Anemia
Introduction
The function of red blood cells is to transport oxygen to tissues. This is accomplished by the hemoglobin. The hemoglobin protein is composed of two alph and two beta subunits. Each of the subunits contains a central iron containing protein called a heme protein. It is the iron atom in the heme protein that binds to molecular oxygen. As a result of the four iron-containing heme groups, each molecule of hemoglobin can carry four atoms of oxygen.
Definition
Anemia is a condition in which there is a reduced number of red blood cells or decreased concentration of hemoglobin in those cells or both.
Pathophysiology
Anemia can be caused by:
1- Decreased red cell production, which may be due to lack of nutrient (B12, folic acid, iron) or bone marrow failure.
2- Increased red cell destruction secondary to hemolysis.
3- Increased red cell loss caused by acute or chronic bleeding.
Morphologic classification of anemias by red blood cell size (microcytic, normocytic, macrocytic) and hemoglobin content (hypochromic, normochromic, hyperchromic) is as follows (see figure-1):
Macrocytic (Megaloblastic) anemia: Vitamin B12 deficiency (pernicious) and folic acid deficiency anemia.
Microcytic, hypochromic anemia: Iron deficiency
Normochromic, normocytic: Recent blood loss and Hemolysis
Figure-1: illustrating microcytic hypchromic and macrocytic hyperchromic anemia
Signs and Symptoms
Onset of anemia can be acute or can develop slowly, resulting in tissue hypoxia caused by the decreased oxygen-carrying capacity of the reduced red cell mass.
Slowly developing anemias can be asymptomatic initially or include symptoms such as slight exertional dyspnea, and fatigue. In severe anemia, heart rate, and stroke volume often increase in an attempt to improve oxygen delivery to tissues. These changes in heart rate and stroke volume can result in angina pectoris and high output congestive heart failure.
Microcytic hypochromic anemias (Iron Deficiency Anemia)
Iron deficiency is the most common cause of anemia worldwide. Iron deficiency is a state of negative iron balance in which the daily iron intake and stores are unable to meet the RBC and other body tissue needs.
Only about 0.5 to 1 mg/day of iron is lost from urine, sweat, and the sloughing of intestinal mucosal cells that contain ferritin. Menstruating women lose approximately 0.6% to 2.5% more iron per day.
Iron is absorbed from the duodenum and upper jejunum by an active transport mechanism. Dietary iron, which is primarily in the ferric state, is converted to the more readily absorbable ferrous form in the acid environment of the stomach.
Animal sources of iron are better absorbed than plant sources. A gastrectomy may decrease the conversion of the ferric form of iron to the ferrous state, thereby diminishing iron absorption.
Etiology and pathophysiology
Iron deficiency anemia can be caused by:
1- Chronic blood loss due to peptic ulcer disease, hemorrhoids, menstruation and ingestion of GI irritants such as NSAIDs.
2- Decreased absorption due to gastrectomy, or ingestion of medications that complex with iron, decreasing its absorption.
3- Increased requirement during infancy, pregnancy and lactation.
4- Inadequate dietary intake of iron (less than 1 to 2 mg/day), as in prolonged non supplemented breast-feeding or bottle-feeding of infants.
Because iron is the functional component of hemoglobin, lack of available iron will result in a decreased hemoglobin synthesis and subsequent impairment of red blood cell oxygen-carrying capacity.
Treatment (Iron Therapy)
The goals of iron therapy are to normalize the Hb concentrations and to replete iron stores.
The preferred route of iron administration is oral route. Oral iron is most readily absorbed in the absence of food,
The ferrous form of iron is absorbed three times more readily than the ferric form. Although ferrous sulfate (contain 20% of elemental iron ), ferrous gluconate (contain 11% of elemental iron), and ferrous fumarate (contain 33% of elemental iron) are absorbed almost equally, each contains a different amount of elemental iron.
The usual adult dose of ferrous sulfate is 325 mg (one tablet) administered three times daily, between meals.
Hematologic response is usually seen in 2 to 3 weeks with a 1 g/dL increase in hemoglobin, anemia can be resolved in 1 to 2 months; however, iron therapy should be continued for 3 to 6 months after the hemoglobin is normalized to replete iron stores.
Side effects
Oral iron therapy produces dark stools. Gastric side effects, which occur in 5% to 20% of patients, include nausea, epigastric pain, constipation, abdominal cramps, and diarrhea.
Drug-drug interactions
Food, especially dairy products, decreases the absorption of iron by 40% to 50%. Drugs that increase the pH of the stomach (antacids, proton pump inhibitors, and H2 blockers) will decrease the solubility of ferrous salts and thus reduce iron absorption.
Because the absorptions of both iron and tetracycline are decreased when administered concomitantly, the iron should be taken 2 hours before or 3 hours after the tetracycline and drugs that increase gastric pH.
Parenteral Iron Therapy
Parenteral iron therapy is indicated when there is failure to respond to oral therapy (due to nonadherence, or malabsorption). Iron can be given parenterally in the form of ferric gluconate, iron dextran, and iron sucrose.
Iron dextran can be administered undiluted intramuscularly or by very slow intravenous infusion after dilution in 0.9% NaCl.
Ferric gluconate and iron sucrose can be administered undiluted as a slow IV injection or as an IV infusion after dilution in 0.9% NaCl.
Side effects of parentral iron
Anaphylactoid reactions can occur in about 1% of patients treated with parenteral iron therapy. Other side effects seen with parenteral iron agents include hypotension, nausea and vomiting, cramps, and diarrhea.
Megaloblastic Anemias
Megaloblastic anemia is a common disorder that caused by either vitamin B12 deficiency or folic acid deficiency. Megaloblastic anemia results from impaired DNA synthesis in replicating cells, which is signaled by a large immature nucleus.
Folic Acid Deficiency Anemia
Etiology
Folate deficiency can result from decreased intake or increased requirement (during pregnancy). Folate deficiency also can occurs due to ingestion of drugs that alter folate metabolism (e.g., trimethoprim, pyrimethamine, methotrexate, sulfasalazine anticonvulsants)
Pathogenesis and symptoms
Once absorbed, the inactive dihydrofolate is methylated and reduced to methyl tetrahydrofolate (folinic acid) by dihydrofolate reductase. Within the cells the methyl group is removed (in a reaction requiring vitamin B12) to form the active tetrahydtofolate which acts as a coenzyme involved in a number of reactions including DNA and RNA symthesis. Defect in DNA synthesis mainly affect cells with rapid turnover such as red blood cells and gastrointestinal cells, hence sore tongue and anemia seen in folate deficiency.
Treatment
Folate deficiency is usually managed by replacement therapy. The normal daily requirement of folic acid is about 100 mcg/ day. Despite this, the usual treatment doses given are 1-5 mg /day of oral folic acid. Even in malabsorption states sufficient folate is absorbed because of these large doses.
The RBC morphology should begin to revert back to normal within 24 to 48 hours after therapy is initiated, and the anemia should be corrected in 1 to 2 months.
Large doses of folate can partially reverse hematologic abnormalities caused by vitamin B12 deficiency; however, folate cannot correct neurologic damage caused by vitamin B12 deficiency. Therefore, folate deficiency absolutely must be differentiated from vitamin B12 deficiency before folate therapy is initiated. Otherwise, the progression of the neurologic sequelae of vitamin B12 deficiency can occur.
Vitamin B12 Deficiency Anemia
The typical diet contains 5 to 15 mcg/day of vitamin B12, an amount sufficient to replace the 2 mcg lost daily. The total body stores of vitamin B12 range from 2,000 to 5,000 mcg. Because body stores are extensive, 3 to 4 years are required before symptoms of vitamin B12 deficiency develop (the onset of the vitamin B12 deficiency anemia is slow).
In the stomach, the vitamin B12 bound to intrinsic factor, which protects it from degradation by GI microorganisms. Intrinsic factor is essential for the absorption of vitamin B12. Specific mucosal receptors in the distal ileum allow for attachment of the intrinsic factor-B12 complex. In the liver, vitamin B12 is converted to coenzyme B12, which is essential for hematopoiesis, maintenance of myelin throughout the entire nervous system, and production of epithelial cells.
Aetiology
Vitamin B12 deficiency can result from decreased intake or malabsorption. Malabsorption occur if the distal ilium is removed. In addition, the gastric mucosa may be unable to produce intrinsic factor under conditions such as total and partial gastrectomy or autoimmune destruction (Pernicious anemia).
Pathogenesis and symptoms
Vitamine B12 is acoenzyme for the removal of a methyl group from methyltetrahydrofolate. Lack of vitamin B12 traps the folate as methyltetrahydrofolate and prevents DNA synthesis. So vitamin B12 is a coenzyme essential for hematopoiesis, maintenance of myelin throughout the entire nervous system, and production of epithelial cells. Therefore, vitamin B12 deficiency is associated with sore tongue, and numbness or tingling in the extremities (peripheral neuropathy)
Treatment
Parenteral vitamin B12 in a dose sufficient to provide the daily requirement of approximately 2 mcg, and to replenish tissue stores (about 2,000 to 5,000 mcg;) is given for treatment of vitamin B12 deficiency anemia. To replete vitamin B12 stores, cyanocobalamin (1,000 mcg) IM once a week for 4 to 6 weeks followed by 1,000 mcg/month for lifetime maintenance therapy in case of pernicious anemia .
Sickle Cell Anemia
Patients with sickle cell anemia have HbS (normal Hb is HbA). HbS has valine substituted for glutamic acid as the sixth amino acid in the beta chain of Hb.
The hemoglobin produced from such a substitution has a more negative charge than normal HbA, and the deoxygenated state favors hemoglobin aggregation and polymerization, which forms sickled RBC. Sickled RBCs are more rigid and may become “lodged” when passing through microvasculature, resulting in vascular occlusions. In addition, the sickled RBCs surface contains aminophospholipids, which augments the ability of the RBC to initiate coagulation and adhere to vascular endothelium leading to vaso-occlusive episodes and multiorgan damage.
Symptoms and treatment
The kidney is commonly affected by microinfarction. Although, vaso-occlusive events are uncommon. If they do occur, they usually are caused by hypoxic conditions resulting from excessive exercise or high altitudes.
Treatment of sickle cell anemia is largely directed toward prophylaxis against infections and supportive management of vaso-occlusive crises.
The following are symptoms and complications of sickle cell disease
Hemolytic Anemia
Hemolytic anemia in patients with sickle cell disease is caused by splenic sequestration of abnormal RBC. Sequestration reduces the RBC life span from 120 days to 15 to 25 days. Management of the underlying anemia may include splenectomy following the first splenic sequestration event. Alternatively, patients can be treated with transfusions and careful observation.
Infections
Patients with sickle cell disease have a high incidence of infections especially pneumococcal infections, due to altered B-cell immunity and granulocyte function.
Pneumonia caused by S. pneumoniae can worsen hypoxia, causing progression to vaso-occlusion. Because of such complications, the prophylactic administration of penicillin has significantly reduced morbidity and mortality from pneumonia in children <3 years of age, but prophylaxis is recommended to be continued through age 5.
Vascular Occlusion Episodes
Vascular occlusion episodes, or “sickle cell crises,” cause severe pain and organ damage. The pain typically lasts 2 to 6 days and should be managed with narcotic analgesics.
Treatment for Frequent Vaso-occlusive Crises
Hemoglobin F (HbF) has a protective effect against hemoglobin polymerization. Hydroxyurea has been found to increase HbF synthesis, which, in turn, may decrease sickling of RBC and the occurrence of disease-related complications. Hydroxyurea is used prophylactically in patients with recurrent vaso-occlusive crises, but not in treatment of the crises.
Thallasemia.
Patients with α-thalassemia have a decrease in α-globin chain production relative to β-globin chain, with the formation of β4 (HbH) inclusion bodies. Red blood cells bearing these inclusion bodies are removed rapidly from the circulation by the reticuloendothelial system, shortening their survival. The resulting mild anemia is compensated partially by an increase in red blood cell production.
In contrast, patients with β-thalassemia have a decrease in β-globin chain production relative to α-globin chain production, which leads to an excess of α-globin chains. Unbound α-globin chains are extremely insoluble and precipitate in red blood cell precursors leading to defective erythroid maturation (ineffective erythropoiesis). The few cells that do emerge into the peripheral circulation are removed rapidly in the spleen and liver.
Clinical manifestation
The resulting profound anemia increases circulating levels of erythropoietin and causes a massive expansion of bone marrow. In sever cases this lead to bone abnormalities and growth retardation. The spleen is actively involved in removing the abnormal mature cells from the circulation and become enlarged (spleenomegaly).
Treatment
There is currently no effective treatment for thalassemia. Many patients with sever forms are blood transfusion dependant from early age. Although intensive blood transfusion programs have led to markedly improved survival, patients die from iron overload unless chelation therapy is instituted and maintained. Desferrioxamine and deferiprone are used for chelation of iron.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency anemia
Pathophysiology
G6PD is essential for the production of the reduced form of NADPH in erythrocytes. NADPH is needed to keep glutathione in a reduced form. Reduced glutathione maintain Hb in a reduced form and help erythrocytes deal with oxidative stress. In G6PD deficiency, if the erythrocytes are exposed to an oxidizing agent, the Hb becomes oxidized and forms what are known as Heinz bodies. The cell membrane damaged and some red cells hemolysed and removed from ciculation by the spleen.
Clinical manifestations
The milder form of G6PD deficiency that occurs in black population results in an acute self limiting hemolytic anemia following exposure to an oxidizing agent e.g. infection, acute illness, fava beans or some drugs. The hemolytic anemia is self limiting because the younger cells produced by the bone marrow have higher level of G6PDactivity than older cells.
In the Mediterranean form of G6PD deficiency, the enzyme activity is very low and the hemolysis is not usually self limiting and so some patients have chronic hemolytic anemia despite the absence of an obvious causative factor
Drugs to be avoided in all types of G6PD deficiencies include ciprofloxacine, nalidixic acid, sulphonamides including trimethoprim, dapsone and primaquine,
Drugs to be avoided only in sever type of G6PD deficiencies are aspirin, chloramphenicol, chloroquine, probenicid, quinidine and quinine.
Treatment
There is no specific treatment for this disorder. It is important to avoid known precipitating factors to prevent acute episode. During the acute episode the causative factor should be stopped and the patient must kept well hydrated to ensure good urine flow and prevent renal damage. Some times blood transfusions may be necessary.
Renal Insufficiency-Related Anemia
The cause of the anemia is complex but involves reduced erythropoietin (EPO) production and a shortened RBC life span. Because EPO is secreted in the kidney in response to anoxia and is responsible for normal differentiation of RBC from other stem cells, EPO is used to treat anemia in patients with renal failure.
No comments:
Post a Comment