Megaloblastic anemia (or megaloblastic anaemia) is an anemia (of macrocytic classification) that results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle 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, specifically a deficiency of vitamin B and/or folic acid. Vitamin B deficiency alone will not cause the syndrome in the presence of sufficient folate, as the mechanism is loss of B dependent folate recycling, followed by folate-deficiency loss of nucleic acid synthesis (specifically thymine), leading to defects in DNA synthesis. Folic acid supplementation in the absence of vitamin B prevents this type of anemia (although other vitamin B-specific pathologies may be present). Loss of micronutrients may also be a cause. 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.

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 neutrophils (those exhibiting five or more nuclear lobes ("segments"), with up to four lobes being normal). These hypersegmented neutrophils can be detected in the peripheral blood (using a diagnostic smear of a blood sample).

Microcytic anaemia is any of several types of anaemia characterized by small red blood cells (called microcytes). The normal mean corpuscular volume (abbreviated to MCV on full blood count results) is 80-100 fL, with smaller cells (100 fL) as macrocytic (the latter occur in macrocytic anemia).The MCV is the average red blood cell size.

In microcytic anaemia, the red blood cells (erythrocytes) are usually also hypochromic, meaning that the red blood cells appear paler than usual. This is reflected by a lower-than-normal mean corpuscular hemoglobin concentration (MCHC), a measure representing the amount of hemoglobin per unit volume of fluid inside the cell; normally about 320-360 g/L or 32-36 g/dL. Typically, therefore, anemia of this category is described as "microcytic, hypochromic anaemia".

Typical causes of microcytic anemia include:

- Childhood

- Iron deficiency anemia, by far the most common cause of anemia in general and of microcytic anemia in particular

- Thalassemia

- Adulthood

- Iron deficiency anemia

- Sideroblastic anemia, In congenital sideroblastic anemia the MCV (mean corpuscular volume) is either low or normal. In contrast, the MCV is usually high in the much more common acquired sideroblastic anemia.

- Anemia of chronic disease, although this more typically causes normochromic, normocytic anemia. Microcytic anemia has been discussed by Weng et al.

- Lead poisoning

- Vitamin B (pyridoxine) deficiency

Other causes that are typically thought of as causing normocytic anemia or macrocytic anemia must also be considered, and the presence of two or more causes of anemia can distort the typical picture.

There are five main causes of microcytic anemia forming the acronym TAILS. Thalassemia, Anemia of chronic disease, Iron deficiency, Lead poisoning and Congenital sideroblastic anemia. Only the first three are common in most parts of the world. In theory, these three can be differentiated by their red blood cell (RBC) morphologies. Anemia of chronic disease shows unremarkable RBCs, iron deficiency shows anisocytosis, anisochromia and elliptocytosis, and thalessemias demonstrate target cells and coarse basophilic stippling. In practice though elliptocytes and anisocytosis are often seen in thalessemia and target cells occasionally in iron deficiency. All three may show unremarkable RBC morphology. Coarse basophlic stippling is one reliable morphologic finding of thalessemia which does not appear in iron deficiency or anemia of chronic disease. The patient should be in an ethnically at risk group and the diagnosis is not confirmed without a confirmatory method such as hemoglobin HPLC, H body staining, molecular testing or another reliable method. Course basophlic stippling occurs in other cases as seen in Table 1

The blood film can point towards vitamin deficiency:

- Decreased red blood cell (RBC) count and hemoglobin levels

- Increased mean corpuscular volume (MCV, >100 fL) and mean corpuscular hemoglobin (MCH)

- Normal mean corpuscular hemoglobin concentration (MCHC, 32–36 g/dL)

- The reticulocyte count is decreased due to destruction of fragile and abnormal megaloblastic erythroid precursor.

- The platelet count may be reduced.

- Neutrophil granulocytes 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).

- Macrocytes (larger than normal RBCs) are present.

- Ovalocytes (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 hematopoetic 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 (not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic hyperplasia.

1- Red cell indices and blood film appearances suggest iron deficiency, although peripheral blood changes are not usually as marked as in moderate or severe iron deficiency.

2- Erythropoiesis is abnormal because of ineffective iron utilisation with poor haemoglobinisation of red cell precursors and

3- Bone marrow iron stores are normal or increased and sideroblasts may be frequent and abnormal.

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency. Management is supportive, sometimes with blood transfusions.

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. Parvovirus infection almost completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.

1- Secondary anaemias

- Chronic infection/inflammation

- Malignancy

2- Thalassaemia

3- Sideroblastic anaemia

The vast majority of those with hereditary elliptocytosis require no treatment whatsoever. They have a mildly increased risk of developing gallstones, which is treated surgically with a cholecystectomy if pain becomes problematic. This risk is relative to the severity of the disease.

Folate helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis.

Because the spleen breaks down old and worn-out blood cells, those individuals with more severe forms of hereditary elliptocytosis can have splenomegaly. Symptoms of splenomegaly can include:

- Vague, poorly localised abdominal pain

- Fatigue and dyspnoea

- Growth failure

- Leg ulcers

- Gallstones.

Removal of the spleen (splenectomy) is effective in reducing the severity of these complications, but is associated with an increased risk of overwhelming bacterial septicaemia, and is only performed on those with significant complications. Because many neonates with severe elliptocytosis progress to have only a mild disease, and because this age group is particularly susceptible to pneumococcal infections, a splenectomy is only performed on those under 5 years old when it is absolutely necessary.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:

- Drug-induced autoimmune hemolytic anemia

- Drug-induced nonautoimmune hemolytic anemia

A total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.

The presentation of individuals with alpha-thalassemia consists of:

Diagnosis of alpha-thalassemia is primarily by laboratory evaluation and haemoglobin electrophoresis. Alpha-thalassemia can be mistaken for iron-deficiency anaemia on a full blood count or blood film, as both conditions have a microcytic anaemia. Serum iron and serum ferritin can be used to exclude iron-deficiency anaemia.

Those with hereditary elliptocytosis have a good prognosis, only those with very severe disease have a shortened life expectancy.

Hereditary pyropoikilocytosis (HPP) is an autosomal recessive form of hemolytic anemia characterized by an abnormal sensitivity of red blood cells to heat and erythrocyte morphology similar to that seen in thermal burns. Patients with HPP tend to experience severe haemolysis and anaemia in infancy that gradually improves, evolving toward typical elliptocytosis later in life. However, the hemolysis can lead to rapid sequestration and destruction of red cells. Splenectomy is curative when this occurs.

HPP has been associated with a defect of the erythrocyte membrane protein spectrin and with spectrin deficiency.It was characterized in 1975.It is considered a severe form of hereditary elliptocytosis.

Acute PCH tends to be transient and self-limited, particularly in children. Chronic PCH associated with syphilis resolves after the syphilis is treated with appropriate antibiotics. Chronic idiopathic PCH is usually mild.

Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. The risk is especially high in cytotoxic chemotherapy for leukemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs), in some rare instances, may also cause bone marrow suppression. The decrease in blood cell counts does not occur right at the start of chemotherapy because the drugs do not destroy the cells already in the bloodstream (these are not dividing rapidly). Instead, the drugs affect new blood cells that are being made by the bone marrow. When myelosuppression is severe, it is called myeloablation.

Because the bone marrow is the manufacturing center of blood cells, the suppression of bone marrow activity causes a deficiency of blood cells. This condition can rapidly lead to life-threatening infection, as the body cannot produce leukocytes in response to invading bacteria and viruses, as well as leading to anaemia due to a lack of red blood cells and spontaneous severe bleeding due to deficiency of platelets.

Parvovirus B19 inhibits erythropoiesis by lytically infecting RBC precursors in the bone marrow and is associated with a number of different diseases ranging from benign to severe. In immunocompromised patients, B19 infection may persist for months, leading to chronic anemia with B19 viremia due to chronic marrow suppression.

Genetic testing for the presence of mutations in protein molecules is considered to be a confirmatory testing technique. It is important to know the risks regarding the transmission and dangers of HPP.

People with PCH, a polyclonal IgG anti-P autoantibody binds to red blood cell surface antigens in the cold. This can occur in a susceptible individual as blood passes through cold extremities in cold weather. When the blood returns to the warmer central circulation, the red blood cells are lysed with complement, causing intravascular hemolysis. Hemoglobinuria and anemia can then occur. The anemia may be mild or severe.

Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.

There are three types:

X-linked sideroblastic anemia or "X-linked dominant erythropoietic protoporphyria", associated with ALAS2 (aminolevulinic acid synthase), has also been described. X-linked dominant erythropoietic protoporphyria (XDEPP) is caused by a gain of function mutation in the ALAS2 (5-aminolevulinate synthase) gene; that gene encodes the very first enzyme in the heme biosynthetic pathway. The mutation is caused by a frameshift mutation caused by one of two deletions in the ALAS2 exon 11, either c. 1706-1709 delAGTG or c. 1699-1700 delAT. This alters the 19 and 20 residues of the C-terminal domain thereby altering the secondary structure of the enzyme. The delAT mutation only occurred in one family studied whereas the delAGTG mutation occurred in several genetically distinct families. The delAGTG causes a loss of an α-helix which is replaced by a β-sheet.

Previously known mutations in the ALAS2 resulted in a loss-of-function mutation causing X-linked sideroblastic anemia. Erythropoietic protoporphyria (EPP) has similar symptoms as X-linked dominant erythropoietic protoporphyria but the mutation occurs as a loss-of-function in the FECH (ferrochelatase) enzyme; the very last enzyme in the pathway. All individuals studied presented symptoms without mutations in the FECH enzyme. The patterns of inheritance led the researchers to conclude the mutation must come from an enzyme on the X-chromosome with ALAS2 being the most likely candidate.

X-linked dominant erythropoietic protoporphyria is distinct from EPP in that there is no overload of Fe ions. Additionally, unlike the other condition the arises out of a mutation of the ALAS2 gene, there is no anaemia. XDEPP is characterized by a buildup of protoporphyrin IX caused by in increased level of function in the ALAS2 enzyme. Because there is a buildup of protoporphyrin IX with no malfunction of the FECH enzyme, all the available Fe is used in the production of heme, causing the FECH enzyme to use Zn in its place, causing a buildup of zinc-protoporphyrin IX.

X-linked dominant erythropoietic protoporphyria is a relatively mild version of porphyria with the predominant symptom being extreme photosensitivity causing severe itching and burning sensation of the skin due to the buildup of protoporphyrin IX. One possible treatment was discovered when treating an individual with supplemental iron for a gastric ulcer. Levels of free protoporphyrin decreased significantly as there was iron available for the FECH to produce heme. Levels of zinc-protoporphyrin, however did not decrease.

Bahima Disease is a birth defect caused by iron deficiency in infants which are fed exclusively on cow's milk. It is characterized by a tower-shaped skull, of the diploe, and no signs of thalassaemia, sickle cell or other haemolytic anaemia.

It occurs most frequently in the Bahima people in Ankole, Uganda, from which it derives its name. The Bahima are a tribe that relies heavily on herding of long-horned cattle for survival.

Atrophic gastritis (also known as Type A or Type B Gastritis more specifically) is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues. As a result, the stomach's secretion of essential substances such as hydrochloric acid, pepsin, and intrinsic factor is impaired, leading to digestive problems. The most common are vitamin B deficiency which results in a megaloblastic anemia and malabsorbtion of iron, leading to iron deficiency anaemia. It can be caused by persistent infection with "Helicobacter pylori", or can be autoimmune in origin. Those with the autoimmune version of atrophic gastritis are statistically more likely to develop gastric carcinoma, Hashimoto's thyroiditis, and achlorhydria.

Type A gastritis primarily affects the body/fundus of the stomach, and is more common with pernicious anemia.

Type B gastritis primarily affects the antrum, and is more common with "H. pylori" infection.

Bone marrow suppression due to azathioprine can be treated by changing to another medication such as mycophenolate mofetil (for organ transplants) or other disease-modifying drugs in rheumatoid arthritis or Crohn's disease.

Patients with atrophic gastritis are also at increased risk for the development of gastric adenocarcinoma. The optimal endoscopic surveillance strategy is not known but all nodules and polyps should be removed in these patients.

Hereditary stomatocytosis describes a number of inherited autosomal dominant human conditions which affect the red blood cell, in which the membrane or outer coating of the cell 'leaks' sodium and potassium ions.