L04. Chapter 17 - Hemoglobinopathies PDF

6/28/2024 Chapter 17 Hemoglobinopathies and Thalassemia Preamble PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. PowerPoints DO NOT cover the details needed for the Unit exam Each student is responsible for READING the TEXTBOOK...

6/28/2024 Chapter 17 Hemoglobinopathies and Thalassemia Preamble PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. PowerPoints DO NOT cover the details needed for the Unit exam Each student is responsible for READING the TEXTBOOK for details to answer the UNIT OBJECTIVES Unit Objectives are your study guide (not this PowerPoint) Test questions cover the details of UNIT OBJECTIVES found only in your Textbook! 1  6/28/2024 Hemoglobin Defects and Disease vs. Trait The hemoglobinopathies encompass a heterogeneous group of disorders associated with genetic mutations in both the α-globin and β-globin genes. Genetic mutations in these genes produce qualitative protein changes; instead of producing hemoglobin A, A2, and F, patients produce Hgb S, C, D, G, E, etc. Mendelian genetics determine overall zygosity and quantity of hemoglobin produced. In the genetic manifestation of the hemoglobinopathies, the distinction between the disease state and the trait condition is made. A disease is defined as either the homozygous occurrence of the gene for the abnormality or the possession of a heterozygous, dominant gene that produces a hemolytic condition. A trait is described as the heterozygous and normally asymptomatic state. In the case of sickle cell anemia, the trait must be inherited from both parents. 3 Demographics SCD and -thalassemias are the most common monogenic diseases of man. They are found in the “malaria belt” that extends from the Mediterranean and sub-Saharan Africa through Southeast Asia and southern China. These hemoglobin mutations occur at high incidences in these regions because heterozygotes have a selective advantage against infection with Plasmodium falciparum. 4 2  6/28/2024 Etiology Hemoglobinopathies, for example, SCD, are inherited single-gene disorders that affect the amino acid residual sequence or production of normal hemoglobin. It is estimated that around 7% of the world population carries a globin-gene mutation, and in the majority of cases, it is inherited as an autosomal recessive trait. Disorders associated with autosomal recessive genes need to be in the homozygous state to produce the disease. Some disorders are caused by the inheritance of an autosomal dominant gene that will produce hemolytic disease in its heterozygous state. Hemoglobinopathies may have a hemolytic manifestation. Approximately 25% of all hemoglobinopathies demonstrate the decreased red cell survival due to red cell membrane deformity that characterizes hemolytic disease. Although hemoglobinopathies and thalassemias are two genetically distinct disease groups, the clinical manifestations of both include anemia of variable severity and variable pathophysiology. 5 Abnormal Hemoglobin Abnormal hemoglobins including hemoglobinopathies and thalassemias can be classified into three major categories: Abnormal molecular structure of one or more of the polypeptide chains of globulin in the hemoglobin molecule, for example, sickle cell anemia A defect in the rate of synthesis of one or more particular polypeptide chains of globulin in the hemoglobin molecule, for example, the thalassemias Disorders that are a combination of abnormal molecular structure with a synthesis defect, for example, Hb E–β-thalassemia Normal adult hemoglobin contains the following components: Hb A (95% to 98%), Hb A2 (2% to 3%), Hb A1 (3% to 6%), and fetal hemoglobin (Hb F) (less than 1%). The major fraction is Hb A. Typically, an individual with a hemoglobinopathy will demonstrate an alteration in hemoglobin distribution. 6 3  6/28/2024 Sickle Cell Disease (SCD) #1 SCD is a general term for abnormalities of hemoglobin structure in which the sickle gene is inherited from at least one parent. These genetic disorders are characterized by the production of Hb S, anemia, and acute and chronic tissue damage secondary to the blockage of blood flow produced by abnormally shaped red blood cells. Sickle cell anemia (Hb SS), the most common form of hemoglobinopathy, is an expression of the inheritance of a sickle gene from both parents (see Chapter 3). Other sickle cell disorders result from the coinheritance of the sickle gene. Common variants include Hb SC disease and β-thalassemia. 7 Etiology The sickle cell gene must be inherited from both parents in sickle cell anemia. Hb S is different from Hb A because of a single nucleotide change (GAT to GTT) that results in the substitution of valine for glutamic acid at the sixth position on the  chain of the hemoglobin molecule. Hb S results in abnormalities in polymerization (or gelation), with deoxygenation that leads to sickling. The end result of the polymerization is a permanently altered membrane protein. Two thirds of the red blood cells (RBCs) are removed by extravascular mechanisms. 8 4  6/28/2024 Epidemiology SCD is found most commonly in persons of African ancestry, but it also affects persons of Mediterranean, Caribbean, South and Central American, Arab, and East Indian ancestry. The sickle cell carrier state confers a selective advantage to Plasmodium falciparum malaria, because of preferential sickling of only the parasitized cells. The prevalence of the disease in some regions reflects this selective advantage or protective mechanism. 9 Pathophysiology: Sickling #1 Polymerization of Hb S occurs under conditions of extremely reduced oxygen and increased acidity in the blood. Sickling is promoted by low oxygen tension, low pH, increased 2,3- diphosphoglycerate, high cellular concentration of hemoglobin, loss of cell water, Hb C, and Hb O–Arab. Sickling is retarded by Hb A, Hb F (at least 30%), Hb J, and α thalassemia. When sickling occurs, it subsequently leads to an increased mean corpuscular hemoglobin concentration (MCHC) in proportion to the number of molecules in the deoxygenated state. Deoxyhemoglobin S is less soluble than deoxyhemoglobin A or oxyhemoglobin S. 10 5  6/28/2024 Pathophysiology: Sickling #2 Recently, the understanding of the molecular basis of SCD has progressed rapidly. It is now possible to describe the structure of the gel of polymerized deoxyhemoglobin S and to begin to understand the mechanism of the formation of this gelatinous hemoglobin solution in red cells. It is believed that with deoxygenation, a continuum of cellular changes begins. 11 Pathophysiology: Sickling #3 The first stage progresses from the formation of small amounts of polymer to larger amounts of highly ordered polymer as the result of severe and prolonged deoxygenation. This polymerization produces the resultant sickling. Because cells that have large amounts of ordered polymer may be caught in the capillaries and venules, some cells at relatively high oxygen saturation with polymer but no deformability may have difficulty traversing the constriction of the precapillary arterioles. When the sickled cells attempt to travel through these small vessels, they become stuck and the vessels become obstructed. This initiates a pattern of blood not flowing properly to the tissue and creating a lack of oxygen. The lack of oxygen causes more sickling and more deprivation of oxygen to the tissues. This process can cause intense pain and tissue necrosis. The decreased oxygen tension of the spleen makes it vulnerable to tissue necrosis after vasoocclusion. This causes splenic dysfunction and the presence of Howell-Jolly bodies in mature RBCs. 12 6  6/28/2024 Pathophysiology: Sickling #4 When sickled cells receive oxygen, they return to their normal shape. Repeated cycles of sickling and unsickling lead to the RBCs becoming permanently damaged. This process ends in hemolysis, which leads to anemia. In addition, repeated episodes of this type lead to the necrosis of body tissues. The ability to revert back to normal shape is called reversibility, which produce reversible sickles. The morphology of reversible sickles is boat shaped. As the disorder progresses, reversibility diminishes and production of irreversible sickles ensues. This is a sign of poorer prognosis for the patient as they become resistant to treatment. Morphology of irreversible sickles is serpentine-like, more slender with pronounced pointed ends. 13 Pathophysiology: Vasoocclusion The adherence of sickled erythrocytes to the vascular endothelium may contribute to painful vasoocclusion. Patient presents in the hospital with symptoms of a vasoocclusive crisis: fever, acute pain, dehydration, cyanosis, and extreme sensitivity to cold. Patients also have increased susceptibility to opportunistic infections. 14 7  6/28/2024 Clinical Signs and Symptoms #1 Acute crises are caused by recurrent obstruction of the microcirculation by intravascular sickling. Sickling takes its toll on the body in other ways. Through the years, the cumulative damage from vascular occlusion can lead to organ and tissue failure. 15 Clinical Signs and Symptoms #2 There is significant activation of coagulation with consequent increase in fibrinolysis during both the sickle cell crisis and in the steady state. There is variation in the severity of SCD. Many patients are reasonably well and have relatively few complications. However, 5% to 10% of patients account for 40% to 50% of hospital visits. Complications may include the following: Enlarged heart Progressive loss of pulmonary or renal function Stroke Arthritis Liver damage Other complications 16 8  6/28/2024 Symptoms in Children and Pregnancy Children Splenic dysfunction is a life-threatening complication that develops during infancy. Infant is vulnerable to shock and infection from encapsulated bacteria due to the sickles getting trapped in the spleen. Symptoms appear after 6 months of age. Vasoocclusive disease develops between 1 and 6 years. Development delays and growth delays. Destruction of bone and joints with ischemia and infarction of the spongiosa. Pregnancy No increase disease manifestations But there is an increase in maternal mortality of 20% and fetal mortality of 20% 17 Clinical Manifestations in Adults SS homozygotes have severe HA with Hct values between 15% and 30% RBCs with low Hb F have shortened life spans. Risk of early death is inversely associated with Hb F levels. Erythropoietic suppression are caused by either: Aplastic crises Megaloblastic erythropoiesis Acute chest syndrome is a significant cause of death. Higher blood viscosity leads to complications including: Shoulder and hip abnormalities Multiorgan dysfunction Pain Pigmented gallstones in 30% to 60% of adults Papillary necrosis Leg ulcers 18 9  6/28/2024 General Signs and Symptoms #1 Pain Hallmark of the disease and most common complaint. Vasoocclusive crises are predominantly what sends patient to the hospital. High-dose methylprednisolone decreases pain duration in children. Pulmonary complications (atelectasis and infiltrates) Thoracic bone infarction is common in hospitalized SCD patients with acute chest pain. Incentive spirometry can prevent atelectasis. 19 General Signs and Symptoms #2 Stroke 24% of SCD patients have a stroke by 45 years. Cerebral infarction in SCD is associated with an occlusive vasculopathy involving the distal intracranial segments of the internal carotid as well as the proximal middle and anterior cerebral arteries. Blood transfusions decrease stroke risk but should be used with prudence due to: Alloimmunization Iron overload Transfusion withdrawal New possibilities include the following: Modulating Hb F production to attenuate stroke risk 20 10  6/28/2024 Laboratory Testing #1 In addition to decreased hemoglobin (5 to 9.5 g/dL), hematocrit, and red blood cell count, a persistent increase in the white blood cell (WBC) count of 12,000 to 15,000 × 109/L is common. The red cell morphology on peripheral blood smear can include moderate to significant anisocytosis, poikilocytosis, and hypochromia. Red cell abnormalities may include target cells, microcytes, polychromatophilia, and basophilic stippling. Howell-Jolly bodies may be present if hyposplenism is present. If the patient is in an acute crisis state, sickled red cells (drepanocytes) may be seen on peripheral smears. 21 Laboratory Testing #2 Reticulocytosis (8% to 12%) An increased mean corpuscular volume (MCV) to levels up to 100 fL Elevated serum; unconjugated bilirubin and methemalbumin Decreased serum haptoglobin and hemopexin Increased serum lactate dehydrogenase (LDH) Mildly increased aspartate transaminase (AST) Increased urine urobilinogen 22 11  6/28/2024 Special Laboratory Testing Thin-layer isoelectric focusing (IEF). High-pressure liquid chromatography (HPLC). Globin DNA analysis is also advocated as an alternative method, although the procedure is costly and limited in the number of genotypes it can identify. 23 Prenatal Diagnosis #1 Prenatal diagnosis of abnormal hemoglobin is important because of the high frequency of SCD. Fetal diagnosis can be made by amniocentesis at about the 14th week of gestation. The current widespread use of chorionic villus biopsy allows DNA diagnosis to be performed at the 7th to 10th week of gestation. 24 12  6/28/2024 Screening of Newborns for Sickle Cell Anemia and Carriers #1 The principal hemoglobin in the newborn is Hb F. The distribution is 80% Hb F and 20% Hb A in a normal term infant. Hb F is composed of two α- and two γ-globins. During the last trimester, there is a progressive increase in β-globin synthesis and a decrease in γ-chain synthesis. In a normal term infant, approximately 80% of the non-α globulin is γ-globin and 20% is β- globin. Screening for SCD in newborns at birth is mandated in all 50 states and the District of Columbia. Sickle cell anemia (Hb SS) affects 1 in 375 African American newborns born in the United States and smaller proportions of children in other ethnic groups. Without prompt diagnosis and the initiation of prophylactic antibiotics and pneumococcal conjugate vaccination by 2 months of age, children with sickle cell anemia are vulnerable to life-threatening pneumococcal infections. 25 Screening of Newborns for Sickle Cell Anemia and Carriers #2 Screening tests will identify approximately 50 sickle cell carriers for every infant diagnosed with SCD. An infant with sickle cell trait (AS) has both a normal β gene and a β S gene, and the infant will have a predominance of Hb F and both Hb A and Hb S. There always will be more Hb A than Hb S in these infants because α chains preferentially pair with normal β chains. Screening of newborn infants is an important step in disease control. Although universal newborn screening can reliably identify all infants with sickle cell hemoglobinopathies, the initial screening result must not be considered the definitive diagnosis. Confirmatory testing should occur no later than 2 months of age. Blood collection on the first day of life poses no problem for hemoglobin screening, provided the infant has not received a blood transfusion. Samples collected onto a filter paper from a heelstick remain stable for at least 1 week at room temperature. Extremely premature infants may have false-positive results. In the United States, most state-based screening programs use either thin-layer IEF or HPLC as the initial screening techniques performed on capillary blood collected from a heelstick and absorbed onto a filter paper. 26 13  6/28/2024 Management and Treatment of Sickle Cell Disease The management of SCD consists of the following: Monitoring the severity of the anemia and transfusing blood only when necessary Treating acute and chronic pain according to a rational guideline Diagnosing organ failure and administering appropriate therapy; over time, recurrent vasoocclusion and its associated vasculopathy result in significant progressive organ failure. Treatment consists of: Bone marrow transplant offers the only potential cure for sickle cell anemia. General supportive care includes daily oral folate supplementation, antibiotic prophylaxis in childhood, Pneumovax, Haemophilus influenzae vaccine, meningococcal vaccine, a yearly flu shot, a yearly eye examination, prompt treatment of infections, and avoidance of dehydration BREAK TIME 27 Experimental Treatment Gene therapy: inserting a normal gene or turning off the defective gene in SCD patients Butyric acid: food additive that may increase Hb F Clotrimazole: over the counter antifungal medication that helps prevent water loss and mitigate sickle formation Nitric oxide: inhibits vasoconstriction of the blood vessels to prevent vasoocclusive crises Nicosan: herbal treatment in early trials that prevents sickle crises; originally used in Nigeria, West Africa 28 14  6/28/2024 Infectious Diseases Prevention of infectious diseases is a priority. Vaccinations include the following: Pneumococcal Influenza A H. influenzae Splenectomy is also recommended to minimize splenic sequestration and autosplenectomy. 29 Blood Transfusion Major indications for blood transfusion: Improve oxygen-carrying capacity and transport Dilute circulating sickle cells to microvascular perfusion Should be considered when: Hb less than 5.0 g/dL with significant signs of anemia and hypoplasia Angina or high-output failure Acute hemorrhage Acute CNS complications Acute chest syndrome with hypoxia Sequestration crisis Preoperative preparation 30 15  6/28/2024 Drug Therapy Hydroxyurea, a ribonucleotide reductase inhibitor, stimulates the production of Hb F but suppresses bone marrow production. Fetal hemoglobin is a potent inhibitor of the polymerization of deoxyhemoglobin S. 31 Novel Pharmaceutical Therapies Novel therapies can do the following: Increase the production of fetal hemoglobin Improve red blood cell hydration Increase the availability of nitric oxide Possess anti-inflammatory effects Novel therapies include the following: Nitric oxide Anti-inflammatory agents, such as statins Anticoagulants and antiplatelet agents 32 16  6/28/2024 Prevention Genetic counseling may be useful in the prevention of sickle cell anemia. When the parents are both Hb SA (carriers), antenatal diagnosis can be performed during the 18th to 20th weeks of pregnancy by analyzing DNA from amniotic fluid Experimental therapy includes induction of Hb F by short-chain fatty acids (FA) and membrane-active drugs Short chain FA appear to modulate gene expression directly by interacting with transcriptionally active elements of the genes 33 Sickle Cell Syndromes Pathogenesis and New Approaches Sickle β-thalassemia Sickle-C disease Sickle cell trait 34 17  6/28/2024 Sickle Cell Trait Approximately 8% of Black Americans are heterozygous for Hb S. Sickle cell trait provides a survival advantage over individuals with normal hemoglobin in regions where malaria, P. falciparum, is endemic. 35 Thalassemia: Demographics Thalassemia is a growing global public health problem, with an estimated 900,000 births of clinically significant thalassemia disorders expected to occur in the next 20 years. Hb E–β-thalassemia and Hb H disease account for much of the projected increases in thalassemia. Worldwide, Hb E–β-thalassemia is one of the most frequent hemoglobinopathies. The incidence of Hb E approaches 60% of the populations in many regions of Southeast Asia. In coastal regions of North America, its prevalence is rapidly growing. α Thalassemia diseases, often considered benign, are now recognized to be more severe than originally reported. 36 18  6/28/2024 Thalassemia: Etiology Thalassemias are caused by an abnormality in the rate of synthesis of the globin chains. This is in contrast to an inherited structural defect in one of the globin chains that produces hemoglobin with abnormal physical or functional characteristics. Inheritance of thalassemia is autosomal; whether it is autosomal dominant or recessive is questionable because heterozygotes are not always symptomatic. Mutations that affect gene structure and function implicated in thalassemia are as follows: Nonsense mutation leading to early termination of the globin chain Mutation in one of the noncoding intervening sequences of the original globin chain gene, which causes inefficient splicing to mRNA Mutation in the promoter area that decreases the rate of gene expression Mutation at the termination of the gene that leads to lengthening of the globin chain with additional amino acids rendering the mRNA unstable Total or partial depletion of a globin gene, probably due to unequal chromosomes crossing over 37 Thalassemia: Pathophysiology #1 Thalassemias are characterized by the absence or decrease in the synthesis of one of the two constituent globin subunits of a normal hemoglobin molecule. Can be classified as alpha (a) or beta () depending on the affected subunit. Mendelian genetics determines zygosity and quantity of hemoglobin produced. Alpha thalassemias have higher severity than beta thalassemias since alpha chains comprise all normal hemoglobin fractions. In beta thalassemias, overall quantity of A1 is diminished, which is compensated by an increase in gamma and delta chain production. 38 19  6/28/2024 Thalassemia: Pathophysiology #2 In α thalassemia, decreased synthesis of α globin results in accelerated red cell destruction because of the formation of insoluble Hb H inclusion in the mature erythrocyte. The more severe β thalassemia reflects the extreme insolubility of α globin, which is present in excess in the red cell because of decreased β-globin synthesis. Studies of RNA metabolism in erythroid cells have suggested that many patients with α thalassemia have a defect in RNA processing. This defect affects efficient RNA splicing during protein globin synthesis. 39 Beta (β) Thalassemia Beta (β) thalassemia is one of the most common single-gene disorders. More than 200 point mutations in or around the β-globin gene are known to cause decreased production of β globin, which in turn leads to the excess accumulation of unstable α-globin chains, ineffective erythropoiesis, and shortened red cell survival. Ineffective erythropoiesis now appears to be caused by accelerated apoptosis. 40 20  6/28/2024 Laboratory Findings #1 In β thalassemia, hematological findings include decreased hemoglobin, hematocrit, and red cell count. The hemoglobin concentration can be as low as 2 or 3 g/dL in homozygous patients. Peripheral blood smears reveal anisocytosis, poikilocytosis, hypochromia, target cells, polychromatophilia, and few to many nucleated red cells. Erythrocytes are significantly microcytic and hypochromic. The red cell indices (MCV, MCH, MCHC) are significantly reduced. 41 Laboratory Findings #2 In addition, the red cell distribution width (RDW) is increased because of the anisocytosis. Other laboratory findings include increased reticulocyte formation (5% to 10%), decreased osmotic fragility, moderately increased bilirubin, increased serum iron, and saturated total iron- binding capacity (TIBC). Serum ferritin is a marker in determination of iron status. Soluble transferring receptor index is useful and is more specific than soluble transferring receptor because serum ferritin may be increased because of other pathology. 42 21  6/28/2024 Laboratory Findings #3 Hemoglobin electrophoresis reveals increased Hb F and decreased Hb A. A variable form of homozygous α thalassemia demonstrates no Hb A, increased Hb A2, and decreased Hb F. The absence of Hb A is owing to the absence of β-chain synthesis. Heterozygous β thalassemia could be mistaken for a mild iron deficiency anemia on a peripheral blood smear. Other laboratory findings include decreased MCV, increased Hb A2 on electrophoresis, and decreased osmotic fragility. 43 Prenatal Diagnosis Prenatal diagnosis of β thalassemia ideally is conducted in the first trimester of pregnancy using chorionic villus tissue for DNA analysis by PCR to detect point mutations or deletions. Later, second trimester fetal blood analysis is done to estimate relative rates of synthesis of globin chains of hemoglobin. This is performed to estimate relative rates of synthesis of globin in mid-trimester fetuses and base the diagnosis on the beta-to- alpha (βÚα) biosynthetic ratio. 44 22  6/28/2024 Newborn Screening Testing for hemoglobinopathies is incorporated into existing programs because of the increasing prevalence of hemoglobinopathies in the United States. Initial screening methods differ between states, but most newborn screening programs employ HPLC or IET as the preferred first-line technique to make a presumptive diagnosis of a clinically significant hemoglobinopathy. If an abnormal is identified, ethnicity information and parental studies are helpful in guiding the sequence of diagnostic tests for specific hemoglobinopathies. 45 Treatment and Prevention Treatment: Severe anemia requires blood transfusions. Bone marrow or PSC transplant. Frequent transfusion cause iron overload. Address with iron chelators (3): Deferiprone (unlicensed in North America) Deferoxamine Deferastrox (newest) Combined use of deferiprone and deferoxamine are effective at improving cardiac function and patient QoL. Prevention: Careful counseling and prenatal diagnosis in Sardinia reduced the incidence of homozygous β thalassemia by more than 90%. 46 23  6/28/2024 Alpha (a) Thalassemia #1 In contrast to β thalassemia, with most cases caused by point mutations, the major cause of a thalassemia is deletions that remove one or both α-globulin genes from the affected chromosome 16. a Thalassemias can be classified into four types on the basis of genotype and the total number of abnormal genes that result: Silent carrier state (one inactive/deleted a gene) a-thalassemia trait (two inactive/deleted a genes) Hb H disease (three inactive/deleted a genes) a Thalassemia major; Hydrops fetalis with Hb Bart (four inactive/deleted α genes) 47 Other Hemoglobinopathies Hemoglobin C disease This hemoglobinopathy is prevalent in the same geographic area as Hb S (sickle cell) disease. Hb C differs from Hb A by the substitution of a single amino acid residual, lysine, for glutamic acid in the sixth position from the amino (NH2) terminal end of the β chain. This is the exact point of substitution of Hb S; however, the amino acid is different. 48 24  6/28/2024 Hemoglobin SC Disease #1 This disorder results from the inheritance of one gene for Hb S from one parent and one gene for Hb C from the other parent. The course of this disease is generally milder than SCD, although Hb C tends to aggregate and potentiate the sickling of Hb S. Clinical signs and symptoms are similar to mild sickle cell anemia. Laboratory examination of a peripheral blood smear usually reveals target cells, folded erythrocytes, and occasionally, intracellular crystals. 49 Hemoglobin D Disease Hb D has several variants. Patients who are homozygous or heterozygous are asymptomatic. Some target cells may be seen on examination of a peripheral blood smear. 50 25  6/28/2024 Hemoglobin E Disease This hemoglobinopathy occurs with the greatest frequency in Southeast Asia. Hb E/β thalassemia is now a worldwide clinical problem. In some areas of Thailand, the frequency of the Hb E trait is almost 50%. Hb E syndromes appear in both homozygous (E/E) and heterozygous forms (A/E) and as compound heterozygotes in combination with α-, β thalassemias, and other structural variants. Hb E results from the substitution of lysine for glutamic acid in the β chain of hemoglobin. Clinical presentation is diverse. It can range from entirely asymptomatic to mildly anemic to severely anemic. 51 Hemoglobin H Disease Hb H disease is a mild to severe chronic hemolytic anemia. The disease most frequently results from an absence of three of the four α-globin genes. Primarily affects individuals throughout Southeast Asia, the Mediterranean islands, and parts of the Middle East. Because of the large influx of immigrants from Southeast Asia in the past 20 to 30 years, the prevalence of Hb H disease in the United States has increased significantly. 52 26  6/28/2024 Methemoglobinemia Methemoglobinemia is a disorder associated with elevated methemoglobin levels in the circulating blood. Causes of methemoglobinemia include acquired toxic substances, Hb M variants, and NADH- methemoglobin reductase (also called diaphorase) deficiency. Hb M has five variant forms. It displays a dominant inheritance resulting from a single substitution of an amino acid in the globin chain that stabilizes iron in the ferric form. NADH- diaphorase is the enzyme that reduces cytochrome b5, which converts naturally occurring ferric iron back to the ferrous state. 53 Unstable Hemoglobins #1 Unstable hemoglobins are hemoglobin variants in which amino acid substitutions or deletions weaken the binding forces that maintain the internal portion of the globin chains of the hemoglobin molecule. Most unstable hemoglobins are inherited as autosomal dominant disorders. Instability may cause abnormal hemoglobin to denature and precipitate in erythrocytes such as Heinz bodies of an oxidizing drug or an infection. Heinz bodies are associated with α- or β-chain abnormalities. Tetramers of normal chains, such as Hb Bart and Hb H, appear in thalassemias. 54 27  6/28/2024 Hereditary Persistence of Fetal Hemoglobin (HPFH) Retention of Hb F (fetal hemoglobin) into adult life is abnormal. It is a benign condition in which significant fetal hemoglobin production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced. The level of expression is 15% to 30% of total hemoglobin. This abnormality is referred to as hereditary persistence of Hb F. 55 Postamble READ the TEXTBOOK for the details to answer the UNIT OBJECTIVES. USE THE UNIT OBJECTIVES AS A STUDY GUIDE All test questions come from detailed material found in the TEXTBOOK (Not this PowerPoint) and relate back to the Unit Objectives 28