Argomenti di Ematologia: le anemie non sideropeniche

1. Argomenti di Ematologia: le anemie non sideropeniche La anemia megaloblastica Dipartimento di Scienze Biomediche – Sezione di Ematologia Università degli Studi di Catania

2. Cobalamin (vitamin B12) Deficiency Folate Deficiency Megaloblastic/Macrocytic Anemia

3. Cobalamin (vitamin B12) Terminal ileum Meat Fish Milk Cheese cobalamin gastric intrinsic factor (IF) Small bowel cobalamin DNA and methyonine synthesis 3-9 µg/day Needs ≤ 2µg/day Methyl B12 Liver store (5mg) methylmalonate to succynil Deossi B12 Serum B12 levels 193-982 pg/ml Toh B-H et al, N Engl Med 1997 Babior BM, Hamson’s Principles of Int Med, 2001

4. Folate Fruits and vegetables Duodenum Jejunum (Conjugase) Amino acid and nucleic acid metabolism 100-200 µg/day Low liver store (5-10 mg) (2-4 months) Methionina synthesis Serum folate 3.0-17.0 ng/ml (folate intake-dependent) Red-cell folate 225-640 ng/ml (cobalamin levels-dependent) (ratio 1/30) Pawson R et al, Aliment Pharmacol Ther 1998 Gregory JF et al, Annu Rev Nutr 2002

6. B12 deficiency Low intake (rare) Alcohol Drugs (antisecretories) Malabsorption related to the lack of intrinsic factor autoimmune gastritis (genetic predisposition) gastrectomy Malabsorption related to terminal ileum tropic sprue chron celiac disease resection (blind gut syndrome) limphoma irradiation genetic conditions (IF or transcobalamin I/II deficiency) Consumption Infections (botriocephalus) Toh B-H et al, N Engl Med 1997 Half danarson TR et al, Blood 2007 Pancreatitis

7. Folate Deficiency Low intake ethilism toxicomania elderly Malabsorption tropic sprue celiac disease Drugs (diidrofolate reductase inhibitors, intestinal”conjugase”) antifolates (metotrexate, pirimetamine, thrimetoprim, sulfasalazine) purine analogs (mercaptopurine, thioguanine, azathioprine, aciclovir) pirimidine analogs (fluorouracile, zidovudine) RNA reductase inhibitors (hydroyurea, cytarabine) anticonvulsive (difenilidantoine, phenobarbital) Others (anaesthetic, contraceptives) Increased needs pregnancy chronic hemolytic anemia, leukemias, chron, rheumatoid arthritis dermatitis Increased loss Halfdanarson TR et al, Blood 2007 dialysis

8. Megaloblastic Anemia: “pernicious” Autoimmune chronic gastritis Parietal cell H+/K+-ATPase autoantibodies Type A gastritis Antrum spared Antibodies to parietal cells and IF Low serum pepsinogen I levels Achlorhydria Hypergastrinemia B12-deficient megaloblastosis Submucosal and lamina propria infiltration (Plasmacells, macrophages and CD4 T cells) gastric juice autoantibodies to vit B12-binding site of IF Acid- and IF secreting parietal cells and pepsinogen- secreting zymogenic cells Stomach fundus and body Toh B-H et al, N Engl J Med 1997 Fyfe JC et al, Blood 2004

12. Protean H pylori: perhaps “pernicious” too? Type B gastritis Bacterial chronic gastritis H pylori infection Antrum involved H pylori infection Hypogastrinemia years or decades Type A gastritis Stomach antrum H pylori camouflage (H+K+-ATPase) Gastrin-producing cells Hershko C et al, Blood 2006

14. Clinical Presentation Anemia Fatigue Gastrointestinal Manifestation Atrophic glossitis Malabsorption Diarrhea Weight loss Neurologic Complications (acid methylmalonic) Peripheral neuropathy(paresthesias, numbness) Spinal cord posterior column (loss of vibration and position sense, and sensory ataxia with positive Romberg) Spinal cord lateral column (limb weakness, spasticity, and extensor plantar responses) Cerebral manifestation (mild personality defects, memory loss, frank psychosis “megaloblastic madness”) Cancer complications (gastric carcinoma and gastric carcinoid tumors due to trophic action of hypergastrinemia, colon and uterus tumor due to megaloblastic metaplasia) Toh B-H et al, N Engl J Med 1997

15. Laboratory Diagnosis – Hematologic studies Peripheral-Blood smear Macrocytosis with hypersegmented polymorphonuclear leukocytes Peripheral blood Anemia (normocromic/macrocytic) Leukopenia Thrombocytopenia Pancytopenia Blood marrow smear (ineffective myelopoiesis) Megaloblasts and large myeloid precursors (“giant metamyelocytes”) Bone marrow biopsy (MDS) Normal B12, folate and homocysteine and hyposegmented polymorphonuclear B12 - Laboratory Low serum vit B12, normal or high serum folate and low red cell folate Elevated serum homocysteine and methylmalonic acid Schilling’test Low serum holotranscobalamin II (holoTC saturation) Folate - Laboratory Low serum and red cell folate Elevated serum homocysteine and normal serum methylmalonic acid FIGLU test Elevated urinary formiminoglutammic acid Toh B-H et al, N Engl J Med 1997 Halfdanarson TR et al, Blood 2007 It is recommended combined mesurements of both vitamins

17. Old and New vit B12 absorption test Traditional Shilling’s test Labeled B12 Holo-TC Absorption test Non labeled B12 Used to investigate whether lack of the vitamin is caused by lack of IF Used to investigate whether lack of the vitamin is caused by lack of IF Measurement of holoTC before and 24 hours after intake of B12 without rhIF and again 24 hours after intake of B12 together with rhIF (rhIF-B12) Urinary excretion of orally administered labeled B12 without IF Low free B12 rhIF-B12 Labeled B12 with IF mild holoTC increase high holoTC increase Normal Hvas AM et al, Haematologica 2006

20. Laboratory Diagnosis - Serologic and bioptic Studies B12 Serum and juice autoantibodies to gastric parietal cells Serum and juice autoantibodies to IF type I (block the binding vit B12/IF “70%”) Serum and juice autoantibodies to IF type II (block vit B12/IF complex “35-40%”) Mild indirect hyperbilirubin Gastric biopsy Toh B-H et al, N Engl J Med 1997

21. TREATMENT Regular daily intramuscolar injections of 100 μg of vit B12 for two weeks. Regular weekly intramuscolar injections of 100 µg of vit. B12 until normalization of hemoglobin. Indefinite monthly intramuscolar injections of 100 µg of vit. B12 in patients with chronic disease. Tablets of 25 μg to 1 mg of vit B12 daily to prevent the deficiency in elderly patients with gastric atrophy Regular daily oral of 1-5 mg of folate for two years. Vidal-Alaball J et al, Cochrane Database Syst Rev 2005 Halfdanarson TR vet al, Blood 2007