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Megaloblastic Anemia

Megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis Synthesis Polymerase Chain Reaction (PCR) in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies, which can be due to low dietary intake, underlying malabsorptive conditions, and medications. Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor includes anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types and GI symptoms, with neurologic manifestations more commonly seen in B12 deficiency. Laboratory tests show macrocytic anemia Macrocytic anemia Anemia characterized by larger than normal erythrocytes, increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (mMCH). Anemia: Overview and Types (elevated mean Mean Mean is the sum of all measurements in a data set divided by the number of measurements in that data set. Measures of Central Tendency and Dispersion corpuscular volume) and low B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 levels. Confirmatory tests can be performed if levels are borderline. Treatment focuses on identifying the cause of the deficiency and replacing the deficient vitamin either orally or parenterally.

Last updated: 23 Apr, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types is a subset of macrocytic anemias characterized by increased RBC size and an arrest in nuclear maturation arising from abnormal cell division Cell Division A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle in erythroid precursors.

Epidemiology

  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency has been less common in the United States owing to folic acid fortification of grain products and the use of prenatal vitamins.
  • The most common causes of megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types in developed countries are pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types (for vitamin B12 deficiency) and medications.

Causes

  • Vitamin B12 ( cobalamin Cobalamin A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12) deficiency:
    • Intrinsic factor Intrinsic factor A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12 (cyanocobalamin). Deficiency of intrinsic factor leads to vitamin B12 deficiency and anemia, pernicious. Gastritis deficiency (pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types)
    • Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion (Crohn disease, celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease, chronic pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis, prior gastric or ileal surgery)
    • Vegan diet (vegan)
    • Nitrous oxide Nitrous oxide Nitrogen oxide (N2O). A colorless, odorless gas that is used as an anesthetic and analgesic. High concentrations cause a narcotic effect and may replace oxygen, causing death by asphyxia. Inhaled Anesthetics abuse/ toxicity Toxicity Dosage Calculation
    • Diphyllobothrium Diphyllobothrium Diphyllobothriasis represents an intestinal parasitic infection caused by the cestode Diphyllobothrium. Diphyllobothriasis is acquired by ingestion of late larvae in undercooked or raw fish. The clinical presentation of diphyllobothriasis varies from asymptomatic, nonspecific symptoms to intestinal obstruction, and/or vitamin B12 deficiency. Diphyllobothrium/Diphyllobothriasis latum ( fish tapeworm Fish tapeworm Diphyllobothriasis represents an intestinal parasitic infection caused by the cestode diphyllobothrium. Diphyllobothriasis is acquired by ingestion of late larvae in undercooked or raw fish. The clinical presentation of diphyllobothriasis varies from asymptomatic, nonspecific symptoms to intestinal obstruction, and/or vitamin B12 deficiency. Diphyllobothrium/Diphyllobothriasis) infestation 
    • Drugs ( immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants, isoniazid Isoniazid Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. Antimycobacterial Drugs, metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs, colchicine Colchicine A major alkaloid from colchicum autumnale l. And found also in other colchicum species. Its primary therapeutic use is in the treatment of gout. Gout Drugs, H2 blockers, proton pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors)
    • HIV HIV Anti-HIV Drugs
    • Genetic disorders 
  • Folic acid deficiency: 
    • Increased demand: pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, hemolytic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, chronic dermatitis Dermatitis Any inflammation of the skin. Atopic Dermatitis (Eczema), hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome
    • Alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome
    • Dietary deficiency (restricted diets, countries without folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 fortification of foods)
    • Drugs (antimetabolites such as methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy, tetracyclines Tetracyclines Tetracyclines are a class of broad-spectrum antibiotics indicated for a wide variety of bacterial infections. These medications bind the 30S ribosomal subunit to inhibit protein synthesis of bacteria. Tetracyclines cover gram-positive and gram-negative organisms, as well as atypical bacteria such as chlamydia, mycoplasma, spirochetes, and even protozoa. Tetracyclines, penicillins Penicillins Beta-lactam antibiotics contain a beta-lactam ring as a part of their chemical structure. Drugs in this class include penicillin G and V, penicillinase-sensitive and penicillinase-resistant penicillins, cephalosporins, carbapenems, and aztreonam. Penicillins, nitrofurantoin, phenobarbital Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs, phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs, trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim)
    • Intestinal dysfunction: Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion occurs in surgery ( gastric bypass Gastric bypass Surgical procedure in which the stomach is transected high on the body. The resulting small proximal gastric pouch is joined to any parts of the small intestine by an end-to-side surgical anastomosis, depending on the amounts of intestinal surface being bypasses. This procedure is used frequently in the treatment of morbid obesity by limiting the size of functional stomach, food intake, and food absorption. Gastroesophageal Reflux Disease (GERD)).
  • Rare disorders:
    • Orotic aciduria Orotic aciduria Orotic aciduria is an extremely rare genetic disorder that can result in crystalluria, megaloblastic anemia, developmental delay, and failure to thrive. The disorder is caused by an enzyme deficiency in the pyrimidine synthesis pathway resulting in the accumulation of orotic acid. Orotic Aciduria: Deficiency of uridine monophosphate Uridine monophosphate 5′-uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2. Purine and Pyrimidine Metabolism synthase leads to ↓ de novo pyrimidine synthesis Synthesis Polymerase Chain Reaction (PCR) that is unresponsive to B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 replacement.
    • Methylmalonic acidemia Acidemia Respiratory Acidosis: inborn error Error Refers to any act of commission (doing something wrong) or omission (failing to do something right) that exposes patients to potentially hazardous situations. Disclosure of Information of amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism

Pathophysiology

Vitamin B12 and folic acid

  • Vitamin B12 ( cobalamin Cobalamin A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12):
    • Sources:
      • Animal products (meats, especially liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, dairy, eggs)
      • Fortified food
      • Not found in plants Plants Cell Types: Eukaryotic versus Prokaryotic
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
      • B12 in food is bound to protein and gets bound to salivary haptocorrins in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy.
      • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption requires an acid environment ( stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy) to be dissociated from protein and pancreatic proteases Proteases Proteins and Peptides to cleave off the haptocorrins.
      • Once unbound, B12 binds to intrinsic factor Intrinsic factor A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12 (cyanocobalamin). Deficiency of intrinsic factor leads to vitamin B12 deficiency and anemia, pernicious. Gastritis produced by the gastric parietal Parietal One of a pair of irregularly shaped quadrilateral bones situated between the frontal bone and occipital bone, which together form the sides of the cranium. Skull: Anatomy cells.
      • B12 intrinsic factor Intrinsic factor A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12 (cyanocobalamin). Deficiency of intrinsic factor leads to vitamin B12 deficiency and anemia, pernicious. Gastritis complex is taken up in the ileum Ileum The distal and narrowest portion of the small intestine, between the jejunum and the ileocecal valve of the large intestine. Small Intestine: Anatomy.
      • In the bloodstream, B12 is then endocytosed by cells. 
  • Vitamin B9 (folic acid):
    • Sources:
      • Plant products (especially dark green, leafy vegetables)
      • Animal products
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
      • Dependent on carrier Carrier Vaccination systems
      • Absorbed in the jejunum Jejunum The middle portion of the small intestine, between duodenum and ileum. It represents about 2/5 of the remaining portion of the small intestine below duodenum. Small Intestine: Anatomy (conjugase converts folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 polyglutamate to monoglutamate)
      • Subsequently reduced to dihydrofolate → tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim (THF) → 5,10-methylene THF → L-5-methyl-THF (predominant plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products form)
      •  L-5-methyl-THF is taken up by cells.
  • Both are water-soluble (↓ risk of overdose, as they are excreted in the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat).
  • Vitamin deficiencies arise from conditions that affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment intake and absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption and that interfere with other essential factors (i.e., intrinsic factor Intrinsic factor A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12 (cyanocobalamin). Deficiency of intrinsic factor leads to vitamin B12 deficiency and anemia, pernicious. Gastritis, carrier Carrier Vaccination system).
Role of vitamin b12 and folic acid in dna synthesis

Role of vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 and folic acid in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR):

From the bottom:
Dietary folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 is absorbed in the intestine in the form of 5-methyl-tetrahydrofolate (THF). Vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12–dependent methionine synthetase converts 5-methyl-THF to THF. The same process generates methionine from homocysteine and methionine converts to S-adenosylmethionine or SAM SAM Anterior displacement of the mitral valve during systole. Hypertrophic Cardiomyopathy (also necessary for DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids).
The THF produced is converted to 5, 10-methylene-THF.
A methyl group is donated from methylene-THF to the 5-carbon of uridylate to form thymidylate.
As a consequence of donating the methyl group, methylene-THF becomes dihydrofolate.
Dihydrofolate is reduced by reductase to re-generate tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim.

Image by Lecturio.

B12 and folic acid in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)

  • Both B12 and folic acid: 
    • Critical in the synthesis Synthesis Polymerase Chain Reaction (PCR) of nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids
    • Act as cofactors in the synthesis Synthesis Polymerase Chain Reaction (PCR) of thymidylate, the rate-limiting step in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR):
      • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 supplies the methyl groups (via methylene-THF).
      • B12 is a cofactor in the reaction converting 5-methyl-THF to THF.
  • Methionine and folic acid cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation with DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR):
    1. Dietary folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 is absorbed in the intestine in the form of 5-methyl-THF.
    2. Vitamin B12–dependent methionine synthetase converts 5-methyl-THF to THF.  
      • The same process generates methionine from homocysteine.
      • Methionine converts to S-adenosylmethionine ( SAM SAM Anterior displacement of the mitral valve during systole. Hypertrophic Cardiomyopathy) (in the methionine cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation), which is also necessary for DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids.
    3. The THF produced is converted to methylene-THF. 
    4. A methyl group is donated from methylene-THF to the 5-carbon of uridylate to form thymidylate (deoxythymidine monophosphate). 
    5. As a consequence of donating the methyl group, methylene-THF becomes dihydrofolate. 
    6. Dihydrofolate is reduced to regenerate tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim.

Consequences of defective DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)

Rapidly dividing cells in the body are most sensitive to impaired DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) due to B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency.

  • Impaired erythropoiesis Erythropoiesis The production of red blood cells (erythrocytes). In humans, erythrocytes are produced by the yolk sac in the first trimester; by the liver in the second trimester; by the bone marrow in the third trimester and after birth. In normal individuals, the erythrocyte count in the peripheral blood remains relatively constant implying a balance between the rate of erythrocyte production and rate of destruction. Erythrocytes: Histology:
    • Megaloblastic changes:
      • Slow nuclear division → immature, abnormal nuclei + normal cytoplasm → dyssynchrony between nuclear and cytoplasmic maturation
      • Increased mitotic figures → giant metamyelocytes + finely stippled, lacy nuclear chromatin Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure pattern
    • Intramedullary hemolysis: 
      • Caused by premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis death of abnormally developing erythroid precursors
      • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow becomes hypercellular owing to ongoing apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage → ↑ hemolysis, ↓ reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count
  • Reduced DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids:
    • Significant epigenetic modification → methyl groups added to DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure → results in modification of gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expression
    • Results in defects in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair and fragmentation Fragmentation Chronic Apophyseal Injury
    • Enhances chance of translational errors including the possibility of malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology
    • Believed to contribute to neuronal dysfunction in B12 deficiency:
      • Methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids and proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (i.e., myelin basic protein) in the neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology
      • ↓ Myelin basic protein contributes to demyelination Demyelination Multiple Sclerosis.

Clinical Presentation

General manifestations

  • B12 deficiency develops over years, whereas folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency develops in weeks to months.
  • Depending on the degree of deficiency and time of onset, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can be asymptomatic.
  • Signs and symptoms of anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types:
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea 
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Palpitations Palpitations Ebstein’s Anomaly
    • Pallor
    • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • GI symptoms (related to underlying GI conditions such as inflammatory bowel disease):
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Bloating Bloating Constipation
    • Epigastric/ abdominal pain Abdominal Pain Acute Abdomen

Specific manifestations

  • Neurologic symptoms most commonly due to B12 deficiency: 
    • Subacute combined degeneration Subacute combined degeneration A neuropathy due to vitamin B12 deficiency or to excessive nitrous oxide inhalation. It is associated with overproduction of the myelinolytic tumor necrosis factor-alpha. Posterior Cord Syndrome (classic finding):
      • Dorsal column Dorsal column Spinal Cord: Anatomy: vibration Vibration A continuing periodic change in displacement with respect to a fixed reference. Neurological Examination, proprioception Proprioception Sensory functions that transduce stimuli received by proprioceptive receptors in joints, tendons, muscles, and the inner ear into neural impulses to be transmitted to the central nervous system. Proprioception provides sense of stationary positions and movements of one’s body parts, and is important in maintaining kinesthesia and postural balance. Neurological Examination ( wide-based gait Wide-based gait Normal Pressure Hydrocephalus)
      • Lateral corticospinal tracts Corticospinal Tracts Central Cord Syndrome: spasticity Spasticity Spinal Disk Herniation
      • Dorsal spinocerebellar: ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
    • Neuropathy Neuropathy Leprosy: tingling Tingling Posterior Cord Syndrome, numbness
    • Psychosis, depression, irritability
    • Cognitive impairment, forgetfulness
    • Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders
  • Additional findings in B12 deficiency:
    • Oral mucosa Oral mucosa Lining of the oral cavity, including mucosa on the gums; the palate; the lip; the cheek; floor of the mouth; and other structures. The mucosa is generally a nonkeratinized stratified squamous epithelium covering muscle, bone, or glands but can show varying degree of keratinization at specific locations. Stomatitis pathology (present in 50%–60% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
      • Glossitis
      • Angular cheilitis Cheilitis Inflammation of the lips. It is of various etiologies and degrees of pathology. Oral Cancer
      • Recurrent oral ulcers Oral ulcers A loss of mucous substance of the mouth showing local excavation of the surface, resulting from the sloughing of inflammatory necrotic tissue. It is the result of a variety of causes, e.g., denture irritation, aphthous stomatitis; necrotizing gingivitis, toothbrushing, and various irritants. Chédiak-Higashi Syndrome
      • Diffuse erythematous mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis/mucosal atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation
      • Mouth soreness/burning sensation
    • Cutaneous hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi
    • ↑ Risk of gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer in pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency: ↑ risk of neural tube defects Neural tube defects Neural tube defects (NTDs) are the 2nd-most common type of congenital birth defects. Neural tube defects can range from asymptomatic (closed NTD) to very severe malformations of the spine or brain (open NTD). Neural tube defects are caused by the failure of the neural tube to close properly during the 3rd and 4th week of embryological development. Neural Tube Defects ( congenital Congenital Chorioretinitis anomaly)
Peculiar cutaneous hyperpigmentation from cases with megaloblastic anemia

Hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi in a patient with vitamin B12 deficiency

Image: “Peculiar cutaneous hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi from cases with megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types” by Department of Pathology, Pondicherry Institute of Medical Sciences, Puducherry, India. License: CC BY 2.0

Diagnosis

History

  • Diet: vegan or vegetarian
  • Medical and social history Social History Adult Health Maintenance: look for autoimmune disorders, alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome
  • Surgical history: gastric or ileal resection
  • GI symptoms
  • Neurologic symptoms
  • Medications

Laboratory tests

  • Hematologic tests:
    • ↓ Hemoglobin/ hematocrit Hematocrit The volume of packed red blood cells in a blood specimen. The volume is measured by centrifugation in a tube with graduated markings, or with automated blood cell counters. It is an indicator of erythrocyte status in disease. For example, anemia shows a low value; polycythemia, a high value. Neonatal Polycythemia 
    • MCV > 100
    • Likely decreased leukocyte and/or platelet count
    • Low reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count
  • Cobalamin Cobalamin A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12/B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 levels :
    • Deficiency:
      • Low B12/ cobalamin Cobalamin A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 (normal, > 300 pg/mL)
      • Low folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 levels (normal, > 4 ng/mL)
      • RBC folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 can be an alternative for folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 level (though not frequently used).
    • For borderline levels of B12 (200–300 pg/mL) or folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 (2–4 ng/mL), proceed with obtaining homocysteine and methylmalonic acid (MMA) level:
      • Serum homocysteine level: elevated in both vitamin B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency
      • Serum MMA level: elevated in vitamin B12 deficiency
  • Additional workup:
    • Pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types:
      • Anti-intrinsic factor antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions: high specificity Specificity Specificity is the probability of correctly determining the absence of a condition. Immunoassays for pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
      • Antiparietal cell antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions: can be present in gastritis Gastritis Gastritis refers to inflammation of the gastric mucosa. Gastritis may occur suddenly (acute gastritis) or slowly over time (chronic gastritis). Gastritis may be asymptomatic or with symptoms, including burning abdominal pain (which either worsens or improves with eating), dyspepsia, nausea, and vomiting. Gastritis
      • ↑ Serum gastrin Gastrin A family of gastrointestinal peptide hormones that excite the secretion of gastric juice. They may also occur in the central nervous system where they are presumed to be neurotransmitters. Gastrointestinal Secretions levels: not specific to pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Orotic aciduria Orotic aciduria Orotic aciduria is an extremely rare genetic disorder that can result in crystalluria, megaloblastic anemia, developmental delay, and failure to thrive. The disorder is caused by an enzyme deficiency in the pyrimidine synthesis pathway resulting in the accumulation of orotic acid. Orotic Aciduria: normal urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance with ↑ orotic acid levels
  • Peripheral-blood smear:
    • Macrocytosis
    • Marked RBC size variation: anisocytosis
    • Abnormal and variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables RBC morphology: poikilocytosis
    • Hypersegmented neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation:

Additional tests

  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow aspirate:
    • Not routinely done 
    • If done, findings include:
      • Hypercellularity
      • Erythroid predominance with decreased myeloid to erythroid ratio
      • Nuclear cytoplasmic dyssynchrony with immature nuclei combined with normal-appearing cytoplasm
      • Abnormal granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology: giant metamyelocytes and bands
      • Abnormally large megakaryocytes
      • In severe cases, dysplastic changes can be seen.
  • Gastric biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
    • Not necessary for the diagnosis of pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • If done, will reveal chronic autoimmune atrophic gastritis Atrophic gastritis Gastritis with atrophy of the gastric mucosa, the gastric parietal cells, and the mucosal glands leading to achlorhydria. Atrophic gastritis usually progresses from chronic gastritis. Gastritis
  • Schilling test for pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Infrequently used
    • Supplanted by serologic testing for parietal cell Parietal cell Rounded or pyramidal cells of the gastric glands. They secrete hydrochloric acid and produce gastric intrinsic factor, a glycoprotein that binds vitamin B12. Gastroesophageal Reflux Disease (GERD) and intrinsic factor Intrinsic factor A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12 (cyanocobalamin). Deficiency of intrinsic factor leads to vitamin B12 deficiency and anemia, pernicious. Gastritis antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
Bone marrow aspirate in megaloblastic anemia with cutaneous hyperpigmentation

Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
A: Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow aspirate
B: Hypercellularity and megaloblasts (arrow)
C: Giant abnormally shaped stab forms (arrow)

Image: “ Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow aspirate in megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types with cutaneous hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi” by Department of Pathology, Pondicherry Institute of Medical Sciences, Puducherry, India. License: CC BY 2.0

Management

Principles

  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can be asymptomatic or deficiency can be an incidental finding.
  • In the majority of cases, there is a gradual development of symptoms, so treatment can be given over weeks.
  • Intervention is needed urgently in for the following:
    • Symptomatic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Neurologic/neuropsychiatric manifestations (as effects can be irreversible)
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (fetus is affected)
    • Neonates and infants (growth is affected)

Treatment

  • Vitamin B12:
    • Intramuscular/parenteral route for neurologic symptoms or in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion or extensive gastric/bowel resections
    • Oral route for deficiency owing to low dietary intake or to continue replacement from parenteral route (if appropriate)
    • Watch for thrombocytosis and hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia in severe cases.
  • Folic acid: 
    • Always check for concomitant B12 deficiency.
    • 1–5 mg/day, with the higher dose for pregnant women, alcoholics, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on antiepileptic medications
  • Replacement can be lifelong if underlying condition is permanent (i.e., gastric bypass Gastric bypass Surgical procedure in which the stomach is transected high on the body. The resulting small proximal gastric pouch is joined to any parts of the small intestine by an end-to-side surgical anastomosis, depending on the amounts of intestinal surface being bypasses. This procedure is used frequently in the treatment of morbid obesity by limiting the size of functional stomach, food intake, and food absorption. Gastroesophageal Reflux Disease (GERD) surgery).
  • As anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types resolves, iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements levels may become depleted; monitor and replace as necessary.
  • Treatment of other associated conditions:
    • Pernicious anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: in addition to replacement, screen for gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
    • Uridine triacetate: for orotic aciduria Orotic aciduria Orotic aciduria is an extremely rare genetic disorder that can result in crystalluria, megaloblastic anemia, developmental delay, and failure to thrive. The disorder is caused by an enzyme deficiency in the pyrimidine synthesis pathway resulting in the accumulation of orotic acid. Orotic Aciduria

Differential Diagnosis

  • Alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome and alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease: Alcohol is one of the top causes of macrocytosis, usually due to a toxic effect directly on the RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology (without damage to DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure replication). Chronic alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome also leads to liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease, ranging from a fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis. Management aims at alcohol abstinence for reversal at certain stages; addressing contributing factors, such as viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease or drugs; and minimizing damage to the hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy.
  • Chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease: Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis is the late stage of hepatic necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage and scarring Scarring Inflammation. Chronic cellular damage causes extensive distortion Distortion Defense Mechanisms of the normal hepatic architecture, which can lead to impairment of normal blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure through the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy. Chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease of diverse etiologies can cause macrocytic anemia Macrocytic anemia Anemia characterized by larger than normal erythrocytes, increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (mMCH). Anemia: Overview and Types owing to effects in lipid composition of RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology.
  • Myelodysplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: a group of hematologic malignancies due to germline mutations associated with one or more cytopenias Cytopenias IPEX Syndrome, including macrocytic anemia Macrocytic anemia Anemia characterized by larger than normal erythrocytes, increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (mMCH). Anemia: Overview and Types: Dysplastic changes in the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, such as hyposegmented granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology and blasts Blasts Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. Blunt Chest Trauma, are seen. Cytogenetic analysis Cytogenetic analysis Examination of chromosomes to diagnose, classify, screen for, or manage genetic diseases and abnormalities. Following preparation of the sample, karyotyping is performed and/or the specific chromosomes are analyzed. Non-Hodgkin Lymphomas identifying mutations linked to myelodysplastic disease helps establish the diagnosis.
  • Aplastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: a disorder of bone marrow failure Bone marrow failure Inherited or acquired diseases characterized by insufficient and/or dysplastic blood cells. Paroxysmal Nocturnal Hemoglobinuria characterized by absence of erythroid precursors due to exposure Exposure ABCDE Assessment to drugs, radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma, chemicals, viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology, autoimmune disease, or genetic factors (hereditary or acquired): The bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow is hypocellular, with < 30% cellularity. Some cytopenias Cytopenias IPEX Syndrome involve ≥ 2 cell lines. 
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: a condition characterized by a deficiency of thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types: Iodine Iodine A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126. 90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. Thyroid Hormones deficiency is the most common cause worldwide, but Hashimoto disease ( autoimmune thyroiditis Autoimmune thyroiditis Inflammatory disease of the thyroid gland due to autoimmune responses leading to lymphocytic infiltration of the gland. It is characterized by the presence of circulating thyroid antigen-specific T-cells and thyroid autoantibodies. The clinical signs can range from hypothyroidism to thyrotoxicosis depending on the type of autoimmune thyroiditis. Thyroiditis) is the leading etiology in non–iodine-deficient regions. Features of acquired hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism include fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias, cold intolerance, and exertional dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Diagnosis is by thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy function tests. Elevated thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones and a low free thyroxine Thyroxine The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroid Hormones (T4) are noted. Treatment is with synthetic T4. Macrocytic anemia Macrocytic anemia Anemia characterized by larger than normal erythrocytes, increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (mMCH). Anemia: Overview and Types is seen in 55% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism.

References

  1. Hesdorffer CS, Longo DL. (2015). Drug-induced megaloblastic anemia. N Engl J Med 373:1649–1658 https://pubmed.ncbi.nlm.nih.gov/26488695/
  2. Kim J, Kim MJ, Kho HS. (2016). Oral manifestations in vitamin B12 deficiency patients with or without history of gastrectomy. https://pubmed.ncbi.nlm.nih.gov/27234214/
  3. Means R,  Fairfield K. (2021). Clinical manifestations and diagnosis of vitamin B12 and folate deficiency. UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency
  4. Means R, Fairfield K. (2021). Causes and pathophysiology of vitamin B12 and folate deficiencies. UpToDate. Retrieved April 5, 2021, from https://www.uptodate.com/contents/causes-and-pathophysiology-of-vitamin-b12-and-folate-deficiencies
  5. Means R, Fairfield K. (2021). Treatment of vitamin B12 and folate deficiencies. UpToDate. Retrieved April 5, 2021, from https://www.uptodate.com/contents/treatment-of-vitamin-b12-and-folate-deficiencies
  6. Socha DS, DeSouza SI, Flagg A, Sekeres M, Rogers HJ. (2020). Severe megaloblastic anemia: vitamin deficiency and other causes. Cleve Clin J Med https://pubmed.ncbi.nlm.nih.gov/32127439/

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