Pathology of blood

blood disorders affecting systemically and orally.

1. PATHOLOGY OF BLOOD Prepared by: Dr. Shaimaa P.G student Dept. of oral pathology

2. CONTENTS: RED CELL DISORDERS Anemia of Blood Loss: Hemorrhage Hemolytic Anemias Hereditary Spherocytosis Sickle Cell Anemia Thalassemia Glucose-6-Phosphate Dehydrogenase Deficiency Paroxysmal Nocturnal Hemoglobinuria Immunohemolytic Anemias Hemolytic Anemias Resulting from Mechanical Trauma to Red Cells Malaria Anemias of Diminished Erythropoiesis : Iron Deficiency Anemia Anemia of Chronic Disease Megaloblastic Anemias Aplastic Anemia Myelophthisic Anemia Polycythemia

3. RED CELL DISORDERS Disorders of red cells can result in anemia or, less commonly, polycythemia (an increase in red cells also known as erythrocytosis ).

4. Blood Loss Acute: trauma Chronic: gastrointestinal tract lesions, gynecologic disturbances Increased Destruction ( Hemolytic Anemias ) Intrinsic ( Intracorpuscular ) Abnormalities Hereditary Membrane abnormalities Membrane skeleton proteins: spherocytosis , elliptocytosis Membrane lipids: abetalipoproteinemia Enzyme deficiencies Enzymes of hexose monophosphate shunt: glucose-6-phosphate dehydrogenase , glutathione synthetase Glycolytic enzymes: pyruvate kinase , hexokinase Disorders of hemoglobin synthesis Structurally abnormal globin synthesis ( hemoglobinopathies ): sickle cell anemia , unstable hemoglobins Deficient globin synthesis: thalassemia syndromes Acquired Membrane defect: paroxysmal nocturnal hemoglobinuria

5. Extrinsic ( Extracorpuscular ) Abnormalities Antibody-mediated Isohemagglutinins : transfusion reactions, immune hydrops ( Rh disease of the newborn) Autoantibodies : idiopathic (primary), drug-associated, systemic lupus erythematosus Mechanical trauma to red cells Microangiopathic hemolytic anemias : thrombotic thrombocytopenic purpura , disseminated intravascular coagulation Defective cardiac valves Infections : malaria

6. Impaired Red Cell Production Disturbed proliferation and differentiation of stem cells: aplastic anemia , pure red cell aplasia Disturbed proliferation and maturation of erythroblasts Defective DNA synthesis: deficiency or impaired utilization of vitamin B12and folic acid ( megaloblastic anemias ) Anemia of renal failure (erythropoietin deficiency) Anemia of chronic disease (iron sequestration, relative erythropoietin deficiency) Anemia of endocrine disorders Defective hemoglobin synthesis Deficient heme synthesis: iron deficiency, sideroblastic anemias Deficient globin synthesis: thalassemias Marrow replacement: primary hematopoietic neoplasms (acute leukemia , myelodysplastic syndromes) Marrow infiltration ( myelophthisic anemia ): metastatic neoplasms , granulomatous disease

7. ANEMIA OF BLOOD LOSS: HEMORRHAGE acute blood loss exceeding 20% of blood volume. hypovolemic shock rather than anemia hemodilution begins at once and achieves its full effect within 2 to 3 days Recovery from blood loss anemia is enhanced by a compensatory rise in the erythropoietin level, which stimulates increased red cell production and reticulocytosis within a period of 5 to 7 days . chronic blood loss , iron stores are gradually depleted

8. HEMOLYTIC ANEMIAS Anemias caused by accelerated red cell destruction are termed hemolytic anemias . Destruction can be from intrinsic ( intracorpuscular ) red cell defects, which are usually inherited, or extrinsic ( extracorpuscular ) factors, which are usually acquired. Features shared by all uncomplicated hemolytic anemias include (1) a decreased red cell life span, (2) a compensatory increase in erythropoiesis , and (3) the retention of the products of degraded red cells (including iron) by the body.

9. Hemolytic Anemias are associated with erythroid hyperplasia in the marrow and increased numbers of reticulocytes in the peripheral blood. In severe hemolytic anemias , extramedullary hematopoiesis may appear in the liver, spleen, and lymph nodes. Haptoglobin , a circulating protein that binds and clears free hemoglobin, is completely depleted from the plasma, which also usually contains high levels of lactate dehydrogenase (LDH) as a consequence of its release from hemolyzed red cells in case of intravascular hemolysis .

10. Hereditary Spherocytosis This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to the formation of spherocytes , nondeformable cells that are highly vulnerable to sequestration and destruction in the spleen. Hereditary spherocytosis is usually transmitted as an autosomal dominant trait; a more severe, autosomal recessive form of the disease affects a small minority of patients.

11. A shared feature of the pathogenic mutations is that they weaken the vertical interactions between the membrane skeleton and the intrinsic membrane proteins. This defect somehow destabilizes the lipid bilayer of the red cells, which shed membrane vesicles into the circulation as they age. Little cytoplasm is lost in the process and as a result the surface area to volume ratio decreases progressively over time until the cells become spherical. PATHOGENESIS

12. Clinical Features The characteristic clinical features are anemia, splenomegaly , and jaundice . severe crises are triggered by parvovirus B19, which infects and destroys erythroblasts in the bone marrow.. Splenectomy provides relief for symptomatic patients by removing the major site of red cell destruction. Partial splenectomy is gaining favor , because this approach may produce hematologic improvement while maintaining protection against sepsis.

13. MORPHOLOGY:

14. Sickle cell anemia Sickle cell anemia is the most common familial hemolytic anemia in the world.In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a small but significant protective effect of HbS against Plasmodium falciparum malaria. In the United States, approximately 8% of blacks are heterozygous for HbS , and about 1 in 600 have sickle cell anemia.

15. PATHOGENESIS The three most important factors are: The presence of hemoglobins other than HbS . The intracellular concentration of HbS The transit time for red cells through the microvasculature

16. Two major consequences arise from the sickling of red cells. First, the red cell membrane damage and dehydration caused by repeated episodes of sickling produce a chronic hemolytic anemia.The mean life span of red cells in sickle cell anemia is only 20 days (one sixth of normal). Second, red cell sickling produces widespread microvascular obstructions, which result in ischemic tissue damage and pain crises. Vaso -occlusion does not correlate with the number of irreversibly sickled cells and therefore appears to result from factors such as infection, inflammation, dehydration, and acidosis that enhance the sickling of reversibly sickled cells.

17. MORPHOLOGY: In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells are evident. Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the heart, liver, and renal tubules. There is a compensatory hyperplasia of erythroid progenitors in the marrow.

18. Clinical Course: Gender predilection is controvertial . Homozygous sickle cell disease usually is asymptomatic until 6 months of age when the shift from HbF to HbS is complete. From its onset, the disease runs an unremitting course punctuated by sudden crises. The most serious of these are the vaso-occlusive,or pain, crises. he acute chest syndrome and stroke are the two leading causes of ischemia-related death. A second acute event, aplastic crisis, is caused by a sudden decrease in red cell production. patients with sickle cell disease are prone to infections. the marrow often causes bone resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull resembling a “ crewcut ” in radiographs. Extramedullary hematopoiesis may appear in the liver and spleen . In children there is moderate splenomegaly ( splenic weight up to 500 g) due to red pulp congestion caused by entrapment of sickled red cells. Vascular congestion, thrombosis, and infarction can affect any organ

19. CREW CUT APPEARANCE OF SKULL BONE

20. Oral manifestations: Bone changes in dental radiographs consisting of mild to severe generalized osteoporosis and a loss of trabeculation of the jaw bones with the appearance of large, irregular marrow spaces. Changes in scrapings of oral epithelial cells showed nuclear enlargement, binucleation and an atypical chromatin distribution. Laboratory findings: The red cell count may reach 1,000,000 cells or less per cubic millimetre with a decreased haemoglobin level. On blood smear, typical sickle shaped red cell are seen. Haemoglobin electrophoresis can be done to differentiate homozygous and heterozygous.

21. Thalassemia The thalassemias are inherited disorders caused by mutations that decrease the synthesis of α- or β- globin chains. As a result, there is a deficiency of Hb and additional red cell changes due to the relative excess of the unaffected globin chain.

22. A diverse collection of α- globin and β- globin mutations underlies the thalassemias , which are autosomal codominant conditions. As described previously, adult hemoglobin, or HbA , is a tetramer composed of two α chains and two β chains. The α chains are encoded by two α- globin genes, which lie in tandem on chromosome 11, while the βchains are encoded by a single β- globin gene located on chromosome 16. The clinical features vary widely depending on the specific combination of mutated alleles that are inherited by the patient. β- Thalassemia -The mutations associated with β- thalassemia fall into two categories: (1) β , in which no β- globin chains are produced; and (2) β + , in which there is reduced (but detectable) β- globin synthesis.

23. In smears the red cells are small ( microcytic ) and pale ( hypochromic ), but regular in shape. Often seen are target cells,cells with an increased surface area-to-volume ratio that allows the cytoplasm to collect in a central, dark-red “puddle.” On the other end of the spectrum, in β- thalassemia major, peripheral blood smears show marked microcytosis,hypochromia , poikilocytosis (variation in cell size), and anisocytosis (variation in cell shape). Nucleated red cells ( normoblasts ) are also seen that reflect the underlying erythropoietic drive. β- Thalassemia intermedia and HbH disease are associated with peripheral smear findings that lie between these two extremes.

24. Clinical Course β- Thalassemia minor and α- thalassemia trait (caused by deletion of two α- globin genes) are often asymptomatic. There is usually only a mild microcytic hypochromic anemia ; generally, these patients have a normal life expectancy. β- Thalassemia major manifests postnatally as HbF synthesis diminishes. Affected children suffer from growth retardation that commences in infancy. They are sustained by repeated blood transfusions,which improve the anemia and reduce the skeletal deformities associated with excessive erythropoiesis . With transfusions alone, survival into the second or third decade is possible, but systemic iron overload gradually develops owing to inappropriate uptake of iron from the gut and the iron load in transfused red cells. Cachexia Hemosiderosis skeletal deformities

25. The child affected has yellowish pallor to the skin and has fever, chills, malaise and a generalised weakness. Splenomegaly and hepatomegaly Face develops mongoloid features due to prominence of cheek bones, protrusion or flaring of the maxillary anterior teeth, and the depression of the bridge of the nose which gives rise to the characteristic rodent facies . Whereas thalassemia minor is generally without clinical manifestations

26. Lateral view of the skull reveals typical thickening and widening of the cranial vault due to marrow hyperplasia in the diploe . The outer table is displaced and ill defined and there is a "hair-on-end" or sun ray appearance due to vertical alignment of the coarse major trabeculae . Even the upper portion of the occiput shares in the generalized thickening of the cranial vault, as well as the base of the skull and the anterior fossa . There is marked hyperplasia of the facial bones, maxillae and mandible, with virtual obliteration of the paranasal sinuses and mastoid sinuses. There is also a disproportionate overgrowth of the upper maxilla with ventral and lateral extension of the alveolar ridge producing malocclusion of the jaws and a "rodent facies ."

27. Thalassemia . Extramedullary hematopoiesis . Lobulated soft tissue opacities are noted overlying the ribs anteriorly and posteriorly .

28. Glucose-6-Phosphate Dehydrogenase Deficiency Red cells are constantly exposed to both endogenous and exogenous oxidants, which are normally inactivated by reduced glutathione (GSH). Abnormalities affecting the enzymes responsible for the synthesis of GSH leave red cells vulnerable to oxidative injury and lead to hemolytic anemias . G6PD gene is on the X chromosome most important variants is G6PD A-

29. G6PD deficiency produces no symptoms until the patient is exposed to an environmental factor (most commonly infectious agents or drugs) that produces oxidants. The drugs incriminated include antimalarials (e.g., primaquine ), sulfonamides , nitrofurantoin , phenacetin , aspirin (in large doses), and vitamin K derivatives. More commonly, episodes of hemolysis are triggered by infections, which induce phagocytes to generate oxidants as part of the normal host response.

30. Oxidants, such as hydrogen peroxide, are normally sopped up by GSH, which is converted to oxidized glutathione in the process. Because regeneration of GSH is impaired in G6PD-deficient cells, oxidants are free to “attack” other red cell components including globin chains, which have sulfhydryl groups that are susceptible to oxidation. Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies,which can damage the cell membrane sufficiently to cause intravascular hemolysis . Other, less severely damaged cells lose their deformability and suffer further injury when splenic phagocytes attempt to “pluck out” the Heinz bodies, creating so-called bite cells. Such cells become trapped upon recirculation to the spleen and are destroyed by phagocytes ( extravascular hemolysis ).

31. The  complement system  is a part of the   immune system  that enhances (complements) the ability of  antibodies  and  phagocytic  cells to clear  pathogens  from an organism. It is part of the  innate immune system , [1]  which is not adaptable and does not change over the course of an individual's lifetime. However, it can be recruited and brought into action by the  adaptive immune system . The complement system consists of a number of small proteins found in the blood, in general synthesized by the  liver , and normally circulating as inactive precursors  When stimulated by one of several triggers,  proteases  in the system cleave specific proteins to release  cytokines  and initiate an amplifying cascade of further cleavages. The end result of this  complement activation  or  complement fixation  cascade is massive  amplification  of the response and  activation  of the cell-killing  membrane attack complex . Over 30 proteins and protein fragments make up the complement system, including  serum proteins ,  serosal  proteins, and  cell membrane receptors . They account for about 10% of the  globulin  fraction of blood serum and can serve as  opsonins .

32. Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder worthy of mention because it is the only hemolytic anemia that results from an acquired somatic mutation in myeloid stem cells.

33. Pathophysiology : All cells have proteins attached to their membranes, often serving as a mode of communication or signaling between the cell and the surrounding extracellular milieu. These signaling proteins are physically attached to the cell membrane in various ways, commonly anchored by glycolipids such as  glycosyl phosphatidylinositols  (GPI). PNH occurs as a result of a defect in the assembling of these glycolipid -protein structures on the surface of blood cells. The most common defective enzyme in PNH is  phosphatidylinositol glycan A  (PIGA), one of several enzymes needed to make GPI. A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell membrane. When this mutation occurs in a  hematopoietic stem cell  in the bone marrow, all of the cells it produces will also have the defect

34. Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the  complement system , and, without these anchors, the cells are more easily targeted by the complement proteins. Although red blood cells, white blood cells and platelets are targeted by complement, red blood cells are particularly vulnerable to lysis

35. A small proportion of patients report attacks of  abdominal pain ,  difficulty swallowing  and  pain during swallowing , as well as  erectile dysfunction  in men; this occurs mainly when the breakdown of red blood cells is rapid, and is attributable to spasm of  smooth muscle  due to red cell breakdown products. Forty percent of people with PNH develop  thrombosis  (a blood clot) at some point in their illness. This is the main cause of severe complications and death in PNH

36. Immunohemolytic Anemias Some individuals develop antibodies that recognize determinants on red cell membranes and cause hemolytic anemia . These antibodies may arise spontaneously or be induced by exogenous agents such as drugs or chemicals. Immunohemolytic anemias are uncommon and classified on the basis of the nature of the antibody and the presence of predisposing conditions

37. The diagnosis of immunohemolytic anemias depends on the detection of antibodies and/or complement on red cells. This is done with the direct Coombs antiglobulin test ,in which the patient’s red cells are incubated with antibodies against human immunoglobulin or complement. In a positive test result, these antibodies cause the patient’s red cells to clump (agglutinate). The indirect Coombs test ,which assesses the ability of the patient’s serum to agglutinate test red cells bearing defined surface determinants, can then be used to characterize the target of the antibody

38. Hemolytic Anemias Resulting from Mechanical Trauma to Red Cells Abnormal mechanical forces result in red cell hemolysis in a variety of circumstances. Traumatic hemolysis can occur incidentally during any activity involving repeated physical blows or their equivalent (e.g., marathon racing, karate chopping, bongo drumming) but is of little clinical importance. More significant mechanical hemolysis is sometimes produced by defective cardiac valve prostheses (the blender effect), which can create sufficiently turbulent blood flow to shear red cells. Microangiopathic hemolytic anemia is observed in pathologic states

39. Other causes of microangiopathic hemolytic anemia include malignant hypertension, systemic lupus erythematosus , thrombotic thrombocytopenic purpura , hemolytic uremic syndrome, and disseminated cancer. The morphologic alterations in the injured red cells ( schistocytes ) are striking and quite characteristic; “burr cells,” “helmet cells,” and “triangle cells” may be seen

40. Malaria It is estimated that malaria affects 500 million and killsmore than 1 million people per year, making it one of the most widespread afflictions of humans. Malaria is endemic in Asia and Africa, but with widespread jet travel cases are now seen all over the world. It is caused by one of four types of protozoa. Of these, the most important is Plasmodium falciparum , which causes tertian malaria ( falciparum malaria), a serious disorder with a high fatality rate. The other three species of Plasmodium that infect humans—Plasmodium malariae , Plasmodium vivax , and Plasmodium ovale —cause relatively benign disease. All forms are transmitted by the bite of female Anopheles mosquitoes, and humans are the only natural reservoir.

41. Clinical Features The distinctive clinical and anatomic features of malaria are related to the following factors: • Showers of new merozoites are released from the red cells at intervals of approximately 48 hours for P. vivax , P. ovale,and P. falciparumand 72 hours for P. malariae . The episodic shaking, chills, and fever coincide with this release. • The parasites destroy large numbers of infected red cells, thereby causing a hemolytic anemia . • A characteristic brown malarial pigment derived from hemoglobin called hematin is released from the ruptured red cells and produces discoloration of the spleen, liver, lymph nodes, and bone marrow. • Activation of defense mechanisms in the host leads to a marked hyperplasia of mononuclear phagocytes, producing massive splenomegaly and occasional hepatomegaly

42. ANEMIAS OF DIMINISHED ERYTHROPOIESIS The category of anemias involving diminished erythropoiesis includes anemias that are caused by an inadequate dietary supply of nutrients, particularly iron, folic acid, and vitamin B12. Other anemias of this type are those associated with bone marrow failure ( aplastic anemia), systemic inflammation (anemia of chronic disease), or bone marrow infiltration by tumor or inflammatory cells ( myelophthisic anemia).

43. Iron deficiency anemia Iron deficiency arises in a variety of settings: Chronic blood loss - gastrointestinal tract (e.g., peptic ulcers, colonic cancer, hemorrhoids ) and the female genital tract (e.g., menorrhagia , metrorrhagia , cancers). vegetarian diets Increased demands-infancy and pregnancy Malabsorption can occur with celiac disease or after gastrectomy

44. Iron stores are depleted first, marked by a decline in serum ferritin and the absence of stainable iron in the bone marrow. These changes are followed by a decrease in serum iron and a rise in the serum transferrin . Ultimately, the capacity to synthesize hemoglobin , myoglobin , and other ironcontaining proteins is diminished, leading to microcytic anemia , impaired work and cognitive performance, and even reduced immunocompetence .

45. Diagnostic criteria include anemia , hypochromic and microcytic red cell indices, low serum ferritin and iron levels, low transferrin saturation, Increased total iron-binding capacity, and, ultimately, response to iron therapy.

46. Plummer-Vinson or Paterson-Kelly syndrome presents as a classical triad of dysphagia , iron-deficiency anemia and esophageal webs. the syndrome is extremely rare middle-aged women, in the fourth to seventh decade of life but the syndrome has also been described in children and adolescents. Clinical picture: The dysphagia is usually painless and intermittent or progressive over years, limited to solids and sometimes associated with weight loss. weakness, pallor, fatigue, tachycardia glossitis , angular cheilitis and koilonychia Enlargement of the spleen and thyroid most important clinical aspects of Plummer-Vinson syndrome is the association with upper alimentary tract cancers

47. Eitiology : The most important possible etiological factor is iron deficiency. Other possible factors include malnutrition, genetic predisposition or autoimmune processes. Since Plummer-Vinson syndrome is associated with an increased risk of squamous cell carcinoma of the pharynx and the esophagus , the patients should be followed closely.

48. Anemia of Chronic Disease Anemia associated with chronic disease is the most common form of anemia in hospitalized patients. It superficially resembles the anemia of iron deficiency but arises instead from the suppression of erythropoiesis by systemic inflammation. It occurs in a variety of disorders associated with sustained inflammation, including: • Chronic microbial infections, such as osteomyelitis , bacterial endocarditis , and lung abscess • Chronic immune disorders, such as rheumatoid arthritis and regional enteritis • Neoplasms , such as Hodgkin lymphoma and carcinomas of the lung and breast

49. PATHOGENESIS The anemia of chronic disease stems from high levels of plasma hepcidin,which blocks the transfer of iron to erythroid precursors by downregulating ferroportin in macrophages. The elevated hepcidin levels are caused by pro-inflammatory cytokines such as IL-6, which increase hepatic hepcidin synthesis. In addition, chronic inflammation blunts erythropoietin synthesis by the kidney, lowering red cell production by the marrow. The functional advantages of these adaptations in the face of systemic inflammation are unclear; they may serve to inhibit the growth of irondependent microorganisms or to augment certain aspects of host immunity.

50. Clinical Features As in anemia of iron deficiency, the serum iron levels usually are low in the anemia of chronic disease, and the red cells may even be slightly hypochromic and microcytic . Unlike iron deficiency anemia, however, storage iron in the bone marrow is increased, the serum ferritin concentration is elevated, and the total iron-binding capacity is reduced. Administration of erythropoietin and iron can improve the anemia, but only effective treatment of the underlying condition is curative.

51. Megaloblastic Anemias The two principal causes of megaloblastic anemia are folate deficiency and vitamin B12 deficiency . Both vitamins are required for DNA synthesis and the effects of their deficiency on hematopoiesis are essentially identical.

52. P athogenesis: Many megaloblasts are so defective in DNA synthesis that they undergo apoptosis in the marrow (ineffective hematopoiesis ). Others mature into red cells but do so after fewer cell divisions, further diminishing the output of red cells. Granulocyte and platelet precursors are also affected (although not as severely) and most patients present with pancytopenia (anemia, thrombocytopenia, and granulocytopenia ).

53.   Patients may have a sore tongue and canker sores. A spectrum of mental changes, from a change in personality to psychosis, as well as peripheral neuropathy, can occur in both folate and cobalamin deficiencies. Peripheral neuropathy presents as numbness, pain, tingling, and burning in a patient’s hands and feet. Patients may report loss of sensation and that they feel like they are wearing a thin stocking or glove.

54. Folate (Folic Acid) Deficiency Anemia The risk of clinically significant folate deficiency is high in those with a poor diet (the economically deprived, the indigent, and the elderly) or increased metabolic needs (pregnant women and patients with chronic hemolytic anemias ). Folate is present in nearly all foods but is destroyed by 10 to 15 minutes of cooking. Thus, the best sources are fresh uncooked vegetables and fruits. Food folates are predominantly in polyglutamate form and must be split into monoglutamates for absorption, a conversion that is hampered by concurrent consumption of acidic foods and substances found in beans and other legumes.

55. Phenytoin ( dilantin ) and a few other drugs also inhibit folate absorption, while others, such as methotrexate , inhibit folate metabolism. The principal site of intestinal absorption is the upper third of the small intestine; thus, malabsorptive disorders that affect this level of the gut, such as celiac disease and tropical sprue , can impair folate uptake.

56. Clinical features : Vitamin B12 deficiency can also cause a demyelinating disorder of the peripheral nerves and the spinal cord. There are many causes of vitamin B12deficiency. The term pernicious anemia,a relic of days when the cause and therapy of this condition were unknown, applies to vitamin B12 deficiency that results from defects involving intrinsic factor.

57. onset of the anemia of folate deficiency is insidious, being associated with nonspecific symptoms such as weakness and easy fatigability. Vitamin B12 deficiency can also cause a demyelinating disorder of the peripheral nerves and the spinal cord.

58. Intrinsic factor plays a critical role in the absorption of vitamin B12, a multistep process that proceeds as follows: 1. Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called haptocorrin . 2. On entering the duodenum, haptocorrin–B12complexes are processed by pancreatic proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa. 3. The intrinsic factor–B12 complexes pass to the distal ileum and attach to cubulin , a receptor for intrinsic factor, and are taken up into enterocytes . 4. The absorbed vitamin B12 is transferred across the basolateral membranes of enterocytes to plasma transcobalamin , which delivers vitamin B12 to the liver and other cells of the body.

59. Pernicious anemia/ Addisonian anemia/ Biermer anemia/ Hunter-Addison anemia/ Lederer anemia/ Biermer -Ehrlich anemia/Addison- Biermer anemia It is the most frequent cause of vitamin B12 deficiency.This disease seems to stem from an autoimmune reaction against parietal cells and intrinsic factor itself, which produces gastric mucosal atrophy. an autoimmune disorder with a genetic predisposition and the disease is associated with human leucocyte antigen (HLA) types A2, A3, and B7 and A blood group. Antiparietal cell antibodies occur in 90% of patients with pernicious anemia

60. Three types of antibodies have been found: parietal canalicular antibodies, which bind to the mucosal parietal cells; blocking antibodies, which disrupt the binding of vitamin B12 to intrinsic factor; and intrinsic factor–B12complex antibodies, which prevent the complex from binding to cubulin .

61. • Pernicious anemia frequently occurs concomitantly with other autoimmune diseases, such as Hashimoto thyroiditis , Addison disease, type 1 diabetes mellitus and acquired agammaglobulinemia . Chronic vitamin B12 malabsorption is also seen after gastrectomy (owing to loss of intrinsic factor–producing cells) or ileal resection (owing to loss of intrinsic factor–B12complex–absorbing cells), and in disorders that disrupt the function of the distal ileum (such as Crohn disease, tropical sprue , and Whipple disease). Particularly in older persons, gastric atrophy and achlorhydria may interfere with the production of acid and pepsin, which are needed to release the vitamin B12 from its bound form in food.

62. Clinical Features Pernicious anemia is rare before the age of 30 years and increases in frequency with advancing age. The disease is often characterized by the presence of a triad of symptoms: generalized weakness, a sore, painful tongue, and numbness or tingling of the extremities.

63. stiffness and difficulty in walking, general irritability, depression or drowsiness as well as incoordination and loss of vibratory sensation. the degeneration of posterior and lateral tracts of the spinal cord with loss of nerve fibers and degeneration of myelin sheaths. Degeneration of the peripheral nerves also occurs.

64. In some cases the lingual manifestations are the first sign of the disease . tongue is ‘beefy red’ in color, either in entirety or in patches scattered over the dorsum and lateral borders. small and shallow ulcers — resembling aphthous ulcers — occur on the tongue. Characteristically, with the glossitis , glossodynia and glossopyrosis , there is gradual atrophy of the papillae of the tongue that eventuate in a smooth or ‘bald’ tongue which is often referred to as Hunter’s glossitis or Moeller’s glossitis and is similar to the ‘bald tongue of Sandwith ’ seen in pellagra. the inflammation and burning sensation extend to involve the entire oral mucosa but, more frequently, the rest of the oral mucosa exhibits only the pale yellowish tinge noted on the skin.

65. Laboratory findings: The red blood cell count is seriously decreased, often to 1,000,000 or less per cubic millimeter. Poikilocytosis is seen in peripheral smear. The hemoglobin content of the red cells is increased but the mean corpuscular hemoglobin concentration is normal. Leukocytes reduced in number, but are increased in average size, innumber of lobes to the nucleus (becoming the so-called macropolycytes ) and anisopoikilocytosis . Mild to moderate thrombocytopenia is noticed. Coexistent iron deficiency is common because achlorhydria prevents solubilization of dietary ferric iron from foodstuffs. Striking reticulocyte response and improvement in hematocrit values after parenteral administration of cobalamin is characteristic.

66. Serum. The indirect bilirubin may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin . The serum lactic dehydrogenase usually is markedly increased. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased. Serum antibodies for IF are highly specific. Bone marrow. hypercellular and show trilineage differentiation. Erythroid precursors are large and often oval. The nucleus is large and contains coarse chromatin clumps, providing a checkerboard appearance.

67. History findings to help identify a cobalamin deficiency are as follows: Evidence for achlorhydria such as abdominal discomfort, reflux, early satiety, and abdominal bloating: This condition can impair cobalamin absorption. Pernicious anemia : These patients may have signs of other autoimmune disorders such as thyroid disorders, type I diabetes, or Addison disease. Family history, HLA (HLA A2, A3, B7, B12), and type A blood (Scandinavians and African Americans) History of a gastrectomy Conditions that affect the terminal ileum (site of cobalamin absorption), such as inflammatory bowel disease, sprue , or ileal resection Conditions in which cobalamin is competitively consumed: History of abdominal surgery might suggest a blind loop syndrome. Exposure to raw fish might suggest  D   latum infestation . Zollinger -Ellison syndrome or pancreatic insufficiency: There is impaired binding of cobalamin to intrinsic factor .

68. Strict vegetarian with no consumption of eggs and dairy products A history of folate administration without vitamin B-12 therapy: This should alert one to the possibility of the progression of neuropsychiatric complications in a patient who is not anemic . A history of megaloblastosis since childhood: This would suggest a hereditary cause of cobalamin deficiency.

69. History findings to help identify folate deficiency are as follows: Poor nutrition, alternative diets, and excessive heating and dilution of foods Chronic alcoholism Conditions that interfere with folate absorption, including inflammatory bowel disease, sprue or gluten sensitivity, and amyloidosis Conditions that increase folate consumption, such as pregnancy, lactation, hemolytic anemia , hyperthyroidism, and exfoliative dermatitis Hyperalimentation and hemodialysis Medications that affect folate Hereditary disorder: A lifelong history of megaloblastosis or folate deficiency would suggest a hereditary disorder as the cause.

70. Aplastic Anemia Aplastic anemia is a bone marrow failure syndrome characterized by peripheral pancytopenia and general lack of bone marrow activity. It may affect not only the red blood cells but also the white cells and platelets, resulting in a pancytopenia . Paul Ehrlich, introduced the concept of aplastic anemia in 1888 when he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 when this disorder was termed aplastic anemia by Chauffard .

71. Primary aplastic anemia is a disease of unknown etiology which occurs most frequently in young adults, develops rapidly and usually terminates fatally. A disease known as Fanconi’s syndrome consists of congenital, and sometimes familial, aplastic anemia associated with a variety of other congenital defects including bone abnormalities, microcephaly , hypogenitalism and a generalized olive-brown pigmentation of the skin. Secondary aplastic anemia , on the other hand, is of known etiology, occurs at any age and presents a better prognosis, particularly if the cause is removed. The etiology of this secondary anemia is the exposure of the patient to various drugs or chemical substances or to radiant energy in the form of X-rays, radium or radioactive isotopes.

72. Drugs such as cetophenetidine , amidopyrine , organic arsenicals, particularly sulfarsphenamine , benzol , chloramphenicol , qui nacrine hydrochloride ( Atabrine ), trinitrotoluene, dinitrophenol , colloidal silver, bismuth, mercury, sulfonamides and penicillin, although many others have also produced the disease. On few occasions aplastic anemia is preceded by infection by hepatitis viruses, Epstein-Barr virus (EBV), HIV, parvovirus, and mycobacterial infections.

73. Pathophysiology of acquired aplastic anemia .  The figure stresses the crucial and related roles of the hematopoietic stem-cell compartment as a target for the immune response. An inciting event, such as a virus or medical drug, provokes an aberrant immune response, triggering oligoclonal expansion of cytotoxic T cells that destroy hematopoietic stem cells (left panel, Onset). Bone marrow transplantation or immunosuppressive therapy leads to complete response (CR) or partial response (PR) by eradicating or suppressing pathogenic T-cell clones (middle panel, Recovery). Relapse occurs with recurrence of the immune response, and the immunologically stressed and depleted stem-cell compartment also allows selection of abnormal hematopoietic clones that manifest as paroxysmal nocturnal hemoglobinuria , myelodysplasia (MDS), and occasionally acute myelogenous leukemia (AML)

74. Clinical Course Aplastic anemia affects persons of all ages and both sexes. The slowly progressive anemia causes the insidious development of weakness, pallor, and dyspnea . Thrombocytopenia often manifests with petechiae and ecchymoses . Granulocytopenia may be manifested by frequent and persistent minor infections or by the sudden onset of chills, fever, and prostration Aplastic anemia does not cause splenomegaly ; if it is present, another diagnosis should be sought. Typically, the red cells are normochromic and normocytic or slightly macrocytic . Reticulocytes are reduced in number ( reticulocytopenia ).

75. Oral Manifestations . Petechiae purpuric spots or frank hematomas of the oral mucosa may occur at any site, while hemorrhage into the oral cavity, especially spontaneous gingival hemorrhage , is present in some cases. Such findings are related to the blood platelet deficiency. As a result of the neutropenia there is a generalized lack of resistance to infection, and this is manifested by the development of ulcerative lesions of the oral mucosa or pharynx. These may be extremely severe and may result in a condition resembling gangrene because of the lack of inflammatory cell response.

76. Laboratory Findings. The red blood cell count is as low as 1,000,000 cells per cubic millimeter , with a corresponding reduction in the hematocrit and hemoglobin levels. The thrombocytopenia results in a prolonged bleeding time; the clotting time remains normal. Clot retraction is poor and the tourniquet test is positive. The degree of cytopenia is useful in assessing the severity of aplastic anemia . The presence of teardrop poikilocytes and leucoerythroblastic changes suggest marrow aplasia from infiltrative and dysplastic causes

77. Bone marrow smears the marrow appears normal or even hyperplastic . In pancytopenia there is hypoplasia of all marrow elements. In cases of less severe damage, moderate numbers of primitive cells persist. In severe cases, hypocellular bone marrow with fatty replacement and relatively increased nonhematopoietic elements such as plasma cells and mast cells may be found. Hemoglobin electrophoresis and blood group testing may show elevated fetal hemoglobin and red cell 1 antigen suggesting stress erythropoiesis , which is observed in both aplastic anemia and myelodysplastic syndromes.

78. POLYCYTHEMIA Polycythemia , or erythrocytosis,denotes an increase in red cells per unit volume of peripheral blood, usually in association with an increase in hemoglobin concentration. Three forms of disease are recognized: relative polycythemia , primary polycythemia or erythremia ( polycythemia rubra vera ) of unkown etiology and secondary polycythemia or erythrocytosis , due to some known stimulus.

79. Relative polycythemia is an apparent increase in the number of circulating red blood cells that occurs as a result of loss of blood fluid with hemoconcentration of cells, and is seen in cases of excessive loss of body fluids such as chronic vomiting, diarrhea, or loss of electrolytes with accompanying loss of water. This increase in the number of red blood cells is only relative to the total blood volume, and therefore, is not a true polycythemia .

80. Primary polycythemia , or polycythemia rubra vera , is characterized by a true idiopathic increase in the number of circulating red blood cells and of the hemoglobin level. It is characterized by bone marrow with an inherent increased proliferative activity.

81. Secondary polycythemia the etiology is known. Secondary polycythemia is caused due to absolute increase in red blood cell mass resultant to enhanced stimulation of red blood cell production. In general, the stimulus responsible for producing a secondary polycythemia is either bone marrow anoxia or production of an erythropoietic stimulating factor.

82. Bone marrow anoxia may occur in numerous situations such as pulmonary dysfunction, heart disease, habitation at high altitudes or chronic carbon monoxide poisoning. Erythro poietic stimulatory factors include a variety of drugs and chemicals such as coal-tar derivatives, gum shellac, phosphorus, and various metals such as manganese, mercury, iron, bismuth, arsenic and cobalt. Some types of tumors such as certain brain tumors, liver and kidney carcinomas and the uterine myoma have also been reported associated with polycythemia . The mechanism for increased production of the red blood cells by these tumors is unknown, but has been postulated as due to elaboration of a specific factor which stimulates erythropoiesis .

83. Polycythemia Vera ( Polycythemia rubra vera , erythremia , Vaquez’s disease, Osler’s disease) Polycythemia vera (PV) is a chronic stem cell disorder with an insidious onset characterized as a panhyperplastic , malignant, and neoplastic marrow disorder. The most prominent feature is an absolute increase in the number of circulating red blood cells and in the total blood volume because of uncontrolled redblood cell production. This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation

84. Clinical Features . Polycythemia vera often manifests itself primarily by headache or dizziness, weakness and lassitude, tinnitus, visual disturbances, mental confusion, slurring of the speech and inability to concentrate. The skin is flushed or diffusely reddened, as a result of capillary engorgement and high red cell mass, as though the patient were continuously blushing. the digits may be cyanotic. Increased red blood cell mass increases blood viscosity and decreases tissue perfusion, and also predisposes for thrombosis. Splenomegaly Gastric complaints such as gas pains, belching and peptic ulcers are common Pruritus results from increased histamine levels released from increased basophils and mast cells

85. Oral Manifestations. The oral mucous membranes appear deep purplish red, the gingiva and tongue being most prominently affected. The cyanosis is due to the presence of reduced hemoglobin in amounts exceeding 5 gm/dl. The gingivae are often engorged and swollen and bleed upon the slightest provocation . Submucosal petechiae are also common, as well as ecchymoses and hematomas. Intercurrent infection may occur , but this is not related directly to the disease

86. Laboratory Findings . Red blood cell mass and plasma volume can be measured directly using radiochromiumlabeled red blood cells which show an increase in mass with a normal or slightly decreased plasma volume. The red blood cell count is elevated and may even exceed 10,000,000 cells per cubic millimeter Because of the great number of cells present, both the specific gravity and the viscosity of the blood are increased. Leukocytosis is usual, as is a great increase in the number of platelets (400,000–800,000/dl)

87. To be continued….