Megaloblastic anemia is a type of
macrocytic anemia. An
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
is a
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of
DNA synthesis during red blood cell production.
When DNA synthesis is impaired, the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis.
Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias.
The defect in red cell DNA synthesis is most often due to
hypovitaminosis
Vitamin deficiency is the condition of a long-term lack of a vitamin. When caused by not enough vitamin intake it is classified as a ''primary deficiency'', whereas when due to an underlying disorder such as malabsorption it is called a ''seconda ...
, specifically
vitamin B12 deficiency
Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. Symptoms can vary from none to severe. Mild deficiency may have few or absent symp ...
or
folate deficiency
Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folat ...
. Loss of micronutrients may also be a cause.
Megaloblastic anemia not due to hypovitaminosis may be caused by antimetabolites that poison DNA production directly, such as some chemotherapeutic or antimicrobial agents (for example
azathioprine or
trimethoprim).
The pathological state of megaloblastosis is characterized by many large immature and dysfunctional red blood cells (
megaloblasts) in the bone marrow
and also by
hypersegmented neutrophil
Neutrophil hypersegmentation can be defined as the presence of neutrophils whose nuclei have six or more lobes or the presence of more than 3% of neutrophils with at least five nuclear lobes. This is a clinical laboratory finding. It is visualized ...
s (defined as the presence of neutrophils with six or more lobes or the presence of more than 3% of neutrophils with at least five lobes). These hypersegmented
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s can be detected in the
peripheral blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the ...
(using a diagnostic smear of a blood sample).
Causes
*
Vitamin B12 deficiency
Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. Symptoms can vary from none to severe. Mild deficiency may have few or absent symp ...
:
**
Achlorhydria-induced malabsorption
** Deficient intake
** Deficient
intrinsic factor, a molecule produced by cells in the stomach that is required for B12 absorption (
pernicious anemia
Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
or
gastrectomy
A gastrectomy is a partial or total surgical removal of the stomach.
Indications
Gastrectomies are performed to treat stomach cancer and perforations of the stomach wall.
In severe duodenal ulcers it may be necessary to remove the lower porti ...
)
**
Coeliac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...
** Biological competition for vitamin B12 by
diverticulosis
Diverticulosis is the condition of having multiple pouches ( diverticula) in the colon that are not inflamed. These are outpockets of the colonic mucosa and submucosa through weaknesses of muscle layers in the colon wall. Diverticula do not ...
,
fistula, intestinal
anastomosis
An anastomosis (, plural anastomoses) is a connection or opening between two things (especially cavities or passages) that are normally diverging or branching, such as between blood vessels, leaf veins, or streams. Such a connection may be norm ...
, or infection by the marine parasite ''
Diphyllobothrium latum (fish tapeworm)''
** Selective
vitamin B12
Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...
malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
(congenital—
juvenile megaloblastic anemia 1—and drug-induced)
**
Chronic pancreatitis
Chronic pancreatitis is a long-standing inflammation of the pancreas that alters the organ's normal structure and functions. It can present as episodes of acute inflammation in a previously injured pancreas, or as chronic damage with persistent pa ...
** Ileal resection and bypass
** Nitrous oxide anesthesia (usually requires repeated instances).
*
Folate deficiency
Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folat ...
:
**
Alcoholism
Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomi ...
** Deficient intake
** Increased needs:
pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
,
infant
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used t ...
, rapid cellular proliferation, and
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
**
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
(
congenital
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
and drug-induced)
** Intestinal and
jejunal
The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialised for the absorption by enterocytes of small nutrient molecules which have been previous ...
resection
** (indirect) Deficient
thiamine
Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...
and factors (e.g., enzymes) responsible for
abnormal folate metabolism.
* Combined Deficiency: vitamin B12 & folate.
* Inherited Pyrimidine Synthesis Disorders:
Orotic aciduria
Orotic aciduria (AKA hereditary orotic aciduria) is a disease caused by an enzyme deficiency resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the ''de novo'' pyrimidine synthesis pathway.
...
* Inherited
DNA Synthesis Disorders
* Toxins and Drugs:
**
Folic acid
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...
antagonists (
methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
)
**
Purine
Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
synthesis antagonists (
6-mercaptopurine
Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's dis ...
,
azathioprine)
**
Pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The othe ...
antagonists (
cytarabine
Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by i ...
)
**
Phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
**
Nitrous Oxide
Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and ha ...
*
Erythroleukemia
Acute erythrocyte leukemia is a rare form of acute myeloid leukemia (less than 5% of AML cases) where the myeloproliferation is of erythrocytic precursors. It is defined as type "M6" under the FAB classification.
Signs and symptoms
The most com ...
* Inborn genetic mutations of the
Methionine synthase gene
*
Di Guglielmo's syndrome
*
Congenital dyserythropoietic anemia
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) ...
*
Copper deficiency resulting from an excess of zinc from unusually high oral consumption of zinc-containing denture-fixation creams has been found to be a cause.
Pathophysiology
There is a defect in
DNA synthesis in the rapidly dividing cells and to a lesser extent,
RNA and
protein synthesis
Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
are also impaired. Therefore, unbalanced
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...
and impaired
cell division
Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ...
occur as a result of arrested nuclear maturation so the cells show nuclear-cytoplasmic asynchrony.
In the
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
, most megaloblasts are destroyed prior to entering the peripheral blood (
intramedullary hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing ( lysis) of red blood cells (erythrocytes) and the release of their contents ( cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in viv ...
). Some can escape the bone marrow (
macrocytes) to peripheral blood but they are destroyed by the
reticulo-endothelial system (extramedullary hemolysis).
Diagnosis
The gold standard for the diagnosis of Vitamin B deficiency is a low blood level of Vitamin B. A low level of blood Vitamin B is a finding that normally can and should be treated by injections, supplementation, or dietary or lifestyle advice, but it is not a diagnosis. Hypovitaminosis B can result from a number of mechanisms, including those listed above. For determination of cause, further patient history, testing, and empirical therapy may be clinically indicated.
A measurement of
methylmalonic acid (methylmalonate) can provide an indirect method for partially differentiating Vitamin B and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency. Direct measurement of blood
cobalamin
Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...
remains the gold standard because the test for elevated methylmalonic acid is not specific enough. Vitamin B is one necessary prosthetic group to the enzyme
methylmalonyl-coenzyme A mutase. Vitamin B deficiency is but one among the conditions that can lead to dysfunction of this enzyme and a buildup of its substrate, methylmalonic acid, the elevated level of which can be detected in the urine and blood.
Due to the lack of available radioactive Vitamin B, the
Schilling test is now largely a historical artifact. The
Schilling test was performed in the past to help determine the nature of the vitamin B deficiency. An advantage of the
Schilling test was that it often included Vitamin B with intrinsic factor.
Blood findings
The
blood film can point towards vitamin deficiency:
*Decreased
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
(RBC) count and
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythroc ...
levels
*Increased
mean corpuscular volume
The mean corpuscular volume, or mean cell volume (MCV), is a measure of the average volume of a red blood corpuscle (or red blood cell). The measure is obtained by multiplying a volume of blood by the proportion of blood that is cellular (the hem ...
(MCV, >100
fL) and
mean corpuscular hemoglobin (MCH)
*Normal
mean corpuscular hemoglobin concentration (MCHC, 32–36 g/dL)
*Decreased
reticulocyte count due to destruction of fragile and abnormal megaloblastic erythroid precursor.
*The
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
count may be reduced.
*
Neutrophil granulocyte
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s may show
multisegmented nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils, which increase numbers of nuclear segments with age.
*
Anisocytosis (increased variation in RBC size) and
poikilocytosis (abnormally shaped RBCs).
*
Macrocyte
Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). The enlarged er ...
s (larger than normal RBCs) are present.
*
Ovalocyte
Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the person's red blood cells are elliptical rather than the typical biconcave disc shape. Such morphologically distinctive ...
s (oval-shaped RBCs) are present.
*
Howell-Jolly bodies (chromosomal remnant) also present.
Blood chemistries will also show:
*An increased
lactic acid dehydrogenase (LDH) level. The isozyme is LDH-2 which is typical of the serum and hematopoietic cells.
*Increased
homocysteine and
methylmalonic acid in Vitamin B deficiency
*Increased homocysteine in folate deficiency
Normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty.
Bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
(not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic
hyperplasia
Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferatio ...
.
See also
*
List of circulatory system conditions
*
List of hematologic conditions
:''This is an incomplete list, which may never be able to satisfy certain standards for completion.''
There are many conditions of or affecting the human hematologic system—the biological system that includes plasma, platelets, leukocytes, an ...
References
External links
GeneReview/NCBI/NIH/UW entry on Thiamine-Responsive Megaloblastic Anemia SyndromeRare Anemias Foundation
{{DEFAULTSORT:Megaloblastic Anemia
Nutritional anemias
Hematopathology
de:Anämie#Hyperchrome_makrozytäre_Anämie