMOGLOBINOPATHIES

HEMOGLOBINOPATHIES
Dr. Swapna V. Goley
DEFINITION:
Inherited abnormalities of hemoglobin synthesis
characterised by structurally abnormal
hemoglobin variants.
SICKLE CELL ANEMIA
• Prototype of hereditary
hemoglobinopathies. It occurs due to
production of a physiochemically abnormal
hemoglobin. It offers a protection against
malaria for unknown reasons.
• Nearly 20 million people affected in India.
• It is inherited as an autosomal recessive
trait.
• Presents as sickle cell trait (heterozygous)
and sickle cell disease(homozygous).
• Normal hemoglobin
2 alpha and 2 beta chains
form a 4 chain tetramer
• HbS:
Valine substituted for
glutamic acid in both beta
chains (HbSS).
This occurs due to single
point mutation at sixth
position of beta globin chain
which has thymine instead
of adenine.
PATHOGENESIS
•Due to the change in the amino acid
sequence,there is an alteration in
charge at the site.
•This allows for aggregation &
polymerisation of HbS
molecules.(formation of tactoids)
•Acidosis,Hb concentration,presence
of other types of Hb affect
polymerisation.
•It is a relatively reversible
phenomenon but with repeated cycles
it becomes irreversible.
PATHOGENESIS
Arterial pO2
oxyHbS(soluble)
Stiff,viscous sickle cell
Capillary venule occlusion
Microinfarction
Ischemic tissue pain
Ischemic organic malfn.
Venous pO2 deoxyHbS
polymerised)
Membrane changes
Ca2+ influx,K+leakage
Shortened red cell survival
Anemia, jaundice
CLINICAL COURSE
• Disease is not evident in newborns.
• 2-4 months : Symptoms of Hemolytic Anemia start
developing like anemia, jaundice. This
is parallel to replacement of HbF by
HbS.
• 5-6 months : Symptoms arising due to infarction
and ischemia start developing.
• By the age of 5 yrs almost 95% are functionally
asplenic.
INFARCTION
• Slow, tortuous circulation leads to repeated
infarctions.
• Effects of the HbS polymerisation, infarction and
ischemia are seen in most of the body organs :
• Bones
• Spleen
• Kidney
• Lungs
• Liver
• Brain
DACTYLITIS
(HAND-FOOT SYNDROME)
• First overt manifestation
• Painful, usually symmetric
swelling with erythema of
dorsa of hands & feet.
• Sudden in onset and lasts
for 1-2 weeks.
• Needs medical attention.
• Radiographic changes
appear 2-3 weeks after
appearance of symptoms.
SPLENIC INVOLVEMENT
•Marked congestion of
the red pulp due to
trapping of sickled red
cells in splenic cords.
•The spleen is palpable
in most of the children
by the age of 9
months.(increased
almost up to 500gms.)
• Continued scarring causes
progressive shrinkage of the
spleen. Finally leading to
autosplenectomy
• Hence they are more prone
to infection
• Penicillin prophylaxis is begun
at 3 months.
ACUTE CHEST SYNDROME
•Presents with
tacypnea,fever,cough,chest
pain,arterial O2
desaturation.
•Can mimic
pneumonia,pulmonary
embolism.
•Thought to reflect in situ
sickling within the lung
causing temporary and
permanent dysfunction.
PNEUMONIA
Frequently seen in children with SCA, has high severity
because of the relative immunodeficiency. The
commonest organism is pneumococcus.
GALL STONES
Frequent complication of hemolytic anemias
OTHER FEATURES
•Abdominal crises: severe abdominal pain & signs of peritoneal
irritation.
•Aplastic crises: infection in adult sicklers with parvovirus B19
results in severe red cell aplasia.
•Liver cells may undergo sequestration with severe pain due to
capsular stretching.
•Aseptic necrosis of head of femur,humerus.
•Chronic osteomyelitis: Salmonella sp. most frequently seen
organism.
•Priapism: due to pooling of blood in corpora cavernosa.
•Chronic leg ulcers: seen in adult sicklers. Non healing
ulcers usually present on the medial aspect of leg.
•Eyes: retinal infarcts, preretinal hemorrhage.
•Kidney:limited capacity of H+
excretion,hematuria,hypoastheniuria.
•CNS:strokes, focal deficits may occur.
DIAGNOSIS
• Evidence of red cell destruction:
• peripheral blood smear
• plasma haptoglobin,hemopexin
• Evidence of red cell generation:
• reticulocytosis, extramedullary
hematopoeisis
• Laboratory diagnosis
• Blood picture
Marrow expansion
Hair on end
appearance
LAB DIAGNOSIS
• SICKLE TEST:Red cells with HbS take a sickle
shape when mixed with a freshly prepared solution
of the reducing agent sodium metabisulphite.(2%)
Giving an appearance of turbidity.
• SOLUBILITY TEST:Hb added to solution of
sodium dithionite(reducing agent) in phosphate
buffer.Turbidity shows presence of HbS.
• Hb ELECTROPHORESIS
Hb ELECTROPHORESIS
BLOOD PICTURE
• Hb : 6-9gm%, may be lower
• Anemia: normocytic,normochromic
• MCV,MCH: Normal
• Stained film:Moderate
anisopoikilocytosis,sickle cells,oval cells,occ
target cells,Howell-Jolly bodies
• Reticulocytosis (10-20%)
MANAGEMENT
•Vaso-occlusive crises managed by aggressive
rehydration, oxygen therapy, adequate analgesia and
antibiotics.
•Prophylactic antibiotics: Penicillin prophylaxis to
protect against infections which are lethal in presence
of asplenia.
•Vaccination against pneumococcus, hepatitis B and
haemophilus.
• Transfusion to suppress HbS production and
maintain HbS levels below 30%.
• Fetal Hb induction with hydroxyurea
(hydroxycarbamide) replaces some HbSS with
HbF. As high level of HbF inhibits polymerization
• Bone marrow or stem cell transplant appears to be
potentially curative.
• PROPHYLAXIS Factors that promote sickling
should be avoided that is hypoxia, dehydration,
acidosis etc.
OTHER
HEMOGLOBINOPATHIES
•Hemoglobin H. Hemoglobin H is a tetramer composed of
four beta globin chains. Hemoglobin H occurs only with
extreme limitation of alpha chain availability. Hemoglobin H
forms in people with three-gene alpha thalassemia
•Hemoglobin Barts. Hemoglobin Barts develops in fetuses
with four-gene deletion alpha thalassemia. Due to this
deletion no alpha chain is produced. The gamma chains
produced during fetal development combine to form gamma
chain tetramers. These molecules transport oxygen poorly.
Most individuals with four-gene deletion thalassemia and
consequent hemoglobin Barts die in utero (hydrops fetalis).
•Hemoglobin C. Hemoglobin C results from a
mutation in the beta globin gene and is the
predominant hemoglobin found in people with
hemoglobin C disease. (a2bC2).It has Lysine for
glutamic acid at 6th position in beta chain.
Hemoglobin C disease is relatively benign, producing a
mild hemolytic anemia and splenomegaly. Hemoglobin
C trait is benign.
•Hemoglobin E. This variant results from a mutation
in the hemoglobin beta chain. People with hemoglobin
E disease have a mild hemolytic anemia and mild
splenomegaly. Hemoglobin E trait is benign.
•Hemoglobin D: It has the glutamic acid at
the 121st position on the beta chain instead of
glutamine. It is relatively benign, producing a
mild hemolytic anemia and splenomegaly.
•Other examples: Hb-Koln, Hb-Zurich, HbSydney, HbO-Arab etc.
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