Haemoglobin Opa Thies

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Transcript of Haemoglobin Opa Thies

  • TRANSCRIBED GEN CAMATO HAEMOGLOBINOPATHIES

    HEMATOLOGY 1 | LECTURE

    1

    2 2 6GluVal = Hb S

    Qualitative Haemoglobinopathies

    2 2 6GluLys = Hb C

    val his leu thr

    pro

    NH2

    glu

    lys

    glu

    146

    val

    lys

    COOH

    1

    6

    chain

    HAEMOGLOBINOPATHIES } Disorders of globin synthesis rather than haem synthesis.

    Qualitative Disorders

    } Abnormal haemoglobins are formed when the sequence of globin chain amino acids is altered. There is usually only a single amino acid substitution in one of the globin (polypeptide) chains.

    Quantitative Disorders

    } Thalassaemias result from a lack of production of particular globin chains to maintain adequate Hb levels. Hereditary persistence of fetal haemoglobin (HPFH) results from a failure to switch from fetal to adult Hb.

    GLOBIN CHAIN SYNTHESIS

    } Occurs on the ribosomes of developing red cells. Various inherited genes direct the process.

    } Each gene results in a specific polypeptide chain. A nucleated red cell contains four alpha (), two zeta (), two beta (), two delta (), two epsilon () and four gamma () genes.

    } Alpha (1, 2) and zeta genes are on chromosome 16. } Beta, delta, epsilon and gamma genes (G, A) on

    chromosome 11. } Products are alpha, zeta, beta, delta, epsilon and gamma

    chains. } Epsilon and zeta chains only appear during embryonic

    development. } These two chains, plus the alpha and gamma chains, form

    the embryonic haemoglobins: Hb Gower 1 (22), Hb Gower 2 (22) and Hb Portland (22).

    } Epsilon and zeta chains are produced till 3 months after conception.

    } Gamma chain production is most active from the third fetal month until birth. The major haemoglobin in the fetus is Hb F (22). By two years, Hb F falls to less than 2%.

    } Gamma chains occur as a mixture of two types: G-gamma (G) and A-gamma (A).

    } Beta chain production rises gradually prenatally and reaches adult percentages by 6 months postnatally.

    } Normal adult haemoglobins are tetramers consisting of 2 alpha plus 2 non-alpha globin chains.

    } Adult red cells contain the following: 95-97% Hb A (22), 2-3% Hb A2 (22) and

  • TRANSCRIBED GEN CAMATO HAEMOGLOBINOPATHIES

    HEMATOLOGY 1 | LECTURE

    2

    Dactylitis

    Leg ulcers

    Hb A

    Hb F

    Hb S

    Hb A2, C

    Negative Positive Test Test

    } Hb SS is usually diagnosed early in life, when the level of Hb F declines. Patients have severe chronic haemolytic anaemia with many complications.

    } Major manifestations are referred to as sickle crisis: Aplastic crisis

    (low retics); marrow is overworked. Haemolytic crises

    Hb falls, reticulocytosis, jaundice, splenomegaly / autosplenectomy.

    Vaso-occlusive crises

    pain, tissue damage, necrosis. CLINICAL FEATURES OF SICKLE DISEASE

    } Abnormal growth (bone and joint abnormalities, e.g. dactylitis and "hand-foot" syndrome).

    } Renal (pyelonephritis and renal necrosis). } Spleen and liver (autosplenectomy, hepatomegaly and

    jaundice). } Cardiopulmonary (enlarged heart, heart murmurs and

    pulmonary infarction). } Eye (retinal haemorrhages). } Leg ulcers. } Infections (major cause of mortality).

    LABORATORY DIAGNOSIS

    } The anaemia of Hb SS is severe (60-80g /L). } Red cell indices are normochromic and normocytic.

    RBC INDICES MCV Mean Corpuscular Volume Normal MCH Mean Cell Hemoglobin Normal MCHC Mean Corpuscular Hemoglobin

    Concentration Normal

    } PBF can be striking with numerous target cells, fragmented

    red cells, polychromasia, NRBCs and usually sickle cells. Siderotic [iron deposits] granules and Howell Jolly bodies may be seen as a result of rapid red cell turnover and "stressed" erythropoiesis.

    } The retic count ranges between 5 and 20% (except during

    an aplastic crisis). Normal Value of Reticulocyte 0.5-1.5%

    } There may be neutrophilia (due to infection) with a shift to the left [ in young forms of WBC], and thrombocytosis (due to autosplenectomy). Platelet circulation in the Spleen

    } The definitive test for Hb S is haemoglobin electrophoresis at

    alkaline pH, followed if necessary by electrophoresis at acid pH.

    } Hbs D and G migrate to the same position as Hb S at alkaline pH but not at acid pH.

    } The patient with Hb SS has no Hb A on electrophoresis (unless recently transfused).

    } Hb S = >80%, Hb F = 1 to 20%, Hb A2 = approx. 3%.

    SOLUBILITY TESTS

    } Solubility tests are available which cause the abnormal Hb S to precipitate. Sodium metabisulphite and sodium dithionite are reducing substances which will induce sickling in vitro.

    } The test solution becomes opaque in a positive solubility test and lines behind the test tube are hidden.

    } Lines can still be seen behind a negative test solution.

  • TRANSCRIBED GEN CAMATO HAEMOGLOBINOPATHIES

    HEMATOLOGY 1 | LECTURE

    3

    Hb C red cell morphology: Target cells and bar of gold crystals.

    SICKLE CELL TRAIT } Heterozygous form of the disease:

    2116Glu-Val

    } The carrier state (Hb AS) is practically asymptomatic. 45% Hb S in the red cell allows sickling to occur if the hypoxia is severe enough, e.g. anaesthetic accidents or very high altitude.

    } The PBF in sickle cell trait is usually normal. Solubility screening tests are positive. Electrophoresis at alkaline pH shows 60% Hb A, 40% Hb S and usually elevated Hb A2 (mean 3.6%).

    } At acid pH one band is present in the A position (Hb A + Hb A2), while the other band moves to the S position.

    HAEMOGLOBIN C

    } Found almost exclusively in Negro populations.

    } Hb C differs from normal Hb A by the single amino acid substitution of lysine for glutamic acid in the sixth position from the NH2 terminal end of the chain 226Glu-Lys

    } This is the same substitution point as in Hb S.

    } Homozygous Hb C occurs in West Africa (Northern Ghana and Nigeria) and is most common in Mali.

    } Clinical manifestations are mild chronic haemolytic anaemia

    with associated splenomegaly and abdominal discomfort.

    } Hb is usually >100 g/L. Red cell morphology is typically normocytic, normochromic, with numerous target cells (50 to 90%) and occasionally microspherocytes and fragmented cells.

    } Haemoglobin C crystals (bar of gold crystals) occur particularly in splenectomized patients. The retic count is slightly increased.

    } Alkaline Hb electrophoresis shows approximately 95% Hb C plus Hb A2,

  • TRANSCRIBED GEN CAMATO HAEMOGLOBINOPATHIES

    HEMATOLOGY 1 | LECTURE

    4

    Heterocellular distribution of Hb F

    A F S

    C

    ?

    ?

    METHAEMOGLOBIN (Hi) } Methaemoglobinaemia exists when Hi levels exceed 1% of

    the total Hb. } Hi contains the oxidised ferric form of iron (Fe+++) rather than

    the ferrous form (Fe++). } The molecule is unable to bind oxygen and results in

    cyanosis and possibly mild haemolytic anaemia. } The blood is chocolate-brown in colour. } There are three causes of methaemoglobinaemia:

    1. Hb M variants (dominant inheritance). Amino acid substitution stabilises iron in the ferric form.

    2. NADH-diaphorase deficiency (recessive inheritance).

    3. Toxic substance (acquired). Hb M variants can be detected electrophoretically

    and most can be distinguished from Hi A by their absorption spectra.

    Hb VARIANTS WITH ALTERED OXYGEN AFFINITY

    } High-affinity Haemoglobins There is a shift to the left in the oxygen dissociation

    curve. Oxygen is bound more readily and released less easily to the tissues.

    The result is hypoxia, which stimulates increased erythropoietin production resulting in a congenital polycythaemia.

    } Decreased Oxygen Affinity Haemoglobins

    The oxygen dissociation curve shifts to the right. Oxygen is readily released to the tissues. As more oxygen is released per unit of haemoglobin, erythropoietin levels fall.

    This results in decreased Hb concentration and mild anaemia develops.

    UNSTABLE HAEMOGLOBINS

    } These are variants in which amino acid substitutions or deletions have weakened the binding forces that maintain the structure of the molecule.

    } The instability may cause the Hb to denature and precipitate in the red cells to form Heinz bodies.

    } Most unstable haemoglobins are inherited as autosomal

    dominant disorders, however, new mutations can occur. } Many have high oxygen affinity and therefore may not cause

    anaemia. } Haemolysis varies considerably. } Most patients have a mild compensated condition until

    "stressed" by infection or exposure to oxidative drugs. } Reticulocytosis is variable. Hypochromasia may be seen and

    the MCHC can be low because unstable Hb may be denatured and "pitted" out of the cell by macrophages in the spleen.

    } Hb electrophoresis is usually not helpful. } Isopropanol precipitation and heat denaturation tests are the

    procedures of choice.

    HEREDITARY PERSISTENCE OF FETAL Hb (HPFH) } i.e. persistence of Hb F synthesis into adult life. Different

    types of HPFH exist, depending on the genetic defect responsible:

    Swiss type (heterocellular) Individuals have up to 3% Hb F.

    There appears to be no abnormalities of the delta and beta genes. The condition is asymptomatic.

    Negro type (pancellular) Deletion of beta and delta globin

    genes (delta-beta *thalassaemia). Hb F constitutes 100%