Macrocytic anemia overview

# 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. Macrocytic anemia are the anemia which has MCV>100fL. Macrocytic anemia may be classified into 2 subtypes/groups: Megaloblastic anemia and non megaloblastic anemia. 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. In 60% of anemic patients, megaloblastic anemia affects 2-4% of population. Patients of all age groups may develop megaloblastic anemia. The incidence of megaloblastic anemia increases with age. Megaloblastic anemia commonly affects older age group. Males are more commonly affected by megaloblastic anemia than females. 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.

# Historical Perspective
Megaloblastic anemia and pernicious anemia was first discovered by Osler and Gardner in 1877 at Montreal. Increase in bone marrow cells was noted by Cohnheim in 1876.

# 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
In 60% of anemic patients, megaloblastic anemia affects 2-4% of population. Patients of all age groups may develop megaloblastic anemia. The incidence of megaloblastic anemia increases with age. Megaloblastic anemia commonly affects older age group. Males are more commonly affected by megaloblastic anemia than females.

# Risk Factors
Common risk factors of megaloblastic anemia include nutritional factors like alcoholism, elderly, pregnant, vegans, and malabsorptive syndromes

# Screening
There is insufficient evidence to recommend routine screening for megaloblastic anemia

# Natural History, Complications, and Prognosis
The symptoms of megaloblastic anemia typically develop many years after defieciency of Vitamin B12. If left untreated, patients with megaloblastic anemia may progress to develop Subacute combined degeneration of spinal cord, Peripheral neuropathy, and Dementia.

# 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 Babinskis 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.