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MOLECULAR PATHOGENESIS OF PREVALENT HEMOGLOBINOPATHIES
- 1. MOLECULAR PATHOGENESIS OF PREVALENT HEMOGLOBINOPATHIES BY OSAYANDE CHELSEA IMUETINYANOSA A SEMINAR PRESENTATION IN PARTIAL FULFILMENT FOR INTERNSHIP IN HAEMATOLOGY LABORATORY/ BLOOD TRANSFUSION SCIENCE. SEMINAR SUPERVISOR: SCT. ENEJA M. ADAORA(PMLS) CO-ORDINATOR: SCT. ENEJA M. ADAORA(PMLS) 23rd JUNE, 2022
- 2. OUTLINE INTRODUCTION HEMOGLOBIN MOLECULE HEMOGLOBINOPATHIES HISTORY EPIDEMIOLOGY CLASSIFICATION PATHOPHYSIOLOGY LABORATORY INVESTIGATION MANAGEMENT AND TREATMENT CONCLUSION
- 3. INTRODUCTION Red blood cells have the important function of carrying oxygen from lungs to body tissues. In order to perform this function, RBC's contain hemoglobin. Normal hemoglobin consists of four globin chains, each holding a heme molecule that contains iron. Globin is a complex protein containing a precise sequence of amino acids that allows it to fold into a complex conformational pattern. It is variations in the globin chains that leads to the hemoglobinopathies (Goonasekera et al., 2018). Fig 1: Red blood cells transporting oxygen (Rahimi, 2013)
- 4. HEMOGLOBIN MOLECULE (Hemoglobin: Structure, Function & Impairment, 2020)
- 5. Table 1: Embryonic, fetal, and adult hemoglobins summarized PERIOD OF LIFE HEMOGLOBIN SPECIES GLOBULIN CHAINS % PRESENT IN ADULT Embryonic Gower-1 Gower-2 Portland-1 Two zeta, two epsilon Two alpha, two epsilon Two zeta, two gamma 0% Fetal Hemoglobin F Two alpha, two gamma <1% Adult Hemoglobin A Hemoglobin A2 Two alpha, two beta Two alpha, two delta 95%–97% <3.5% (Dasgupta & Wahed, 2021)
- 6. HEMOGLOBINOPATHIES Hemoglobinopathies are congenital disorders resulting from hemoglobin abnormalities. Major forms are often severe, their management is difficult and associated with a great psychosocial impact on patients and their families (Dahmani et al., 2017). These hemoglobinopathies may be due to alterations in certain globin chains that include: Absence of production Diminished production Abnormal structure (Rahimi, 2013) The clinically significant hemoglobinopathies include α- and β-thalassemia, sickle cell disease, HbE disease, and HbC disease (Goonasekera et al., 2018).
- 7. HISTORY Dr. James B. Herrick 1910 Dr. Ernest Irons Dr. Linus Pauling 1951 (Ayandele, 1971)
- 8. EPIDEMIOLOGY Europe Hemoglobin D also occurs in those of European ancestry China Hemoglobin H, found in many groups in the Old World India Hemoglobin E is widespread in Southeast Asia, Nigeria Hemoglobin C (Hb C) is relatively common among African blacks (Goonasekera et al., 2018).
- 9. CLASSIFICATION OF HEMOGLOBINOPATHIES HEMOGLOBINOPATHIES QUALITATIVE STRUCTURAL ABNORMALITIES CHEMICAL ABNORMALITIES QUANTITATIVE PRODUCTION ABNORMALITIES Thalassemias Hb variants Methemoglobinemia (Percy et al., 2009)
- 10. QUALITATIVE DISORDERS Hemoglobinopathies can be due to alpha chain defect, beta chain defect, gamma chain defect, or delta chain defect. Commonest beta chain defect hemoglobinopathies are: • Hb S (seen most often in African Americans) • Hb C (seen most often in African Americans) • Hb E (seen most often in Asians) Commonest alpha chain defect: • Hb G (seen most often in African Americans) Commonest delta chain defect: • Hb A2` (seen most often in African Americans) (Rappaport et al., 2004).
- 11. MOLECULAR PATHOGENESIS GLU GLU GLU Normal HB Chromosome 11 6 26 121 VAL GLU GLU HB S 6 26 121 LYS GLU GLU HB C 6 26 121 GLU GLU GLN HB D 6 26 121 GLU LYS GLU HB E 6 26 121 (AUTHOR’S ILLUSTRATION) 5 3 5’ 3’ 5’ 3’ 5’ 3’ 5’ 3’
- 12. PATHOGENESIS OF HB S The genetic defect-producing sickle hemoglobin is a single nucleotide substitution at codon 6 of the beta-globin gene on chromosome 11 that results in a point mutation in beta-globin chain of hemoglobin (substitution of valine for glutamic acid at sixth position). Hemoglobin S is formed when two normal alpha-globin combines with two mutant beta- globin. Because of this hydrophobic amino acid substitution, Hb S polymerizes upon deoxygenation and multiple polymers bundle to rod-like structure resulting in deformed RBC (Pinto et al., 2019).
- 13. QUANTITATIVE DISORDER Thalassemia is an inherited autosomal recessive blood disorder characterized by abnormal hemoglobin which may cause anemia. Therefore, thalassemia syndrome is not due to structural defect in globin chain but due to lack of sufficient synthesis of globin chain. This is due to mutations which disrupt gene expression. When there is reduced amount of alpha chain synthesis, the condition is termed alpha-thalassemia. When beta chain synthesis is reduced, the condition is termed beta-thalassemia. Similarly, delta and delta beta- thalassemia may also occur (Rappaport et al., 2004).
- 14. Table 2: Major features of alpha-thalassemia DISEASE NUMBER OF DELETED GENE COMMENTS Alpha- thalassemia silent carrier One of four gene deletions Asymptomatic May have low MCV, MCH Alpha- thalassemia trait Two of four gene deletions Asymptomatic or mild microcytic hypochromic anemia Hemoglobin H disease (Alpha- thalassemia major) Three of four gene deletions Microcytic hypochromic Anemia. Hb H found in adults and Hb Bart ’ s found in neonates. Hemoglobin H may coexist with hemoglobin Constant Spring, a more severe disease than Hb H. Hydrops fetalis Four of four gene deletions Hemoglobin Bart’s disease Most severe form may cause stillbirth/Hydrops fetalis (Sriiam et al., 2012).
- 15. Table 3: Major features of beta-thalassemia. DISEASE NUMBER OF DELETED GENE COMMENTS Beta-thalassemia One gene defect Asymptomatic Beta-thalassemia intermedia Both genes defective Variable degree of severity as some beta-globin is still produced Beta-thalassemia major Both genes defective Severe impairment or no beta-globin synthesis. Severe disease with anemia, splenomegaly, requiring lifelong transfusion. (Farashi and Harteveld, 2018).
- 17. LABORATORY INVESTIGATION OF HEMOGLOBINOPATHIES Multiple methodologies exist to detect hemoglobinopathies and thalassemias. Several methods that are routinely employed include • Complete blood count • Gel electrophoresis, • High- performance liquid chromatography (HPLC), • Capillary electrophoresis, and • Isoelectric focusing. If any one method detects an abnormality, a second method must be used to confirm the abnormality. In addition, relevant clinical history, review of the complete blood count (CBC), and peripheral smear pro- vide important correlation in the pursuit of an accurate diagnosis (Smaldone et al., 2008).
- 18. PERIPHERAL SMEAR SICKLE CELL DISEASE HB C DISEASE Berjaoui et al., 2016
- 19. HemoType SC HAEMATOLOGY LAB, NATIONAL HOSPITAL ABUJA, 2022
- 20. HB ELECTROPHPRESIS TRAUMA CENTER, NATIONAL HOSPITAL ABUJA, 2022
- 21. MANAGEMENT AND TREATMENT Early Diagnosis (neonatal screen practiced in some countries) Prompt management of vaso-occlusive crises. Early diagnosis and prompt treatment of other crises and infections. Transfusion therapy Iron chelation therapy whether subcutaneous Desferoxamine and/or oral Chelators Bone marrow transplants can provide a cure for haemoglobinopathy. This does not change the genetics of the patient, but it can relieve them of symptoms. This procedure does have side-effects such as infertility Gene therapy (Goonasekera et al., 2018).
- 22. CONCLUSION Hemoglobinopathies are a public health issue in today’s multiethnic population. Adequate care of the affected patients requires a wide variety of diagnostic and therapeutic measures.
- 23. SELECTED REFERENCES Hemoglobin: Structure, Function & Impairment. (2020, November 10). Retrieved from https://study.com/academy/lesson/hemoglobin-structure-function-impairment.html. Percy MJ, Butt NN, Crotty GM, Drummond MW, Harrison C, Jones GL, et al. Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis. Haematologica. 2009Sep1;94(9):1321–2. Dasgupta, A., & Wahed, A. (2021). Hemoglobinopathies and thalassemia. Clinical Chemistry, Immunology and Laboratory Quality Control, 457–487. doi:10.1016/b978-0-12-815960-6.00005-4 RahimiZ.Genetic,epidemiology,hematologicalandclinicalfeaturesofhemoglobinopathies in Iran. Biomed Res Int 2013;2013:803487 Goonasekera HW, Paththinige CS, Dissanayake VHW. Population screening for hemoglobin- opathies. Annu Rev Genomics Hum Genet 2018;19:355–80. Rappaport VJ, Velazquez M, Willaims K. Hemoglobinopathies in pregnancy. Obset Gynecol Clin N Am 2004;31:287– 317. SriiamS,LeecharoenkiatA,LithanatudomP,WannatungT,etal.Proteomicanalysisofhemo- globin H Constant Spring (HB H- CS) erythroblasts. Blood Cells Mol Dis 2012;48:77–85. Farashi S, Harteveld CL. Molecular basis of α-thalassemia. Blood Cells Mol Dis 2018;70:43–53.
- 24. SELECTED REFERENCES PintoVM,BaloccoM,QuintinoS,ForniGL.Sicklecelldisease:areviewfortheinternist.Intern Emerg Med 2019;14:1051–64. LubinB,WitkowskaE,KlemanK.Laboratorydiagnosisofhemoglobinopathies.ClinBiochem 1991;24:363–74. Ngo DA, Aygun B, Akinsheye I, Hankins JS. Fetal hemoglobin levels and hematological char- acteristics of compound heterozygous for hemoglobin S and deletional hereditary persistence of fetal hemoglobin. Br J Haematol 2012;156:259– 64. Smaldone A. Glycemic control and hemoglobinopathy: when A1C may not be reliable. Dia- betes Spectrum 2008;21:46– 9. Berjaoui, Zeina & Youness, Mohamad & Matar, Jad & Ariss, Abdel. (2016). PREVALENCE OF SICKLE CELL TRAIT IN THE SUBURBS OF BEIRUT, LEBANON. Mediterranean Journal of Hematology and Infectious Diseases. 8. e2016015. 10.4084/mjhid.2016.015. Ayandele, E. (1971). James Africanus Beale Horton, 1835-1883: Prophet of Modernization in West Africa. African Historical Studies, 4(3), 691-707. doi:1. Retrieved from http://www.jstor.org/stable/216537 doi:1 Dahmani, F., Benkirane, S., Kouzih, J., Woumki, A., Mamad, H., & Masrar, A. (2017). Profil épidémiologique des hémoglobinopathies: étude autour du cas index: étude transversale descriptive. Pan African Medical Journal, 27. doi:10.11604/pamj.2017.27.150.11477 10.11604/pamj.2017.27.150.11477
Editor's Notes
- Hemoglobin is a tetramer composed of two α-globin and two non- α -globin chains working in conjunction with heme to transport oxygen in the blood Hemoglobin, the oxygen-carrying pigment of erythrocytes, consists of a heme portion (protoporphyrin IX, a heterocyclic organic compound containing four pyrrole rings, chelated with iron) and four globin chains. Heme synthesized in the mitochondria Globin synthesized in cytosol by ribosomes
- Six distinct species of normal hemoglobin are found in human, three in normal adults, and three in fetal life. The globulins associated with hemoglobin molecule (both embryonic stage and after birth) include alpha chain (α-chain), beta chain (β-chain), gamma chain (γ-chain), delta chain (δ-chain), epsilon chain (ε-chain), and zeta chain (ζ-chain) Each alpha chain contains 141 amino acids in length and each beta chain contains 146 amino acids The gene for the alpha and zeta chain is located in chromosome 16 (two genes in each chromosome, a total of four genes), while genes for beta, delta,gamma and episilon (one gene in each chromosome, a total of two genes) gamma and delta chains are located on chromosome 11.
- 1910 is regarded as the date of the discovery of sickle cell disease, but just what does it mean to say the disease was “discovered”? The disorder we call “Sickle Cell Disease” had been present in Africa for at least five thousand years and has been known by many names in many tribal languages. What we call its “discovery” in 1910 occurred, not in Africa, but in the United States. A young man named Walter Clement Noel from the island of Grenada, a dental student studying in Chicago, went to Dr. James B. Herrick with complaints of pain episodes, and symptoms of anemia. Herrick was a cardiologist and not too interested in Noel’s case so he assigned a resident, Dr. Ernest Irons to the case. Irons examined Noel’s blood under the microscope and saw red blood cells he described as “having the shape of a sickle”. When Herrick saw this in the chart, he became interested because he saw that this might be a new, unknown, disease. He subsequently published a paper in one of the medical journals in which he used the term “sickle shaped cells”. In 1927, Hahn and Gillespie discovered that red blood cells from persons with the disease could be made to sickle by removing oxygen. This was exciting because red cells are the oxygen transporters of the body. In the late 1940’s and early 1950’s the nature of the disease began to become clearer. In 1949, two articles appeared independently showing conclusively that SCD was inherited and that people with sickle trait were heterozygous (carriers or AS) for the gene whereas people with the disease were homozygous Two years later, in 1951, the famous Nobel Prize-winning chemist, Dr. Linus Pauling and his colleague Dr. Harvey Itano, discovered that the red, oxygen-carrying protein called “hemoglobin” had a different chemical structure in persons with SCD. This led Dr. Pauling to coin the term “molecular disease” for disorders that resulted from proteins with abnormal chemical structures.
- Hemoglobinopathies are prevalent in malaria-endemic regions (the Mediterranean, Asia, and sub-Saharan Africa) owing to natural selection. They have also become increasingly prevalent in nonendemic Europe, North America, and Australia owing to population migrations. As a result, hemoglobinopathies become a global health problem (Goonasekera et al., 2018). Hemoglobin C (Hb C) is relatively common among African blacks living north of the Niger River and is found in 2–3 percent of blacks in the United States. Hemoglobin D is found mainly in people of Afghan, Pakistani, and northwestern Indian descent, but it also occurs in those of European ancestry Hemoglobin E is widespread in Southeast Asia, being found especially among Thai, Cambodian, Laotian, Malaysian, Indonesian, Vietnamese, and Burmese peoples Hemoglobin H, found in many groups in the Old World (e.g., Chinese, Thai, Malayans, Greeks, Italians), has almost always been identified in combination with thalassemia; symptoms resemble those of thalassemia. Nigeria has a population of 112 million with an annual growth rate of 3.2%. About 25% of adults throughout the country have the sickle cell trait, AS, while the Hb C trait is largely confined to the Yoruba people of southwestern Nigeria in whom it occurs in about 6%. Other variant hemoglobins including beta thalassemia are rare, but alpha thalassemia occurs in 39% (32% with 3 alpha-globin genes; 7% with 2 alpha-globin genes). Of a total of 5.4 million expected live births in 1988, about 90,000 will have SCD and 1.1 million the trait, AS.
- The Hb S variant decreases the risk of infection by P. falciparum. The mechanism of red blood cells (RBC) resistance in sickle cell trait (AS) individuals could be due to the lack of parasite development and accelerating Hb S polymerization in low O2 tension and higher rates of phagocytosis of parasite-infected sickle erythrocyte by host immune cells
- The terminology “sickle cell disease” (SCD) includes all manifestations of abnormal hemoglobin S (HbS), which includes sickle cell trait (Hb AS), homozygous sickle cell disease (Hb SS), and a range of mixed heterozygous hemoglobinopathies such as hemoglobin SC disease, hemoglobin SD disease, hemoglobin SO Arab disease, and hemoglobin S combined with beta- thalassemia. In sickle cell disease, normal round shape of red blood cell (RBC) is changed into a crescent shape and hence the name “sickle cell”. In the heterozygous form (Hb AS), sickle cell disease protects from infection of Plasmodium falci- parum malaria but not in the more severe form of homozygous sickle cell dis- ease (Hb SS) (Pinto et al., 2019).
- There are two genetic loci for alpha gene resulting in four genes (alleles) for alpha hemoglobin (α/α, α/α) on chromosome 16. Two alleles are inherited from each parent. Alpha-thalassemia occurs when there is a defect or deletion in one or more of four genes responsible for alpha-globin production. When there is underproduction of the alpha-globin chain, then the body tries to com- pensate by increased production of beta, gamma, and delta globin chains. Four beta-globin chains may form a novel hemoglobin called Hb H. Four gamma- globin chains may form another novel hemoglobin called Hb Bart’s.
- Painful Bone Crisis Most common of VOC; 1 st manifest. Is usually Hand-foot syndrome; shift from the peripheral to central skeleton with age. Acute Chest syndrome Pul. Infarction; pneumonitis, common cause of death. Priapism Painful persistent penile erection Acute Brain syndrome Stroke, maybe fatal Acute Abdomen Mesenteric sickling
- Principle. HemoTypeSC™ is a competitive lateral flow immunoassay incorporating monoclonal antibodies for determination of the presence of hemoglobin A, S, and C. It performs rapid detection of hemoglobin phenotypes HbAA, HbSS, HbSC, HbCC, HbAS, and HbAC.