vitamin b12 deficiency.pptx

vitamin b12 functions,symptoms of deficiency,diagnosis and treatment of vit b12 deficiency

1. VITAMIN B12 DEFICIENCY DR G VENKATA RAMANA MBBS DNB FAMILY MEDICINE

2. VITAMIN B12 W ater-soluble B vitamin Also called cobalamin ( Cbl ). R esistant to cooking and boiling Synthesized by gut flora Present in foods derived from animal products . V itamin B 12 deficiency is virtually never caused by inadequate intake except in vegetarians who scrupulously avoid milk and eggs The liver stores enough vitamin B 12 to last for approximately 3 years and this, together with the enterohepatic circulation , means that vitamin B 12 deficiency takes years to become manifest , even if all dietary intake is stopped or severe B 12 malabsorption supervenes . Normal vitamin B12 requirements Adults – 2.4 mcg per day Pregnancy – 2.6 mcg per day Lactation – 2.8 mcg per day

3. Physiologic roles of vitamin B12 DNA synthesis, RNA synthesis, DNA methylation   Vitamin B12 play a critical role in DNA and RNA synthesis. B12 deficiency can therefore impair DNA synthesis, which in turn can cause a cell to arrest in the DNA synthesis (S) phase of the cell cycle, make DNA replication errors, and/or undergo apoptotic death Hematopoiesis   Hematopoietic precursor cells are among the most rapidly dividing cells in the body and hence are one of the cell types most sensitive to abnormal DNA synthesis.

4. Two major effects of the deficiency on hematopoiesis Megaloblastic changes   caused by slowing of the nuclear division cycle relative to the cytoplasmic maturation cycle ( ie , nuclear-cytoplasmic dyssynchrony ). Ineffective erythropoiesis   occurs when there is premature death ( eg , phagocytosis or apoptosis) of the developing erythropoietic precursor cells in the bone marrow . There may be hypercellularity of the bone marrow laboratory findings of hemolysis, including elevated serum iron, indirect bilirubin, and lactate dehydrogenase (LDH), and low haptoglobin . The reticulocyte count is typically low . Neuronal function   Vitamin B12 deficiency is known to adversely affect neuronal function, but the exact mechanisms remain elusive . Reduced methylation of neuronal lipids and neuronal proteins, such as myelin basic protein, have been hypothesized to play a role in some of the neurologic deficits. Myelin basic protein makes up approximately one-third of myelin, and demyelination in the setting of vitamin B12 deficiency may explain many of the neurologic findings 

5. VITAMIN B12 FUNCTIONS 1. Vit B12 is essential for the conversion of homocysteine to methionine Methionine is needed as a methyl group donor in many metabolic reactions and for protein synthesis . This reaction is also critical in making tetrahydrofolic acid (THFA) available for reutilization. In B12 deficiency THFA gets trapped in the methyl form and a number of one carbon transfer reactions suffer Purine and pyrimidine synthesis is affected primarily due to defective ‘one carbon’ transfer because of ‘ folate trap ’. The most important of these is inavailability of thymidylate for DNA production. 2 .Vit B12 is essential for conversion of methylmalonyl CoA to succinyl CoA I mportant step in propionic acid metabolism. It links the carbohydrate and lipid metabolisms Responsible for demyelination seen in B12 deficiency 3. Vit B12 is essential for conversion of Methionine to S- adenosyl methionine More important in the neurological damage of B12 deficiency, because it is needed in the synthesis of phospholipids and myelin.

6. VITAMIN B12 ABSORPTION

7. VITAMIN B12 ABSORPTION Two mechanisms exist for cobalamin absorption . One is passive, occurring equally through buccal , duodenal, and ileal mucosa; it is rapid but extremely inefficient, with <1% of an oral dose being absorbed by this process . The normal physiologic mechanism is active; it occurs through the ileum and is efficient for small (a few micrograms) oral doses of cobalamin , and it is mediated by gastric intrinsic factor (IF ). 1 . Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called haptocorrin . 2 . On entering the duodenum, haptocorrin –B12 complexes 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 cubilin , 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 .

8. It is stored in the liver, which normally contains reserves sufficient to support bodily needs for 5 to 20 years. Because of these large liver stores, clinical presentations of vitamin B12 deficiency typically follow years of unrecognized malabsorption The metabolic defects responsible for the anemia of vitamin B12 deficiency are intertwined with folate metabolism . Vitamin B12 is required for recycling tetrahydrofolate,which , as described previously, is the form of folate that is needed for DNA synthesis In keeping with this relationship, the anemia of vitamin B12 deficiency is reversed with the administration of folate . By contrast, folate administration does not prevent and may in fact worsen certain neurologic symptoms that are specific to vitamin B12 deficiency

9. Causes of vitamin B12 deficiency Gastric abnormalities Pancreatitis Autoantibodies to intrinsic factor or gastric parietal cells (pernicious anemia) Pancreatic insufficiency Gastrectomy /bariatric surgery Diet Gastritis Breastfed infant of a mother with vitamin B12 deficiency Autoimmune metaplastic atrophic gastritis Strict vegan diet Small bowel disease Vegetarian diet in pregnancy Malabsorption syndrome Agents that block or impair absorption Ileal resection or bypass Neomycin IBD ( eg , Crohn disease) Biguanides ( eg , metformin) Celiac disease Proton pump inhibitors Bacterial overgrowth H2 receptor antagonists Blind loop Nitrous oxide (N 2 O) gas, used for anesthesia or recreationally Dibothriocephalus latus   (fish tapeworm) Inherited transcobalamin II deficiency

10. CLINICAL PRESENTATION Macrocytic anemia   Symptoms of anemia-fatigue , irritability, cognitive decline,chest pain, shortness of breath,palpitations,light -headedness Gastrointestinal symptoms G lossitis (including pain, swelling, tenderness, and loss of papillae and/or hyperpigmentation of the tongue) Neuropsychiatric changes   S ymmetric paresthesias or numbness and gait problems . The neuropathy is typically symmetric and affects the legs more than arms . S ubacute combined degeneration of the dorsal (posterior) and lateral columns (white matter) of the spinal cord due to demyelination . It is associated with progressive weakness, ataxia, and paresthesias that may progress to spasticity and paraplegia.

11. Subacute combined degeneratio n (A) T2W demonstrating hyperintensity (brightness) in the posterior columns from mid-C2 level to mid-C6 level (white arrows). (B) T1W demonstrating iso -intensity of the posterior columns with the anterior columns (white arrows) MRI T2W axial view of the cervical spinal cord demonstrating symmetrical hyperintensities in the posterior columns (black arrows). 

12. Depression or mood impairment Irritability, Insomnia Cognitive slowing Forgetfulness Dementia Psychosis Visual disturbances, which may be associated with optic atrophy Peripheral sensory deficits Weakness , which may progress to paraplegia and incontinence if severe Impaired position and vibration sense Lhermitte sign, a shock-like sensation that radiates to the feet during neck flexion Ataxia or positive Romberg test Abnormal deep tendon reflexes Extrapyramidal signs ( eg , dystonia, dysarthria, rigidity) Restless legs syndrome Nonspecific fatigue 

13. Infants and maternal vitamin B12 deficiency   P resent with pancytopenia and/or macrocytosis ; there may be associated developmental delay or regression, feeding difficulties, hypotonia , irritability, tremors, or convulsions  Skin   Skin hyperpigmentation and hypopigmentation can occur  hyperpigmentation on the hands and feet Cancer   Increased risk of gastric cancer in individuals with pernicious anemia.

14. HYPERPIGMENTATION OF HANDS RETICULATE PIGMENTAION TONGUE IN VITB12 DEFICIENCY

15. Findings supporting the diagnosis of vitamin B 12 deficiency are ( 1) Low serum vitamin B 12 levels , ( 2) N ormal or elevated serum folate levels, ( 3) Moderate to severe macrocytic anemia, ( 4) Leukopenia with hypersegmented granulocytes (5 ) A dramatic reticulocytic response (within 2 to 3 days) to parenteral administration of vitaminB 12 .

16. LABORATORY FINDINGS CBC and blood smear Anemia Macrocytic red blood cells (MCV >100 fL ) or macro- ovalocytosis An MCV > 115 fL is more specific to vitamin B12 or folate deficiency Mild leukopenia and/or thrombocytopenia Low reticulocyte count Hypersegmented neutrophils on the peripheral blood smear ( ie , > 5% of neutrophils with ≥5 lobes or ≥1 % of neutrophils with ≥6 lobes ) Increased lactate dehydrogenase,Increased bilirubin Serum vitamin B12 Above 300 pg /mL (above 221 pmol /L) – Normal; deficiency unlikely 200 to 300 pg /mL (148 to 221 pmol /L) – Borderline; deficiency is possible and additional testing is useful . Below 200 pg /mL (below 148 pmol /L) – Low; consistent with deficiency Levels of cobalamins fall in normal pregnancy Spuriously low B12 v alues occur in women using the oral contraceptive pill and in patients with myeloma, in whom paraproteins can interfere with vitamin B12 assays H igh serum B12levels are usually due to raised serum TC I levels and can be due to the presence of liver, renal, or myeloproliferative diseases or to cancer of the breast, colon, or liver

17. PERIPHERAL SMEAR Peripheral smear shows marked macro- ovalocytosis in a patient with vitamin B12 deficiency. In this case, teardrop cells are an advanced form of macro- ovalocytes . Peripheral blood smear showing a hypersegmented neutrophil (seven lobes) and macroovalocytes , a pattern that can be seen with vitamin B12 ( cobalamin ) or folate deficiency.

18. MMA and homocysteine Normal  – No deficiency of vitamin B12 or folate . MMA and homocysteine elevated   Deficiency of vitamin B12 (does not eliminate the possibility of folate deficiency). MMA normal, homocysteine elevated   No deficiency of vitamin B12. Consistent with deficiency of folate . B ut may be raised in other conditions, for example, chronic renal disease, alcoholism, smoking, pyridoxine deficiency, hypothyroidism, and therapy with steroids, cyclosporine, and other drugs. Autoantibodies to intrinsic factor   Antiparietal cell antibodies,autoantibodies to IF-Pernicious anemia   serum gastrin raised in pernicious anemia serum pepsinogen I low in pernicious anemia

19. Bone marrow in severe megaloblastic anemia M arrow is hypercellular . The cells are larger than normoblasts , and an increased number of cells with eccentric lobulated nuclei or nuclear fragments may be present . Giant and abnormally shaped metamyelocytes and enlarged hyperpolyploid megakaryocytes are characteristic

20. TREATMENT Vitamin B12 is   not given intravenously Intravenous use will result in urinary excretion of most of the vitamin B12. Dosage: Intramuscular First week-1000 mcg  IM daily F/B 1000mcg once per week for 4 weeks F/B 1000mcg once every 1-3 months Oral –In patients with normal absorption 1000 mcg once per day In patients with impaired absorption –vitamin B12 2000 mcg daily It is wise to add 1–5 mg of oral folic acid and an iron preparation, because reinstitution of brisk haemopoiesis may unmask deficiency of these factors Preparations Cyanocobalamin Hydroxocobalamin Methylcobalamin Because of higher protein binding and better retention in blood, hydroxocobalamin is preferred for parenteral administration to treat vit B12 deficiency.

21. Adverse effects Allergic reactions have occurred on injection, probably due to contaminants. Anaphylactoid reactions (probably to sulfite contained in the formulation) have occurred on i.v. injection Duration of therapy   Lifelong replacement is necessary for individuals with a condition that is not reversed ( eg , gastric bypass surgery, autoantibodies to intrinsic factor [pernicious anemia]). If the cause of the deficiency can be treated or eliminated ( eg , excessively restrictive diet, drug-induced deficiency, reversible cause of malabsorption ), supplementation can be discontinued after the deficiency is corrected. Annual monitoring for vitamin B12 deficiency is recommended for patients receiving  Metformin Prevention Individuals at risk for  vitamin B12  deficiency ( eg , vegan or strict vegetarian diet, gastric or bariatric surgery) should receive oral vitamin B12 supplements