Materiały źródłowe

• #1 Vitamin deficiency anemia – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/vitamin-deficiency-anemia/symptoms-causes/syc-20355025

  Vitamin deficiency anemia is a lack of healthy red blood cells caused by lower than usual amounts of vitamin B-12 and folate. […] This can happen if you don’t eat enough foods containing vitamin B-12 and folate, or if your body has trouble absorbing or processing these vitamins. […] Without these nutrients, the body produces red blood cells that are too large and don’t work properly. This reduces their ability to carry oxygen. […] Vitamin deficiency anemia can occur if you don’t eat enough foods containing vitamin B-12 and folate, or if your body has trouble absorbing or processing these vitamins. […] Low levels of vitamin B-12 can be caused by: […] Pernicious anemia. This condition occurs when the body’s immune system attacks cells in the stomach that produce a substance called intrinsic factor. Without this substance, B-12 can’t be absorbed in the intestines.

• #2 Vitamin Deficiency Anemia: Symptoms & Causes

  https://my.clevelandclinic.org/health/diseases/17732-vitamin-deficiency-anemia

  Vitamin deficiency anemia is a condition that develops when you have low levels of vitamin B12 or B9 (folate). In this type of anemia, your body doesnt produce enough healthy red blood cells. […] Vitamin deficiency anemia is a condition in which your body doesnt produce enough healthy red blood cells. It happens primarily when you have low levels of vitamin B12 or B9 (folate or folic acid). […] Both vitamins are crucial in many processes in your body, including making red blood cells. Without enough B12 or folic acid, your body doesnt make normal red blood cells and those cells die more quickly than normal cells so they cant carry oxygen to all of your body tissues. This lack of normal red blood cells is anemia. […] Vitamin deficiency anemia occurs when you have low vitamin B12 or folate levels. Causes of vitamin deficiency anemia may include: Certain medications, such as some anti-seizure drugs. Excessive alcohol use. Health conditions that affect nutrient absorption. History of gastric surgery. Intestinal problems such as tapeworms. Diet that doesnt include adequate meats/fish, dairy products, eggs, or specific vegan options (B12) or dark green veggies, beans, nuts, seeds (folate).

• #2 Vitamin Deficiency Anemia: Symptoms & Causes

  https://my.clevelandclinic.org/health/diseases/17732-vitamin-deficiency-anemia

  Treatment for vitamin deficiency anemia aims to increase your levels of the vitamin youre lacking. Your provider will determine the best dosage and type of treatment. […] Most people dont have long-term complications from vitamin deficiency anemia. With treatment, the condition often goes away. But its important to get treatment for vitamin deficiency anemia. Without treatment, vitamin deficiency anemia could lead to: Difficulty getting pregnant. Heart problems, including heart failure. Nerve problems. Pregnancy complications. […] Vitamin deficiency anemia is when your body doesnt make enough healthy red blood cells. It commonly develops because of a deficiency in vitamins B12 or B9. You have a higher risk of developing vitamin deficiency anemia if you have a diet that could be better, or if you have a condition that makes it difficult for your body to absorb certain nutrients. Treatment for this type of anemia focuses on restoring your B12 or B9 levels. You may take supplements by mouth, injection or through an IV.

• #3 Vitamin B12 Deficiency – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441923/

  Vitamin B12 is a cofactor for the enzyme methionine synthase, which is used in the conversion of homocysteine to methionine. As a byproduct of this reaction, methyltetrahydrofuran (methyl-THF) is converted to THF, which is converted to intermediates used in the synthesis of pyrimidine bases of deoxyribonucleic acid (DNA). In B12 deficiency, homocysteine cannot be converted to methionine, and thus, methyl-THF cannot be converted to THF. As a result, homocysteine levels accumulate, and pyrimidine bases cannot be formed, slowing down DNA synthesis and can cause megaloblastic anemia. […] Vitamin B12 is also used as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. In patients with B12 deficiency, methylmalonic acid (MMA) levels will accumulate, as it cannot be converted to succinyl-CoA. A hypothesis states that elevated levels of MMA, along with elevated levels of homocysteine, contribute to myelin damage, accounting for the neurologic deficits, such as neuropathy and ataxia, seen in these patients.

• #4 Vitamin B12 Deficiency: Recognition and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2017/0915/p384.html

  Vitamin B12 deficiency is a common cause of megaloblastic anemia, various neuropsychiatric symptoms, and other clinical manifestations. […] Vitamin B12 (cobalamin) is crucial for neurologic function, red blood cell production, and DNA synthesis, and is a cofactor for three major reactions: the conversion of methylmalonic acid to succinyl coenzyme A; the conversion of homocysteine to methionine; and the conversion of 5-methyltetrahydrofolate to tetrahydrofolate. […] Pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12. […] Patients diagnosed with vitamin B12 deficiency whose history and physical examination do not suggest an obvious dietary or malabsorptive etiology should be tested for pernicious anemia with anti-intrinsic factor antibodies (positive predictive value = 95%), particularly if other autoimmune disorders are present.

• #5 Pernicious anemia – Wikipedia

  https://en.wikipedia.org/wiki/Pernicious_anemia

  The body needs enough intrinsic factor to absorb and reabsorb vitamin B12 from the bile, the lack of which reduces the time needed to develop a deficiency. […] B12 is required by enzymes for two reactions: the conversion of methylmalonyl-CoA to succinyl-CoA, and the conversion of homocysteine to methionine. […] During B12 deficiency, this reaction cannot proceed, which leads to the accumulation of levomefolic acid. […] This accumulation depletes the other types of folate required for purine and thymidylate synthesis, which are required for the synthesis of DNA. […] Inhibition of DNA replication in maturing red blood cells results in the formation of large, fragile megaloblastic erythrocytes. […] The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl-CoA due to the requirement of B12 as a cofactor to the enzyme methylmalonyl-CoA mutase.

• #5 Pernicious anemia – Wikipedia

  https://en.wikipedia.org/wiki/Pernicious_anemia

  Pernicious anemia refers to a type of vitamin B12 deficiency anemia that results from lack of intrinsic factor. […] Lack of intrinsic factor is most commonly due to an autoimmune attack on the cells that create it in the stomach. […] Because pernicious anemia is due to a lack of intrinsic factor, it is not preventable. […] Pernicious anemia is the most common cause of clinically evident vitamin B12 deficiency worldwide. […] Although the healthy body stores three to five years’ worth of B12 in the liver, the usually undetected autoimmune activity in one’s gut over a prolonged period of time leads to B12 depletion and the resulting anemia; pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12.

• #6 Vitamin B12 deficiency – Wikipedia

  https://en.wikipedia.org/wiki/Vitamin_B12_deficiency

  Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. […] Causes are usually related to conditions that give rise to malabsorption of vitamin B12 particularly autoimmune gastritis in pernicious anemia. […] Deficiency can also be caused by inadequate dietary intake such as with the diets of vegetarians, and vegans, and in the malnourished. […] Diagnosis is typically based on blood levels of vitamin B12 below 148185 pmol/L (200 to 250 pg/mL) in adults. […] Vitamin B12 deficiency causes particular changes to the metabolism of two clinically relevant substances in humans: Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia and Methylmalonic acid (methylmalonyl-CoA to succinyl-CoA, of which methylmalonyl-CoA is made from methylmalonic acid in a preceding reaction).

• #7

  https://step1.medbullets.com/hematology/107042/b12-deficiency

  vitamin B12 deficiency results in a megaloblastic anemia […] vitamin B12 serves as a coenzyme for methionine synthase to produce methionine, which serves a vital role in methylation reactions […] vitamin B12 deficiency impairs DNA synthesis significantly affecting rapidly dividing cells (e.g., hematopoietic precursor cells) and leads to megaloblastic changes, which is caused by slowing of nuclear division due to nuclear-cytoplasmic dyssynchrony […] ineffective erythropoiesis (intramedullary hemolysis) occurs as erythropoietic precursor cells within the bone marrow prematurely die, resulting in a reticulocytopenia […] the mechanism of impaired neuronal function is not fully clear but hypothesized to be due to decreased methylation of neuronal lipids and proteins (e.g., myelin basic protein).

• #8 Megaloblastic anaemia: Folic acid and vitamin B12 metabolism | Revista Médica del Hospital General de México

  https://www.elsevier.es/en-revista-revista-medica-del-hospital-general-325-articulo-megaloblastic-anaemia-folic-acid-vitamin-S0185106315000426

  Folic acid and cobalamin are B-group vitamins that play an essential role in many cellular processes. Deficiency in one or both of these vitamins causes megaloblastic anaemia, a disease characterized by the presence of megaloblasts. Megaloblasts occur when inhibition of DNA synthesis causes asynchronous maturation between the nucleus and the cytoplasm. […] The pathophysiology of this group of anaemias has its origins in ineffective erythropoiesis secondary to intramedullary apoptosis of hematopoietic precursor cells. This, in turn, is caused by DNA synthesis abnormalities. […] Remember, both folate and cobalamin deficiency ultimately lead to thymidylate deficiency. DNA contains 2 purine bases (adenine and guanine) and 2 pyrimidine bases (thymine and cytosine). […] When there is insufficient thymidylate or thymine at the position in the DNA strand where these nitrogenous bases should occur, they are replaced by uracil. This happens primarily when uracil is incorporated at 2 similar positions in opposite strands. When uracil is incorporated into what should be a purely DNA structure, the repair enzymes detect the error and try to correct it, albeit unsuccessfully. As a result, first 1, then both DNA strands are destroyed, with the resulting p53-mediated cellular apoptosis.

• #8 Megaloblastic anaemia: Folic acid and vitamin B12 metabolism | Revista Médica del Hospital General de México

  https://www.elsevier.es/en-revista-revista-medica-del-hospital-general-325-articulo-megaloblastic-anaemia-folic-acid-vitamin-S0185106315000426

  Cobalamin deficiency causes subacute combined degeneration of the posterior and lateral grey column of the spinal cord due to methionine deficiency. Methionine is needed for the production of myelin. Myelin deficiency causes demyelination and gliosis of the grey column, which is further aggravated by the neurotoxicity of methylmalonic acid.

• #9 Megaloblastic Anemia: Folate Deficiency & Vitamin B12 Deficiency – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/megaloblastic-anemia-folate-deficiency-vitamin-b12-deficiency

  Megaloblastic anemia is primarily caused by a deficiency in folate or vitamin B12, which results in DNA/RNA asynchrony. DNA maturation and cell division become delayed, while RNA translation and protein production continue. This causes the cell division in the red blood cells to be impaired due to poor DNA maturation while the cytoplasm continues to grow, resulting in an increase in the mean cell volume (MCV) and the production of megaloblasts – large nucleated red blood cells. Furthermore, the abnormal red blood cells undergo apoptosis or are phagocytosed by macrophages, leading to fewer red blood cells in circulation. This also explains the low reticulocyte count noticed in patients with this condition. […] Vitamin B12 (cobalamin) is a coenzyme that aids in methyltransferase reactions, including the conversion of homocysteine to methionine. A deficiency in vitamin B12 can cause megaloblastic anemia because insufficient amounts impair red blood cell division and maturation. Causes of vitamin B12 deficiency include following a strict vegan diet, chronic alcohol consumption, conditions that lead to achlorhydria or lack of gastric acid, decreased production of intrinsic factor, pernicious anemia, and conditions affecting the ileum such as Crohn’s disease or parasitic infection by Diphyllobothrium latum. Pancreatic insufficiency can also lead to vitamin B12 deficiency.

• #9 Megaloblastic Anemia: Folate Deficiency & Vitamin B12 Deficiency – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/megaloblastic-anemia-folate-deficiency-vitamin-b12-deficiency

  Vitamin B12 deficiency can cause neuropsychiatric impairment due to its role in myelin synthesis, which is crucial for the proper functioning of nerve cells. This leads to subacute combined degeneration, characterized by injury to both the dorsal and lateral columns due to demyelination. The motor pathways in the lateral pyramidal tracts and the sensory pathways in the dorsal spinal column also degenerate, causing symptoms such as weakness, paralysis, paresthesias, numbness, and sensory ataxia.

• #10 Megaloblastic anaemia: Folic acid and vitamin B12 metabolism | Revista Médica del Hospital General de México

  https://www.elsevier.es/pt-revista-revista-medica-del-hospital-general-325-articulo-megaloblastic-anaemia-folic-acid-vitamin-S0185106315000426

  Folic acid and cobalamin are B-group vitamins that play an essential role in many cellular processes. Deficiency in one or both of these vitamins causes megaloblastic anaemia, a disease characterized by the presence of megaloblasts. Megaloblasts occur when inhibition of DNA synthesis causes asynchronous maturation between the nucleus and the cytoplasm. […] The pathophysiology of this group of anaemias has its origins in ineffective erythropoiesis secondary to intramedullary apoptosis of hematopoietic precursor cells. This, in turn, is caused by DNA synthesis abnormalities. […] Remember, both folate and cobalamin deficiency ultimately lead to thymidylate deficiency. DNA contains 2 purine bases (adenine and guanine) and 2 pyrimidine bases (thymine and cytosine). […] When there is insufficient thymidylate or thymine at the position in the DNA strand where these nitrogenous bases should occur, they are replaced by uracil. This happens primarily when uracil is incorporated at 2 similar positions in opposite strands.

• #11 Pernicious Anemia: Definition, Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/22377-pernicious-anemia

  Pernicious anemia, one of the causes of vitamin B12 deficiency, is an autoimmune condition that prevents your body from absorbing vitamin B12. […] Pernicious anemia is an autoimmune condition that happens when your immune system produces antibodies that attack cells in the mucosal lining of your stomach and nerve cells. Your immune systems response affects your bodys ability to absorb vitamin B12. […] The antibodies also block a critical protein called intrinsic factor. Normally, intrinsic factor carries the vitamin B12 we get from food to special cells in your small intestine. From there, the vitamin B12 is transported into your bloodstream. Other proteins then carry the vitamin B12 to your bone marrow, where the vitamin is used to make new red blood cells. This process cant happen when your immune system blocks your intrinsic factor.

• #11 Pernicious Anemia: Definition, Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/22377-pernicious-anemia

  Long-term low vitamin B12 levels caused by pernicious anemia can affect your nervous system. […] You may also develop vitamin B12 deficiency if: […] You have medical conditions that affect your digestive system like celiac disease or Crohns disease that make it hard for your body to absorb enough vitamin B12. […] Most people begin feeling better shortly after starting treatment. Pernicious anemia cant be cured, but increasing your vitamin B12 intake may eliminate most symptoms. The neurologic complications of pernicious anemia, however, can persist even after B12 stores are fully replaced.

• #12 Pernicious Anaemia: Mechanisms, Diagnosis, and Management | EMJ

  https://www.emjreviews.com/hematology/article/pernicious-anaemia-mechanisms-diagnosis-and-management/

  Pernicious anaemia (PA) is an autoimmune disease of multifactorial aetiology involving environmental and immunological factors. It is the most common cause of cobalamin deficiency anaemia worldwide. The disease is a macrocytic anaemia caused by a vitamin B12 deficiency, which, in turn, is the result of intrinsic factor deficiency, a protein that binds avidly to dietary vitamin B12 and promotes its transport to the terminal ileum for absorption. […] The deficiency of IF is a consequence of the presence of atrophic gastritis, which results in the destruction of the oxyntic mucosa and thus the loss of parietal cells, which normally produce hydrochloric acid as well as IF. […] PA is a complex, autoimmune, multifactorial disease. The environment appears to play a crucial, independent role in the pathogenesis of PA.

• #13 Pernicious Anaemia: Mechanisms, Diagnosis, and Management | EMJ

  https://www.emjreviews.com/hematology/article/pernicious-anaemia-mechanisms-diagnosis-and-management/

  H. pylori are ubiquitous organisms invading the gastric mucosa and are a global burden. They cause superficial gastritis, destruction of gastric parietal cells, and atrophic gastritis, resulting in reduced availability of IF for vitamin B12 transport. This causes an interference with vitamin B12 absorption, thus leading to vitamin B12 deficiency and its clinical manifestations. […] Patients with PA have been shown to have two types of antibodies: one to parietal cells and the other to IF (IFA) or its binding site in the small bowel. The immune response is directed against the gastric H+/K+-ATPase, which accounts for the associated achlorhydria. […] The atrophic gastritis is caused by the action of autoreactive CD4+ T cells that recognise H+/K+-ATP ase, which leads to their immune destruction.

• #14 Pernicious Anemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/204930-overview

  Pernicious anemia is an autoimmune disorder that leads to insufficient intrinsic factor levels either as a result of auto-antibody mediated destruction of parietal cells and/or the intrinsic factor protein itself. […] Impaired IF production leads to vitamin B12 deficiency and megaloblastic anemia. […] Pernicious anemia is the most common cause of severe vitamin B12 deficiency worldwide and is due to autoimmune destruction of parietal cells and/or intrinsic factor. […] Cobalamin deficiency may result from dietary insufficiency of vitamin B12; disorders of the stomach, small bowel, and pancreas; certain infections; and abnormalities of transport, metabolism, and utilization. […] Classic pernicious anemia produces cobalamin deficiency due to failure of the stomach to secrete IF. […] In adults, pernicious anemia is associated with severe gastric atrophy and achlorhydria, which are irreversible. […] Autoimmune phenomena and thyroid disease frequently are observed. […] Patients with pernicious anemia have a 2- to 3-fold increased incidence of gastric carcinoma.

• #15 Pernicious Anaemia: Mechanisms, Diagnosis, and Management | EMJ

  https://www.emjreviews.com/hematology/article/pernicious-anaemia-mechanisms-diagnosis-and-management/

  Studies have reported IFA positivity in 40-60% of patients with PA. These antibodies lead to cobalamin malabsorption in the terminal ileum that leads to cobalamin deficient megaloblastic PA. […] The clinical management of patients with PA has two different aspects: the treatment of cobalamin deficiency and the monitoring of iron deficiency onset. PA is caused by inadequate secretion of gastric IF, which is necessary for vitamin B12 absorption and thus cannot be treated with oral vitamin B12 supplements.

• #16 Vitamin deficiency anemia – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/vitamin-deficiency-anemia/symptoms-causes/syc-20355025

  A folate deficiency can occur when people don’t eat foods containing folate or their bodies are unable to absorb folate from food. […] Absorption problems may be caused by: […] A lack of folate can cause birth defects during pregnancy. […] Being deficient in vitamin B-12 or folate increases your risk of many health problems, including: […] Untreated, vitamin B-12 deficiency can lead to neurological problems, such as persistent tingling in the hands and feet or problems with balance. It can lead to mental confusion and forgetfulness because vitamin B-12 is necessary for healthy brain function. […] You can prevent some forms of vitamin deficiency anemia by choosing a healthy diet that includes a variety of foods.

• #17 Severe megaloblastic anemia: Vitamin deficiency and other causes | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/3/153

  Decreased intrinsic factor leads to significantly reduced absorption of dietary vitamin B12, resulting in pernicious anemia. […] Nearly every step of this pathway can be disrupted in various pathologic states, but lack of intrinsic factor secondary to pernicious anemia is the cause of vitamin B12 deficiency in most cases. […] Vitamin B12 deficiency can cause subacute combined degeneration of the dorsal and lateral columns of the spinal cord. […] Megaloblastic anemia due to folate deficiency and other causes shares the same hematologic manifestations as vitamin B12 deficiency but lacks the neurologic features. […] The laboratory and clinical findings were consistent with vitamin B12 deficiency, and the presence of anti-intrinsic factor antibody confirmed the diagnosis of pernicious anemia. […] In severe vitamin deficiency, dysplastic features can be observed, most often involving the erythroid lineage in the form of nuclear irregularities, eg, binucleation, multinucleation, nuclear fragmentation, and nuclear budding, which resemble features seen in myelodysplastic syndrome.

• #18 Pathology Outlines – Folate deficiency anemia

  https://www.pathologyoutlines.com/topic/hematofolatedefanemia.html

  Folate deficiency is a low level of folic acid (Vitamin B9) in the body […] Characterized by macrocytic anemia […] Also called Vitamin B9 deficiency […] Inadequate ingestion of folate containing foods due to: alcoholism (alcohol dehydrogenase binds folate), psychiatric morbidities, elderly […] Impaired absorption: celiac disease, tropical sprue, achlorhydria, anticonvulsant drugs (Dilantin), zinc deficiency, bacterial overgrowth in blind loops, strictures, jejunal diverticula […] Impaired metabolism, leading to inability to utilize absorbed folate: methotrexate and trimethoprim (folate antagonists) […] Hypothyroidism (decreases hepatic levels of dihydrofolate reductase) […] Congenital deficiency of enzymes of folate metabolism […] Increased requirement: infancy, pregnancy, lactation, malignancy, concurrent infection (immunoproliferative response), chronic hemolytic anemia (increased hematopoiesis)

• #19 Folate-deficiency anemia – UF Health

  https://ufhealth.org/conditions-and-treatments/folate-deficiency-anemia

  Folate-deficiency anemia is a decrease in red blood cells (anemia) due to a lack of folate. Folate is a type of B vitamin. It is also called folic acid. […] In folate-deficiency anemia, the red blood cells are abnormally large. Such cells are called macrocytes. They are also called megaloblasts, when they are seen in the bone marrow. That is why this anemia is also called megaloblastic anemia. […] The goal is to identify and treat the cause of the folate deficiency. […] Folate-deficiency anemia most often responds well to treatment within 3 to 6 months. It will likely get better when the underlying cause of the deficiency is treated. […] In pregnant women, folate deficiency has been associated with neural tube or spinal defects (such as spina bifida) in the infant.

• #20 Vitamin B12 deficiency anemia: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000574.htm

  Vitamin B12 deficiency anemia is a low red blood cell count due to a lack (deficiency) of vitamin B12. […] Your body needs vitamin B12 to make red blood cells. In order to provide vitamin B12 to your cells: […] Certain health conditions can make it difficult for your body to absorb enough vitamin B12. They include: […] Pernicious anemia, a condition that occurs when your body destroys cells in your stomach that make intrinsic factor, which may lead to vitamin B12 deficiency and anemia […] Long-term vitamin B12 deficiency can cause nerve damage. This may be permanent if you do not start treatment promptly after your symptoms begin. […] Vitamin B12 deficiency anemia most often responds well to treatment. It will likely get better when the underlying cause of the deficiency is treated.

• #21 Vitamin B12-Associated Neurological Diseases: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1152670-overview

  Vitamin B12 deficiency can lead to a range of neurological manifestations, including cognitive impairment, peripheral neuropathy, and myelopathy. […] Notably, subacute combined degeneration (SCD) of the spinal cord, a hallmark of B12 deficiency, presents with symptoms like numbness, weakness, and gait disturbances. […] In addition to B12 deficiency related to dietary causes, neurological complications can also arise from malabsorption conditions, such as pernicious anemia or prolonged nitrous oxide exposure. […] Timely recognition and treatment are essential to prevent irreversible neurological damage. […] Its causes are mainly nutritional and malabsorptive, pernicious anemia (PA) being most common. […] 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.

• #22 Vitamin B12-Associated Neurological Diseases: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1152670-overview

  Reduced SAM or elevated methylmalonic acid (MMA) may be involved. […] Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission. […] More recent studies propose a very different paradigm: B12 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. […] These observations provide evidence that the clinical and histological changes of vitamin B12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors. […] Nitrous oxide (N2O) can oxidize the cobalt core of vitamin B12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive, inhibiting HC conversion to methionine and depleting the supply of SAM.

• #23 Pernicious Anemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK540989/

  SAM is the methyl donor to key substrates, such as nucleic acids, proteins, phospholipids, and neurotransmitters. As a donor in DNA methylation, it plays an important role in epigenetic adaptability to developmental and environmental factors. […] Elevated plasma total homocysteine is associated with white matter damage, neurofibrillary tangles, brain atrophy, cognitive decline, and dementia.

• #24 The anemia of vitamin A deficiency: epidemiology and pathogenesis | European Journal of Clinical Nutrition

  https://www.nature.com/articles/1601320

  Objective: To gain insight into vitamin A deficiency as a cause of anemia. […] Although vitamin A deficiency is recognized to cause anemia, vitamin A deficiency anemia lacks complete characterization as a distinct clinical entity. Vitamin A appears to be involved in the pathogenesis of anemia through diverse biological mechanisms, such as the enhancement of growth and differentiation of erythrocyte progenitor cells, potentiation of immunity to infection and reduction of the anemia of infection, and mobilization of iron stores from tissues. […] Further work is needed to elucidate the biological mechanisms by which vitamin A causes anemia.

• #25 Vitamin B12 Deficiency | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/0301/p979.html

  However, the presence of parietal cell antibodies is nonspecific and occurs in other autoimmune states. […] The phenomenon of food-bound malabsorption occurs when vitamin B12 bound to protein in foods cannot be cleaved and released. […] Any process that interferes with gastric acid production can lead to this impairment. […] As mentioned previously, the widespread and prolonged use of histamine H2-receptor blockers and proton pump inhibitors for ulcer disease also may cause impaired breakdown of vitamin B12 from food, causing malabsorption and eventual depletion of B12 stores. […] Thus, the utility of the Schilling test has been brought into question. […] The Schilling test also has fallen out of favor because it is complicated to perform, the radiolabeled vitamin B12 is difficult to obtain, and interpretation of test results can be problematic in patients with renal insufficiency.

• #25 Vitamin B12 Deficiency | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/0301/p979.html

  Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anemia and has been implicated in a spectrum of neuropsychiatric disorders. […] Diagnosis of vitamin B12 deficiency is typically based on measurement of serum vitamin B12 levels; however, about 50 percent of patients with subclinical disease have normal B12 levels. […] A more sensitive method of screening for vitamin B12 deficiency is measurement of serum methylmalonic acid and homocysteine levels, which are increased early in vitamin B12 deficiency. […] Vitamin B12 deficiency is associated with hematologic, neurologic, and psychiatric manifestations. […] It is a common cause of macrocytic (megaloblastic) anemia and, in advanced cases, pancytopenia. […] Neurologic sequelae from vitamin B12 deficiency include paresthesias, peripheral neuropathy, and demyelination of the corticospinal tract and dorsal columns (subacute combined systems disease).

• #25 Vitamin B12 Deficiency | AAFP

  https://www.aafp.org/pubs/afp/issues/2003/0301/p979.html

  Vitamin B12 deficiency also has been linked to psychiatric disorders, including impaired memory, irritability, depression, dementia and, rarely, psychosis. […] In addition to hematologic and neuropsychiatric manifestations, vitamin B12 deficiency may exert indirect cardiovascular effects. […] Similar to folic acid deficiency, vitamin B12 deficiency produces hyperhomocysteinemia, which is an independent risk factor for atherosclerotic disease. […] The classic disorder of malabsorption is pernicious anemia, an autoimmune disease that affects the gastric parietal cells. […] Destruction of these cells curtails the production of intrinsic factor and subsequently limits vitamin B12 absorption. […] Laboratory evidence of parietal cell antibodies is approximately 85 to 90 percent sensitive for the diagnosis of pernicious anemia.

• #26 Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk – GOV.UK

  https://www.gov.uk/drug-safety-update/metformin-and-reduced-vitamin-b12-levels-new-advice-for-monitoring-patients-at-risk

  Decreased vitamin B12 levels, or vitamin B12 deficiency, is now considered to be a common side effect in patients on metformin treatment, especially in those receiving a higher dose or longer treatment duration and in those with existing risk factors. […] Metformin can commonly reduce vitamin B12 levels in patients, which may lead to vitamin B12 deficiency. […] The mechanism is currently thought to be multifactorial, comprising altered intestinal motility, bacterial overgrowth, and reduced uptake of vitamin B12 within the small intestine (or a combination of these factors). […] The risk of this adverse reaction occurring increases with increasing metformin dose and treatment duration and in patients with risk factors known to cause vitamin B12 deficiency.

• #27 Cobalamin (vitamin B12) and Folate Deficiency – Province of British Columbia

  https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/vitamin-b12

  B12 deficiency may also cause a macrocytic (megaloblastic) anemia BUT, in the presence of folate supplementation, this anemia may be masked so that B12 deficiency may present with exclusively neurologic features. Therefore, in patients with neurologic symptoms do not rely on the complete blood cell count (CBC) to help rule in or out B12 deficiency. […] Vitamin B12 deficiency is associated with either long-term proton inhibitor (PPI) or Histamine-2 receptor blocker (H2 blocker) use, but a causal relationship is not established. […] Once a diagnosis of B12 deficiency due to poor absorption of B12 has been made, therapy should be maintained lifelong.

• #28 Pernicious Anemia Presenting With Pancytopenia and Hemolysis: A Case Report | Gladstone | Journal of Medical Cases

  https://www.journalmc.org/index.php/JMC/article/view/3269/2563

  Cobalamin deficiency can lead to both intramedullary and extramedullary hemolysis. Intramedullary hemolysis is more common and occurs due to macrophage destruction of megaloblastic cells in the bone marrow. Conversely, extramedullary hemolysis in cobalamin deficiency (pseudothrombotic microangiopathy) occurs due to fragmentation of erythrocytes in capillaries. This appears to be multifactorial. Cobalamin deficiency leads to decreased deformability of the red blood cell (RBC) membrane as well hyperhomocysteinemia promoting endothelial dysfunction. […] The most common cause of deficiency is pernicious anemia. Pernicious anemia is caused by autoantibodies targeting intrinsic factor or gastric parietal cells. […] Diagnosing deficiency usually begins with testing of the serum vitamin B12 level. The Schilling test is not routinely used anymore. Confirmation of deficiency should be performed by measuring levels of homocysteine and methylmalonic acid. Both will be elevated in vitamin B12 deficiency, as opposed to folate deficiency where MMA will be normal. The CBC may show an elevated mean corpuscular volume. On a peripheral smear one may observe hypersegmented neutrophils. Hypersegmented neutrophils possess five lobes. A bone marrow evaluation is likely to reveal a markedly hypercellular marrow with megaloblastic erythroid hyperplasia, giant metamyelocytes, and frequent mitoses.

• #29 Vitamin B12 deficiency – Wikipedia

  https://en.wikipedia.org/wiki/Vitamin_B12_deficiency

  Early changes include a spongiform state of neural tissue, along with edema of fibers and deficiency of tissue. […] In later phases, fibric sclerosis of nervous tissues occurs. […] Those changes occur in dorsal parts of the spinal cord and to pyramidal tracts in lateral cords and are called subacute combined degeneration of spinal cord. […] Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. […] A diagnosis of vitamin B12 deficiency is determined by blood levels lower than 200 or 250 picograms per ml (148 or 185 picomoles per liter).

• #30

  https://journals.lww.com/ljms/fulltext/2018/02030/vitamin_b12_deficiency_presenting_as_hemolytic.7.aspx

  Vitamin B12 deficiency is not an uncommon condition. Commonly patient presents with megaloblastic anemia and pancytopenia. […] Vitamin B12 deficiency is a relatively common condition. The etiology is usually nutritional, pernicious anemia, and drug induced. The usual presentation is that of megaloblastic anemia or pancytopenia. Other presentations are rare. […] Vitamin B12 functions as a cofactor or coenzyme that participates in various biochemical reactions, including DNA synthesis, which promotes normal maturation of blood cells. It also contributes to the myelination of central nervous system as well as maintenance of its function. Deficiency of Vitamin B12 can lead to megaloblastic anemia and neuropathy. Intramedullary destruction or hemolysis of fragile and abnormal red blood cell precursors is the results of ineffective erythropoiesis secondary to defective DNA and cell maturation.

• #31 Pernicious anemia | Pathophysiology, Symptoms, & Treatment | Britannica

  https://www.britannica.com/science/pernicious-anemia

  Pernicious anemia is a disease in which the production of red blood cells (erythrocytes) is impaired as a result of the body’s inability to absorb vitamin B12, which is obtained in the diet and is necessary for red blood cells to mature properly in the bone marrow. […] In pernicious anemia vitamin B12 is unavailable owing to a lack of intrinsic factor, a substance responsible for intestinal absorption of the vitamin. […] When intrinsic factor is prevented from binding with vitamin B12 or when the parietal cells are unable to produce intrinsic factor, the vitamin is not absorbed and pernicious anemia results. This effect is thought to stem from an autoimmune reaction in which the malfunctioning immune system produces antibodies against intrinsic factor and against the parietal cells. […] Without an adequate amount of vitamin B12, the body is unable to synthesize DNA properly. This in turn affects red blood cell production: the cells divide, but their nuclei remain immature. These cells, called megaloblasts, are for the most part destroyed in the bone marrow and are not released to the circulation. Some megaloblasts mature to become large red blood cells called macrocytes; they reach the circulation but function abnormally. A deficiency of white blood cells (leukopenia) and platelets (thrombocytopenia) in the blood may occur.

• #32 Megaloblastic anemia due to severe vitamin B12 deficiency | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/89/1/8

  Macrocytic and megaloblastic anemia from vitamin B12 deficiency leads to defective DNA synthesis in hematopoietic precursors manifesting as pancytopenia and hemolysis owing to ineffective hematopoiesis. […] In this patient, megaloblastic anemia was diagnosed based on clinical and laboratory findings of severe vitamin B12 deficiency, for which subtotal gastrectomy is a known predisposing factor. […] These findings, consistent with megaloblastic anemia, confirmed the diagnosis of megaloblastic anemia due to vitamin B12 deficiency.

• #33 Vitamin B12 deficiency – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/vitamin-b12-deficiency/

  Vitamin B12 deficiency is caused by insufficient dietary intake, malabsorption, or increased demand and can result in megaloblastic anemia and various neurological disturbances. […] Pernicious anemia is the most common type of vitamin B12 deficiency and is caused by autoimmune gastritis (AIG). Vitamin B12 deficiency in AIG is due to mucosal atrophy, achlorhydria, and loss of intrinsic factor, which is crucial for vitamin B12 absorption. […] Malabsorption, autoimmune gastritis (pernicious anemia), gastrectomy, gastric bypass, nitric oxide misuse, and inherited disorders can cause severe vitamin B12 deficiency. […] Vitamin B12 is a water-soluble cofactor for enzymes involved in DNA synthesis (i.e., methionine synthase) and odd-chain fatty acid metabolism (i.e., methylmalonyl-CoA mutase), and deficiency leads to enzymatic dysfunction. Enzymatic dysfunction has the following consequences:

• #34 Vitamin B12 deficiency – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/vitamin-b12-deficiency/

  Methionine synthase demethylates 5-methyltetrahydrofolate, producing tetrahydrofolic acid, a cofactor in purine synthesis, and also converts homocysteine to methionine. […] Large, nucleated hematopoietic cells, including megaloblasts, are produced, which undergo apoptosis or are phagocytosed by macrophages. […] Pancytopenia (including megaloblastic anemia). […] Accumulation of methylmalonyl-CoA and its precursor propionyl-CoA, as well as their associated odd-chain fatty acids, which cannot be completely metabolized. […] Propionyl CoA replaces acetyl CoA in neuronal membranes demyelination neurological manifestations. […] AIG causes chronic destruction of gastric parietal cells, leading to mucosal atrophy, achlorhydria, and loss of intrinsic factor. Vitamin B12 deficiency is a late manifestation of AIG, termed pernicious anemia.

• #35 Vitamin deficiency anemia // Middlesex Health

  https://middlesexhealth.org/learning-center/diseases-and-conditions/vitamin-deficiency-anemia

  Being deficient in vitamin B-12 or folate increases your risk of many health problems, including: […] Untreated, vitamin B-12 deficiency can lead to neurological problems, such as persistent tingling in the hands and feet or problems with balance. It can lead to mental confusion and forgetfulness because vitamin B-12 is necessary for healthy brain function. […] Vitamin deficiency anemia is treated with doses of whichever vitamin is lacking. For pernicious anemia, vitamin B-12 is usually delivered via injection and may need to be taken regularly for the rest of your life.

• #36 Vitamin B12 & folate anaemia | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/nutritional/vitamin-b12-or-folate-deficiency-anaemia/

  A lack of vitamin B12 (with or without anaemia) can cause neurological problems (issues affecting your nervous system), such as: vision problems, memory loss, pins and needles (paraesthesia), loss of physical coordination (ataxia), which can affect your whole body and cause difficulty speaking or walking, damage to parts of the nervous system (peripheral neuropathy), particularly in the legs. […] A lack of folate (with or without anaemia) can also cause complications, some of which are outlined below.

• #37 Vitamin B12 or folate deficiency anaemia

  https://www2.hse.ie/conditions/vitamin-b12-or-folate-deficiency-anaemia/

  Vitamin B12 or B9 (folate) deficiency anaemia happens when you have a shortage of either of these vitamins. The body responds by producing abnormally large red blood cells that do not function properly. […] Pernicious anaemia is where your immune system attacks healthy cells in your tummy. This prevents your body from absorbing vitamin B12 from the food you eat. It’s the most common cause of vitamin B12 deficiency. […] Coeliac disease is a condition where your immune system attacks your own tissues when you eat gluten. This can also lead to B12 deficiency anaemia. […] Vitamin B12 or folate deficiency can lead to complications. But this is not common. Complications are more likely if you have a deficiency in the vitamin for some time. Some will improve with the right treatment. Others can be permanent, such as problems with the nervous system.

• #38 Vitamin deficiency anemia – Diagnosis & treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/vitamin-deficiency-anemia/diagnosis-treatment/drc-20355031

  Vitamin deficiency anemia is treated with doses of whichever vitamin is lacking. For pernicious anemia, vitamin B-12 is usually delivered via injection and may need to be taken regularly for the rest of your life. […] The amount of vitamin B-12 and folate in the blood […] The presence of antibodies to intrinsic factor, which indicates pernicious anemia. […] Causes and pathophysiology of vitamin B12 and folate deficiency.

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