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Activitate: Însușirea terminologiei în hematologie - anemii megaloblastice (lucrari practice)

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Activitate: Însușirea terminologiei în hematologie - anemii megaloblastice (lucrari practice)

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OBIECTIVE:
1. să defineasca temenul de anemie megaloblastică

2. să enumere posibilele cauze ale aparitiei carenței de vitamina B12

3. să detalieze tabloul clinic si paraclinic la prezentare a unui pacient cu anemie megaloblastica

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Dragi studenti, va rog sa numiti in comentarii cate o cauza sau manifestare clinica a deficitului de vitamina B12. Mult succes!

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Afectarea sinezei de ADN si a ciclului celular

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Afectarea sinezei de ADN si a ciclului celular

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Anemiile megaloblastice sunt afectiuni produse din cauza alterarii sintezei de ADN. Sinteza aberanta a ADN-ului afecteaza iesirea din ciclul celular cauzand maturatia intarziata a nucleului.
poza: khanacademy.org

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Aspectul maduvei hematogene (Imagine de aspirat medular)
Hiperplazia liniei eritroide cu asincronism nucleo-citoplasmatic.
poza: www.pathologyoutlines.com/topic/bonemarrowmegaloblasticanemia

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Formula mnemotehnica

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Aspect frotiu sanguin periferic.

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Proteina R - Celula parietala gastrica - factor intrinsec - amilaze pancreatice - enterocit din ileonul terminal
poza: xeragenx.com, stomach problematic

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Articol

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Are We Missing Vitamin B₁₂ Deficiency in the Primary Care Setting?

Bryan RH
J Nurse Pract. 2010;6:519-522

Article Summary

Vitamin B ₁₂ deficiency is present in 5%-20% of the elderly population and may have existed for many years, although there is a paucity of research to demonstrate this suspicion. If it is true that vitamin B ₁₂ deficiency begins in middle age, are clinicians missing this diagnosis in their primary care patients?

Vitamin B ₁₂, or cobalamin, is crucial for DNA synthesis in cells, particularly those with rapid turnover, such as hematopoietic cells, which are vital to the optimal function of the immune system. Demands for vitamin B ₁₂ increase during times of physical stress. Exogenous sources of B ₁₂ are meat and dairy products, which provide the B ₁₂ that we absorb on a daily basis in the presence of an acidic stomach and intrinsic factor.

Vitamin B ₁₂ deficiency is one of the major causes of macrocytic anemia but may also be present in normocytic patients. A deficiency of vitamin B ₁₂ promotes neurologic deficits, such as bilateral paresthesias of the lower extremities, loss of vibratory sensation, and disequilibrium. Memory loss, irritability, and dementia may also be caused by axonal degeneration in the central nervous system. Glossitis, vaginal atrophy, and mild diarrhea are among many other symptoms that might be associated with vitamin B ₁₂ deficiency.

One common cause of vitamin B ₁₂ deficiency, malabsorption, is affected by many factors encountered in primary care settings, including prolonged use of proton pump inhibitors or metformin or as a result of gastric bypass surgery. The traditional sign of vitamin B ₁₂ deficiency, macrocytic anemia, can be masked by the folic acid-supplemented cereals and grains we now ingest because this enrichment was mandated by the US Food and Drug Administration in 1998. Although obesity does not contribute to vitamin deficiency, obesity can play a role in development of Vitamin B ₁₂ deficiency if the patient undergoes gastric bypass surgery. This procedure results in removal of a significant portion of the stomach, including the parietal cells that produce the intrinsic factor that facilitates absorption of vitamin B ₁₂. Type 2 diabetes mellitus is another complication of obesity, and prolonged treatment with metformin can affect the absorption of vitamin B ₁₂ in the ileum by antagonizing the calcium-dependent ileal membrane.

Prolonged or critical illness places massive demands on the body's metabolism and is often an unrecognized cause of vitamin B ₁₂ deficiency. Thus, any patient recovering from a critical illness, regardless of age, should be screened for vitamin B ₁₂ deficiency.

Vitamin B ₁₂ deficiency is also found in patients inflammatory bowel disease, such as Crohn's disease, and in patients diagnosed with HIV. The latter patients can have poor nutrition and/or chronic diarrhea.

Vitamin B ₁₂ deficiency causes neurologic deficits that significantly affect quality of life, making this nutritional deficit worthy of recognition and treatment.

Serum vitamin B ₁₂ levels have a wide range of normal, with a low reference range of 200 to 220 pg/mL. Methylmalonic acid (MMA) is a substance produced in the body when there is a deficiency of vitamin B ₁₂, and so MMA concentration is considered to be a sensitive and specific indicator or vitamin B ₁₂ deficiency. MMA level will increase when vitamin B ₁₂ levels are less than 400 pg/mL. For patients with vitamin B ₁₂ levels less than 400 pg/mL, begin daily supplement with vitamin B ₁₂ at 1000-2000 mcg per day. Vitamin B ₁₂ may be given parenterally, nasally, or orally. Adequate treatment may be provided by any of these routes.

Viewpoint

Whereas most clinicians would include pernicious anemia in their differential diagnosis for patients with neurologic problems, considering vitamin B ₁₂ deficiency in a broader range of presentations is the major suggestion of this article. The development of Vitamin B ₁₂ deficiency is often insidious and warrants consideration in younger and older patients who are at risk.

The route of providing vitamin B ₁₂ supplementation has traditionally been parenteral. However, oral supplementation with high doses of vitamin B ₁₂ is usually adequate. Bryan suggests that even for patients with pernicious anemia who are unable to actively absorb vitamin B ₁₂, passive absorption in the small bowel enables an absorption rate of 1%, and this would result in absorption of 10-20 mcg daily, substantially more than the recommended daily amount of 2.4 mcg/day.

New to many clinicians is the use of a prescription vitamin B ₁₂ that comes as a nasal gel. This product is relatively expensive and should be reserved for patients with pernicious anemia who have persistent low serum vitamin B ₁₂ and elevated MMA after a trial of oral supplementation. If patients have significant neurologic symptoms, therapy might be started with parenteral medication and then followed by oral preparations. Compliance with supplementation will need to be assessed whichever route the patient selects.

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vitamin b12 associated neurologic disease

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vitamin b12 associated neurological disease

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A Diagnosis to Consider: Vitamin B12 Deficiency

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Bryan RH J Nurse Pract. 2010;6:519-522 Article Summary Vitamin B 12 deficiency is present in 5%-20% of the elderly population and may have existed for many years, although there is a paucity of research to demonstrate this suspicion. If it is true that vitamin B 12 deficiency begins in middle age, are clinicians missing this diagnosis in their primary care patients?

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Pentru cei cu memorie auditiva.

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Vitamin B12 deficiency - causes, symptoms, diagnosis, treatment, pathology

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Pentru aprofundare

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Vitamin B-12 structure

Vitamin B-12 (cobalamin) is a complex molecule in which a cobalt atom is contained in a corrin ring. Vitamin B-12 is available in animal protein.

Body stores

Total body stores are 2-5 mg, of which half is stored in the liver. The recommended daily intake is 2 mcg/d in adults; pregnant and lactating women require 2.6 mcg/d. Children require 0.7 mcg/d and, in adolescence, 2 mcg/d. Because vitamin B-12 is highly conserved through the enterohepatic circulation, cobalamin deficiency from malabsorption develops after 2-5 years and deficiency from dietary inadequacy in vegetarians develops after 10-20 years. Its causes are mainly nutritional and malabsorptive, PA being most common.

Physiology of absorption

After ingestion, the low stomach pH cleaves cobalamin from other dietary protein.The free cobalamin binds to gastric R binder, a glycoprotein in saliva, and the complex travels to the duodenum and jejunum, where pancreatic peptidases digest the complex and release cobalamin. Free cobalamin can then bind with gastric intrinsic factor (IF), a 50-kd glycoprotein produced by the gastric parietal cells, the secretion of which parallels that of hydrochloric acid. Hence, in states of achlorhydria, IF secretion is reduced, leading to cobalamin deficiency. Importantly, only 99% of ingested cobalamin requires IF for absorption. Up to 1% of free cobalamin is absorbed passively in the terminal ileum. This why oral replacement with large vitamin B-12 doses is appropriate for PA.

Once bound with IF, vitamin B-12 is resistant to further digestion. The complex travels to the distal ileum and binds to a specific mucosal brush border receptor, cublin, which facilitates the internalization of cobalamin-IF complex in an energy-dependent process. Once internalized, IF is removed and cobalamin is transferred to other transport proteins, transcobalamin I, II, and III (TCI, TCII, TCIII). Eighty percent of cobalamin is bound to TCI/III, whose role in cobalamin metabolism is unknown. The other 20% binds with TCII, the physiologic transport protein produced by endothelial cells. Its half-life is 6-9 min, thus delivery to target tissues is rapid.

The cobalamin-TCII complex is secreted into the portal blood where it is taken up mainly in the liver and bone marrow as well as other tissues. Once in the cytoplasm, cobalamin is liberated from the complex by lysosomal degradation. An enzyme-mediated reduction of the cobalt occurs by cytoplasmic methylation to form methylcobalamin or by mitochondrial adenosylation to form adenosylcobalamin, the 2 metabolically active forms of cobalamin.

Vitamin B-12 role in bone marrow function

In the cytoplasm, methylcobalamin (see image below) serves as cofactor for methionine synthesis by allowing transfer of a methyl group from 5-methyl-tetrahydrofolate (5-methyl-THF) to homocysteine (HC), forming methionine and demethylated tetrahydrofolate (THF). This results in reduction in serum homocysteine, which appears to be toxic to endothelial cells. Methionine is further metabolized to S-adenosylmethionine (SAM).

Vitamin B-12-associated neurological diseases. Cobalamin and folate metabolism. TS = thymidylate synthase, DHFR = dihydrofolate reductase, SHMT = serine methyl-transferase.

THF is used for DNA synthesis. After conversion to its polyglutamate form, THF participates in purine synthesis and the conversion of deoxyuridylate (dUTP) to deoxythymidine monophosphate (dTMP), which is then phosphorylated to deoxythymidine triphosphate (dTTP). dTTP is required for DNA synthesis; therefore, in vitamin B-12 deficiency, formation of dTTP and accumulation of 5-methyl-THF is inadequate, trapping folate in its unusable form and leading to retarded DNA synthesis. RNA contains dUTP (deoxyuracil triphosphate) instead of dTTP, allowing for protein synthesis to proceed uninterrupted and resulting in macrocytosis and cytonuclear dissociation.

Because folate deficiency causes macrocytosis and cytonuclear dissociation via the same mechanisms, both deficiencies lead to megaloblastic anemia and disordered maturation in granulocytic lineages; therefore, folate supplementation can reverse the hematologic abnormalities of vitamin B-12 deficiency but has no impact on the neurologic abnormalities of vitamin B-12 deficiency, indicating both result from different mechanisms.

Vitamin B-12 role in the peripheral and central nervous systems

The neurologic manifestation of cobalamin deficiency is less well understood. CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear. Reduced SAM or elevated methylmalonic acid (MMA) may be involved.

SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which may account for the encephalopathy and myelopathy. In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be relevant to mental status changes may occur. Parenthetically, SAM is being studied as a potential antidepressant.

Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin, adenosylcobalamin (see image below), a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission.

Vitamin B-12-associated neurological diseases. Cobalamin deficiency leads to reduced adenosylcobalamin, which is required for production of succinyl-CoA. D-methylmalonyl-CoA is converted to methylmalonic acid.

More recent studies propose a very different paradigm: B-12 and its deficiency impact a network of cytokines and growth factors, ie, brain, spinal cord, and CSF TNF-alpha; nerve growth factor (NGF), IL-6 and epidermal growth factor (EGF), some of which are neurotrophic, others neurotoxic. Vitamin B-12 regulates IL-6 levels in rodent CSF. In rodent models of B-12 deficiency parenteral EGF or anti-NGF antibody injection prevents, like B-12 itself, the SCD-like lesions.

In the same models, the mRNAs of several cell-type specific proteins (glial fibrillary acidic protein, myelin basic protein) are decreased in a region specific manner in the CNS, but, in the PNS myelin, protein zero and peripheral myelin protein 22 mRNA remain unaltered.

In human and rodent serum and CSF, concomitantly with a vitamin B-12 decrease, EGF levels are decreased, while at the same time, TNF-alpha increases in step with homocysteine levels. These observations provide evidence that the clinical and histological changes of vitamin B-12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors.

N

N ₂ O can oxidize the cobalt core of vitamin B-12 from a 1⁺ to 3⁺ valance state, rendering methylcobalamin inactive, inhibiting HC conversion to methionine and depleting the supply of SAM. Patients with sufficient vitamin B-12 body stores can maintain cellular functions after N ₂ O exposure, but in patients with borderline or low vitamin B-12 stores, this oxidation may be sufficient to precipitate clinical manifestations.

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vitamin b-12 associated neurological diseases overview

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Vitamin B-12 Associated Neurological Diseases

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The association of anemia and gastrointestinal and neurologic abnormalities referable to the brain, spinal cord, and peripheral nerves has been recognized in several clinical and postmortem case reports and series by Combe, Addison, and Fenwick since the early 19th century. In 1877, Gardner and Osler coined the term pernicious anemia (PA) to...