Macrocytic anemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]
Overview
The word "hematology," which appears to have been first used in this country in 1811, is older than might be expected, for in 1743, Thomas Schwencke (1694-1768) wrote Hamatologia, sive Sanguinis Historia, Experimentis passim superstructa etc. Hagae Comitum. Hematology, like bacteriology, has developed as the result of laboratory methods and the applications of physics and chemistry.Inflammatory cytokines induce increased amounts of hepcidin by the liver. Hepcidin blocks ferroportin from releasing iron from the body stores. Inflammatory cytokines also decrease ferroportin expression and stops erythropoiesis by increasing bone marrow erythropoietin resistance. Apart from iron sequestration, white blood cells production is promoted by inflammatory cytokines. Bone marrow stem cellsproduce both red blood cells and white blood cells cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This may also have a role in inhibition of erythropoiesis ,even when erythropoietin levels are normal, and aside from the effects of hepcidin. Conditions that can lead to anemia of chronic disease include autoimmune disorders, such as Crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis, Cancer including lymphoma and Hodgkin's disease, chronic kidney disease, liver cirrhosis, long-term infections, such as bacterial endocarditis, osteomyelitis (bone infection), HIV/AIDS, hepatitis B or hepatitis C, less production of erythropoietin (EPO) by kidneys, resistance of bone marrow to EPO., decreased half life of red blood cells, hospitalized for severe acute infections, trauma, or other conditions that cause inflammation and aging process may cause inflammation and anemia. The primary goal in the treatment of anemia of chronic disease it to treat the disease itself. Supplemental iron is recommended, as needed, to keep the transferrin saturation of above 20 percent and a serum ferritin level of above100 ng/mL. Intravenous iron is more effective than oral supplementaion. Stable patients can be administered synthetically prepared erythropoiesis-stimulating agent such as erythropoietin. It is important to give oral iron supplementation to all the patients receiving erythropoietin or darbepoetin, in order to maintain a transferrin saturation more than 20 percent and a serum ferritin more than 100 ng/mL. In case of severe disease, blood transfusion is recommended.
Historical Perspective
The word "hematology," which appears to have been first used in this country in 1811, is older than might be expected, for in 1743, Thomas Schwencke (1694-1768) wrote Hamatologia, sive Sanguinis Historia, Experimentis passim superstructa etc. Hagae Comitum. Hematology, like bacteriology, has developed as the result of laboratory methods and the applications of physics and chemistry.
Classification
Macrocytic anemia are the anemia which has MCV>100fL. Macrocytic anemia may be classified into 2 subtypes/groups: Megaloblastic anemia and non megaloblastic anemia.
Pathophysiology
Folate is important in the production of various building blocks necessary for the production of biologic macromolecules. By combining with carbon moieties, tetrahydrofolate (THF) becomes methelenetetrahydofolate. This molecule is then able to donate carbon moieties to form purines, dTMP, and methionine. Of note, Vitamin B12 is also a cofactor in the production of methionine. THF is the resulting molecule after donation of carbon moieties except in the synthesis of dTMP from dUMP. DHF (dihydrofolate) results from this reaction. DHF reductase must act on DHF to participate in reactions again. The two metabolically active forms of Vitamin B12 are Methycobalamin and Adenosylcobalamin. The former is important in methionine synthesis. Methionine is necessary for the production of cholinephospholipids. Adenosylcobalamin is necessary to convert methylmalonyl CoA to succinyl-CoA. Interruption of this reaction eventually leads to nonphysiologic fatty acid production and abnormal neuronal lipid production. B12 deficiency also leads to folate metabolism derangement. Tissue folate levels are reduced in the setting of Vitamin B12 deficiency through a complicated biochemical pathway. This is known as the “folate trap hypothesis” and explains why large doses of folate will help the hematological manifestations. The mechanism of the neurologic manifestations remains independent of folate metabolism.
Causes
The common causes of megaloblastic anemia are less dietray intake, autoimmune disorders like pernicious anemia, alcoholism, increased demands like in pregnancy and due to drugs.
Differentiating from Other Diseases
The most important differential is whether the patient has ACD alone or ACD with ongoing iron deficiency anemia (ACD/IDA). The following parameters will distinguish the two: Soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also. Percentage of hypochromic red cells and reticulocyte hemoglobin may help.
Epidemiology and Demographics
30 to 60 percent of patients in rheumatoid arthritis patients have anemia. More than 30 of cancer patients have anemia. The rate reached 63 percent. In elderly patients, about one third of the cases of anemia are ACD.
Risk Factors
Risk factors for anemia of chronic disease include autoimmune disorders, chronic infection, trauma, major surgery, malignancy, HIV infection, rheumatologic disorders, inflammatory bowel disease, castleman disease, heart failure, older adults, renal insufficiency and chronic obstructive pulmonary disease.
Screening
There is insufficient evidence to recommend routine screening for anemia of chronic disease. Age-appropriate health screening and evaluations directed at any patient symptoms can be done to find out the underlying cause of ACD.
Natural History, Complications, and Prognosis
Potentially life-threatening complications include congestive heart failure, Angina, arrhythmia, myocardial infarction and high-output heart failure. If left untreated, anemia of chronic disease usually manifests as congestive heart failure, angina, arrhythmia, myocardial infarction and high-output heart failure.The anemia will improve when the disease that is causing it is successfully treated.
Diagnosis
Diagnostic Study of Choice
Homocysteine and methylmalonic acid levels can be helpful in confirmation. Both serum homocysteine and methylmalonic acid (MMA) levels are increased in helpful confirmatory tests for cobalamin and folate deficiencies. Homocysteine but not methylmalonic acid is increased in folate deficiency.
History and Symptoms
History may include higher MCV specially in neonates and infants, alcohol use, medications (eg, anticonvulsants, zidovudine, immunosuppressive agents), congenital heart disease, Down syndrome, reticulocytosis, bone marrow failure/dysplasia, liver disease, thyroid disease, hemolytic anemias with reticulocytosis and myelodysplastic syndromes (MDS). Macrocytosis is a common feature of MDS, especially in older adults. Patients with B12 deficiency show neurologic dysfunction, anemia symptoms such as fatigue, dyspnea, lightheadedness, and anorexia, high output cardiac failure, angina, diarrhea, cheilosis, glossitis, subacute combined degeneration, broad based gait, ataxia, numbness or paresthesias, Rhomberg and Babinski’s sign. Dementia may progress to frank “Megaloblastic Madness”
Physical Examination
Common physical examination findings of megaloblastic anemia include glossitis, pallor, mouth ulcers, vitiligo, subacute combined degeneration, and positive Romberg's sign.
Laboratory Findings
The lab findings include measuring levels of vitamin b12, folate, methylmalonic acid, and homocysteine.
Electrocardiogram
There are no echocardiogram/ultrasound findings associated with megaloblastic anemia. However, an echocardiogram may be helpful in the diagnosis of complications of megaloblastic anemia which include features of myocardial infarction when associated with hyperhomocysteinemia and dilated cardiomyopathy, and an ultrasound may show complication like splenomegaly.
X-ray
There are no x-ray findings associated with megaloblastic anemia
Echocardiography and Ultrasound
There are no echocardiogram/ultrasound findings associated with megaloblastic anemia. However, an echocardiogram may be helpful in the diagnosis of complications of megaloblastic anemia which include features of myocardial infarction when associated with hyperhomocysteinemia and dilated cardiomyopathy, and an ultrasound may show complication like splenomegaly.
CT scan
There are no CT scan findings associated with megaloblastic anemia.
MRI
There are no MRI findings associated with megaloblastic anemia. However, an MRI may be helpful in the diagnosis of complications of megaloblastic anemia, which include subacute combined degeneration
Other Imaging Findings
There are no other imaging findings associated with megaloblastic anemia
Other Diagnostic Studies
There are no other diagnostic findings associated with megaloblastic anemia
Treatment
Medical Therapy
In deficiencies of vitamin b12 and folate causing megaloblastic anemia, supplementation are made with Cyanocobalamine and Folic Acid respectively based on the severity and the cause. LDH falls in 2 days. Hypokalemia requiring replacement can occur in the acute phase as new cells are being generated rapidly. A reticulocytosis begins in 3-5 days and peaks in 10 days. The Hematocrit will rise within 10days. If it does not, suspect another disorder. Hypersegmented polymorphonuclear cells disappear in 10-14 days.
Interventions
Surgery
Surgical intervention is not recommended for the management of megaloblastic anemia
Primary Prevention
Green leafy vegetables and meat are a good source of Vitamin B-12. Alcohol consumption can lead to macrocytic anemia. These are some of the primary ways to reduce the incidence of macrocytic anemia.
Secondary Prevention
Folic acid supplementation in conditions which need more folate like pregnancy and lactation or in malabsorption e.g., celiac disease or a loss e.g., chronic hemolytic disorder. Folic acid supplementation in pregnant women can also prevent fetal neural tube defects.