Megaloblastic Anemia

Megaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis 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 includes anemia and GI symptoms, with neurologic manifestations more commonly seen in B12 deficiency. Laboratory tests show macrocytic anemia (elevated mean 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.

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Overview

Definition

Megaloblastic anemia is a subset of macrocytic anemias characterized by increased RBC size and an arrest in nuclear maturation arising from abnormal cell division in erythroid precursors.

Epidemiology

  • Folate 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 in developed countries are pernicious anemia (for vitamin B12 deficiency) and medications.

Causes

  • Vitamin B12 (cobalamin) deficiency:
    • Intrinsic factor deficiency (pernicious anemia)
    • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. 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 Chronic pancreatitis Chronic pancreatitis is due to persistent inflammation, fibrosis, and irreversible cell damage to the pancreas, resulting in a loss of endocrine and exocrine gland function. The most common etiologies are alcohol abuse and pancreatic duct obstruction. Patients often present with recurrent epigastric abdominal pain, nausea, and features of malabsorption syndrome (diarrhea, steatorrhea, and weight loss). Chronic Pancreatitis, prior gastric or ileal surgery)
    • Vegan diet (vegan)
    • Nitrous oxide abuse/toxicity
    • 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) 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, metformin, colchicine, H2 blockers, proton pump inhibitors)
    • HIV
    • Genetic disorders 
  • Folic acid deficiency: 
    • Increased demand: pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, chronic dermatitis, hemodialysis
    • Alcoholism
    • 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, 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, phenytoin, 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 Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion occurs in surgery (gastric bypass).
  • 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 synthase leads to ↓ de novo pyrimidine synthesis 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: inborn error 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):
    • 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, dairy, eggs)
      • Fortified food
      • Not found in plants
    • 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.
      • 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) to be dissociated from protein and pancreatic proteases to cleave off the haptocorrins.
      • Once unbound, B12 binds to intrinsic factor produced by the gastric parietal cells.
      • B12–intrinsic factor complex is taken up in the ileum.
      • In the bloodstream, B12 is then endocytosed by cells. 
  • Vitamin B9 (folic acid):
    • Sources:
      • Plant products (especially dark green, leafy vegetables)
      • Animal products
    • Absorption:
      • Dependent on carrier systems
      • Absorbed in the jejunum (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 (THF) → 5,10-methylene THF → L-5-methyl-THF (predominant plasma form)
      •  L-5-methyl-THF is taken up by cells.
  • Both are water-soluble (↓ risk of overdose, as they are excreted in the urine).
  • Vitamin deficiencies arise from conditions that affect intake and absorption and that interfere with other essential factors (i.e., intrinsic factor, carrier system).
Role of vitamin b12 and folic acid in dna synthesis

Role of vitamin B12 Vitamin B12 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 and folic acid in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis:

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–dependent methionine synthetase converts 5-methyl-THF to THF. The same process generates methionine from homocysteine and methionine converts to S-adenosylmethionine or SAM (also necessary for DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure methylation).
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.

Image by Lecturio.

B12 and folic acid in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis

  • Both B12 and folic acid: 
    • Critical in the synthesis 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 of thymidylate, the rate-limiting step in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis:
      • Folate 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 with DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis:
    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) (in the methionine cycle), which is also necessary for DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure methylation.
    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.

Consequences of defective DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis

Rapidly dividing cells in the body are most sensitive to impaired DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis 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 Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes:
    • 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 pattern
    • Intramedullary hemolysis: 
      • Caused by premature death of abnormally developing erythroid precursors
      • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow becomes hypercellular owing to ongoing apoptosis → ↑ hemolysis, ↓ reticulocyte count
  • Reduced DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure methylation:
    • Significant epigenetic modification → methyl groups added to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → results in modification of gene expression
    • Results in defects in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair and fragmentation
    • Enhances chance of translational errors including the possibility of malignant transformation
    • Believed to contribute to neuronal dysfunction in B12 deficiency:
      • ↓ Methylation of lipids and proteins (i.e., myelin basic protein) in the neurons
      • ↓ Myelin basic protein contributes to demyelination.

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 can be asymptomatic.
  • Signs and symptoms of anemia:
    • Fatigue
    • Shortness of breath 
    • Tachycardia
    • Palpitations
    • 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
    • Bloating
    • Epigastric/abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Specific manifestations

  • Neurologic symptoms most commonly due to B12 deficiency: 
    • Subacute combined degeneration (classic finding):
      • Dorsal column: vibration, proprioception (wide-based gait)
      • Lateral corticospinal tracts: spasticity
      • Dorsal spinocerebellar: ataxia
    • Neuropathy: tingling, numbness
    • Psychosis, depression, irritability
    • Cognitive impairment, forgetfulness
    • Dementia
  • Additional findings in B12 deficiency:
    • Oral mucosa pathology (present in 50%–60% of patients):
      • Glossitis
      • Angular cheilitis
      • Recurrent oral ulcers
      • Diffuse erythematous mucositis/mucosal atrophy
      • Mouth soreness/burning sensation
    • Cutaneous hyperpigmentation
    • ↑ 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
  • Folate 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 anomaly)
Peculiar cutaneous hyperpigmentation from cases with megaloblastic anemia

Hyperpigmentation in a patient with vitamin B12 deficiency

Image: “Peculiar cutaneous hyperpigmentation from cases with megaloblastic anemia” 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: look for autoimmune disorders, alcoholism
  • Surgical history: gastric or ileal resection
  • GI symptoms
  • Neurologic symptoms
  • Medications

Laboratory tests

  • Hematologic tests:
    • ↓ Hemoglobin/hematocrit 
    • MCV > 100
    • Likely decreased leukocyte and/or platelet count
    • Low reticulocyte count
  • Cobalamin/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 (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:
      • 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: high specificity for pernicious anemia
      • 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: 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 levels: not specific to pernicious anemia
    • 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 ammonia 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:
      • ≥ 1% of neutrophils with 6 or more nuclear lobes, OR
      • ≥ 5% of neutrophils with 5 or more nuclear lobes

Additional tests

  • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone 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: giant metamyelocytes and bands
      • Abnormally large megakaryocytes
      • In severe cases, dysplastic changes can be seen.
  • Gastric biopsy:
    • Not necessary for the diagnosis of pernicious anemia
    • If done, will reveal chronic autoimmune atrophic 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
  • Schilling test for pernicious anemia: 
    • Infrequently used
    • Supplanted by serologic testing for parietal cell and 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
Bone marrow aspirate in megaloblastic anemia with cutaneous hyperpigmentation

Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy:
A: Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow aspirate
B: Hypercellularity and megaloblasts (arrow)
C: Giant abnormally shaped stab forms (arrow)

Image: “ Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow aspirate in megaloblastic anemia with cutaneous hyperpigmentation” by Department of Pathology, Pondicherry Institute of Medical Sciences, Puducherry, India. License: CC BY 2.0

Management

Principles

  • Patients 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
    • Neurologic/neuropsychiatric manifestations (as effects can be irreversible)
    • Pregnancy (fetus is affected)
    • Neonates and infants (growth is affected)

Treatment

  • Vitamin B12:
    • Intramuscular/parenteral route for neurologic symptoms or in patients with malabsorption 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 on antiepileptic medications
  • Replacement can be lifelong if underlying condition is permanent (i.e., gastric bypass surgery).
  • As anemia resolves, iron levels may become depleted; monitor and replace as necessary.
  • Treatment of other associated conditions:
    • Pernicious anemia: 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

Differential Diagnosis

  • Alcoholism and alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver Disease: Alcohol is one of the top causes of macrocytosis, usually due to a toxic effect directly on the RBCs (without damage to DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication). Chronic alcoholism 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 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 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 or drugs; and minimizing damage to the hepatocytes.
  • 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 disease: Cirrhosis is the late stage of hepatic necrosis and scarring. Chronic cellular damage causes extensive distortion of the normal hepatic architecture, which can lead to impairment of normal blood flow 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. 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 disease of diverse etiologies can cause macrocytic anemia owing to effects in lipid composition of RBCs.
  • Myelodysplastic anemia: a group of hematologic malignancies due to germline mutations associated with one or more cytopenias, including macrocytic anemia: Dysplastic changes in the bone marrow biopsy, such as hyposegmented granulocytes and blasts, are seen. Cytogenetic analysis identifying mutations linked to myelodysplastic disease helps establish the diagnosis.
  • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia: a disorder of bone marrow failure characterized by absence of erythroid precursors due to exposure to drugs, radiation, chemicals, viruses, autoimmune disease, or genetic factors (hereditary or acquired): The bone marrow is hypocellular, with < 30% cellularity. Some cytopenias 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 hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones: Iodine deficiency is the most common cause worldwide, but Hashimoto disease (autoimmune thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel's thyroiditis). Thyroiditis) is the leading etiology in non–iodine-deficient regions. Features of acquired hypothyroidism include fatigue, bradycardia, 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 function tests. Elevated thyroid-stimulating hormone and a low free thyroxine (T4) are noted. Treatment is with synthetic T4. Macrocytic anemia is seen in 55% of patients with 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 Vitamin B12 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 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 Vitamin B12 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 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. 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 Vitamin B12 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 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 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 Vitamin B12 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 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 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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