MEGALOBLASTIC ANEMIA Norma RBC central palor 13 vs

MEGALOBLASTIC ANEMIA

Norma RBC , central palor (13 vs 23)

Smaller , more pallor , few of target Majority are homogenous : hypochromic microcytic DDX : ID , thalasimia minor , (not liver although there are some target cell , bcz the size)

Target , some sphero , irregular shape

We say in previous lec. Spherocytosis may be in hemolysis case blood film , we say in previous lec. Spherocytosis can be found in blood film of hemolysis case as well as hereditary spherocytosis , so you ca depend on blood film only to determin its herditary sphero. You have to do osmotic fragil test Spherocytosis , not hemolysis (unless there is hemolysis hx as –low habtoglubin is low , LDH high , retic. count high , low Hb) or presence fragmented RBC…. ) see next slide Hx : AD (family Hx , or FX of spleenectomy) Dx : Osmotic fragile test

Intravascular hemolysis , spherocytosis , fragment RBC(hemlet , schistocyts , . . ) Ddx : HUS , DIC

Megaloblastic , nuclear protein abnormalities , folate or Vit. b 12 def. Hyper segmented neutrophiles

MEGALOBLASTIC ANEMIA The RBC at all stages of development are larger than normal (MACROCYTOSIS) in blood film They have an open , fine dispersed nuclear chromatin Delay in the nuclear maturation and progression Giant metamyelocytes and bands are present in the marrow Hypersegmented neutrophils(>4 -5 Lobes)

MEGALOBLASTIC ANEMIA Charachterized by ineffective erythropoiesis , which is a condition where there is active production of RBC , with premature death and finally resulting in anemia. (may see high retic. count , high LDH but not to hemolysis levels) Most of childhood megaloblastic anemia result from vit B 12 and folate deficiency

Vitamin B 12 (Cobalamin) Deficiency Vitamin B 12 is derived from cobalamin in food (mainly animal sources). Humans cannot synthesize vitamin B 12. Vit b 12 is released in the acidity of the stomach where it binds the IF( Intrensic factor), then reaches the distal ileum to be absorbed via specific receptors for the IF Cobalamin binds to a transport protein, transcobalamin II (TC-II), which carries it to the liver, bone marrow, and other tissue storage sites. TC-II enters cells by receptormediated endocytosis.

Vitamin B 12 Deficiency Children and adults have sufficient vitamin B 12 stores to last 3– 5 yr. However, in young infants born to mothers with low vitamin B 12 stores, clinical signs of cobalamin deficiency can become apparent in the first 4– 5 months of life.

Vitamin B 12 Deficiency Etiology Inadequate dietary intake of vitamin B 12 (needs years to occur) lack of IF secretion by the stomach Impaired intestinal absorption of IF- cobalamin. : CF, CELIAC, NE Absence of vitamin B 12 transport protein.

Etiology Dietary deficiency is rare. It may occur in cases of strict vegetarians. In children, occurs in breast-fed infants whose mothers are vegans or themselves have pernicious anemia.

LACK OF INTRINSIC FACTOR Congenital pernicious anemia: a rare autosomal recessive disorder , due to an inability to secrete gastric IF or secretion of functionally abnormal IF. It differs from the typical disease in adults in that : the stomach secretes acid normally and is histologically normal There are no antibodies to parietal cells and no associated endocrine disorders.

LACK OF INTRINSIC FACTOR Juvenile pernicious anemia : occurs in older children It is an immunologic disorder similar to the adult type with atrophy of the gastric mucosa, achlorhydria, and antibodies in serum against IF and parietal cells. These children may have additional immunologic and endocrine abnormalities (cutaneous candidiasis, hypoparathyroidism) ) ﺑﻤﻴﺰﻫﺎ ﻋﻦ ﻳﻠﻲ ﻗﺒﻞ ﺏ ﺍﻟﻌﻤﺮ

IMPAIRED VITAMIN B 12 ABSORPTION Caused by any disease that affects the distal ileum: neonatal necrotizing enterocolitis terminal ileum surgically removed overgrowth of intestinal bacteria within diverticula or duplications of the small intestine. absence of the IF-B 12 receptor in the terminal ileum, (rare disease) it is AR. fish tapeworm (Diphyllobothrium latum infiction) of small intestine

ABSENCE OF VIT B 12 TRANSPORT PROTEIN Transcobalamin II (TC-II) deficiency A congenital deficiency, inherited as an AR This disorder usually manifests in the first weeks of life. The diagnosis of this disorder is suggested by the presence of severe megaloblastic anemia with normal serum vitamin B 12 and folate levels and no evidence of any other inborn errors of metabolism.

Clinical Manifestations nonspecific manifestations: weakness, fatigue, failure to thrive, or irritability pallor, glossitis, vomiting, diarrhea, and jaundice Neurologic symptoms: paresthesias, sensory deficits, hypotonia, seizures, developmental delay, developmental regression, and neuropsychiatric changes, they can be seen in the absence of hematological abnormalities.

Laboratory Finding Macrocytic anemia neutrophils may be large and hypersegmented In advanced cases, neutropenia and thrombocytopenia may occur Confirm the diagnosis Serum vitamin B 12 levels less than 100 pg/m. L serum iron and serum folic acid are normal Serum LDH, bilirubin are elevated RDW high

Diagnosis History: Surgery or disease of small intestine, mother vegetarian, or severe nutritional problem in the child Schilling test

Treatment The physiologic requirement for vitamin B 12 is 1– 5 μg/day Treatment with 1 mg Vit B 12 injected IM If there is evidence of neurologic involvement 1 mg should be injected intramuscularly daily for at least 2 wk. Maintenance therapy is necessary with monthly IM injection of 1 mg vit B 12

Folic Acid Deficiency

Folic Acid Deficiency Folates are abundant in green vegetables, fruits, and animal organs (liver, kidney) Folic acid is absorbed throughout the small intestine. It is reduced by dihydrofolate reductase to tetrahydrofolate, which is transported into tissue cells Body stores of folate are limited, and megaloblastic anemia occurs after 2– 3 mo on a folate-free diet ﺍﻻﻳﺮﻭﻥ ﺑﻌﺪﻱ ﺍﻟﺒﻲ ﺗﻮﻟﻴﻒ ﺍﺳﺮﻉ ﺷﻲ ﺍﻟﻔﻮﻟﻴﻚ ﺑﻌﻌﺪﻳﻦ

Clinical Manifestations Megaloblastic anemia : peak incidence at 4– 7 mo of age, somewhat earlier than iron deficiency anemia, although the two may be present concomitantly in infants with poor nutrition Infants are irritable and fail to gain weight Hemorrhages from thrombocytopenia occur in advanced cases

Etiology occur as a consequence of : inadequate folate intake, decreased folate absorption, acquired and congenital metabolic disorders of folate metabolism

INADEQUATE FOLATE INTAKE conditions where there are increased vitamin requirements (pregnancy, growth in infancy, chronic hemolysis) Human breast milk, pasteurized cow's milk, and infant formulas provide adequate amounts of folic acid. Goat's milk is deficient; folic acid supplement must be given when goat milk is the main source. Folate requirements increase markedly during pregnancy Folate supplementation of at least 400 μg/day is recommended from the start of pregnancy to prevent neural tube defects

DECREASED FOLATE ABSORPTION Malabsorption due to chronic diarrheal states. (celiac disease, chronic infectious enteritis, and inflammatory bowel disease) Certain anticonvulsant drugs (phenytoin, primidone, phenobarbital) can impair absorption of folic acid

CONGENITAL ABNORMALITIES IN FOLATE METABOLISM congenital dihydrofolate reductase deficiency, patients developed severe megaloblastic anemia in early infancy DRUG-INDUCED ABNORMALITIES IN FOLATE METABOLISM some drugs have anti–folic acid activity. eg Methotrexate , trimethoprim

Laboratory Findings macrocytic anemia mean corpuscular volume > 100 f. L). The reticulocyte count is low nucleated RBCs demonstrating megaloblastic morphology Neutropenia and thrombocytopenia may be present in severe cases

Laboratory Findings Normal serum folic acid levels are 5– 20 ng/m. L, in deficiency levels are less than 3 ng/m. L RBC folate level is better indicator of chronic deficiency Levels of iron and vitamin B 12 in serum are normal RBCs folate is more accurate than serum folate

Treatment folic acid may be administered orally or parenterally in a dose of 0. 5– 1 mg/day

The Pancytopenias

The Pancytopenias pancytopenia is a loss of all marrow elements The clinical consequences include anemia, neutropenia, and thrombocytopenia can lead to serious illness and death (due to infection and malignancies”) could be constitutional (inhireted) or acquired

The Acquired Pancytopenias Difficult to identify the cause in all cases of acquired marrow failure in childhood, and these cases are termed “idiopathic”

Etiology of Acquired Aplastic Anemia DRUGS AND CHEMICALS chemotherapy, benzene chloramphenicol, Antiepileptics VIRUSES Cytomegalovirus Epstein-Barr Hepatitis B Hepatitis C Hepatitis non–A, B, C Human immunodeficiency (HIV)

Etiology of Acquired Aplastic Anemia MARROW REPLACEMENT Leukemia Myelodysplasia Myelofibrosis RADIATION

The Constitutional Pancytopenias 1. FANCONI ANEMIA : is the best-recognized constitutional pancytopenia associated with other congenital abnormalities (renal, cardiac, skin, facial) café au-lait spots absent thumb AR inheritance Dx by age 4 -7 yr, survival 30 yr High incidence of AML, liver and gut tumors , infection Treatment : BMT

The Constitutional Pancytopenias 2. Diamond-Blackfan Anemia : The primary defects are in the erythroid progenitor cells in an otherwise normally cellular bone marrow recognized in the 1 st year of life hematologic features are macrocytic anemia, with reticulocytopenia Etiology : majority of cases are sporadic , 20% inherited AR or AD. The big DDX : early vit. B 12 deficiency : by No megaoblastic chandes , normal vit. B 12 levels

Diamond-Blackfan Anemia Clinical Manifestations, babies are pale in the first days after birth; rarely, hydrops fetalis occurs Profound anemia usually becomes evident by 2 – 6 mo of age congenital anomalies, including short stature, craniofacial deformities, triphalangeal thumbs

Diamond-Blackfan Anemia RBCs are macrocytic but there is no hypersegmentation of neutrophils or other peripheral blood characteristics of megaloblastic anemia. Folic acid and vitamin B 12 levels are normal Treatment : Corticosteroid therapy ¾ of patients respond initially, if no response … BMT is the treatment High risk of AML

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