Iron-deficiency anemia is characterized by the sign of pallor (reduced oxyhemoglobin in skin or mucous membranes), and the symptoms of fatigue, lightheadedness, and weakness. None of these symptoms (or any of the others below) are sensitive or specific. Pallor of mucous membranes (primarily the conjunctiva) in children suggests anemia with the best correlation to the disease, but in a large study was found to be only 28% sensitive and 87% specific (with high predictive value) in distinguishing children with anemia [hemoglobin (Hb) <11.0 g/dl] and 49% sensitive and 79% specific in distinguishing severe anemia (Hb < 7.0 g/dl). Thus, this sign is reasonably predictive when present, but not helpful when absent, as only one-third to one-half of children who are anemic (depending on severity) will show pallor.

Because iron-deficiency anemia tends to develop slowly, adaptation occurs to the systemic effects that anemia causes, and the disease often goes unrecognized for some time. In severe cases, dyspnea can occur. Pica may also develop; pagophagia has been suggested to be "the most specific for iron deficiency."

Other possible symptoms and signs of iron-deficiency anemia include:

Hypochromic anemia occurs in patients with hypochromic microcytic anemia with iron overload. The condition is autosomal recessive and is caused by mutations in the SLC11A2 gene. The condition prevents red blood cells from accessing iron in the blood, which causes anemia that is apparent at birth. It can lead to pallor, fatigue, and slow growth. The iron overload aspect of the disorder means that the iron accumulates in the liver and can cause liver impairment in adolescence or early adulthood.

It also occurs in patients with hereditary iron refractory iron-deficiency anemia (IRIDA). Patients with IRIDA have very low serum iron and transferrin saturation, but their serum ferritin is normal or high. The anemia is usually moderate in severity and presents later in childhood.

Hypochromic anemia is also caused by thalassemia and congenital disorders like Benjamin anemia.

Hypochromic anemia is a generic term for any type of anemia in which the red blood cells (erythrocytes) are paler than normal. ("Hypo"- refers to "less", and "chromic" means "color".) A normal red blood cell will have an area of pallor in the center of it; it is biconcave disk shaped. In hypochromic cells, this area of central pallor is increased. This decrease in redness is due to a disproportionate reduction of red cell hemoglobin (the pigment that imparts the red color) in proportion to the volume of the cell. Clinically the color can be evaluated by the Mean Corpuscular Hemoglobin (MCH) or Mean Corpuscular Hemoglobin Concentration (MCHC). The MCHC is considered the better parameter of the two as it adjusts for effect the size of the cell has on its color. Hypochromia is clinically defined as below the normal MHC reference range of 27-33 picograms/cell in adults or below the normal MCHC reference range of 33-36 g/dL in adults.

Red blood cells will also be small (microcytic), leading to substantial overlap with the category of microcytic anemia. The most common causes of this kind of anemia are iron deficiency and thalassemia.

Hypochromic anemia was historically known as chlorosis or green sickness for the distinct skin tinge sometimes present in patients, in addition to more general symptoms such as a lack of energy, shortness of breath, dyspepsia, headaches, a capricious or scanty appetite and amenorrhea.

The symptoms of pernicious anemia come on slowly. Untreated, it can lead to neurological complications, and in serious cases, death. Many of the signs and symptoms are due to anemia itself, when anemia is present. Symptoms may consist of the triad of tingling or other skin sensations (paresthesia), tongue soreness (glossitis), and fatigue and general weakness. It presents with a number of further common symptoms, including depressive mood, low-grade fevers, diarrhea, dyspepsia, weight loss, neuropathic pain, jaundice, sores at the corner of the mouth (angular cheilitis), a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails, and thinning and early greying of the hair. Because PA may affect the nervous system, symptoms may also include difficulty in proprioception, memory changes, mild cognitive impairment (including difficulty concentrating and sluggish responses, colloquially referred to as brain fog), and even psychoses, impaired urination, loss of sensation in the feet, unsteady gait, difficulty in walking, muscle weakness and clumsiness. Anemia may also lead to tachycardia (rapid heartbeat), cardiac murmurs, a yellow waxy pallor, altered blood pressure (low or high), and a shortness of breath (known as "the sighs"). The deficiency also may present with thyroid disorders. In severe cases, the anemia may cause evidence of congestive heart failure. A complication of severe chronic PA is subacute combined degeneration of spinal cord, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response. Other than anemia, hematological symptoms may include cytopenias, intramedullary hemolysis, and pseudothrombotic microangiopathy. Pernicious anemia can contribute to a delay in physical growth in children, and may also be a cause for delay in puberty for adolescents.

Iron-deficiency anemia is associated with poor neurological development, including decreased learning ability and altered motor functions. Causation has not been established, but there is a possible long-term impact from these neurological issues.

Anemia goes undetected in many people and symptoms can be minor. The symptoms can be related to an underlying cause or the anemia itself.

Most commonly, people with anemia report feelings of weakness or tired, and sometimes poor concentration. They may also report shortness of breath on exertion. In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may have symptoms related to this, such as palpitations, angina (if pre-existing heart disease is present), intermittent claudication of the legs, and symptoms of heart failure.

On examination, the signs exhibited may include pallor (pale skin, lining mucosa, conjunctiva and nail beds), but this is not a reliable sign. There may be signs of specific causes of anemia, e.g., koilonychia (in iron deficiency), jaundice (when anemia results from abnormal break down of red blood cells — in hemolytic anemia), bone deformities (found in thalassemia major) or leg ulcers (seen in sickle-cell disease).

In severe anemia, there may be signs of a hyperdynamic circulation: tachycardia (a fast heart rate), bounding pulse, flow murmurs, and cardiac ventricular hypertrophy (enlargement). There may be signs of heart failure.

Pica, the consumption of non-food items such as ice, but also paper, wax, or grass, and even hair or dirt, may be a symptom of iron deficiency, although it occurs often in those who have normal levels of hemoglobin.

Chronic anemia may result in behavioral disturbances in children as a direct result of impaired neurological development in infants, and reduced academic performance in children of school age. Restless legs syndrome is more common in those with iron-deficiency anemia.

Symptoms of iron deficiency can occur even before the condition has progressed to iron deficiency anemia.

Symptoms of iron deficiency are not unique to iron deficiency (i.e. not pathognomonic). Iron is needed for many enzymes to function normally, so a wide range of symptoms may eventually emerge, either as the secondary result of the anemia, or as other primary results of iron deficiency. Symptoms of iron deficiency include:

- fatigue

- dizziness/lightheadedness

- pallor

- hair loss

- twitches

- irritability

- weakness

- pica

- brittle or grooved nails

- hair thinning

- Plummer–Vinson syndrome: painful atrophy of the mucous membrane covering the tongue, the pharynx and the esophagus

- impaired immune function

- pagophagia

- restless legs syndrome

Continued iron deficiency may progress to anaemia and worsening fatigue. Thrombocytosis, or an elevated platelet count, can also result. A lack of sufficient iron levels in the blood is a reason that some people cannot donate blood.

A dimorphic appearance on a peripheral blood smear occurs when there are two simultaneous populations of red blood cells, typically of different size and hemoglobin content (this last feature affecting the color of the red blood cell on a stained peripheral blood smear). For example, a person recently transfused for iron deficiency would have small, pale, iron deficient red blood cells (RBCs) and the donor RBCs of normal size and color. Similarly, a person transfused for severe folate or vitamin B12 deficiency would have two cell populations, but, in this case, the patient's RBCs would be larger and paler than the donor's RBCs. A person with sideroblastic anemia (a defect in heme synthesis, commonly caused by alcoholism, but also drugs/toxins, nutritional deficiencies, a few acquired and rare congenital diseases) can have a dimorphic smear from the sideroblastic anemia alone. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), indicating a wider-than-normal range of red cell sizes, also seen in common nutritional anemia.

Nutritional anemia refers to the low concentration of hemoglobin due to poor diet. According to the World Health Organization, a hemoglobin concentration below 7.5 mmol/L and 8. mmol/L for women and men, respectively, is considered to be anemic. Thus, anemia can be diagnosed with blood tests. Hemoglobin is used to transport and deliver oxygen in the body. Without oxygen, the human body cannot undergo respiration and create ATP, thereby depriving cells of energy.

Nutritional anemia is caused by a lack of iron, protein, B12, and other vitamins and minerals that needed for the formation of hemoglobin. Folic acid deficiency is a common association of nutritional anemia and iron deficiency anemia is the most common nutritional disorder.

Signs of anemia include cyanosis, jaundice, and easy bruising. In addition, anemic patients may experience difficulties with memory and concentration, fatigue, lightheadedness, sensitivity to temperature, low energy levels, shortness of breath, and pale skin. Symptoms of severe or rapid-onset anemia are very dangerous as the body is unable to adjust to the lack of hemoglobin. This may result in shock and death. Mild and moderate anemia have symptoms that develop slowly over time.[5] If patients believe that they are at risk for or experience symptoms of anemia, they should contact their doctor.

Treatments for nutritional anemia includes replacement therapy is used to elevate the low levels of nutrients.[1] Diet improvement is a way to combat nutritional anemia and this can be done by taking dietary supplements such as iron, folate, and Vitamin B12.[2] These supplements are available over-the-counter however, a doctor may prescribe prescription medicine as needed, depending on the patient’s health needs.

Internationally, anemia caused by iron deficiencies is the most common nutritional disorder. It is the only significantly prevalent nutritional deficiency disorder in industrialized countries. In poorer areas, anemia is worsened by infectious diseases such as HIV/AIDS, tuberculosis, hookworm infestation, and Malaria. In developing countries, about 40% of preschool children and 50% of pregnant women are estimated to be anemic. 20% of maternal deaths can be contributed to anemia. Health consequences of anemia include low pregnancy outcome, impaired cognitive and physical development, increased rate of morbidity, and reduced rate of work in adults.

'

Nutritional Anemia has many different causes, each either nutritional or non-nutritional. Nutritional causes are vitamin and mineral deficiencies and non-nutritional causes can be infections. The number one cause of this type of anemia however is iron deficiency.

An insufficient intake of iron, Vitamin B12, and folic acid impairs the bone marrow function.

The lack of iron within a person’s body can also stem from ulcer bacteria. These microbes live in the digestive track and after many years cause ulcer’s in the lining of your stomach or small intestine. Therefore, a high percentage of patients with nutritional anemia may have potential gastrointestinal disorder that causes chronic blood loss. This is common in immunocompromised, elderly, and diabetic people. High blood loss can also come from increases loss of blood during menstruation, childbirth, cancers of the intestines, and a disorder that hinders blood’s ability to coagulate.

Medications can have adverse effects and cause nutritional anemia as well. Medications that stop the absorption of iron in the gut and cause bleeding from the gut (NSAIDs and Aspirin) can be culprits in the development of this condition. Hydrocortisones and valproic acid are also two drugs that cause moderate bleeding from the gut. Amoxicillin and phenytoin are the ability to cause a vitamin B12 deficiency.

Other common causes are thyroid disorders, lead toxcities, infectious diseases (e.g Malaria), Alcoholism, and Vitamin E deficiency.

Symptoms

Symptoms of nutritional anemia can include fatigue and lack of energy. However if symptoms progress, one may experience shortness of breath, rapid pulse, paleness --especially in the hands, eyelids and fingernails---, swelling of ankles, hair loss, lightheadedness, compulsive and atypical cravings, constipation, depression, muscle twitching, numbness, or burning and chest pain.

Those who have nutritional anemia often show little to no symptoms. Often, symptoms can go undetected as mild forms of the anemia have only minor symptoms.

----[1] “Micronutrient deficiencies” World Health Organization. Accessed March 31, 2017. http://www.who.int/nutrition/topics/ida/en/

[2] "Ibid."

[3] "Ibid."

[4] "Ibid"

[5] "Ibid"

[6] "Ibid"

----[1] "Ibid".

[2] “Treatments for Nutritional anemia.” Right Diagnosis. Assessed March 31, 2017. http://www.rightdiagnosis.com/n/nutritional_anemia/treatments.htm

----[1] "Ibid".

[2] “What are the symptoms of anemia?” Health Grades, INC. Accessed March 31, 2017. https://www.healthgrades.com/conditions/anemia--symptoms.

[3] "Ibid."

[4] "Ibid."

[5] "Ibid."

[6] "Ibid"

----[1] "Ibid".

[2] "Ibid".

----[1] "Nutritional Anemia." The Free Dictionary. Accessed March 31, 2017. http://medical-dictionary.thefreedictionary.com/nutritionalanemia.

[2] "Ibid".

[3] "Ibid".

[4] "Ibid".

Nutritional anemia refers to types of anemia that can be directly attributed to nutritional disorders.

Examples include Iron deficiency anemia and pernicious anemia.

It is often discussed in a pediatric context.

Vitamin B deficiency anemia, of which pernicious anemia is a type, is a disease in which not enough red blood cells are present due to a lack of vitamin B. The most common initial symptom is feeling tired. Other symptoms may include shortness of breath, pale skin, chest pain, numbness in the hands and feet, poor balance, a smooth red tongue, poor reflexes, depression and confusion. Without treatment some of these problems may become permanent.

Although pernicious anemia technically refers to cases resulting from not enough intrinsic factor, it is often used to describe all cases of anemia due to not enough vitamin B. Lack of intrinsic factor is most commonly due to an autoimmune attack on the cells that create it in the stomach. It can also occur following the surgical removal of part of the stomach or from an inherited disorder. Other causes of low vitamin B include not enough dietary intake (such as in a vegan diet), celiac disease, or tapeworm infection. When suspected, diagnosis is made by blood and, occasionally, bone marrow tests. Blood tests may show fewer but larger red blood cells, low numbers of young red blood cells, low levels of vitamin B, and antibodies to intrinsic factor.

Pernicious anemia, due to lack of intrinsic factor, is not preventable. Vitamin B deficiency due to other causes may be prevented with a balanced diet or with supplements. Pernicious anemia can be easily treated with either injections or pills of vitamin B. If the symptoms are severe, injections are typically recommended initially. For those who have trouble swallowing pills, a nasal spray is available. Often, treatment is lifelong.

Pernicious anemia due to autoimmune problems occurs in about one per 1000 people. Among those over the age of 60, about 2% have the condition. It more commonly affects people of northern European descent. Women are more commonly affected than men. With proper treatment, most people live normal lives. Due to a higher risk of stomach cancer, those with pernicious anemia should be checked regularly for this. The first clear description was by Thomas Addison in 1849. The term "pernicious" means "deadly", and was used as before the availability of treatment the disease was often fatal.

Microcytosis is a condition in which red blood cells are unusually small as measured by their mean corpuscular volume.

It is also known as "microcythemia". When associated with anemia, it is known as microcytic anemia.

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

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).

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.

Symptoms of sideroblastic anemia include skin paleness, fatigue, dizziness, and enlarged spleen and liver. Heart disease, liver damage, and kidney failure can result from iron buildup in these organs.

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".

Microcytic anemia is not caused by reduced DNA synthesis.

Thalassemia can cause microcytosis. Depending upon how the terms are being defined, thalassemia can be considered a cause of microcytic anemia, or it can be considered a cause of microcytosis but not a cause of microcytic anemia.

There are many causes of microcytosis, which is essentially only a descriptor. Cells can be small because of mutations in the formation of blood cells (hereditary microcytosis) or because they are not filled with enough hemoglobin, as in iron-deficiency-associated microcytosis.

Red blood cells can be characterised by their haemoglobin content as well as by their size. The haemoglobin content is referred to as the cell's colour. Therefore, there are both "normochromic microcytotic red cells" and "hypochromic, microcytotic red cells". The normochromic cells have a normal concentration of haemoglobin, and are therefore 'red enough' while the hypochromic cells do not; thus the value of the mean corpuscular hemoglobin concentration.

Sideroblastic anemia is typically divided into subtypes based on its cause.

- Hereditary or congenital sideroblastic anemia may be X-linked or autosomal.

GLRX5 has also been implicated.

- Acquired, or secondary, sideroblastic anemia develops after birth and is divided according to its cause.

Latent iron deficiency (LID), also called iron-deficient erythropoiesis, is a medical condition in which there is evidence of iron deficiency without anemia (normal hemoglobin level). It is important to assess this condition because it is accepted that individuals with latent iron deficiency will develop iron-deficiency anemia in the weeks or months following diagnoses of LID if they are not treated with iron supplementation. In addition, there is some evidence of a decrease in vitality and an increase in fatigue among individuals that have LID.

The clinical features of LID are in discussion, some studies have not shown a clear difference between individuals with LID and control a group of the same age, gender and origin without LID. But may be it is not wrong to say that the persons with LID have a mild decrease in vitality and increase of fatigue. What seems important for preventive healthcare is to detect this medical condition, because it will avoid the patient probably developing an iron-deficiency anemia.

Though genetic defects causing iron deficiency have been studied in rodents, there are no known genetic disorders of human iron metabolism that directly cause iron deficiency.

In general, signs of anemia (pallor, fatigue, shortness of breath, and potential for heart failure) are present. In small children, failure to thrive may occur in any form of anemia. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, consumption of fava beans due to Favism, the presence of prosthetic heart valve, or other medical illness.

Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones. The continuous release of free hemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).

Normocytic anemia is a type of anemia and is a common issue that occurs for men and women typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years.

A normocytic anemia is defined as an anemia with a mean corpuscular volume (MCV) of 80–100 which is the normal range. However, the hematocrit and hemoglobin is decreased.

The term macrocytic is from Greek words meaning "large cell". A macrocytic class of anemia is an "anemia" (defined as blood with an insufficient concentration of hemoglobin) in which the red blood cells (erythrocytes) are larger than their normal volume. The normal erythrocyte volume in humans is about 80 to 100 femtoliters (fL= 10 L). In metric terms the size is given in equivalent cubic micrometers (1 μm = 1 fL). The condition of having erythrocytes which (on average) are too large, is called macrocytosis. In contrast, in microcytic anemia, the erythrocytes are smaller than normal.

In a macrocytic anemia, the larger red cells are always associated with insufficient "numbers" of cells and often also insufficient hemoglobin content per cell. Both of these factors work to the opposite effect of larger cell size, to finally result in a "total blood hemoglobin concentration" that is less than normal (i.e., anemia).

Macrocytic anemia is not a disease in the sense of having a single pathology but, rather, is a condition. As such, it is the class name for a set of pathologies that all produce somewhat the same red blood cell abnormality. Many specific pathologies are known which result in macrocytic-type anemias. Some of these produce slightly different sets of appearances in blood cells that are detectable from red and white cell morphology, and others are only detectable with chemical testing.

Mild macrocytosis is a common finding associated with rapid blood restoration or production, since in general, "fresh" or newly produced red cells (reticulocytes) are larger than the mean (average) size, due to slow shrinkage of normal cells over a normal red cell circulating lifetime. Thus, chronic obstructive pulmonary disease (COPD), in which red cells are rapidly produced in response to low oxygen levels in the blood, often produces mild macrocytosis. Also, rapid blood replacement from the marrow after a traumatic blood loss, or rapid red blood cell turnover from rapid hemolysis (G6PD deficiency), also often produces mild macrocytosis in the associated anemia.