1. Anemia
Dr Mazin M Fawzi

2. Anemia
Definition. Anemia is defined as Hb level below the normal range .
The normal range varies with age, so anemia can be defined as :
Neonate Hb < 14 gm/dl.
1-12 months Hb < 10 gm/ dl.
1-12 years Hb < 11gm/ dl.

3. It is important to consider the following developmental variations when evaluating an infant or child for anemia:

4. 1-Hemoglobin level and hematocrit are relatively high in the newborn; these values subsequently decline, reaching a nadir at approximately 7 weeks of age for the premature infant and at 2 to 3 months of age for the term infant. (This condition is referred to as the “physiologic anemia” of infancy) .
Total hemoglobin concentration and hematocrit rise gradually during childhood .

5. 2-Hb F is the major hemoglobin of prenatal and early postnatal life.
At cord blood ,Hb F values approached 70% then it decline postnatally; by 9 to 12 months of age, the Hb F values represent <2% of the total hemoglobin concentration.

7. 3-Mean corpuscular volume (MCV) is relatively high during the neonatal period but declines during the latter part of infancy.
The MCV is lowest during infancy, gradually increasing with age during childhood, reaching adult levels during adolescence.

8. Anemia results from one or more of the following mechanisms:
1- reduced red cell production - either due to ineffective erythropoiesis (e.g. iron deficiency, the commonest cause of anaemia) or due to red cell aplasia
2- Increased RBC destruction (hemolysis)
3- blood loss - relatively uncommon cause in children.
There may be a combination of these three mechanisms, e.g. anaemia of prematurity.

9. Anemia due to reduced red cell production
Reduced red cell production may be due to: 1. Ineffective erythropoiesis - here red cell production occurs at a normal or increased rate but differentiation or survival of the red cells is defective (e.g. iron deficiency, folate deficiency ,chronic inflamation). 2. complete absence of red cell production (red cell aplasia ) e.g( Parvovirus 19 inf, aplastic anemia, leukemia).

10. Anemia due to reduced red cell production
Diagnostic clues to ineffective erythropoiesis are: 1- normal reticulocyte count . 2-abnormal mean cell volume (MCV) of the red cells: low in iron deficiency and raised in folic acid deficiency .

11. Red cell aplasia
Causes: 1-congenital red cell aplasia ('Diamond-Blackfan anaemia') 2-transient erythroblastopenia of childhood 3-parvovirus B19 infection: this infection only causes red cell aplasia in children with inherited haemolytic anaemias and not in healthy children.

12. Red cell aplasia
Diagnosis: 1-low reticulocyte count despite low Hb 2-normal bilirubin 3-negative direct antiglobulin test (Coombs' test) 4-absent red cell precursors on bone marrow examination.

13. Diamond-Blackfan anaemia
Diamond-Blackfan anaemia (DBA) is a rare disease. There is a family history in 20% of cases; the remaining 80% are sporadic. Gene mutation (RPS19) is implicated in some cases. Most cases present at 2-3 months of age but 25% present at birth. Affected infants have symptoms of anaemia; some have other congenital anomalies, such as short stature or abnormal thumbs. Treatment is by monthly blood transfusion and oral steroid.

14. Transient erythroblastopenia of childhood
Transient erythroblastopenia of childhood (TEC) is usually triggered by viral infections and has the same haematological features as DBA. The main differences between them is that TEC always recovers, usually within several weeks, there is no family history or RPS19 mutation and there are no congenital anomalies.

15. Classification of anemia
In clinical practice, anemias are classified according to the morphologic appearance (i.e., color and size) of the red blood cells on peripheral smear as well as the MCV.
1-Hypochromic microcytic (small, pale RBCs; a low MCV)
2-Macrocytic (large RBCs; a high MCV)
3-Normochromic normocytic (cells of normal size and shape; a normal MCV)

16. Hypochromic, microcytic anemias
Defect. Hypochromic, microcytic red blood cells indicate impaired synthesis of the heme or globin components of hemoglobin.
Defective heme synthesis may be the result of iron deficiency, lead poisoning, chronic inflammatory disease, pyridoxine deficiency, sideroblastic anemia, or copper deficiency.
Defective globin synthesis is characteristic of the thalassemia syndromes.

17. Evaluation. Laboratory studies that are useful in evaluating the hypochromic, microcytic anemia
1-CBC and blood film.
2- Serum ferritin.
3-Total serum iron-binding capacity.
4- Soluble transferrin receptor (sTR).
5- Quantitative measurements of the Hb A1 , Hb A2 and Hb F levels.

18. Iron deficiency anemia

19. The commonest cause of iron deficiency in children is:
1- Inappropriate diet.
2- Blood loss.
3- Malabsorption.

20. Inadequate intake of iron is common in infants because additional iron is required for the increase in blood volume accompanying growth and to build up the child's iron stores. A 1-year-old infant requires an intake of iron of about 8 mg/day, which is about the same as his father (9 mg/day) but only half that of his mother (15 mg/day).

21. Iron may come from: 1-breast milk (low iron content but 50% of the iron is absorbed) 2-infant formula (supplemented with adequate amounts of iron) 3-cow's milk (higher iron content than breast milk but only 10% is absorbed) 4-solids introduced at weaning, e.g. cereals (cereals are supplemented with iron but only 1% is absorbed).

22. Infants should not be fed unmodified cow's milk as its iron content is low and poorly absorbed.

23. Changes in body iron during infancy.

24. Clinical features.
Iron deficiency is most commonly seen between 6 and 24 months of age. The typical patient is on a diet consisting almost exclusively of milk.
Symptoms. Although mild iron deficiency is relatively asymptomatic, as it becomes more severe, the infant manifests
1-irritability,
2-anorexia,
3-lethargy,
4-pica ,
5-apathy
6-and easy fatigability.

25. Signs. On physical examination, the infant is
1-fatty,
2-pale ,
3-other findings include tachycardia and a systolic murmur. If the anemia is very severe or if the patient has complications that put added stress on the cardiovascular system, there may be signs of congestive heart failure .
4-other signs (such as koilonychia or angular cheilitis) are rare.

26. stages of iron depletion

27. Iron deficiency causes serial changes in the blood before anemia develops.
Serum ferritin is reduced and eventually a microcytic, hypochromic anemia results. Usually the MCV (mean cell volume) and MCH (mean cell hemoglobin) fall before the hemoglobin, but the changes can occur together.

28. Investigations
1-CBC: Anemia may vary from very mild to very severe, depending on the degree and duration of iron deficiency.
Small, pale RBCs are evident on the peripheral smear; the reduction in MCV, mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) is usually proportional to the severity of the anemia.
Platelets count some time are elevated in IDA.

29. 2-The serum iron level is decreased, whereas the iron-binding capacity (transferrin level) is increased, and the percentage of saturation is low (usually <15%).
3-The serum ferritin level is decreased (which is a reflection of low iron stores in the bone marrow).

30. In an otherwise healthy child, a therapeutic trial of iron is the best diagnostic study for iron deficiency as long as the child is re-examined and a response is documented. The response to oral iron includes rapid subjective improvement, especially in neurologic function (within hours) and reticulocytosis (48-72 hours); increase in hemoglobin levels (4-30 days); and repletion of iron stores (in 1-3 months).

31. Differential diagnosis
1.Anemia of chronic disease or ‘anemia of inflammation’ 2.Thalassemia traits , these require measurement of hemoglobins A2 and F. 3.Sideroblastic anemias .
4.Lead poisoning.

32. Therapy
Iron deficiency anemia can be managed by administration of iron.
This can be provided by the oral route at a dosage of 6 mg/kg/day of elemental iron.
Therapy is continued for a period of 2 to 3 months after the hemoglobin level has returned to normal; this allows replenishment of tissue iron stores.
Dietary counseling must be simultaneously provided to caregivers to give the patient adequate amounts of dietary iron.

33. Absorption of iron is enhanced by vitamin C and proteins, but is inhibited by a number of constituents of food and drink, for example tannins (in tea ), phytates (in unrefined cereals), phosphates (in eggs), oxalates (in spinach) and polyphenols (in spinach, coffee).
When a child fails to respond to iron therapy, the commonest reason is failure of adherence.

34. Bottle-fed infants should receive an iron-containing formula until 12 months of age, and breastfed infants older than 6 months of age should receive an iron supplement. The introduction of iron-enriched solid foods at 6 months of age, followed by a transition to a limited amount of cow's milk and increased solid foods at 1 year, can help prevent iron deficiency anemia

35. Anemia of inflammation and chronic disease

36. The anemia of chronic disease is associated with a variety of disorders, including:
1-Chronic inflammatory disease (e.g., Crohn disease , juvenile inflammatory arthritis)
2-Chronic infection (e.g., tuberculosis)
3-Malignancy
4-A mild and transient form of anemia of inflammation may occur following infections, including common viral infections

37. Mechanism:
1-Iron is not released from its storage sites in the macrophages; thus, it is unavailable for hemoglobin synthesis in developing erythroblasts.
2- Modest decrease in the survival of RBCs. 3- Limited erythropoietin response to the anemia.

38. Diagnosis
The anemia is mild in degree (i.e., hemoglobin concentration is 7–10 g/dL) often with hypochromic, microcytic indices.
As in iron deficiency anemia, the serum iron level is reduced. However, in contrast with iron deficiency anemia, the iron-binding capacity is normal or reduced, and the serum ferritin level is increased or normal.

39. Therapy
The anemia resolves when the underlying disease process is treated adequately.
Therapy with iron is unnecessary unless concomitant iron deficiency is present.

40. Increased red cell destruction (hemolytic anemia)
Hemolytic anemia is characterized by reduced red cell lifespan due to increased red cell destruction in the circulation (intravascular haemolysis) or liver or spleen (extravascular haemolysis).

41. The lifespan of a normal red cell is 120 days and the bone marrow produces million red cells per day. In haemolysis, red cell survival may be reduced to a few days but bone marrow production can increase about eightfold, so haemolysis only leads to anaemia when the bone marrow is no longer able to compensate for the premature destruction of red cells.

42. The main cause of haemolysis in children is intrinsic abnormalities of the red blood cells: 1-red cell membrane disorders (e.g. hereditary spherocytosis) 2-red cell enzyme disorders (e.g. glucose-6-phosphate dehydrogenase deficiency) 3-haemoglobinopathies (abnormal haemoglobins, e.g. β-thalassaemia major, sickle cell disease).

43. Diagnosis of hemolytic anemia: 1-anaemia 2-reticuloendothelial hyperplasia - hepatomegaly and splenomegaly 3-raised reticulocyte count (on the blood film this is called 'polychromasia’) 4-unconjugated bilirubinaemia . 5-abnormal appearance of the red cells on a blood film (e.g. spherocytes, sickle shaped) . 6-positive direct antiglobulin test (only if an immune cause as this test identifies antibody-coated red blood cells) 7-increased erythropoiesis in the bone marrow.

44. Glucose-6-phosphate dehydrogenase (G6PD) deficiency

45. G6PD
G6PD deficiency is the commonest red cell enzymopathy, affecting over 100 million people worldwide. It has a high prevalence (10-20%) in individuals originating from central Africa, the Mediterranean, the Middle East and the Far East. Many different mutations of the gene have been described, leading to different clinical features in different populations.

46. G6PD is the rate-limiting enzyme in the pentose phosphate pathway and is essential for preventing oxidative damage to red cells. Red cells lacking G6PD are susceptible to oxidant-induced haemolysis. G6PD deficiency is X-linked and therefore predominantly affects males , but female may be affected in certain conditions.

47. In Mediterranean, Middle Eastern and Oriental populations, affected males have very low or absent enzyme activity in their red cells. Affected Afro-Caribbeans have 10-15% normal enzyme activity. Young red blood cells may have normal enzyme activity whilst older cells are deficient.

48. Clinical presentation
Children usually present clinically with:
neonatal jaundice - onset is usually in the first 3 days of life. Worldwide it is the most common cause of severe neonatal jaundice requiring exchange transfusion.
acute haemolysis - precipitated by:
infection, the most common precipitating factor
certain drugs.
fava beans (broad beans)
naphthalene in mothballs

49. Clinical pictures : Intravascular haemolysis is associated with: 1- fever. 2-malaise. 3- passage of dark urine, as it contains haemoglobin as well as urobilinogen. 4- The haemoglobin level falls rapidly.

50. Diagnosis The diagnosis is made by measuring G6PD activity in red blood cells. During a haemolytic crisis, G6PD levels may be misleadingly elevated due to the higher enzyme concentration in reticulocytes, which are produced in increased numbers in response to the destruction of mature red cells. A repeat assay after 8 weeks is then required in the steady state to confirm the diagnosis.

51. Management: 1- The parents should be given advice about the signs of acute haemolysis (jaundice, pallor and dark urine) and provided with a list of drugs, chemicals and food to avoid. 2-Blood transfusions.

52. Sickle cell disease
Sickle cell disease is the collective name given to haemoglobinopathies in which HbS is inherited. HbS forms as a result of a point mutation in codon 6 of the β-globin gene which causes a change in the amino acid encoded from glutamine to valine.

53. There are four main forms of sickle cell disease:
1-Sickle cell anaemia (HbSS) - patients are homozygous for HbS, i.e. virtually all their Hb is HbS; they have no HbA because they have no normal β-globin genes.
2-SC disease (HbSC) - affected children inherit HbS from one parent and HbC from the other parent (HbC is formed as a result of a different point mutation in β-globin), so they also have no HbA because they have no normal β-globin genes.

54. 3-Sickle β-thalassaemia - affected children inherit HbS from one parent and β-thalassaemia trait from the other. They have no normal β-globin genes and most patients can make no HbA and therefore have similar symptoms to those with sickle cell anaemia. 4-Sickle trait - inheritance of HbS from one parent and a normal β-globin gene from the other parent, so approximately 40% of the haemoglobin is HbS. They do not have sickle cell disease but are carriers of HbS, so can transmit HbS to their offspring. They are asymptomatic and are only identified as a result of blood tests.

55. Pathogenesis In HbSS, the haemoglobin molecule becomes deformed (insoluble) in the deoxygenated state. HbS polymerises within red blood cells forming rigid tubular spiral bodies which deform the red cells into a sickle shape. Irreversibly sickled red cells have a reduced lifespan and may be trapped in the microcirculation, resulting in thrombosis and therefore ischaemia in an organ or bone. This is exacerbated by low oxygen tension, dehydration and cold.

56. Clinical presentation: 1- Anemia. 2- Infection. 3- Painfull crises
Clinical presentation: 1- Anemia. 2- Infection. 3- Painfull crises. 4- Acute anemia(hemolytic crises, aplastic crises and splenic sequestration crises). 5- Priapism. 6- Splenomegaly early in life. 7- Long term complication.

58. Management: 1- Immunization against st. pn and H infl inf
Management: 1- Immunization against st. pn and H infl inf. 2- daily folic acid. 3- Vaso-occlusive crises should be minimized by avoiding exposure to cold, dehydration, excessive exercise, undue stress or hypoxia. 4- oxygen in case of hypoxia Hydroxyurea :a drug which increases HbF production and helps protect against further crises

59. 6- Exchange transfusion is indicated for acute chest syndrome, stroke and priapism. 7- Treatment of painful crises by oral or intravenous analgesia according to need (may require opiates) and good hydration (oral or intravenous as required). 8- Infection should be treated with antibiotics. 9- BM transplantation ,this is the only cure for sickle cell disease.

60. Hereditary spherocytosis (HS)
It usually has an autosomal dominant inheritance, but in 25% there is no family history and it is caused by new mutations. The disease is caused by mutations in genes for the skeletal proteins of the red cell membrane (mainly spectrin, ankyrin or band 3). This results in the red cell losing part of its membrane when it passes through the spleen.

61. HS
This reduction in its surface-to-volume ratio causes the cells to become spheroidal, making them less deformable than normal red blood cells and leads to their destruction in the microvasculature of the spleen.

62. HS The clinical picture:
1-jaundice : usually develops during childhood but may cause severe hemolytic jaundice in the first few days of life.
2-anaemia .
3- mild to moderate splenomegaly - depends on the rate of hemolysis.
4- aplastic crisis - uncommon, associated with parvovirus B19 infection
5- gallstones - due to increased bilirubin excretion.

63. HS Diagnosis: 1-The blood film is usually diagnostic.
2- Increased osmotic fragility.
3- dye binding test.
Antibody-induced anaemia is also associated with spherocytes and this should be excluded with a direct antibody test in the absence of a family history of hereditary spherocytosis.

64. PS
Treatment 1- Folic acid. 2- Splenectomy : but is only indicated for poor growth or troublesome symptoms of anaemia (e.g. severe tiredness) and is usually deferred until after 7 years of age because of the risks of post-splenectomy sepsis. 3- Blood transfusion for aplastic crises. 4- Cholecystectomy for gall stone.

65. Thalassemia

66. Definition. Thalassemia is hereditary hemolytic anemia characterized by decreased or absent synthesis of one or more globin subunits of the hemoglobin molecule.
α-Thalassemia results from reduced synthesis of α-globin chains.
β-thalassemia results from reduced synthesis of β-globin chains.

67. An imbalance in globin chain production is a hazard to the RBC because excess unpaired globin chains produce insoluble tetramers that precipitate, causing membrane damage.
This makes RBCs susceptible to destruction within the reticuloendothelial system of the bone marrow (resulting in ineffective erythropoiesis) as well as the reticuloendothelial system of the liver and spleen (resulting in hemolytic anemia).

68. Normal % in older children
   The types and quantities of different hemoglobins in infancy and adulthood
HbA2
HbF
HbA
Type of Hb
α2δ2
α2γ2
α2β2
Notation 1 80 20
Normal % at birth 2 98
Normal % in older children

69. α-Thalassemias
α-Thalassemias are usually the result of α gene deletion.
α-Thalassemia variants are found most often in populations of African or East Asian ancestry.
Normally there are four α-globin genes; clinical manifestations of α-thalassemia variants reflect the number of genes affected

70. β-Thalassemias
The clinical phenotype of β-thalassemia is related to the degree of globin chain imbalance.
1-Heterozygous β-thalassemia
(β-thalassemia minor).
2-Homozygous β-thalassemia
(β-thalassemia major, Cooley anemia, and intermedia).

71. Heterozygous β-thalassemia (β-thalassemia minor, trait)
Clinical features.
1- Mild anemia (Hb about 10 gm/dl)
2- Normal growth and development.
3- Blood film: Hypochromia, microcytosis, and anisocytosis.
4- Hemoglobin electrophoresis shows elevation of the Hb A2 level and, sometimes, elevation of the Hb F level.
5- RBC count is elevated.

72. Therapy: No treatment is necessary.
It is important, however, that thalassemia minor is distinguished from iron deficiency to prevent inappropriate therapy with medicinal iron.
Folic acid may be given.
Genetic counseling is also important.

73. Homozygous β-thalassemia
Homozygous β-thalassemia (β-thalassemia major, Cooley anemia, and intermedia).
Its autosomal recesisive inheretance of mutation in B globin chain genes.
Defect. Molecular defects range from complete absence of β-globin synthesis (genotype β0/β0) to partial reduction in the gene product from the affected locus (genotype β+/β+).

74. Clinical features Beginning in the middle of the first year of life
1- the infant manifests a progressively severe hemolytic anemia and jaundice .
2- marked hepatosplenomegaly.
3- failure to thrive.
4- the bone marrow hyperplasia produces characteristic features such as tower skull, frontal bossing, maxillary hypertrophy with prominent cheekbones, and overbite.

75. 5- Hemochromatosis: Even in the untransfused state, iron overload develops in thalassemic patients because of hyper absorption of dietary iron. The iron load becomes even greater with chronic transfusion therapy. When the bone marrow storage capacity for iron is exceeded, iron accumulates in parenchymal organs such as the liver, heart, pancreas, gonads, and skin, producing the complications of hemochromatosis .
Many patients succumb to congestive heart failure , hypogonadism , DM , hypothyroidism, liver cirrhosis and short stature.

78. Investigations:
1-CBC : hypochromic microcytic anemia, with nucleated RBC and reticulocytopeni.
2-Elevated unconjucated bilirubin.
3-On hemoglobin electrophoresis, Hb A is either markedly decreased or totally absent. Of the total hemoglobin concentration, 30% to 90% is Hb F.
4-Bone marrow hyperplasia is seen in bone XR.
5-Elevated S.ferretin & transferrin saturation.

80. Treatment:
1- The mainstay of treatment is transfusion with packed RBCs using irradiated CMV –ve blood, a post transfusion Hb level of 10 gm/dl is the goal.
2- In an effort to prevent hemochromatosis, patients who receive chronic transfusion regimens are treated with chelating agents (e.g., deferoxamine, deferasirox) that promote iron removal from the body through excretion in the urine and the stool.

81. 3- Splenectomy is usually considered when transfusion requirements exceed 250 ml/kg/year.
4- Stem cell transplantation can cure the patients .
5- Genetic counseling .