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Clinical Competencies
After this session: Students can describe: - the etiology of megaloblastic anemia caused by vitamin B12 and folate deficiency - the pathophysiology of megaloblastic anemia - the principal management of megaloblastic anemia caused by vitamin B12 and folate deficiency Students can diagnose megaloblastic anemia based on clinical features and laboratory findings
Clinical Competencies
After this session: Students can describe: - the etiology of megaloblastic anemia caused by vitamin B12 and folate deficiency - the pathophysiology of megaloblastic anemia - the principal management of megaloblastic anemia caused by vitamin B12 and folate deficiency Students can diagnose megaloblastic anemia based on clinical features and laboratory findings
Introduction
Based on the appearance of developing erythroblasts in the bone marrow: megaloblastic & non-megaloblastic.
Megaloblastic anemia A heterogeneous group of anemia characteristics: - RBC are larger: nuclear-to-cytoplasmic ratio > normoblast - The maturation of nuclei is delayed, cytoplasmic development is normal
There are several causes, but megaloblastic anemia is usually caused by vitamin B12 or folate deficiency.
Etiology
In clinical practice: vitamin B12 (cobalamine) or folate deficiency.
Causes of vitamin B12 deficiency Nutritional Malabsorption: gastric and intestinal causes Causes of folate deficiency Nutritional Malabsorption Excess urinary folate loss Drugs Excess utilization Mixed
Gastric causes
Intestinal causes
Pernicious anemia Congenital lack or abnormality of intrinsic factor Total or partial gastrectomy Intestinal stagnant loop syndrome jejunal diverticulosis, blind loop, stricture, etc Chronic tropical sprue Ileal resection and Crohns disease Congenital selective malabsorption with proteinuria (autosomal recessive megaloblastic anemia) Fish tapeworm
Pathological
- Hematological diseases: hemolytic anemia, myelofibrosis - Malignant diseases: carcinoma, lymphoma, myeloma - Inflammatory diseases: Crohns disease, tuberculosis, rheumatoid arthritis, psoriasis, exfoliative dermatitis, malaria Mixed: liver disease, alcoholism, intensive care
Pathophysiology
The molecular basis: a failure in the synthesis and assembly of DNA.
Cobalamin & folate metabolism are intricately related, and abnormalities in these pathways are believed to lead to the attenuated production of DNA. Megaloblastosis is caused by interference of folate metabolism by the inhibition of methionine synthesis.
Dietary folate deficiency: the size of the deoxythymidine triphosphate (dTTP) pool is normal or increased in persons with megaloblastosis.
Pathophysiology..
Impairment in the deoxyuridine monophosphate (dUMP) and deoxythymidine monophosphate (dTMP) pathway may be responsible for nutritional megaloblastosis. The cobalamin-related neuropathy: megaloblastic changes in hematopoietic cells.
Hypothesis for the cause of cobalamin neuropathy: a defect exists in the conversion of adenosyl-cobalamindependent conversion of methylmalonyl coenzyme A to succinyl coenzyme A.
Pathophysiology..
A hallmark of megaloblastic anemia is ineffective erythropoiesis, as evidenced by : - erythroid hyperplasia in the bone marrow - a decreased peripheral reticulocyte count - an elevation in lactate dehydrogenase (LDH) and indirect bilirubin levels. The pathogenesis: the intramedullary destruction of fragile and abnormal megaloblastic erythroid precursors.
Diagnosis
Based on: clinical features and laboratoy findings Clinical features Mildly jaundice (lemon yellow tint) Glossitis (a beefy-red, sore tongue) Angular stomatitis Mild symptoms of malabsorption with loss of weight caused by epithelial abnormality Purpura as a result of thrombocytopenia and widespread melanin pigmentation
Diagnosis..
Clinical features (contd) Vitamin B12 neuropathy Neural tube defect (anencephaly, spina bifida or encephalocele) in the fetus Cardiovascular disease: myocardial infarct, peripheral & cerebral vascular disease & venous thrombosis Other tissues abnormalities - Sterility is frequent in either sex with severe B12 or folate deficiency - Morphological abnormalities of cervical, buccal, bladder and other epithelia
Glossitis
Laboratory Findings
Pancytopenia Increased MCV and MCHC Hypersegmented neutrophils (five lobes or more in segmented neutrophils) Increased bilirubin Increased LDH Hyperplasia in the bone marrow Decreased M:E ratio Reticulocytopenia
Treatment
Treatment of vitamin B12 deficiency Compound: hydroxocobalamine Route: intramuscular, oral Dose: 1000 g Initial dose: 6x1000 g over 1-3 weeks Maitenance: 1000 g every 3 months Prophylactic: total gastrectomy, ileal resection
Treatment..
Treatment of folate deficiency Compound: folic acid Route: oral Dose: 5 mg Initial dose: daily for 4 months Maitenance: depends on underlying disease; life-long therapy may be needed in chronic inherited hemolytic anemia, myelofibrosis, renal dialysis Prophylactic: pregnancy, severe hemolytic anemia, dialysis, prematurity
Modul Task
Case: A 3 year-old boy, body weight 11kgs History taking: pale 4 weeks; no bleed; no fever; feeding difficulties (patient dont like meat and sea-food) Physical examination: conjunctiva palpebra anemic; stomatitis; glossitis; bleeding (-); lymph nodes, liver and spleen are not palpable; neuropathy on lower limbs bilateral Laboratory results: Hb 8.9 g/dl; white blood cells 5640/mm3; platelet 284,000mm3; MCV high, MCH and MCHC normal
Questions: 1.What are THE WORKING DIAGNOSIS and DIFFERENTIAL DIAGNOSIS of this patient? 2.Describe in brief THE CAUSES of this disease! 3.What are THE MECHANISMS of this disease? 4.How TO DIAGNOSE this disease based on the clinical features and laboratory findings? 5.How TO TREAT this patient?