1) Anemias Dr. Anwar Sheikha

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1 1) Anemias Dr. Anwar Sheikha DEFINITION: Anemia can be defined as a reduction in the concentration of hemoglobin below what is normal for age and sex of the patient. This reduction of hemoglobin is usually associated with a fall of the red cell count; however, this is not a universal feature and it is possible for the red cell count to be normal or even increased despite a low hemoglobin. Examples are patients with thalassemia minor and mild iron deficiency; obviously this is due to the low hemoglobin content of individual cells. PATHOPHSIOLOGY: Hemoglobin is responsible for the transport of oxygen from the lungs to the tissues. Anemia by reducing the oxygen carrying capacity of the blood reduces the amount of oxygen available to the tissues, i.e., it results in tissue hypoxia. This hypoxia causes impairment of function of the body tissues and the symptoms and signs of anemia are therefore referred to many systems. That does not mean that a student with a hemoglobin of 16 gm/dl will score twice as good in the hematology examination as another student with a hemoglobin of 8 gm/dl. Body tissues try to compensate for the reduced oxygenation by bringing into play several mechanisms designed to make the most effective use of the available hemoglobin; these are :- (1). Increased delivery of oxygen to the tissues by the red cell; this is achieved by increasing the concentration of 2,3 Diphosphoglycerate (2,3 DPG) which combines with the hemoglobin, shifting the oxygen dissociation curve to the right and increasing delivery of oxygen to the tissues. (2). An increase in the cardiac output & in the rate of blood circulation. (3). Maintenance of total blood volume by expansion of the plasma volume. (4). Redistribution of blood flow from tissues with lesser oxygen requirement like the skin to those with greater requirement like the brain and muscles. CLINICAL FEATURES : The symptoms and signs of anemia are due to: 1. The anemia itself. 2. The disorder causing anemia. Symptoms and signs of anemia are :- 1. Tiredness, lassitude, easy fatigability and generalized muscular weakness are the commonest and often the earliest symptoms of anemia. 2. Pallor, which is the most prominent and characteristic sign; it may be seen in the skin, nail beds, mucous membrane and conjunctivae. However, the skin color does not only depend on the hemoglobin content of the blood, but also on the state of the skin vessels, the amount of fluid in the subcutaneous tissues and on the degree of skin pigmentation ; so one should be careful in interpreting the skin pallor and exclude other causes like myxedema and nephritis. 1

2 3. Cardiovascular manifestations: *. Dyspnea on exertion and Palpitation. *. Angina Pectoris. *. Hemic murmurs : these are usually soft ejection mid-systolic murmur caused by increased velocity of blood flow through the valves. *. The " high output state " which develops with severe anemia *. Congestive cardiac failure especially in older patients. The heart fails because the anoxic myocardium is unable to cope with the extra work resulting from the increase in cardiac output ; the signs are pulmonary congestion, raised JVP, hepatomegaly and peripheral edema. 4. Central Nervous System manifestations: Dizziness, giddiness, faintness, headache, roaring and banging in the ears, tinnitus, spots before the eyes, lack of power of concentration and drowsiness, clouding of consciousness, numbness, coldness and sometimes tingling of the hands and feet. The last group only occur in severe anemias. 5. Reproductive System: Amenorrhea in females. Loss of libido in males. 6. Gastrointestinal manifestations: * Anorexia, nausea and vomiting. These are usually * Flatulence and constipation. causal rather than * Weight loss. being the result of * Slight to moderate smooth hepatomegaly. anemia Approach to an anemic patient : Anemia is not a diagnosis per se. There are tens of causes for anemia and one should reach the diagnosis within the short time spent with the patient through a systematic approach. Unless one has a clear insight into the various causes and types of anemia, it will be extremely difficult to pinpoint the exact type. History and physical examination are invaluable. A correct interpretation of the complete blood count and proper order of extra tests will certainly elucidate the cause of anemia in the majority of cases. The best way to reach the diagnosis is to combine the etiological approach with the complete blood counts and morphological features of the red cells. While the etiology can usually be found through the history taking and physical examination, the complete blood count and blood smear need support of the hematology laboratory. Students and interns are strongly encouraged to visit the hematology laboratory and seek the advise and teaching of the hematologist to solve the problem of their patients. In this way their learning will be more productive and long-lasting. CLASSIFICATION OF ANEMIAS There are two main classifications for anemias: (A) PATHOGENETIC OR ETIOLOGICAL CLASSIFICATION OF ANEMIAS I. Blood Loss:- Acute Post-Hemorrhagic Anemia. Chronic Post-Hemorrhagic Anemia. 2

3 II. Impaired Red Cell Formation:- (A).DISTURBANCE OF BONE MARROW FUNCTION DUE TO DEFICIENCY OF SUBSTANCES ESSENTIAL FOR ERYTHROPOIESIS:- (*). Iron deficiency anemia. (*). Megaloblastic anemia due to B12 or Folate deficiency. (B).DISTURBANCE OF BONE MARROW FUNCTION (NOT) DUE TO DEFICIENCY OF SUBSTANCES ESSENTIAL FOR ERYTHROPOIESIS:- (*). Anemia of Chronic Disorders (ACD):- Chronic Infections ( TB, Brucella, etc.) Chronic Renal Failure. Chronic Liver Diseases. Disseminated Malignancy. Collagen Diseases. (*). Aplastic Anemias. (*). Anemias associated with bone marrow infiltration:- Leukemias Lymphomas Multiple Myeloma Myelofibrosis Malignant marrow metastasis (*). Sideroblastic Anemias. (*). Congenital Dyserythropoietic Anemias ( CDA ). III. Hemolytic Anemias.(This will be described in detail in the next page). *************************** (B). MORPHOLOGICAL CLASSIFICATION OF ANEMIAS This is based on the Mean Cell Volume (MCV):- (i). The NORMOCYTIC anemias in which the MCV is within the normal range (76-96 fl) ; most normocytic anemias are also normochromic (MCH pg). (ii). The HYPOCHROMIC MICROCYTIC anemias in which the MCV is reduced and the MCH and MCHC are also reduced. (iii). The MACROCYTIC anemias, in which the MCV is increased. Most of these cases are normochromic. HEMOLYTIC ANEMIAS I. HEMOLYTIC ANEMIAS DUE TO ABNORMALITIES OF THE RED CELLS Congenital (1). Disorders of the Membrane: Hereditary Spherocytosis Hereditary Elliptocytosis (2). Disorders of the red cell Metabolism : Deficiency of the Glycolytic Enzymes. Deficiency of the Oxido-Reduction System e.g., G6PDH Deficiency. 3

4 (3). The Hemoglobinopathies: Disorders of Synthesis (THALASSEMIAS) Structural Variants (SICKLE CELL ANEMIAS) Acquired Paroxysmal Nocturnal Hemoglobinuria (PNH). II. HEMOLYTIC ANEMIAS DUE TO ABNORMALITIES OF RBC ENVIRONMENT (A). Abnormal Plasma Constituents: ============================= (i). IMMUNE DISORDERS:- * Hemolytic Disease of the Newborn ( HDN ) * Drug Induced Hemolytic Anemias: Immune/ Autoimmune. * Autoimmune Hemolytic Anemias ( AIHA ):- WARM AIHA : 1. Idiopathic 2. Associated with ---- Lymphoma, S.L.E., Other Autoimmune Disorders COLD HEMAGGLUTININ DISEASE ( CHAD ): 1. Acute:- *. Associated with Atypical Mycoplasma Pneumonia. *. Associated with Infectious Mononucleosis. 2. Chronic:- *. Idiopathic *. Associated with Lymphoma (ii). DRUGS & TOXINS WHICH CAUSE DIRECT HEMOLYSIS ************************ (B). Abnormal Physical Environment : ============================== (a). Fragmentation Hemolysis:- * Abnormal Blood Vessels * Malignant Hypertension * March Hemoglobinuria * Micro Angiopathic Hemolytic Anemia (MAHA) * Thrombotic Thrombocytopenic Purpura (TTP) * Mechanical Hemolytic Anemia with Damaged Valves (b). Hypersplenism (c). Hemolysis associated with Severe Burns (C). INFECTIONS : ============= Parasites( Malaria). Bacteria (Cl. Welchii) THE HEMOGLOBINOPATHIES Hemoglobin is a large complex protein molecule, consisting of two pairs of polypeptide chains (GLOBINS), to each of which a (HEM) is attached. There are many types of globin chains, but the important ones are:- Alpha (α) chain consisting of 141 amino acids. Beta (β) chain consisting of 146 amino acids. Delta (δ) chain consisting of 146 amino acids. Gamma (γ) chain consisting of 146 amino acids. 4

5 Hemoglobin types are:- Hb A = α 2, β 2 (This constitutes 97% of adult Hb). Hb A 2 = α 2, δ 2 (This constitutes of adult Hb) Elevation of this Hb is a feature of thalassemia minor. Hb F = α 2, γ 2 (This is the major Hb in the intrauterine life and early neonatal period). The ratio declines rapidly as the child grows. The Hemoglobinopathies are disorders which result either from defective synthesis of normal globin chains (The Thalassemias) or synthesis of structurally abnormal globin chains (Sickle Cell Anemias, Hb C disease, Hb E disease, etc.). THE THALASSEMIAS Thalassemia is a disorder which arises because of defective synthesis of one of the pairs of HbA globin chains; α or β. The small amount of the chain synthesized is structurally normal. This imbalanced synthesis results not only in defective hemoglobinization of the red cell, but also in hemolysis due to the intracellular precipitation of the other chain, which is synthesized in relative excess. There are many types of thalassemias; it depends on the type of the defective globin chain:- β- Thalassemia: Here there is defective synthesis of the β chain, with a relative excess and accumulation of the α chain which exists in the cell as a pool of free α monomers. α- Thalassemia: Here there is defective synthesis of the α chain with a relative excess of β, γ and δ chains. These free chains can form tetrameric hemoglobins. HbH = (β4); Hb Barts = (γ4), etc. 100% α Diagram of the 75% developmental β changes in 50% Human hemoglobin 25% γ chains 3m 6m Birth The β- Thalassemia Syndromes: For proper understanding of this rather important condition, please refer to the diagram on the pathophysiology of the disease. As mentioned earlier, it results from decreased synthesis of the β globin chain. Thalassemia is common in the Mediterranean region, Middle East, India and South East Asia. It is particularly common in Italy, Greece and Arab nationals. HETEROZYGOUS state is called "β thalassemia minor" HOMOZYGOUS state is called " β thalassemia major" In β- thalassemia minor, the patient is usually asymptomatic, but the hematological values are abnormal (hypochromic, microcytic red cells, target cells, basophilic stippling, high red cell count and the most important of all high HbA 2 ). The problem with these patients is that when they get married to a similar carrier person, there is one in four chance of giving birth to offspring with thalassemia major. It is important not to confuse these patients with iron deficiency anemia, because here iron might be present in abundance, and their anemia do not respond to iron therapy, which might be even harmful. β- thalassemia major results from the homozygous state of the β- thalassemia gene. This disease is usually very serious, although the severity varies. Deficiency of β chains result in accumulation of free α chains, which are unstable and precipitate to form inclusion bodies. The marrow does not like these abnormal 5

6 inclusions and that results in red cell destruction, hemolysis and anemia. Even those cells which escape marrow destruction are hemolysed in the spleen because of their abnormal nature. Spleen becomes progressively enlarged until it reaches a tremendous size. At this stage hypersplenism accentuates the anemia and transfusion requirement. α chains will interact with γ chains to produce HbF. Diagnostically, High HbF is the hallmark of the disease. Because oxygen-affinity of HbF is high, it results in tissue hypoxia, which is also compounded by the anemia itself. Tissue hypoxia results in increased erythropoietin, which eventually causes proliferation of the ineffective erythroid mass. Marrow expansion causes skeletal abnormalities (frontal bossing, widening of the nasal bridge, prominent malar eminences, maxillary hypertrophy and exposure of the upper teeth), hypermetabolic state, hyperuricemia and increased iron absorption. Iron overload from transfusion and absorption are the main cause of death in these children. It results in hemochromatosis and liver cirrhosis, when it is deposited in the liver; diabetes, when it is deposited in the pancreas and cardiac death when it is deposited in the heart muscles. Hematologically, there is marked hypochromic, microcytic anemia with prominent aniso-poikilocytosis, target cells and nucleated red cells. HbF is between 60 to 100% depending on the deficiency of the beta chain. Iron store is usually markedly increased. It is important to establish the diagnosis by screening both parents for beta thalassemia minor. TREATMENT is by hypertransfusing these patients to suppress their ineffective marrow; giving them iron chelating agents (desferrioxamine) to get rid of the extra iron, and doing splenectomy when transfusion requirement increases. Bone marrow transplantation (BMT) gives the only hope of complete cure for these patients. In a small city on the Adriatic sea in Italy called Pesaro, Professor Lucarreli has a disease-free survival rate reaching 90% for these patients. That is if they are transplanted early before liver damage has already occurred. Although this procedure is very expensive, it is cost effective if one takes into consideration the amount of transfusion needed to keep these patients alive. These patients usually need hundreds of transfusions before they succumb to the deadly effects of iron overload. Even in the best centers of the world these patients can hardly live to their third or fourth decade. Thus if resources and HLA-compatible siblings are available, all these patients should be transplanted, preferably after the third year of life. Gene therapy is inshalla on the way. Success of BMT depends on the degree of hepatomegaly, presence or absence of portal fibrosis, history of effective iron chelation and of course age at the time of BMT. 2. PORTAL FIBROSIS CLASS PRE-BMT CRITERIA 1. HEPATOMEGALY SUCCESS OF BMT SURVIVIAL in <16 Yr (3 Yr Post-BMT) 3. H/O EFFECTIVE CHELATION DFS in <16 Yr (3 Yr Post-BMT) I 0 90% 83% II % 82% III 3 62% 51% Age > 16 Yrs = III As in III (62%) As in III (51%) At one time, there was a lot of enthusiasm for new red blood cell transfusion (Neocytes). Although this approach reduced transfusion requirement and consequently iron load, it was in 6

7 actual fact very cost-ineffective with a five-fold increase of the preparation cost and also increased the chance of exposure to more donated units. NEOCYTE TRANSFUSION Transfusion Intervals Transfusion Iron Load ( 10-25%) Very Cost-Ineffective (5-Fold) Exposure to Donated Units There is another type of thalassemia called "Thalassemia Intermedia". These patients are chronically anemic but usually not to the limit of needing transfusions. Here, the severity is between that of major and minor. I published a paper in the British Journal of Otology and Laryngology, on a Saudi family with thalassemia intermedia, whose members presented with marrow expansion involving the temporal bone, causing deafness. " PATHOPHYSIOLOGY OF THALASSEMIA MAJOR " γ chains α Chains β chains in F red cells α2 γ 2 EXCESS Selective survival Chain precipitates of HbF red cells Blood Marrow High HbF in Blood* Splenic destruction Marrow destruction Increased "Splenomegaly" Ineffective Erythropoiesis Oxygen Affinity Increased ERYTHROPOIETIN Hypersplenism Hemolysis (ANEMIA) BLOOD TRANSFUSION Proliferation Skeletal changes * Iron Overload of Ineffective Hyper metabolism Erythroid Hyperuricemia Mass * Cardiac death Increased Iron Absorption The presentation for this lecture can be found on lectures.shanyar.com 7